Indian Patents
Title of Invention

4-AMINO-THIENO[3,2-c]PYRIDINE-7-CARBOXYLIC ACID COMPOUNDS
Abstract The present invention relates to compounds of the formula medicaments containing them and the use of these compounds as pharmaceutically active agents. The compounds exhibit activity as Raf kinase inhibitors and therefore may be useful for the treatment of diseases mediated by said kinases, especially as anticancer agents.
Full Text

The ras protein in its normal, unmutated form is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues. See J. Avruch et aL, TIBS (19), 279-283 (1994). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is activated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants, Magnuson et aL, Cancer Biology, 5, 247-253 (1994). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of antisense RNA or by small molecule Raf kinase inhibitors leads to the reversion of transformed cells to the normal growth phenotype, Sridhar et aL, Mol Cancer Ther 2005, 4(4), April 2005 and Bollag et aL, Current Opinion in Investigational Drugs, 4, vol 12, 2003.
The present invention provides 4-amino-thieno [3,2-c] pyridine-7-carboxylic acid derivatives which are small molecule inhibitors of Raf kinase. In addition to inhibiting Raf, these compounds may also inhibit some other important kinases including ABL, BRAF, BRAF(V600E) mutant, EPHA, EPHB, FGFR1, FGFR2, FGFR3, FLT3, FLT4, KIT, PDGFRA, PDGFRB, and VEFGR-2. These compounds can be potent and selective anticancer agents, especially agents for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.

Ring A is selected from the group consisting of aryl, heteroaryl or substituted heteroaryl, cycloalkyl and heterocycle; and
Ring B is selected from the group consisting of aryl, heteroaryl and substituted heteroaryl.

wherein
R1 is selected from the group consisting of hydrogen, lower alkyl, halogen, cyano, trifluoromethyi, lower alkoxy, -C(0)-NH-lower alkyl, -C(0)-NH-lower alkoxy, oxo and N02;
R3 is selected from the group consisting of hydrogen, lower alkyl, lower alky! substituted by -OR4 and -NR4R5;
R4 and R5 are selected from hydrogen; lower alkyl; lower alkyl substituted with OH or lower alkoxy; or
R4 and R5 together with the nitrogen atom to which they are attached form morpholinyl;

Q is hydrogen or a group ;
R2 may be the same or different lower alkenyl, lower aikynyl, methyl sulfonyl, sulfonamide, hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, lower alkoxy, NO2, sulfonyl urea, amide, ester, carbamoyl, carbamate, urea,
-NR4R5; and lower alkyl substituted with -OR4 or -NR4R5; the goup -X-Y- is selected from -OCH2-, -CH20-, -NHCO-, -CONH-, -0-,
-OCH2CH2-, -CH20CH2, -CH2CH20-, -CF=CH-,-CH=CF-, -NH-, -NHCH2-, -CH2NH-,
-SCH2-, -NHS02, -S02NH~, -CH2S-, -SOCH2-, -CH2SO-, -S02CH2-, -CH2S02-5 -S-,
-CH=CH- and lower alkyl;
W isOorNH;
n is 1 or 2;
Ring A is selected from the group consisting of aryl, heteroaryl or substituted heteroaryl, cycloalkyl and heterocycle; and
Ring B is selected from the group consisting of aryl, heteroaryl and substituted heteroaryl.

As a preferred embodiment there are provided 4-amino-thieno [3,2-c] pyridine-7-carboxylic acid derivatives of the formula (I)

or pharmaceutical^ acceptable salts thereof,
wherein
R1 is selected from the group consisting of hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, lower alkoxy and NO2;
R2 is selected from the group consisting of lower alkenyl, lower alkynyl, methyl sulfonyl, sulfonamide, hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, lower alkoxy, NO2; sulfonyl urea, amide, ester, carbamoyl, carbamate, urea, lower alkyl substituted with OR4, and NR4R5;
R3 is selected from the group consisting of hydrogen, lower alkyl, lower alkyl substituted by OR4 and NR4R5;
R4 and R5 are selected from hydrogen, lower alkyl, or lower alkyl substituted with OH or lower alkoxy;
X-Y are selected from the group consisting of -OCH2-, -CH20~, -NHCO-, -CONH-,
-0-, -OCH2CH2-, -CH2OCH2, -CH2CH20~, -CF=CH^-CH=CF-s -NH-, -NHCH2~,
-CH2NH-5 -SCH2-, -CH2S~, ~SOCH2-, -CH2SO-5 -S02CH2-5 -CH2S02-? -S-, -CH-CH- and lower alkyl;

W is -O- or -NH-;
Ring A is selected from the group consisting of aryl, heteroaryl or substituted heteroaryl, cycloalkyl and heterocycle; and
Ring B is selected from the group consisting of aryl, heteroaryl and substituted heteroaryl
Especially preferred are compounds of formula (I-A) or (I) wherein -X-Y- are selected from the group consisting of -OCH2-,-CH20-, -NHCO- and -CONH-.
Also preferred are compounds of formula (I-A) or (I) wherein R1 is selected from the group consisting of-CH3, -CI and -F.
Further preferred are compounds of formula (I-A) or (I) wherein R is selected from the group consisting of-CI, -F, -CF3, -CONH2, lower alkoxy, -NR4R5, and lower alkyl.
Still another preferred embodiment is the compound of formula (I-A) wherein Q is hydrogen, and the remaining substituents have the meanings given above.
Still another preferred embodiment is the compound of formula (I-A) wherein Q is hydrogen, and wherein
R1 is -O-CH3 or -C(0)-NH-CH3;
R3 is ethyl, which is unsubstituted or once substituted with -OH;
W is -O- or -NH-; and
Ring B is phenyl or pyridinyl.
Still another preferred embodiment is the compound of formula (I-A), wherein


the remaining substituents and n have the meanings given above. Still another preferred embodiment is the compound according to formula (I-A), wherein Q

the ring A is selected from pyrimidinyl, pyridinyl, piperidinyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydro-pyranyl, phenyl, pyrazolyl or thiophenyl; and
the ring B is pyrimidinyl, 2-oxo-pyrimidinyl or phenyl; and
the remaining substituents have the meanings given above.
Still another preferred embodiment is the compound of formula (I-A) or (I), wherein both rings A and B are phenyl.
Also preferred are compounds of formula (I-A) or (I) where Ring B is phenyl or pyridinyl.
More preferred are compounds of formula (I-A) or (I) where Ring B is 2,5-di-substituted phenyl.
Also more preferred are compounds of formula (I-A) or (I) where Ring B is 3-hydroxy~2,5-disubstituted pyridinyl.
Especially preferred are compounds

4-Amino-3 - [3 -(4-chloro-3 -trifluoromethyl-phenylcarbamoyl)"phenoxymethyl] -
thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(3-benzyloxy-phenoxymetiiyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl
ester;
4-Amiiio-3-(3-benzy]oxy-phenoxyme1hyl)-thieno[3T2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-cUoro-ben2yloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxyli
acid ethyl ester;
4^Amino-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-tWeno[3,2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3 - [3-(3-cWoro-benzy loxy )-phenoxy^
acid ethyl ester;
4-Amino-3-[3-(3-cWoro-benzyloxy)-phenoxymethyl]-lMeno[3,2-c]pyridin
acid (2-hydroxy-ethyl)-amide;
4- Amino-3 - [3 -(3 -trifluoromethy 1-benzy loxy)-phenoxymethyl] -thieno [3,2«c]pyridine-7-
carboxylic acid ethyl ester;
4-Amino-3-[3-(3-trifluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-(3-benzylsulfanyl-phenoxyme1hyl)-t^
ester;
4-Amino-3-(3-benzylsulfanyl-phenoxymethyl]-tWeno[3,2«c]pyridine-7-carboxyli
hydroxy-ethyl)-amide;
4-Ainino-3-(3-phenylmethaoesulfonyl-phenoxymethyl)"tMeno[3,2-c]pyridine-7-c
acid ethyl ester;
4-Amino-3-(3 phenylmetfaanesulfonyl-phenoxymethyl]-tMeno[3,2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Airuno-343-(3-methoxy-benzyloxy)-phenox^
acid ethyl ester;
4-Amino-3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]4Meno[3,2-c]pyridine«7-carboxylic
acid ethyl ester;

4-Amino-3^3-(4-methoxy-ben2yloxy)-phenoxyme acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-methoxy-3-1xifluoromethyl-benzyloxy)-phenoxymethyl]-tW
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3 - [3-(4-methoxy-3-trifluorom
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino^3"(3-phenoxy-phenoxymethyl)-1iiieno[3,2-c]pyridine-7-carboxylic acid ethyl ester;
4-Amino«3-(3-phenoxy-phenoxymethyl]-thieno[392-c]pyridine-7-carboxylic acid (2*
hydroxy-ethyl)-amide;
4-Amino-3-(3-phenylamino-phenoxyme1hyl)-thieno[3?2-c]pyridine-7-carboxyli
ester;
4-Amino-3-(3-phenylamino-phenoxymethyl]-thieno[3,2»c]pyridine-7-carboxylic acid (2-
hy droxy-ethyl)-amide;
4-Amino-3-(3-benzylamino-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl
este;r
4-Amino-3-(3-benzylamino«phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxyme
ethyl ester; 4-Amino-3-[3-(4-cyano-benzyloxy)"phenoxymethyl]-tMeno[3,2-c]pyridine-7-carboxylic acid;
4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxym^ acid
(2-hydroxy-ethyl)-amide;
4-Aimno-3-[3-(3-cyano-benzyloxy)^
ethyl ester;
4-Amino-3-[3«(3-cyano-benzyloxy)-phenoxymethyl]-tMeno[3,2-c]pyridine acid;
4-Amino-3-[3-(3-cyano-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine«7-carboxyU
(2-hydroxy-ethyl)-amide trifluoroacetic acid salt;
3 -(3 -beii2yloxy-phenoxymethyl)«4-(2-hydroxy-etiiylamino)-lMeno [3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Ammo-3-(3-methoxy-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(3-methoxy-phenoxymeth^
hydroxy-ethyl)-amide;

4-AmmoO-(3-benzoylaiimo^
ester;
4-Amino-3-(3-benzoylamino-phenoxy^
hydroxy-ethyI)-amide;
4-Amino~3-(3~benzoylamino-phenoxymeth^ acid (2-
hydroxy-ethyl)-amide hydrochloride;
4-Ainino-3»(3"beiizoylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide toluene-4-sulfonic acid salt;
4- Amino-3 - [3-(4-chloro-phenylcarbamoyl)-phenoxymethyl] -thieno [3,2-c]pyridine-7-
carboxylic acid ethyl ester;
4-Amino-3-[3-(4-cUoro-phenylcarbamoyl)-phenoxymethyl]-thieno[3,2-c]pyrid
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-fluoro-phenylcarbamoyl)-phenoxymethyl]-tWeno[3?2-c]pyridi^^
carboxylic acid ethyl ester;
4-Amino-3"[3-(4-fluoro-phenylcarbamoyl)-phenoxyme1hyl]-tWeno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic
acid trifluoro-acetic acid salt;
4-Amino-3-[3-(3-chloro-phenylcarbamoyl)-phenoxymethyl]-lMeno[3,2-c]pyridin^
carboxylic acid ethyl ester; 4-Amino-3-[3-(3-cUoro-phenylcarbamoyl)-phenoxymethyl]-tMeno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-cUoro-phenylcarbamoyl)-phenoxymethyl]-tMeno[3,2-c]pyridine-7-carboxylic acid (3-hydroxy-propyl)-amide; 4-Amino-3-[3-(4-cWoro-phenylcarbamoyl)-phenoxymethyl]-thieno[3,2«c]pyridine-7^
carboxylic acid propylamide;
4-Amino-3-[3-(4-chloro-phenylcarbamoyl)-phenoxyme1hyl]-thieno[3,2-c]pyrid
carboxylic acid ethylamide;
4-Amino-3-{3-[(4-chloro-phenyl)-methyl-carbamoyl]-phenoxyme1hyl}-lW
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[3-(l-methyl-piperidin-4^
carboxylic acid ethyl ester;

4-Ammo-3-[3-(5-methyl-pyrid^ carboxylic acid ethyl ester; 4-Amino-343-( 1-methanesulfo^ c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3- {3«[(4-chloro-phenyl)-me1hyl-carbamoyl]-phenoxymethyl} -thieno[3,2-c]pyridine~7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[5-(3-carbamoyl-phenylcarbamoyl)»2-methyl»phenoxymethyl]-tM
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(2-methyl-5-phenylcarbamoyl-phenox^
carboxylic acid ethyl ester;
4- Amino-3 - [3-(4-chloro-benzyloxy)-phenoxymethyl] -thieno [3,2-c]pyridine»7-carboxylic
acid (3»hydroxy-propyl)-amide trifluoro-acetic acid salt;
4-Amino-3-[3-(4-cWoro-phenoxymethyl)-pheM^
carboxylic acid ethyl ester;
4-Ammo-3-{3-[2-(4-cMoro-phenyl)-vm^
carboxylic acid ethyl ester;
4-Ammo-3-{3-[2-(4-chloro-phenyl)-^
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-cWoro-phenoxymethyl)-phenoxymethyl]-tWeno[3,2-c]pyri
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-chloro-phenylcarbamoy^
carboxylic acid (2-hydroxy-ethyl)-methyI-amide;
4-Ammo-3-[3-(4-cWoro-phenylcarbamo
carboxylic acid (2-methoxy-ethyl)»amide;
4*Amino-3-[3-(4-chlorO"phenylcarbamoyl)"phenoxymethyl]-thieno[3?2-c]py^
carboxylic acid methylamide;
3-[4-Amino-7-(morpholine-4«carbonyl)-thieno[3.2-c]pyridin»3-ylmethoxy]-N-(4-cWoro
pheny l)-benzamide;
4-Amino-3-(3-cyclohexylcarbamoyl-phenox
acid ethyl ester;
4-Amino-3 - [3-(tetrahy dro-pyran-4-yte
carboxylic acid ethyl ester;

4-Amino-3-[3-( 1-methanesulfonyl-pipOT
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-( 1 -methy]-piperidin"4"ylcarbamoyl)-phenoxymethyl]'thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyI)-amide;
4-Amino-3^3-phenylaminomethyl-phenoxymet^^ acid
(2-hydroxy-ethyl)-amide trifluoro-acetic acid salt;
4-Amino-3- {3-[2-(4-chloro-phenyl)-ethoxy]-phenoxymethyl} -thieno[3 ?2-c]pyridine»7-
carboxylic acid ethyl ester;
4-Ammo-3-{3-[2-(4-cMoro-phenyl)-efa
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-chloro-benzoylamino)^
acid ethyl ester;
4-Amino-3-[3-(4-cUoro-benzoylamino)-phenoxyme1hyl]-thieno[3?2«c]pyridiB^
acid (2~hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-chloro-benzoylamino)-phenoxy^^
acid (3-hydroxy-propyl)-amide;
4-Ajnino-3-[3«(4-cUoro-benzoylamino)-phenoxyme1hyl]-1hieno[3,2-c]pyri
acid (3-hydroxy-propyl)-amide hydrochloride;
4-Amino-343^4-cWoro4>enzoylamino)-phenoxyme&^
acid (3-hydroxy-propyl)-amide toluene-4-sulfonic acid salt;
4-Amino-3-(2-oxo-1 -phenethyl-1,2-dihydrO"pyrimidin«4-yloxymethyl)-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(2,6-dioxo-3-phenethyl-3 ,6-dihydro-2H-pyrimidin-1 -ylmethyl)-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(2,6-dioxo-3-phenethyl«3,6-dihydro-2H"pyrimidin-l-ylmethyl)4hieno[3?2-
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-342-methoxy-5-(3-metiioxy-phenylcarbam
c]pyridine-7-carboxylic acid ethyl este;
4-Ammo-3 - [ 5-(3,5-dimethoxy-phenylcarbam^
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[5-(4-cUoro-3-me1hyl-phenylcarbamoyl)-2-methoxy-phenoxymethyl]-
thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester;

4-Amino-3-(5-benzylcarbamoyl-2-mfr^
acid ethyl ester;
4-Ajruno-3-(2-methyl-3-phenylcarba^
carboxylic acid ethyl ester;
4-Amino-3-[3-(3?5-dimethoxy-phenylcarbamoyl)»2-methyl-phenoxymethyl]-tW
c]pyridine~7-carboxylic acid ethyl ester;
4-Amino-3«[2-nitro-5-(3-trifluoromethoxy-phenylcarbamoyl)-phenoxyme1hyl^
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[2-methyl-3-(3-trifluoromethox
c]pyridine-7-carboxylic acid ethyl ester;
4-AminO'3-[3-(3-methanesulfonyl-phenylcarbamoyl)»2-me1hyl-phenoxymethyl]-tW
c]pyridine-7-carboxylic acid ethyl ester;
4- Amino-3 - [3 -(3 -chloro-phenylcarbamoyl)-2-methyl-phenoxymethyl] -thieno [3 ,2-c]pyridine-
7-carboxylic acid ethyl ester;
4-Amino-3-[2-methyl-3-(5-methyl-1 H-pyrazol-3-ylcarbamoyl)-phenoxymethyl]-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[3-(3,5-difluoro-benzyloxy)-5-m
carboxylic acid ethyl ester;
4-Ammo-3-[3-(3,4-difluoro-benzyloxy)-5^
carboxylic acid ethyl ester;
4-Amino-3-[3-(5-cWoro-tWophen~2-ylmethoxy^
c]pyridine-7-carboxylic acid ethyl ester;
4-Ammo-3-[3-(3-methyl-benzyto^
acid ethyl ester;
4-Amino-3-[3-(5-chloro4hiophen-2-ylmethoxy)-phenoxymethyl]-tW
carboxylic acid ethyl ester;
4-Amino-3-[3-(2?5-difluoro-benzyloxy)-phenoxy^
acid ethyl ester;
4-Amino-3-[3-(4-fluoro-benzyloxy)-5-m
carboxylic acid ethyl ester;
4-Amino-3-[3-(2,4-difluoro-benzyloxy)-5-m
carboxylic acid ethyl ester;

4-Ammo-3-[3-(2?5-difluoro-benzylo
carboxylic acid ethyl ester;
4-Amino-3-[3-methyl-5-(4-methyl4>enzyloxy)-pte
carboxylic acid ethyl ester;
4-Aixiino-3-[3-methyl-5-(2-methyl-benzyloxy)-phenoxymethyl]-thieno[3,2^
carboxylic acid ethyl ester:
4-Amino-3-[3-(2-fluoro-benzyloxy)-5-me1h^
carboxylic acid ethyl ester;
4-Amino-3 - [3 -(2-methoxy-benzyloxy)-phenoxymethyl] -thieno [3 ?2-c]pyridine-7-carboxylic
acid ethyl ester;
4-Amino-3-{3-[3-(2-morpholin^-yl-ethoxy)-bera^
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino»3-(3-methylcarbamoyl-phenoxymethyl)-lMeno[3,2-c]pyrid
ethyl ester;
4-Amino-3-(3-cyclopropylcarbamoyl-phenoxymethyl)-lMeno[3,2-c]pyridine-7-carboxylic
acid ethyl ester;
4-Amno-3-(3-cyclopentylcarbamoyl-phen^
acid ethyl ester;
4-Ammo-3»(3-cyclohexylcarbamoyl^
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(tetrahydro-pyran-4-ylcarba^
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-(3-methylcarbamoyl-phenoxymethyl)-thieno[3 ,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide;
4-Amino-3-(3-cyclopropylcarbamoyl-phenoxymethyl)-tWeno[3?2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-(3-cyclopen1ylcarbamoyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-(5-methylcarbamoyl~pyridin-3-yto^
acid ethyl ester;
4-AminoT3-(5-methylcarbamoyl-pyridin"3-yloxymethyl)-tMeno[3,2«c]pyri
acid (2-hydroxy-ethyl)-amide?

4-Amino-3-[3-(2-fluoro-benzyloxy)-5-^
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-[3-(3,5-difluoro-benzyloxy)^^
carboxylic acid (2-hydroxy-ethyI)-amide,
4-Amino-3-[3-methyl-5-(2-methyl-benzyl
carboxylic acid (2~hydroxy-ethyl)-amide,
4-Amino-3-[3-(2?5-difluoro-benzyloxy)-phenoxy^^
acid (2-hydroxy-ethyl)«amide,
4-Amino-3-[3-(3-fluoro-benzyloxy)-5-m
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-343-(2,5-difluoro-benzyloxy)-5-m
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-343-methyl-5-(4-methyl-benzyloxy)-phenox
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-[3-(3,4-difluoro-benzyloxy)-5-me^
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-[3-(2,3-difluoro-benzyloxy)-phenoxym^
acid(2-hydroxy-ethyl)-amide,4-Amino-3-[3-(4-chloro^
thieno[3,2-c]pyridine-7-carboxylic acid,
4-Ammo-3-[3-(pyrimi^
acid ethyl ester,
4- Amino-3 - [3 -(pyrimidin-5 -y lmethoxy)-phenoxymethyl] -thieno[3,2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide,
4- Amino-3 - [3 -(4-chloro-benzenesulfonylamino)-phenoxymethyl] -thieno [3,2-c]pyridine-7-
carboxylic acid ethyl ester,
4- Amino-3 - [3-(4-chloro-benzenesulfony lamino)-phenoxymethyl] -thieno [3,2 -c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide5
4»Amino-3-[2-chloro-5-(4-cWoro-benzyloxy)-phenoxymethyl]-lMeno[3,2-c]p^
carboxylic acid ethyl ester,
4-Ammo-3-[2-cWoro-5-(4-cWoro-benz^
carboxylic acid (2-hydroxy-ethyl)-amide,

4-Ammo-3-{3-[(pyridme-2-carbonyl)-a
carboxylic acid ethyl ester,
4-Ammo-3-{3-[(pyridine-2-carbo
carboxylic acid (2-hydroxy-ethyI)-amide,
4-Amino-3-{3-[(6-metbyl-pyridine-3-carbonyI)-amino]-phenoxymethy
c]pyridine-7-carboxylic acid ethyl ester,
4-Amino-3-{3-[(6-methyl-pyridine-3-carbonyl)-amino]"phenoxymethyl}-
thieno[3,2c]pyridine»7-carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-{3-[(pyridine-4-carbonyl)-amino]-phen^
carboxylic acid ethyl ester,
4-Amino-3-{3-[(pyridine-4-carbonyl)-amino]^
carboxylic acid (2-hydroxy~ethyl)-amide,
4-Amino-3-[5-(3-chloro-4-fluoro-benzoylamino)^
cjpyridine-7-carboxylic acid ethyl ester,
4-Amino-3-[5-(3-chloro«4-benzoylaraino)-2-methyl-phenoxymethyl]-tiiieno[3,2-
7-carboxylic acid ethyl ester,
4- Amino-3 - [5 -(3 -chlorO"benzoylamino)-2-methyl-phenoxymethyl] -thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide5
4-Amino-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino)-2-methyl-
phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylicacid(2-hydroxy-ethyl)-amide,
4-Amino-3- {5-t3"Chloro-4-(2-hydroxy-ethylamino)-benzoylamino)-2-methyl-
phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide toluene-4-
sulfonic acid salt,
4-Amino-3- {5-[3-chloro-4-(2-hydroxy-ethylamino)-ben2oylamino]-2-methyl-
phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester; and
4-Amino«3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino]-2-methyl-
phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid amide.
As used herein, the following terms shall have the following definitions.

"Aryltf means a monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 membered aromatic ring system. Preferred aiyl groups include, but are not limited to, phenyl, naphthyl and tolyl.
"Heteroaryl" means an aromatic heterocyclic ring system containing up to two rings. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, pyrazolyl, benzofuran and tetrazolyl.
As used herein, in particular in R , the term
(a) "amide" means a substituent of the formula

(b) "ester" means a substituent of the formula

(c) "carbamoyl" means a substituent of the formula

(d) "carbamate" means a substituent of the formula


(e) "urea" means a substituent of the formula

R4 and R5 are selected from hydrogen; lower alkyl; lower alkyl substituted with OH or lower alkoxy.
"Effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
"Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"Hetero atom" means an atom selected from N, O and S.
"Lower alkyl" alone or in conjunction with another term, e.g. lower alkyl-heterocycle, denotes a straight-chain or branched, saturated aliphatic hydrocarbon having 1 to 6, preferably 1 to 4, carbon atoms. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl and the like.
The term "alkoxy" means a group -O-alkyl, preferably a group -O-lower alkyl, wherein "lower alkyl" has the meaning given above.
The term "alkenyl", alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 20, preferably up to 16 carbon atoms, more preferably up to 10 carbon atoms. Lower-alkenyl groups as described

below also are preferred alkenyl groups. The term "lower-alkenyl" refers to a straight-chain or branched hydrocarbon residue comprising an olefinic (double) bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propenyl. An alkenyl or lower-alkenyl group
may have a substitution pattern as described earlier in connection with the term "alky!".
The term "alkynyl"., alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 20, preferably up to 16 carbon atoms. The term "lower-aUcynyl" refers to a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propinyl. An alkynyl or lower-alkynyl group may have a substitution pattern as described earlier in connection with the term "alkyl".
The term "cycloalkyl" denotes a saturated mono- or bicyclic hydrocarbon with 3 to 10 carbon atoms. Preferred are monocyclic hydrocarbons with 3 to 6 carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexyl and the like.
The term "heterocycle" means a "cycloalkyl" as defined above, wherein one, two or three carbon atoms, preferably one or two carbon atoms, are replaced by a heteroatom selected from N, S or O. Especially preferred are 5- and 6-membered heterocycles. Examples of such heterocycles are piperidine, tetrahydro-pyran, piperazine, morpholine, pyrrolidine, pyrazolidine, tetrahydro-thiophene, imidazolidine and the like.
The term "Pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluene sulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium, lithium, magnesium, calcium and quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. The

chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
"Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
"Substituted" as used herein, for example in substituted alkyl or substituted heteroaryl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options.
"Therapeutically effective amount" means an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or ester thereof, that significantly inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines.
Medicaments containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of the present invention and/or pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert excipients/carriers.
In accordance with the invention the compounds of the present invention as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses, particularly proliferative disorders such as cancer, more particularly colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas. Based on their Raf kinase inhibition and their antiproliferative activity, said compounds are useful for the treatment of diseases such as cancer in humans or animals and for the production of corresponding medicaments. The

dosage depends on various factors such as manner of administration, species, age and/or individual state of health.
The compounds of the present invention can be prepared according to the following reaction schemes and general procedures, wherein unless explicitly otherwise stated all substituents and variables have the meanings given herein before. Unless explicitly described herein all reactions, reaction conditions, abbreviations such as "PG" for protecting group, and substances are known to the man of ordinary skill in the art.
Scheme 1:


Intermediate 1
4-Methyl-2-thiophenecarboxaldehyde

A solution of 3-methylthiophene (58.90 g, 0.60 mol) (Fluka) in anhydrous ether (600 mL) was stirred and cooled in an ice - water bath. This solution was treated dropwise over 15 minutes with n-butyllithium in pentane (2 M? 450 mL, 0.90 mol) (Aldrich). After stirring for 2 hours at room temperature the mixture was cooled in an ice - water bath and treated dropwise over 5 minutes with AyV-dimethylformamide (48.24 g, 0.66 mol) (Fisher) followed by stirring at room temperature over night. The mixture was diluted with ether (600 mL) and washed with water and brine. After drying (sodium sulfate) ether was evaporated on a rotary evaporator without vacuum to give 114 g of red liquid. This liquid was purified by chromatography over a pad of silica gel 60 (1 Kg, 70-230 mesh) eluting with 40% dichloromethane - hexanes. Evaporation without vacuum gave 4-methyl-2-thiophenecarboxaldehyde as a light red oil. (Yielded 56.62 g, 74.7%). This product contained small amounts of hexanes.
Intermediate 2
3-(4-Methyl-thiophen-2-yl)-acrylicacid

A solution of 4-methyl-2-thiophenecarboxaldehyde (56.62 g5 0.448 mol) (from Intermediate 1 supra), malonic acid (186.77 g, 1.79 mol) (Aldrich) and piperidine (1.90 g, 0.022 mol) (Fluka) in pyridine (550 mL) was heated at reflux with stirring over night. Reaction mixture was evaporated to dryness. The resulting residue was dissolve in dichloromethane and washed successively with 3 N hydrochloric acid, water and brine. The organic layer was

dried and evaporated to give 3-(4-methyl-thiophen-2-yl)-acrylic acid as a tan solid. (Yield 49.52 g, 65.7%).

To a solution of 3-(4-methyl-thiophen-2-yl)-acrylic acid (49.52 g, 0.294 mol) (from Intermediate 2 supra) and triethylamine (44.68 g, 0.441 mol) (Aldrich) in acetone (2000 mL) with stirring and cooling in an ice - water bath was added ethyl chloroformate (35.14 g3 0.323 mol) (Aldrich). After stirring at room temperature for 20 minutes, sodium azide (28.70 g, 0.441 mol) (Aldrich) was added and stirring continued for another 20 minutes at room temperature. Acetone was then evaporated off at reduced pressure and residue was diluted with water. This was extracted with dichloromethane. The organic extract was washed with brine, dried and concentrated to give 3-(4-methyl-thiophen-2-yl)-acryloyl azide as a brown solid. (Yield 48.51 g, 85.4%).

3-(4-Methyl-thiophen«2-yl)-acryloyl azide (1.54 g; 7.95 mmol) (from Intermediate 3 supra) was dissolved in meta-xylenes (16 mL). The solution was heated in an oil bath at 105 -115 °C for 30 minutes until nitrogen evolution ceased. At this point a few crystals of iodine were added to the reaction and the oil bath temperature was increased to 145 - 150 °C. The

reaction was heated at reflux for 6 hours. Upon cooling, solid precipitated out of solution. µLtration and drying yielded 3-methyl-5H4taeno[3.2-c]pyridine-4-one. (Yield 1.05 g; 80.1%).
HRMS(EI+) m/z Calcd for CgH7NOS [(M+)]: 165.0248. Found: 165.0250.

A solution of 3-methyl-5H-thieno[392-c]pyridin-4-one (24.27 g, 0.146 mol) (from Intermediate 4 supra) and AµModosuccinimide (34.70 g? 0.154 mol) (Avocado) in dimethylformamide (1000 mL) was stirred at room temperature over night. Reaction mixture was concentrated under reduced pressure and residue was stirred with ether (1000 mL) for 0.5 hour. Suspension was µLtered, washed with ether and sucked dry to give 7-iodo-3-methyl~5H-tWeno[3,2-c]pyridin-4-one as a brown solid. (Yield 41,88 g, 97.9%).

A stirred suspension of 7-iodo-3-methyl-5H-thieno[3,2-c]pyridin-4-one (1.14 g, 3.92 mmol) (from Intermediate 5 supra), triethylamine (2.5 mL, 17,94 mmol) (Aldrich) and bis(triphenylphosphine)palladium(II) chloride (0.14 g, 0.2 mmol) (Aldrich) in ethanol (50 mL) was degassed with argon and then saturated with carbon monoxide. The mixture was stirred with heating in a 75 °C oil bath over night under a blanket of carbon monoxide. After ,

cooling, reaction mixture was concentrated under reduced pressure to remove a portion of ethanol (about 20%). The solid formed was collected by µLtration, washed with ethanol -diethyl ether (1:1) and then diethyl ether and finally dried under vacuum to give 3-methyl-4-oxo-4.5-dihydro-thieno[352-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.78 g, 84.0%). HRMS(EI+) m/z Calcd for CnHnN03S [(M4)]: 237.0460. Found: 237.0451.

A mixture of 3-methyl-4-oxo-4,5-dihydro-thieno[3,2"C]pyridine-7-carboxylic acid ethyl ester (2.43 g, 10.24 mmol) (from Intermediate 6 supra) and AyV-diisopropylethylamine (2.4 mL, 13.87 mmol) (Fluka) was stirred with cooling in an ice - water bath. This mixture was slowly treated with phosphorous oxychloride (7.8 mL? 83.68 mmol) (Fluka) and then allowed to warm to room temperature. A^V-Dimethylformamide (1.0 mL, 12.86 mmol) was then added and the mixture stirred with heating at 70 °C for 30 minutes. A second portion of NJV-dimethylformamide (0.5 mL, 6.43 mmol) was added and the mixture was heated at 70 °C for another 30 minutes. After cooling, ice was added to the solution and the mixture was extracted with ethyl acetate. Organic extract was washed with water, saturated aqueous sodium bicarbonate solution, water and brine. The aqueous phases were back washed with ethyl acetate. The ethyl acetate solutions were combined, dried (sodium sulfate) and concentrated under reduced pressure. This residue was purified by flash chromatography over silica gel (Biotage 65M, 5 : 95 ethyl acetate - hexanes) to give 4-chloro-3-methyl-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 1.57 g? 60.0%). HRMS(EI+) m/z Calcd for CnHioClN02S [(M+)]: 255.0121. Found: 255.0119.


To a solution of 4-chloro-3-methyl-thieno[3,2-c]pyridine~7-carboxylic acid ethyl ester (14.65 g, 57.29 mmol) (from Intermediate 7 supra) in carbon tetrachloride (250 mL) was added N-bromosuccinimide (12.24 g, 68.75 mmol) and 2,2'-azobisisobutyronitrile (0.94 g? 5.73 mmol). The reaction mixture was heated at 80 °C for 24 hours. The mixture was then cooled and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate -hexanes to give 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as white crystals. (Yield 11.73 g). The mother liquid was concentrated and purified by flash chromatography (diethyl ether - hexanes, 1:4, V/V) to give second crop of 3-bromomethyl-4~ chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 4.39 g, 84% combined).












Compound XXDC (18 mmol) (Scheme 10) was dissolved in N,N'-dimethylformamide (10 vol). To this was added potassium carbonate (1.2 equivalents), potassium iodide (1.0 equivalent) and 3-bromomethyl-4-chloro-thieno[352-c]pyridine-7-carboxylic acid ethyl ester (1.0 equivalent) (from Intermediate 8 supra). The reaction was stirred at 70 °C for 16 hours. Water (100 mL) was added and the crude reaction mixture extracted with ethyl acetate (4 x 50 mL). The combined organic layers were dried (MgS04), µLtered and the solvent removed in vacuuo. The crude solid was suspended in ethyl acetate (50 mL). The resulting suspension was µLtered, and the solid washed with a further aliquot of ethyl acetate (20 mL) to give crude product XXX.

Compound XXX (8 mmol) (from General Procedure 1 supra) was dissolved in 2-propanol saturated with ammonia (10 vol). The solution was heat at 160 °C in a microwave reactor for 20 minutes. The reaction solvent was removed in vacuuo. Hot methanol was added and the resulting suspension µLtered. The solid (mainly unreacted starting material) was re-treated under microwave conditions (as above); dioxane (-5 mL) was added to aid solubility in some cases as required. The desired product was contained in the µLtrate, which was evaporated to dryness and analysed. This process was repeated until >90% conversion of starting material to desired product XXXI was achieved.
General Procedure 3 Synthesis of XXXII


Compound XXXI (6 mmol) (from General Procedure 2 supra) was dissolved in 20% trifluoroacetic acid in dichloromethane (10 vol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to dryness to give the product XXXn.

Compound XXXII (160 fimol) (from General Procedure 3 supra) was dissolved in dichloroethane (3 mL) and DMF (1 drop). Thionyl chloride (3 equivalents) was added and the reaction mixture agitated at room temperature until acid chloride formation was complete (monitored by LCMS; -16 hours). Triethylamine (6 equivalents) was added to the crude reaction mixture followed by aniline (3 equivalents). The reaction mixture was agitated at 40 °C for 16 hours during which time a precipitate formed. The reaction mixture was µLtered and the µLtrate washed with IN HC1 (2 mL). The organic layer was passed through a µLter of MgSC>4 and then combined with the precipitate from the reaction mixture. The solvent was removed under reduced pressure and the resulting solid was washed with THF. The collected solid was suspended in a mixture of 2-propanol / chloroform (1:1) and loaded onto a preparative TLC plate (run in 20% m ethanol - dichloromethane). The desired material was removed from the silica by washing with methanol and concentrating to give product XXXIII.
General Procedure 5
Synthesis of XVn


To substituted resorcinol (6.4 mmol) (Scheme 4) dissolved in N,N-dimethylformamide (5 vol.) was added cesium carbonate (1.2 equivalents) and benzyl halide (1 equivalent) (Scheme 4). The reaction was stirred overnight at room temperature. The crude reaction mixture was dissolved in dichloromethane (20 mL) and washed with IN HC1 (2 x 20 mL). The combined aqueous layers were extracted with dichloromethane (2 x 20 mL) and organic layers combined and washed with brine (20 mL), then dried (MgS04). The desired products were purified by chromatography, eluting with heptane then 20% EtOAc / heptane. Yields were typically 30 - 50%.

To alkylated resorcinol XVII (from General Procedure 5 supra) or other substituted phenol XXIV (Scheme 8) dissolved in N?N-dimethylformamide (5 vol) was added potassium carbonate (1.2 equivalents), potassium iodide (1 equivalent) and 3-bromomethyl-4-chloro-thieno[3?2-c]pyridine~7-carboxylic acid ethyl ester (1.0 equivalent) (from Intermediate 8 supra). The reaction was stirred overnight at 75 °C. The crude reaction mixture was dissolved in dichloromethane (20 mL) and washed with IN HC1 (20 mL). The organic layer was collected and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried (MgS04). The desired products were purified by

chromatography, eluting with heptane then 10% EtOAc / heptane, then recrystallisation from acetonitrile. Yields were typically 25 - 30%.
General Procedure 7
Synthesis of XXVI

Compound XXV (from General Procedure 6 supra) was dissolved in 2-propanol saturated with ammonia (10 vol.). The solution was heated at 140 °C in a microwave reactor for 3 x 30 minutes. Any precipitate formed was µLtered and washed with 2-propanol. In cases where no precipitate was formed, the solvent was removed under reduced pressure and the resulting solid was washed with 2-propanol. No further purification was necessary. Yields were typically 60 - 75%.
General Procedure 8
Synthesis of XXVII

To an oven dried vessel was added compound XXVI (from General Procedure 7 supra) dissolved in anhydrous dioxane (25 vol) under nitrogen. Trimethylaluminium (2.0 M in heptane; 4 equivalents) was added dropwise under nitrogen at room temperature, and then the reaction mixture stirred for 10 minutes. Ethanolamine (4 equivalents) was added dropwise and the reaction mixture stirred at room temperature for a further 10 minutes before heating to 95 °C and stirring overnight. Re-treatment using 2 equivalents of reagents may be

necessary, Rochelle's salt (1 vol. of a saturated solution) was added to the cooled reaction mixture and stirred for one hour. The mixture was diluted with dichloromethane (50 mL) and water (50 mL) was added. The organic layer was removed and the aqueous layer extracted with 1:1 CHCl3:2-propanol (3 x 20 mL). The combined organic washings were dried (Na2S04)? µLtered and the solvent removed under reduced pressure. Preparative HPLC was used to purify the final compounds,

A suspension of 3-hydroxybenzoic acid (16.2 g, 117.3 mmol) (Aldrich) in acetic anhydride (20 mL) (Aldrich) was heated at reflux for 5 hours. On heating a clear solution was formed. After cooling to room temperature, mixture was poured into ice -water (400 mL) and stirred. A white crystalline material was formed. This was collected by µLtration, washed with water and dried in vacuum oven to give 3-acetoxybenzoic acid as white crystals in two crops. (Yield 18,97 g5 89.8%).
A suspension of 3-acetoxybenzoic acid (1.80 g, 10 mmol) in a mixture of N,N-dimethyl-formamide (3 drops) and thionyl chloride (3 mL, 40 mmol) (Aldrich) was heated in an 90 °C bath for 2 hours. After cooling, mixture was diluted with toluene (20 mL) and concentrated under reduced pressure to remove excess thionyl chloride. The resulting oil was dissolved in dichloromethane (10 mL) and added dropwise to a solution of 4-chloro-3-(trifluoromethyl)aniiine (1.96 g, 10 mmol) (Aldrich), 4-dimethylamino-pyridine (0.1 g, 0.08 mmol) (Fluka) and N?N-diisopropylethylamine (L6 g, 12.4 mmol) (Aldrich) in dichloromethane (10 mL) with cooling in an ice - water bath and magnetic stirring. When addition was complete, cooling bath was removed and mixture stirred at room temperature for 2 hours. Reaction mixture was then partitioned between water (50 mL) and

dichloromethane (2 X 50 mL). Organic layers were combined, and concentrated to dryness. Residue was dissolved in THF (10 mL), methanol (10 mL) and 1 N aqueous sodium hydroxide (10 mL) and stirred at room temperature for 16 hours. The yellow solution was diluted with water (100 mL) and acetic acid (5 mL) and extracted with ethyl acetate (2 X 100 mL). Ethyl acetate layers were washed with saturated brine (100 mL), combined, dried (MgS04), µLtered, and concentrated. Residue was recrystallized from ethyl acetate - hexanes to give A^-(4-chloro-3-trifluoromethyl-phenyl)-3-hydroxy-benzamide as colorless plates. (Yield 2.54 g, 80.4%).

A suspension of 7V-(4-chloro-3«trifluoromethyl-phenyl)-3-hydroxy-benzamide (0.33 g, LOS mmol) (from Intermediate 9 supra) and potassium carbonate (0.16 g, 1.15 mmol) in N,N-dknethylformamide was heated at 65 °C for 2 hours with magnetic stirring. 3-Bromomethyl-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.33 g, 1 mmol) (from Intermediate 8 supra) was added and mixture heated for another 5 hours at the same temperature. After cooling, mixture was partitioned between ethyl acetate (2X50 mL) and water (2 X 50 mL). Organic layers were washed with brine (50 mL), combined, dried (MgS04), µLtered and concentrated. Residue was recrystallized from ethyl acetate -dichloromethane - hexanes to give 4-chloro-3-[3-(4-chloro-3-trifluoromethyl-phenylcarbamoyl)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester as a white crystalline material. (Yield 0,16 g, 28.5%).
Examples

The following examples are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims.
Example 1
4-Amino-3-[3-(4-chloro-3-trifluoromethyl«phenylcarbamoyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[4-(4-chloro-3-trifluoromethyl-phenyl-carbamoyl)«phenoxymethyl]-thieno[3,2-c]pyridine-7"Carboxylic acid ethyl ester (0.11 g, 0.19 mmol) (from Intermediate 10 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 165 °C for 1,5 days. After cooling, the reaction mixture was concentrated.- The residue was washed with hot methanol and the solid was µLtered. The solution was concentrated. The residue was purified by flash chromatography duting with (40 - 100%) ethyl acetate in hexanes to give 4-amino~3-[3-(4-chloro-3-trifluoromethyl-phenylcarbamoyl)-phenoxym ethyl ester. (Yield 0.05 g, 50%). HRMS (ES4) m/z Calcd for C25H19CIF3N3O4S + H [(M+H)*]: 550.0810. Found: 550.0811.
Intermediate 11 3-(3-Benzyloxy-phenoxymethyl)-4-chloro-1hieno[3?2-c]pyridine-7-carboxylic acid ethyl ester

A suspension of potassium carbonate (0.16g, 1.17 mmol), 3-(benzyloxy)phenol (0.21 g, 1.07 mmol) (TCI-US) and a catalytic amount of 18-crown-6 (Aldrich) in Ar,7^-dimethylformamide (15 mL) was heated at 65 °C for 2 hours. 3"Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was then added.

Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 3-(3-benzyloxy -phenoxymethyl)-4-chloro-thieno[352"C]pyridine-7-carboxylic acid ethyl ester. (Yield 0.14 g, 30%). HRMS (ES+) m/z Calcd for C24H20CINO4S + H [(M+H)*]: 454.0875. Found: 454.0876.
Example 2
4-Ammo-3-(3-benzyloxy-phenoxymethyl)-1^

Ammonia gas was bubbled into a solution of 3-(3-benzyloxy-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.14 g, 0.31 mmol) (from Intermediate 11 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was diluted with dichloromethane and washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 5% ethyl acetate in dichloromethane to give 4-amino-3-(3-benzyloxy-phenoxymethyl)-thieno [3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 80 mg, 62%). HRMS (ES+) m/z Calcd for C24H22N2O4S + H [(M+H)+]: 435.1373. Found: 435.1373.
Example 3
4-Amino-3-(3-ben2^1oxy-phenoxymethyl)-tMeno[3,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyI)-amide


M.W. 449.529 C24H23N3O4S
A solution of 4-amino-3-(3-benzyloxy-phenoxymethyl)-thieno [3,2-c]pyridine-7-carboxylic acid ethyl ester (0.07 g, 0.16 mmol) (from Example 2 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (2,0 mL, 33.24 mmol) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot ethyl acetate and dried to give 4-aminO"3-(3-ben2yloxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyI)-amide as a white solid. (Yield 56 mg, 80%). HRMS (ES+) m/z Calcd for C24H23N3O4S + H [(M+H)4]: 450.1482. Found: 450.1483.
Intermediate 12
3 -(4-Chloro-benzyloxy )-phenol

A suspension of potassium carbonate (2.02 g, 14.6 mmol) and resorcinol (16.08 g, 0.146 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 4-chlorobenzyl bromide (3.0 g, 14.6 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (IX). The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 3-(4-chloro-benzyloxy)-phenol. (Yield 2.62 g, 76%).
Intermediate 13
4-CWoro-3-[3-(4-cWorO"benzyloxy)-phenoxymethyl]4Weno[3?2-c]pyridine-7-carboxylic
acid ethyl ester


A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3~(4-chloro-benzyloxy)-phenol (0.25 g? 1.07 mmol) (from Intermediate 12 supra) and a catalytic amount of 18-crown-6 (Aldrich) in #, N-dimelhylformamide (15 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was.purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-chloro-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.14 g, 28%).
Example 4
4-Amino-3-[3-(4-cUoro-benzyloxy)-phenoxymethyl]-1hieno[3?2-c]pyridine-7-carboxylic
acid ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(4-chloro-benzyloxy)-phenoxy-methyl]-thieno[3s2-c]pyridine-7-carboxylic acid ethyl ester (0.14 g, 0.29 mmol) (from Intermediate 13 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 0.13 g5 100%).

HRMS (ES+) m/z Calcd for C24H21CIN2O4S + H [(M+H)4]: 469.0984. Found: 469.0983.
Example 5
4-Amino-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3?^
acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-[3-(4-cWoro-benzyloxy)^
carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 4 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot ethyl acetate and dried to give 4-amino-3-[3-(4-chloro-ben2yloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 40 mg, 77%). HRMS (ES+) m/z Calcd for C24H22CIN3O4S + H [(M+H)+]: 484.1093. Found: 484.1096.

A suspension of potassium carbonate (2.02 g, 14.6 mmol) and resorcinol (16.08 g, 0.146 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 3-chlorobenzyl bromide (3.0 g, 14.6 mmol) (Aldrich) in acetonitrile (60 mL) was added. Heating at reflux was continued for 2.5 days. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (IX). The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated.

The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 3-(3-chloro-benzyloxy)-phenol. (Yield 2.80 g, 82%).
Intermediate 15
4-Chloro-3-[3-(3n:hloro-benzyloxy)-phenoxymeth^
acid ethyl ester

A suspension of potassium carbonate (0.16 g? 1.17 mmol), 3-(3-chloro-benzyloxy)«phenol (0.25g? 1.07 mmol) (from Intermediate 14 supra) and a catalytic amount of 18-crown-6 in A^TV-dimethylformamide (15 mL) was heated at 65 °C for 2 hours, 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (034 g51.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-chloro-3-[3-(3-chloro-benzyloxy)-phenoxyrnethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester.
(Yield 0.13 g, 26%).
Example 6
4-Amino-3-[3-(3-cUoro-benzyloxy)-phenoxymethyl]4hieno[352-c]pyridine-7-carboxylic
acid ethyl ester


Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(3-chloro-benzyloxy)-phenoxy-methyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.13 g, 0.27 mmol) (from Intermediate 15 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a -sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was recrystallized from methanol to give 4-amino-3-[3-(3-chloro-benzyloxy)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.11 g, 92%). HRMS (ES+) m/z Calcd for C24H21CIN2O4S + H [(M+H)4]: 469.0984. Found: 469.0983.
Example 7
4-Amino-3-[3-(3-cWoro-benzyloxy)-phenoxymethyl]-lMeno[3,2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-[3^3-chloro-benzyloxy>^^
carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 6 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot ethyl acetate and dried to give 4-amino-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3.2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 25 mg, 48%). HRMS (ES+) m/z Calcd for C24H22CIN3O4S + H [(M+H)+]: 484.1093. Found: 484.1095.
Intermediate 16
3-(3-Trifluoromethyl»benzyloxy)-phenol


A suspension of potassium carbonate (1.73 g, 12.6 mmol) and resorcinol (13.87 g, 0.126 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux firoor 1 hour. A solution of 1-bromomethyl-3-trifluoromethyl-benzene (2.3 g, 12.6 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (IX), The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to 3-(3-trifluoromethyl-benzyloxy)-phenol. (Yield 2.29 g, 68%).
Intermediate 17
4-CMoro-3-[3-(3-trifluoromethyl-benzylox
carboxylic acid ethyl ester

A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-(3-trifluoromethyl-benzyloxy)-phenol (0.29 g, 1.07 mmol) (from Intermediate 16 supra) and a catalytic amount of 18-crown-6 (Aldrich) in MA^-dimethylformamide (15 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl"4-chloro-thieno[372"C]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-chloro-3-[3-(3-Mfluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyri-dine-7-carboxylicacid ethyl ester. (Yield 0.13 g, 25%).

Example 8
4-Amino-3-[3 carboxylic acid ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(3-trifluoromethyl-benzyloxy)-phenoxy-methyl]-thieno[3,2"C]pyridine-7»carboxylic acid ethyl ester (0.13 g5 0.25 mmol)(firom Intermediate 17 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol to give 4-amino-3-[3-(3-trifluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7"Carboxylic acid ethyl ester as a white powder. (Yield 0.08 g, 64%). HRMS (ES+) m/z Calcd for C25H21F3N2O4S + H [(M+H)+]: 503.1247. Found: 503.1246.
Example 9
4-Ammo~3 - [3-(3-trifluoromethyl-benzy to
carboxylic acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3«[3-(3-trifluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g? 0.10 mmol) (from Example 8 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot ethyl acetate and dried to give 4-amino-3-[3-(3-trifluoromethyl-benzyloxy)-phenoxy-methyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyI)-amide as a white powder. (Yield 28 mg, 55%).

HRMS (ES+) m/z Calcd for C25H22F3N3O4S + H [(M+H)+]: 518.1356. Found: 518.1356,
Intermediate 18
3-Benzylsulfanyl-phenol

Benzyl bromide (7.61 g, 43.6 mmol) (Fluka) was added to a solution of 3-mercaptophenol (5.0 g, 39.6 mmol) (Aldrich) and sodium hydroxide (1.78 g, 43,6 mmol) in methanol (100 mL). Mixture was stirred at room temperature, overnight then diluted with water (200 mL) and acetic acid (10 mL) and concentrated to remove organic solvent. Resulting precipitate was collected and washed with water to give 3-benzylsulfanyl-phenol. (Yield 7.40 g, 86.3%).
Intermediate 19
3-(3-Benzylsulfanyl-phenoxymethyl)-4-^^
ester

A suspension of potassium carbonate (0.48 g? 3.44 mmol), 3-benzylsulfanyl-phenol (0.69 g9 3.17 mmol) (from Intermediate 18 supra) in tetrahydrofuran / A^jV-dimethylformamide (5:1, 30 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (1.0 g, 2.99 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in

hexanes to give 3-(3-ben2yl-sulfanyl-phenoxy^ carboxylic acid ethyl ester. (Yield 078 g, 56%).
Example 10
4-Amino-3-(3-benzylsulfanyl-pheM acid ethyl
ester

Ammonia gas was bubbled into a solution of 3-(3-benzylsulfanyl-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.78 g, 0.25 mmol) (from Intermediate 19 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was then concentrated. The residue was purified by flash chromatography eluting with 5% ethyl acetate in dichloromethane to give 4-. amino-3-(3-benzylsulfanyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxyH
ester as a white powder. (Yield 0.18 g, 50%).
HRMS (ES+) wt/z Calcd for C24H22N2O3S2 + H [(M+H)*]: 451.1145. Found: 451.1143.
Example 11
4-Amino-3-(3-benzylsulfanyl-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylicacid (2-
hydroxy-ethyl)-amide

A solution of 4-amino-3-(3-benzylsulfanyl-phenoxyme1hyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 10 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed

with hot ethyl acetate and dried to give 4-amino-3-(3-benzylsulfanyl-phenoxymethyl]-thieno[3.2-c]pyridine-7-carboxy-lic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield
23mg,37%).
HRMS (ES+) m/z Calcd for C24H23N3O3S2 + H [(M+H)4]: 466.1254. Found: 466.1255.
Example 12
4-Ammo-3-(3-phenylmethanesulfonyl-phenox
acid ethyl ester

To a solution of 4-amino-3^3-benzylsulfanyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.10 g, 0.22 mmol) (from Example 10 supra) in dichloromethane (10 mL) at -10 °C was added 3-chloro-peroxybenzoic acid (0.16 g, 0.55 mmol) (Aldrich). The reaction mixture was stirred at 0 °C for 3 hours. The mixture was concentrated. The residue was purified by CI8 column chromatography eluting with acetonitrile - water to give 4-amino-3-(3-phenylmetbanesulfonyl-phenoxy acid ethyl ester. (Yield 0.05 g, 45%). HRMS (ES+) m/z Calcd for C24H22N2O5S2 + H [(M+H)4]: 483.1043. Found: 483,1047.
Example 13
4-Amino-3-(3 phenylmethanesulfonyl-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide

M.W. 497.594 C24H23N305S2
A solution of 4-amino-3"(3-phenylmethanesulfonyl-phenoxymethyl)"thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.04 g, 0.08 mmol) (from Example 12 supra) in

dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at
130 °C for 2 hours in a microwave reactor. The crude material was purified by CI 8 column
chromatography eluting with acetonitrile - water to give 4-amino-3-(3-
phenyknethanesulfonyl-phenoxy-methyl]^
hydroxy-ethyl)-amide, (Yield 20 mg, 49%).
HRMS (ES+) m/z Calcd for Cz^NgO^ + H [(M+H)+]: 498.1152. Found: 498.1151.
3 -(3 -Methoxy-benzyloxy)-phenol

M.W. 230.27 C,4HI403
A suspension of potassium carbonate (2.02 g, 14.6 mmol) and resorcinol (16.08 g, 0.146 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 3-methoxybenzyl bromide (2.94 g, 14.6 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered, and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to 3-(3-methoxy-benzyloxy)-phenol. (Yield 2.43 g, 72%).
Intermediate 21
4-Chloro-3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]-thieno[3>2-c]pyridine-7-carboxylic
acid ethyl ester


A suspension of potassium carbonate (0.16 g, 1,17 mmol), 3-(3-methoxy-benzyloxy)-phenol (0.25 g, 1.07 mmol) (from Intermediate 20 supra) in tetrahydrofuran - N,N-dimethylformamide (5:1, 30 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered, and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes gradient to give 4-chloro-3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxyiic acid ethyl ester. (Yield 0.21 g, 43%).
Example 14
4-Amino-3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic
acid ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(3-methoxy-benzyloxy)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0*21 g, 0.43 mmol) (from Intermediate 21 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol to give 4-amino-3-[3-(3-methoxy-benzyl-oxy)-phenoxy-methyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.15 g, 75%). HRMS (ES+) m/z Calcd for C25H24N2O5S + H [(M+H)+]: 465.1479. Found: 465.1479.
Example 15
4-Amino-3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]4hieno[3,2«c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide


A solution of 4-amino-343-(3-methoxy-benzyloxy)-phenoxymethyl]^ 7-carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 14 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hpur in a microwave reactor. The precipitate was µLtered and washed with hot ethyl acetate and dried to give 4-amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 34 mg, 65%). HRMS (ES+) m/z Calcd for C25H25C1N305S + H [(M+H)+]: 480.1588. Found: 480.1587.
Intermediate 22
3-(4-Methoxy-benzy loxy)-phenol

A suspension of potassium carbonate (3,535 25.5 mmol) and resorcinol (28.12 g, 0.26 mol) (Aldriah) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 4-methoxybenzyl chloride (4.0 g, 25.5 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered, and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 3-(4-methoxy-benzyloxy)-phenol. (Yield 0.37 g, 6%).

Intermediate 23
4-Chloro-3 - [3 -(4-methoxy-benzyloxy)-phenoxymethyl] -thieno [3,2 -c]pyridine-7-carboxylic
acid ethyl ester

A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-(4-methoxy-benzyloxy)-phenol (0.25 g, 1.07 mmol) (from Intermediate 22 supra) in tetrahydrofuran - N,N-dimethylformamide (5:1,30 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (034 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X), The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered, and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes gradient to give 4-chloro-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.16 g, 33%).
Example 16
4-Amino-3-[3-(4-me1hoxy-benzyloxy)-phenoxy
acid ethyl ester

M.W. 464.54 C25H24N205S
Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(4-methoxy-benzyloxy)-phenoxy-methyl]-thieno[3r2-c]pyridine-7-carboxylic acid ethyl ester (0.16 g, 0.43 mmol) (from Intermediate 23 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The

residue was washed with hot methanol to give 4-amino-3-[3-(4-methoxy-benzyloxy)-phenoxy-methyl]-1iiieno[332-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.10 g, 67%). HRMS (ES+) m/z Calcd for C25H24N205S + H [(M+H)+j: 465.1479. Found: 465.1477.
Example 17
4-Amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethylH
acid (2-hydroxy-ethyI)-amide

A solution of 4-amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]-thieno[3?2«c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 16 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The reaction mixture was purified by CI 8 column chromatography eluting with acetonitrile - water to give 4-amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 34 mg, 65%). HRMS (ES+) m/z Calcd for C25H25CIN3O5S + H [(M+H)4]: 480.1588. Found: 480.1587.
Intermediate 24
3-(4-Methoxy-3"trifluoromethyl-benzyloxy)-phenol

M.W. 298.26 C15H13F3O3
A suspension of potassium carbonate (1.44 g, 10.4 mmol) and resorcinol (1L01 g, 0.10 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 4-methoxy-3-(trifluoromethyl)-benzyl bromide (2.8 g, 10.4 mmol) (Matrix) in acetonitrile (60 mL) was

added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 3-(4-methoxy-3-trifluoro-methyl-benzyloxy)-phenol. (Yield 0.99 g, 32%).
l«ter»e**e 25
4-Chloro-3™[3-(4-methoxy-3"trifluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester

A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenol (0.32 g, 1.07 mmol) (from Intermediate 24 supra) and a catalytic amount of 18-crown-6 (Aldrich) in 7^,iV-dimethylformamide (15 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3:)2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-chloro«3-[3-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenoxymethyl]-lMeno[3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.12 g, 21%).
Example 18
4-Amino-3-[3-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenoxymethyl]-1iiieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester


Ammonia gas was bubbled into a solution of 4-cMoro-3-[3-(4-methoxy-3-trifluoromethyl-
benzylH^xy)-phenoxymethyl]-thieno[3,2-c]pyridm^^ acid ethyl ester (0.12 g,
0.22 mmol) (from intermediate 25 supra) in dioxane (20 mL) for 20 minutes. The mixture
was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was
concentrated. The residue was purified by flash chromatography eluting with 5% ethyl
acetate in dichloromethane to give 4-amino-3-[3-(4-methoxy-3-trifluoromethyl™benzyl-oxy)-
phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder.
(Yield 0.065 g, 54%).
HRMS (ES+) m/z Calcd for C26H23F3N2O5S + H [(M+H)4]: 533.1353. Found: 533.1352.
Example 19
4-Amino-3-[3-(4-methoxy-3-1rifluorome
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-[3-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine«7-carboxylic acid ethyl ester (0.05 g? 0.10 mmol) (from Example 18 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The crude material was purified by CI 8 column chromatography eluting with acetonitrile - water to give 4-amino-3-[3-(4-methoxy-3-trifluoro-methyl-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylicacid(2-hydroxy-ethyl)-amide as a white powder. (Yield 20 mg, 39%). HRMS (ES+) m/z Calcd for C26H24F3N305S + H [(M+H)+j: 548.1462. Found: 548.1463.

Intermediate 26
4-Chloro-3-(3-phenoxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxyIic acid ethyl ester

A suspension of potassium carbonate (0,16 g, 1.17 mmol), 3-phenoxyphenol (0.20 g, 1.07 mmol) (Aldrich) in tetrahydrofuran - N^N-dimethylformamide (5:1, 30 mL) was heated at 70 °C for 3 hours. 3-Broraomethyl-4-chloro-thieno[3,2-c]pyridine-7"Carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-
chloro-3-(3-phenoxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.22 g, 49%).
Example 20
4-Amino-3-(3-phenoxy"phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-(3-phenoxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.22 g9 0.25 mmol) (from Intermediate 26 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue residue was recrystallized from ethyl acetate - hexanes to give 4-amino-3-(3-phenoxy -phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as white crystals. (Yield 0.10 g, 48%),

HRMS (ES+) m/z Calcd for C23H20N2O4S + H [(M+H)*]: 42L1217. Found: 421.1216,
Example 21
4-Ammo-3^3-phenoxy^^
hydroxy-etbyI)-amide

A solution of 4-amino-3-(3-phenoxy-phenoxymeth^
acid ethyl ester (0.05 g, 0.12 mmol) (from Example 20 supra) in dimethylsulfoxide (0.5 mL)
was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a
microwave reactor. The precipitate was µLtered and washed with hot methanol and dried to
give 4«amino-3-(3-phenoxy-phenoxymethyl]«thieno[3s2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide as a white powder. (Yield 40 mg, 77%).
HRMS (ES+) m/z Calcd for C23H21N3O4S + H [(M+H)+]: 436.1326. Found: 436.1326.
Intermediate 27
4-CUoro-3-(3-phenyIamino-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl
ester

A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-hydroxydiphenylamine (0,20 g, L07 mmol) (Alfa Aesar) in tetrahydrofuran - MA^-dimethylformamide (5:1, 30 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3.2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was

washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes
to give 4-cUoro-3-(3-phenylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxyIic acid ethyl ester. (Yield 0.16 g, 36%).
Example 22 4-Amino-3»(3-phenylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl

Ammonia gas was bubbled into a solution of 4-chloro-3-(3-phenylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.16 g, 0.36 mmol) (from Intermediate 27 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with methanol and dried to give 4-amino-3-(3-phenyiamino-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.10 g, 67%). HRMS (ES+) m/z Calcd for C23H21N3O3S + H [(M+H)"*]: 420.1377. Found: 420.1375.
Example 23
4-Amino-3-(3-phenylamino-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide

A solution of 4-amino-3-(3-phenylamino-phenoxymethyl]-thieno[372-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.12 mmol) (from Example 22 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at

130 °C for 2 hours in a microwave reactor. The crude material was purified by CI8 column chromatography eluting with acetonitrile - water to give 4-amino-3-(3-phenylamino-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white
powder. (Yield 30 mg, 58%).
HRMS (ES+) m/z Calcd for C23H22N4O3S + H [(M+H)*]: 435.1486. Found: 435.1485.

A solution of benzoyl chloride (3.0 g, 21.3 mmol) (J. T. Baker) in tetrahydrofuran (15 mL) was added dropwise at room temperature with magnetic stirring to a solution of m-aminophenol (L09 g, 10 mmol) (Eastman Organic), 4-dimethyl amino-pyridine (20 mg) (Fluka), and triethylamine (2.54 g, 25 mmol) (Aldrich) in tetrahydrofuran (30 mL). After stirring for 1 hour, precipitate was µLtered off and washed with ether* Combined µLtrate was comcentrated under reduced pressure and residue recrystallized from dichloromethnae -hexanes to give benzoic acid 3-benzoylamino-phenyl ester as a tan crystalline solid. (Yield 3.08 g, 97.1%).
Lithium aluminum hydride solution (19 mL, 1M in tetrahydrofuran) (Aldrich) was added slowly to a suspension of the benzoic acid 3-benzoylamino-phenyl ester (2.0 g, 6.3 mmol) (from Intermediate 28 supra) in anhydrous tetrahydrofuran (30 mL) under an argon

atmosphere with magnetic stirring at room temperature (exothermic reaction). When addition was complete, mixture was heated at reflux for 1 hour. Reaction mixture was allowed to cool to room temperature and was quenched by pouring slowly into 15% aqueous ammonium chloride solution (100 mL) and ether (100 mL). After stirring thoroughly, mixture was diluted with ethyl acetate (100 mL) and µLtered through Celite®. µLtercake was washed thoroughly with ethyl acetate. Combined µLtrate and washing was concentrated under reduced pressure. The resulting oil was purified by flash chromatography (Biotage 40M silica gel, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give crude product as a brown oil containing benzyl alcohol. This material was further purified by flash chromatography (Biotage 40L silica gel, 15% then 30% acetone in hexanes as solvent) to give 3-benzylamino-phenol as a colorless oil. (Yield 0.93 g5 74,1%).
Intermediate 30
3-(3-Benzylamino-phenoxymethyl)-4-cWoro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl
ester

A suspension of potassium carbonate (0.32 g, 2.31 mmol), 3-benzylamino-phenol (0.42 g5
2.11 mmol) (from Intermediate 29 supra) in tetrahydrofiiran - A^A^dimethylformamide (5:1,
30 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4«chloro-thieno[3,2-c]pyridine-7-
carboxylic acid ethyl ester (0.68 g, 2.03 mmol) (from Intermediate 8 supra) was added.
Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate
and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic
phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated.
The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes
to give 3-(3-benzyl-amino-phenoxymethyl)-4-c^ acid
ethyl ester. (Yield 0.51 g, 55%),

Example 24
4-Amino-3-(3-benzylammo-ph
ester

Ammonia gas was bubbled into a solution of 3-(3-benzylamino-phenoxymethyl)-4-chloro-tMeno[3,2-c]pyridine~7-carboxylic acid ethyl ester (0.51 g, 0.25 mmol) (from Intermediate 30 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was purified by CI 8 column chromatography eluting with acetonitrile - water to give 4-amin0'3»(3-benzylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.064 g, 13%) and recover starting material. HRMS (ES4) m/z Calcd for C24H23N3O3S + H [(M+H)*]: 434.1533. Found: 434.1532.
Example 25
4-Ammo-3-(3-benzylamino-phenoxym

A solution of 4-amino-3-(3-benzylamino-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 24 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (2.0 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The reaction mixture was puried by CI8 column chromatography eluting with acetonitrile - water to give 4-amino-3'(3-benzylamino-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 22 mg, 42%).

HRMS (ES+) m/z Calcd for C24H24N4O3S + H [(M+H)+]: 449.1642. Found: 449.1640.

A suspension of potassium carbonate (2.11 g, 15.3 mmol) and resorcinol (16.85 g, 0.153 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 4-bromomethyl-benzonitrile (3.0 g, 15.3 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (IX). The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated. The residue was washed with hot methylene chloride. The solid was µLtered and dried to give 4-(3-hydroxy-phenoxymethyl> benzonitrile. (Yield L77 g, 51%).
Intermediate 32
4-CMoro-3-[3-(4-cyano-benzyloxy)-pte
ethyl ester

A suspension of potassium carbonate (0.24 g, 1.71 mmol), 4-(3-hydroxy-phenoxymethyI)-benzonitrile (0.35 g, 1.56 mmol) (from Intermediate 31 supra) in tetrahydrofuran - NyN-dimethylformamide (5:1,18 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.50 g, 1.49 mmol) (from Intermediate 8

supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 0 - 5% ethyl acetate in dichloromethane to give 4-chloro-3«[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyri-dine-7-carboxylic acid ethyl ester. (Yield 0.38 g, 54%).
Example 26
4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid
ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0J6 g5 0,33 mmol) (from Intermediate 32 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.10 g, 67%). HRMS (ES+) m/z Calcd for C25H21N3O4S + H [(M+H)*]: 460.1326. Found: 460.1327.
Example 27
4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3.2-c]pyridine-7-carboxylic acid


An aqueous solution of sodium hydroxide (1.0 N, 0,63 mL, 0.63 mmol) was added to a solution of 4-amino-3-[3-(4-cyano«benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.17 g, 0.37 mmol) (from Example 26 supra) in tetrahydrofuran -methanol (8 mL, 3:1) and the mixture was heated at 40 °C for 1 day. The reaction mixture was concentrated and azeotroped with toluene. The solid residue was triturated with dichloromethane. The solid was then suspended in water and treated with hydrochloric acid (IN, 3 mL). After stirring for 30 minutes, the solid was collected, washed with water and then diethyl ether and dried to give 4»amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid as a white solid which was conteminated with a small amount of 4-amino-3"[3"(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid methyl ester. (Yield 0.086 g, 54%).
Exanple 28
4-Ajnino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-tMeno[3?2-c]pyridine-7*carboxylicacid
(2-hydroxy-ethyl)-amide

4-Amino-3«[3-(4-cyano-benzyloxy)-phenoxymethyl]"thieno[3,2-c]pyridine-7-carboxylicacid (86 mg, 0.13 mmol) (from Example 27 Supra), 1-hydroxybenzotriazole hydrate (43 mg, 0.32 mmol) (Aldrich) and 1,3-diisopropylcarbodiimide (0.044 mL, 0.29 mmol) (Aldrich) were combined in tetrahydrofuran - A^-dimethylformamide (3.6 mL, 5:1) with stirring. After 1 hour, ethanolamine (36 mg, 0.60 mmol) (Aldrich) was added. The mixture was stirred at room temperature for 18 hours and then concentrated. The residue was purified by HPLC eluting with acetonitrile - water to give 4-amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine~7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 65 mg, 68%). HRMS (ES+) m/z Calcd for C25H22N4O4S + Na [(M+Na)4]: 497.1254. Found: 497.1254.

Intermediate 33
3-(3-Hydroxy-phenoxymethyl)-benzonitrile

A suspension of potassium carbonate (2.11 g, 15.3 mmol) and resorcinol (16.85 g, 0.153 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 3-bromomethyl-benzonitrile (3.0 g, 15.3 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (IX). The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 3-(3-hydroxy-phenoxymethyl)~benzonitrile, (Yield 2.89 g, 84%).
Intermediate 34
4-Chloro-3-[3-(3-cyanO'ben2yloxy)«phenoxymethyl]4Weno[3,2-c]pyridme-7-carboxylicacid
ethyl ester

A suspension of potassium carbonate (0.24 g, 1.71 mmol), 3-(3-hydroxy-phenoxymethyl)-benzo-nitrile (0.35 g? 1.56 mmol) (from Intermediate 33 supra) in tetrahydrofuran - N,N-dimethylformamide (5:1,18 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.50 g, 1.49 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried

(magnesium sulfate) µLtered and concentrated. The residue was purified by flash chromatography eluting with 0 - 5% ethyl acetate in dichloromethane to give 4-chloro-3-[3-
(3-cyano-ben2yloxy)-phenoxyme%l]4Weno[3,2-c]pyri-dine-7-carboxylic acid ethyl ester. (Yield 0.43 g, 61%).
Example 29
4-Amino-3-[3-(3-cyano»ben2yloxy)-phenoxymethyl]-tMeno[3,2-c]pyridine-7-carboxyli
ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(3-cyano-benzyloxy)-phenoxy-methyl]-thieno[3,2-c]pyridine-7«carboxylic acid ethyl ester (0.14 g, 0.29 mmol) (from Intermediate 34 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[3-(3-cyano-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.10 g, 77%). HRMS (ES+) m/z Calcd for C25H21N3O4S + H [(M+H)4]: 460.1326. Found: 460.1325.
Example 30
4-Amino-3-[3-(3-cyano-benzyloxy)-phenoxyme1hyl]-lWeno[3?2-c]pyridine-7-carboxylicacid

An aqueous solution of sodium hydroxide (1.0 N, 0.63 mL? 0.63 mmol) was added to a solution of 4-amino-3-[3-(3-cyano-benzyloxy)-phenoxymethyl]-1hieno[3,2«c]pyridine-7-carboxylic acid ethyl ester (0.17 g, 0.37 mmol) (from Example 29 supra) in tetrahydrofuran -

methanol (8 mL, 3:1) and the mixture was heated at 40 °C for 1 day. The reaction mixture was concentrated and azeotroped with toluene. The solid residue was triturated with dichloromethane. The solid was then suspended in water and treated with aqueous hydrochloric acid (1 N, 3 mL). After stirring for 30 minutes, the solid was collected, washed with water and then diethyl ether and dried to give 4-amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid as a white powder which was contaminated with a small amount of 4-amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid methyl ester. (Yield 86 mg, 54%).
Example 31
4-Ammo-3 - [3-(3-cyano-benzy loxy )^
(2-hydroxy-ethyl)-amide trifluoroacetic acid salt
4-amino-3-[3-(3-cyano-benzyloxy>phenoxym
(86 mg, 0.13 mmol) (from Example 30 supra), 1-hydroxybenzotriazole hydrate (43 mg? 0.32 mmol) (Aldrich) and 1,3-diisopropylcarbodiimide (0.044 mL, 0.29 mmol) (Aldrich) were combined in tetrahydrofuran - A^N-dimethylformamide (3.6 mL, 5:1) with stirring. After 1 hour, ethanolamine (0.036 g, 0.60 mmol) (Aldrich) was added. The mixture was stirred at room temperature for 18 hours and then concentrated, The residue was purified by HPLC eluting with acetonitrile - water containing trifluoroacetic acid to give 4-amino-3-[3-(3-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide trifluoroacetic acid salt as a white powder. (Yield 65 mg5 68%). HRMS(ES+)ff2/zCalcdforC25H22N404S + H[(M+H)+]: 475.1435. Found: 475.1434.
Example 32
3-(3-benzyloxy-phenoxymethyl)-4-(2-hydroxy-etnylamino)-thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide


A solution of 3-(3-benzyloxy"phenoxymethyl)-4-cWoro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.16 g, 0.35 mmol) (from Intermediate 11 supra) in dimethylsulfoxide (1.0 mL) was treated with ethanolamine (4.0 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was recrystallized from ethyl acetate - hexanes to give 3-(3-benzyloxy-phenoxymethyl)-4-(2-hydroxyetnyl-amino)-thieno[3,2-c]pyridine"7-carboxylic acid (2-hydroxy-ethyl)-amide as white crystals. (Yield 0.06 g, 35%). HRMS (ES+) m/z Calcd for C26H27N3O5S + H [(M+H)*]: 494.1744. Found: 494.1746

3-Hydroxybenzoic acid (5 g, 36.2 mmol) (Aldrich) was suspended in dry benzene (200 mL) and the mixture was heated to reflux. N, N-Dimethylformamide di-/-butyl acetal (34.7 mL, 0.14 mol) (Aldrich) was added dropwise and the mixture was heated at reflux for a further 1 hour. The cooled solution was washed with water, saturated sodium bicarbonate solution and brine. After drying (magnesium sulfate) and µLtering, the solvent was evaporated. The residue was purified by flash chromatography eluting with 25% hexanes in dichloromethane and 10% ethyl acetate in dichloromethane to give 3-hydroxy-benzoic acid ter/-butyl ester. (Yield 3.47 g, 49%).

Intermediate 36
3-(3-ter^Butoxycarbonyl-phenoxy
ethyl ester

A suspension of potassium carbonate (1.47 g, 10.65 mmol), 3-hydroxy-benzoic acid tert-butyl ester (1.89 g, 9.73 mmol) (from Intermediate 35 supra) and a catalytic amount of 18-crown-6 (Aldrich) in N, N-dimethylformamide (50 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (3.10 g5 9.26 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 3-(3-/er/-butoxycarbonyl-phenoxymethyl)-4»chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 2.5 g, 60%).
Intermediate 37
4-Amino-3-(3-tert-butoxycarbonyl-phenoxymethyl)-tMeno[3?2-c]pyridine-7-carboxylicacid
ethyl ester

Ammonia gas was bubbled into a solution of 3-(3-/er/t-butoxycarbonyI-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.62 g, 1.38 mmol) (from Intermediate 36 supra) in dioxane (20 mL) for 30 minutes. The mixture was heated in a

sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The
residue was washed with hot ethyl acetate, the solid was µLtered and dried to give 4-amino-3-
(3-^r/-butoxycarbonyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester
(0.46 g). The solution was concentrated. The residue was purified by flash chromatography
eluting with 40% ethyl acetate in hexanes to give the product (0.13 g). (Combined yield 0.59
g,100%).
HRMS (ES+) m/z Calcd for C22H24N205S + H [(M+H)+]: 429.1479. Found: 429.1480.
Intermediate 38
4-Amino-3-(3-carboxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester

4-Amino-3-(3-rer/-butoxycarbonyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylicaci^ ethyl ester (0.13 g, 0.30 mmol) (from Intermediate 37 supra) was dissolved in trifluoroacetic acid - dichloromethane (1:1,4 mL). The mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in saturate aqueous sodium carbonate solution and extracted with dichloromethane. The aqueous phase was acidified with 6 N hydrochloric acid. The solid formed was collected, washed with water and dried to give 4-amino-3-(3-carboxy-phenoxymethyl)-thieno[3,2-c]p3ridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.11 g, 100%). HRMS (ES+) m/z Calcd for C18H16N2O5S + H [(M+H)*]: 373.0853. Found: 373.0853,
Intermediate 39
4-Hydroxy-benzoic acid /er/-butyl ester


4-Hydroxybenzoic acid (5.29 g, 38 3 mmol) (Aldrich) was suspended in dry benzene (200 mL) and the mixture was heated to reflux. N,N -Dimethylformamide di-r-butyl acetal (36.7 mL, 0.15 mol) (Aldrich) was added dropwise and the mixture was heated at reflux for a further 1 hour. The cooled solution was washed with water, saturated aqueous sodium bicarbonate solution and brine. After drying (magnesium sulfate) and µLtering, the solvent was evaporated. The residue was purified by flash chromatography eluting with 25% hexanes in dichloromethane and 10% ethyl acetate in dichloromethane to give 4-hydroxy-benzoic acid tert-bxxtyl ester. (Yield 1.72 g, 23%).
Intermediate 40
3-(4-ter^Butoxycarbonyl-phenoxymethyty^

A suspension of potassium carbonate (1.34 g, 9.70 mmol), 4-hydroxy-benzoic acid ter/-butyl ester (1.72 g, 8.86 mmol) (from Intermediate 39 supra) and a catalytic amount of 18-crown-6 (Aldrich) in A^-dimethylformamide (50 mL) was heated at 65 °C for 2 hours. 3~ Bromomethyl-4«chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (2.82 g, 8.43 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X), The combined organic phase was washed with water and brine, dried (magnesium sulfate) µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 3-(4-terf-butoxycarbonyl-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 2.65 g, 70%),

Intermediate 41
4-Amino-3-(4-ter/-butoxycar^^
ethyl ester
Ammonia gas was bubbled into a solution of 3-(4-te^butoxycarbonyl-phenoxymethyl)-4-chloro4hieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (2.70 g, 6.03 mmol) (from Intermediate 40 supra) in dioxane (60 mL) for 30 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was recrystallized from ethyl acetate, the solid was µLtered and dried to give 4-amino-3-(4-/err-butoxycarbonyl-phenoxymethyl)-lMeno[3?2-c]pyridine-7-carboxylic acid ethyl ester (1.3 g). The mother liquid was concentrated. The residue was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to give the product (0.8 g). (Combined yield 2.1 g, 81%). HRMS (ES+) m/z Calcd for C22H24N2O5S + H [(M+H)*]: 429.1479. Found: 429.1480.
Intermediate 42
4-Amino-3-(4-carboxy-phenoxymethyl)-1hieno[3?2-c]pyridine-7-carboxylic acid ethyl ester

4-Ammo-3-(4-/er^butoxycarbonyl-phenoxymethyl)-thieno[3?2-c]pyµMdine-7-carboxylicacid ethyl ester (2.1 g, 4.9 mmol) (from Intermediate 40 supra) was dissolved in trifluoroacetic acid - dichloromethane (1:2, 60 mL). The mixture was stirred at room temperature for 3 hour then concentrated. The residue was dissolved in saturated aqueous sodium carbonate solution and extracted with dichloromethane. The aqueous phase was acidified with aqueous

6 N hydrochloric acid. The solid was collected, washed with water and dried to give 4-amino-3-(4-carboxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 1.83 g, 100%).
HRMS (ES+) m/z Calcd for CjgHi^OsS + H [(M+H)*]: 373.0853. Found: 373.0853.
Example 33
4-Amino-3-(3-methoxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester

This was prepared following the procedure found in Example 2 supra,
HRMS (ES+) m/z Calcd for C18H18N204S + H [(M+H)+]: 359.1060. Found: 359.1058.
Example 34
4-Ammo-3-(3-methoxy-phenoxymeth^
hydroxy-ethyl)-amide

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C18H19N3O4S + H [(M+H)+]: 374.1169. Found: 374.1169.
Example 35
4-Ammo-3-(3-benzoylamino-phenoxyme&^ ethyl
ester


This was prepared following the procedure found in Example 1 supra.
HRMS (ES*) m/z Calcd for C24H21N3O4S + H [(M+H)"*]: 448.1326. Found: 448.1325.
Example 36
4-Amino-3-(3-benzoylamino-phenoxyme1hyl)-thieno[3,2-c]pyridine-7-carboxyli acid (2-
hydroxy-ethyl)-amide

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C24H22N4O4S + H [(M+H)+]: 463.1435. Found: 463.1436.
Example 36a
4-Amino-3-(3-benzoylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide hydrochloride

This was prepared by treating 4-aminO"3-(3-benzoylamino-phenoxymethyl)-thienof3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide with 1 equivalent of hydrochloric acid. HRMS (ES+) m/z Calcd for C24H22N404S + H [(M+H)+]: 463.1435. Found: 463.1437. HRMS (ES+) m/z Calcd for C24H22N4O4S + Na [(M+Na)*]: 485.1254. Found: 485.1256.

Example 36b
4-Amino~3-(3-benzoylamino^
hydroxy-ethyl)-amide toluene-4-sulfonic acid salt

This was prepared by treating 4-anuno-3-(3-benzoylamino-phenoxymethyl)-thieno[3?2»
c]pyridine-7-carboxylic acid (24iydroxy-ethyl)-amide with 1 equivalent of toluene-4-sulfonic
acid,
HRMS (ES+) m/z Calcd for C24H22N4O4S + H [(M+H)4]: 463.1435. Found: 463.1437.
HRMS (ES+) m/z Calcd for C24H22N4O4S + Na [(M+Na)*]: 485.1254. Found: 485.1256.
Example 37
4-Amino-3-[3-(4-cWoro-phenylcarbamoyl)-phenoxymethyl]-tMeno[3,2-c]pyridine-7-
carboxylic acid ethyl ester

To a suspension of 4-amino-3-(3-carboxy-phenoxymethyl)-thieno[352-c]pyridine-7-carboxylic acid ethyl ester (49.2 mg, 0.132 mmol) (from Intermediate 38 supra) in DMF (5 mL) were added diisopropylethylamine (68 mg, 0.528 mmol), HOBt (26.7 mg, 0.198 mmol) (Aldrich) and HBTU (75.0 mg, 0.198 mmol) (Advanced ChemTech). After stirring for 30 minutes, 4-chloroaniline (20.0 mg, 0.158 mmol) (Aldrich) in DMF (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours before it was diluted with EtOAc (80 mL), washed with IN HC1 (10 mL), saturated aqueous Na2C03 solution (10 mL),

brine (2x10 mL), dried (Na2S04) and µLtered. Removal of the solvent followed by column chromatography (CH2C12 / MeOH, 98/2) gave 4-amino-3-[3-(4-chloro-phenylcarbamoyl)-phenoxymethyI]-thieno[3,2-c]pyridme-7-carboxylic acid ethyl ester as a white solid. (Yield
34.1 mg, 53.6%).
HRMS (ES+) m/z Calcd for C24H20CIN3O4S + H [(M+H)*]: 482.0936. Found: 482.0936.
Example 38
4-Amino-3-[3-(4^hloro-phenylcarbamoyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7'
carboxylic acid (2-hydroxy-ethyl)-amide

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C24H2iClN404S + H [(M+H)+]: 497.1045. Found: 497.1045.
Example 39
4-Amino-3-[3-(4«fluoro-phenylcarbamoyl)-phenoxyme1iiyl]-tMeno[352-c]pyridine-7-
carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C24H20FN3O4S + H [(M+H)*]: 466.1232. Found: 466.1230.
Example 40
4-Amino-3-[3-(4-fluorO"phenylcarbamoyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide


This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C24H21FN4O4S + Na [(M+Na)+]: 503.1160. Found: 503.1158.
Example 41
4-Amino-3-[3-(4-cMoro-benzyloxy)-phenoxymeft^
acid trifluoro-acetic acid salt

This was prepared by sodium hydroxide hydrolysis of 4-amino«3-[3-(4-chloro-benzyloxy)« phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) followed by purification with reverse phase chromatography using acetonitrile - water containing 0.1% trifluoroacetic acid as solvent.
Example 42
4-Amino-3-[3-(3-cWorO"phenylcarbamoyl)«phenoxymethyl]-1liieno[3?2-c]pyridine-7-
carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.

HRMS (ES+) m/z Calcd for C24H2oClN304S + H [(M+H)*]: 482.0936. Found: 482.0937.
Example 43
4-Ammo-3-[3-(3-cMoro-phenylcar^
carboxylic acid (2-hydroxy-ethyl)-amide

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for CsµMiClN^S + Na [(M+Na)4]: 519.064. Found: 519.0864.
Example 44
4-Amino-3-[3»(4-chloro-phenylcarbamoyl)-phenoxymethyl]-tWeno[3,2-c]pyridine-7-
carboxylic acid (3-hydroxy-propyl)-amide

This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with amino 1 -propanol. HRMS (ES+) m/z Calcd for C25H23CIN4O4S + Na [(M+Na)*]: 533.1021. Found: 533.1022.
Example 45
4-Amino-3-[3-(4-cUoro-phenylcarbamoyl)-phenoxyme1hyl]4hieno[3?2-c]pyridine-7-
carboxylic acid propylamide


This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with propylamine.
HRMS (ES+) m/z Calcd for C25H23CIN4O3S + Na [(M+Na)+]: 517.1071. Found: 517.1072.
Example 46 4-Amino-3-[3-(4-cMoro-phenylcarbamoyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-
carboxylic acid ethylamide

This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with ethylamine. HRMS (ES+) m/z Calcd for C24H21CIN4O3S + Na [(M+Na)+]: 503.0915. Found: 503.0917.
Example 47
4-Amino-3 - {3 - [(4-chloro-phenyl)-methyl-carbamoyl] -phenoxymethy 1} -thieno [3,2 -
c]pyridine-7-carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.

HRMS (ES+) m/z Calcd for C25H22CIN3O4S + H [(M+H)+]: 496.1093. Found: 496.1088.
Example 48
4-Amino-3-[3-( 1 -methyl-piperidin-4-ylcarbamoyI)-phenoxymethyl]-thieno[
carboxylic acid ethyl ester

This was prepared following the procedure found in Example 3 supra,
HRMS (ES+) m/z Calcd for C24H28N4O4S + H [(M+H)+]: 469.1904. Found: 469.1900.
Example 49
4-Amino-3-[3-(5-methyl-pyridin-2-ylcarbamoyl)-phenoxymethyl]-lWeno[3?2-c]pyri
carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C24H22N4O4S + H [(M+H)*]: 463.1435. Found: 463.1430.
Example 50
4-Amino-3-[3-(l-methanesulfonyl-piperidin-4-ylcarbamoyl)"phenoxymethyl]-thieno[3?2-
c]pyridine-7-carboxylic acid ethyl ester


This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C24H28N4O6S2 + Na [(M+Na)4]: 555.1342. Found: 555.1332.
Example 51
4-Amino-3- {3-[(4-chloro-phenyl)-methyl-carbamoyl]-phenoxymethyl} -thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C25H23CIN4O4S + Na [(M+Na)*]: 533.1021. Found: 533.1016.
Example 52
4-Amino-3-[5-(3-carbamoyl-phenylcarbamoyl)-2-methyl-phenoxymethyl]-thieno[3,2-

This was prepared following General Procedure 4 supra.
LRMS (ES+) m/z Calcd for C26H24N4O5S + H [(M+H)+]: 505. Found: 505.
Example 53
4-Amino-3-(2-methyl-5-phenylcarbamoyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-
carboxylic acid ethyl ester


This was prepared following General Procedure 4 supra.
Example 54
4-Ammo-3-[3-(4-cWoro-benzyloxy)-phen^
acid (3-hydroxy-propyl)~amide trifluoro-acetic acid salt

A solution of 4-ainino-3-[3-(4-cMoro-berizyloxy)-pte^
carboxylic acid ethyl ester (0.04 g, 0.09 mmol) (from Example 4 supra) in dimethylsulfoxide
(0*5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours
in a microwave reactor. The mixture was purified by HPLC eluting with acetonitrile/water
containing 0.1% trifluoroacetuic acid to give 4-amino-3-[3-(4-chloro-benzyloxy)-
phenoxymethyl]-thieno[3?2-c] pyridine-7-carboxylic acid (3-hydroxy-propyl)-amide
trifluoro-acetic acid salt. (Yield 9.0 mg5 17%).
HRMS (ES+) mfz Calcd for C25H24CIN3O4S + H [(M+H)4]: 498.1249. Found: 498.1248.
Example 55
4-Amino-3-[3-(4«chloro-phenoxymethyl)-phenoxymethyl]-thieno[3,2-c]pyridine"7-
carboxyiic acid ethyl ester


N?N-Diisopropylethylamine (19.2 mL, 110 mmol) (Aldrich) was added to a suspension of 3-hydroxybenzaldehyde (12.21 g, 100 mmol) (Aldrich) in dichloromethane (50 mL) with cooling in an ice-water bath. Chloromethylmethyl ether (15.19 mL, 200 mmol) (Aldrich) was then added dropwise and the mixture stirred at room temperature for 3 hours. The mixture was then washed with mixture of brine (30 mL) and water (30 mL), followed by 0.1 N HC1 (3 X 20 mL) and brine (2 X 20 mL). Aqueous layers were back washed with dichloromethane (30 mL). Organic solutions were combined, dried (MgSC>4), µLtered and concentrated. Residue was µLtered through silica gel (Biotage 40M) eluting with dichloromethane. Fractions were combined and concentrated to give 3-methoxymethoxy-benzaldehyde as pale yellow oil, (Yield 13.94 g, 83.9%).
Sodium borohydride (1.14 g, 30 mmol) (Aldrich) was added in small portions to a solution of 3-methoxymethyloxy-benzaldehyde (4.99 g, 30 mmol) in methanol (90 mL) and water (3 mL). Mixture was stirred for 3 hours at room temperature and then diluted with water (50 mL). Mixture was concentrated under reduced pressure and the resulting aqueous suspension extracted with ethyl acetate (2 X 75 mL). Organic layers were washed with water (50 mL) and brine (50 mL), and then combined, dried (MgS04), µLtered and concentrated to give crude (3-methoxymethoxy-phenyl)-methanol as a colorless oil. This was used in the next step without further purification. (Yield 5.04 gs 100%).
A neat mixture of (3-methoxymethoxy-phenyl)-methanol (1.68 g, 10 mmol), 4-chlorophenol (1.29 g, 10 mmol) (Aldrich) and N?N'-dicyclohexylcarbodiimide (2.06 g, 10 mmol) (Aldrich) was heated in a sealed tube at 100 °C for 24 hours. Sample was cooled to room temperature then triturated with ether. Dicyclohexylurea was removed by µLtration. µLtrate was washed with 1 N aqueous hydrochloric acid and brine. Aqueous layers were back washed with ether. Combined ether layers were dried (MgS04), µLtered and concentrated. Residue was µLtered through a Biotage flash cartridge (40S, eluting with dichloromethane) to give (4-chlorophenoxy-methyl)-3-methyloxymethoxy-benzene as a pale yellow oil (Yield 2.07 g, 74.3%).
To a solution of (4-chlorophenoxy-methyl)-3-methyloxymethoxy-ben2;ene (2.07 g, 7.43 mmol) in tetrahydrofuran / 2-propanol (1:1, 40 mL) was added 4M HC1 in dioxane (18.5 mL) (Aldrich). The reaction mixture was stirred at room temperature for 18 hours. The solution was concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous

sodium bicarbonate solution and brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to 3-(4-chloro-phenoxymethyl)-phenol. (Yield 1.72 g, 99%).
A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-(4-chloro-phenoxymethyI)-pbenol (0.25 g, 1.07 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:1.18 mL) was heated at 70 °C for 3 hours. 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, L02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgSO,*) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 4-chloro-3-[3-(4-cWoro-phenoxymethyl)-phenoxymethyl]-thieno[332-c]pyridine-7-carboxylicacid ethyl ester. (Yield 0.19 g, 38%).
Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(4-chloro-phenoxymethyl)-phenoxy-methyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.11 g, 0.23 mmol) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[3-(4-chloro-phenoxymethyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield
0.087g, 79%).
HRMS (ES+) m/z Calcd for C24H21CIN2O4S + H [(M+H)+]: 469.0984. Found: 469.0984.
Example 56
4-Ammo-3-{3-[2-(4-cMoro-phenyl^

Sodium hydride (60% in oil, 1.0 g, 25 mmol) (Aldrich) was added in small portions to a solution of diethyl 4-chlorobenzylphosphonate (2.63 g, 1.0 mmol) (Alfa Aesar), catalytic

amount of 18-Crown-6 (Aldrich) and methanol (0.8 mL, 20 mmol) in dry DMF (15 mL). After stirring for 5 minutes, 3-methoxymethoxy-benzaldehyde (1.66 g, 10 mmol) in dry DMF (5 mL) was added and mixture was stirred at room temperature for 1 hour, then at 120 °C for 5 hours. After cooling to room temperature, mixture was diluted with water (100 mL) and extracted with ether (2 X 100 mL). Organic layers were washed with water and brine, dried (MgSC>4), µLtered and concentrated. Residue was purified by chromatography (Biotage 40M, 20%, then 40% dichloromethane in hexanes as solvent). Product was recrystallized from hexanes to give pure E-[2-(4-chloro»phenyl)-vinyl]-3-methyloxymethoxy-benzene as white crystalline plates. (Yield 2.74 g, 100%).
To a solution of E-[2-(4-chloro«phenyl)-vinyl]-3-methyloxymethoxy-benzene (2.22 g, 8.08 mmol) in tetrahydrofuran / 2-propanol (1:1, 40 mL) was added 4M HC1 in dioxane (15 mL) (Aldrich). The reaction mixture was stirred at room temperature for 18 hours. The solution was concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried (MgSO^O and concentrated. The residue was washed with hot dichloromethane and dried to give 3-[2-(4-chloro-phenyl)-vinyl]-phenol. (Yield 0.81 g, 44%).
A suspension of potassium carbonate (0.16 g, L17 mmol), 3-[2-(4-chloro-phenyl)-vinyl]-phenol (0.25 g, 1.07 mmol) in tetrahydrofuran / N,N»dimethylformamide (5:1, 18 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (034 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgSC>4) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 4-chloro-3-{3-[2-(4-cWoro-phenyl)-vmyl]-phenoxymethyl}-tWeno[3.2-c]pyridine-7-carboxy ethyl ester. (Yield 0.31 g, 63%).
Ammonia gas was bubbled into a solution of 4-chloro-3-{3-[2-(4-chloro-phenyl)-vinyl]-phenoxy-methyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.11 g, 0.23 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-{3-[(E)-2-(4-

cWoro-phenyI)-vmyl]-phenoxy^ acid ethyl ester.
(Yield 0.093 g, 96%).
HRMS (ES+) m/z Calcd for C25H2iClN203S + H [(M+H)*]: 465.1034, Found: 465.1034.
Example 57
4-Amino-3-{3-[2-(4-cMoro-phe^
carboxylic acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 56 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with ethyl acetate and dried to give 4-amino-3-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenoxy-methyl}-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)»amide as a white powder.
(Yield 36.0 mg, 69%).
HRMS (ES+) m/z Calcd for C25H22CIN3O3S + H [(M+H)*]: 480.1143. Found: 480.1144.
Example 58
4-Amino-3-[3-(4-cUoro-phenoxymelhyl)-phenoxymethyl]-1hieno[3?2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-[3-(4-cUoro-phenoxymethyl)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 55 supra) in

dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot methanol and dried to give 4-amino-3-[3-(4-chloro-phenoxymethyl)-phenoxy-methyI]-thieno[3.2-c]pyridine-7-carboxylic acid (2~hydroxy-ethyI)-amide as a white solid. (Yield 25.8 mg, 50%). HRMS (ES+) m/z Calcd for C24H22CIN3O4S + H [(M+H)+]: 484.1093. Found: 484.1096.
Example 59
4-Amino-3-[3-(4-cWoro-phenylcarbamoyl)-phenoxymethyl]-tMeno[3?2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-methyl-amide
This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with 2-methylamino-ethanol. HRMS (ES+) m/z Calcd for C25H23CIN4O4S + Na [(M+Na)*]: 533.1021. Found: 533.1019,
Example 60
4-Amino-3-[3-(4-chloro-phepylcarbamoyl)-phenoxymethyl]-thieno[3?2»c]pyridine-7--
carboxylic acid (2-methoxy-ethyl)-amide


This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with 2-methoxy-ethylamine.
HRMS (ES+) m/z Calcd for C25H23CIN4O4S + Na [(M+Na)4]: 533.1021. Found: 533.1020.
Example 61
4-Ammo-3-[3-(4-cMoro-phenylcarba^
carboxylic acid methylamide

This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with methylamine. HRMS (ES+) m/z Calcd for C23H19CIN4O3S + H [(M+H)*]: 467.0939. Found: 467.0941.
Example 62
3-[4-Amino-7-(morpholine-4-carbonyl)4hieno[3,2-c]pyridin-3-ylmethoxy]-N-(4-chloro-
phenyl)-benzamide

This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37
supra) following the procedure found in Example 27 supra and the resulting acid coupled
withmorpholine.
HRMS (ES+) m/z Calcd for C26H23CIN4O4S + H [(M+H)*]: 523.1202. Found: 523.1202.
HRMS (ES+) m/z Calcd for C26H23CIN4O4S + Na [(M+Na)*]: 545.1021. Found: 545.1022.

Example 63
4-Aimno-3 acid ethyl ester

This was prepared following the procedure found in Example 1 supra,
HRMS (ES+) m/z Calcd for C24H27N3O4S + H [(M+H)*]: 454.1795. Found: 454.1797.
Example 64
4- Amino-3 - [3 »(tetrahydro-pyran-4-ylcarbamoyl)-phenoxymethyl] -thieno [3,2-c]pyridine-7-

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C23H25N3O5S + H [(M+H)+]: 456.1588. Found: 456,1590.
Example 65
4-Amino-3-[3-(l-methanesulfonyl-piperidin-4-ylcarbamoyl)«phenoxymetiiyl]4hieno[3?2-


This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C24H29N506S2 + H [(M+H)*]: 548.1632. Found: 548.1636.
HRMS (ES+) m/z Calcd for C24H29N5O6S2 + Na [(M+Na)*]: 570.1451. Found: 570.1453.
Example 66
4-Amino-3-[3-( 1 -methyl-piperidin-4--ylcarbamoyl)-phenoxymethyl]-thieno[3 „2-c]pyridine-7-

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C24H29N5O4S + H [(M+H)+]: 484.2013. Found: 484.2012;
Example 67
4-Amino-3-(3-phenylaminomethyl-phenoxymethyl)-thieno[3?2-c]pyridine"7-carboxylic acid

A suspension of 3-acetoxybenzoic acid (1.80 g? 10 mmol) in a mixture of N5N-dimethylformamide (3 drops) and thionyl chloride (3 mL, 40 mmol) (Aldrich) was heated in a 90 °C bath for 2 hours. After cooling, mixture was diluted with toluene (20 mL) and concentrated under reduced pressure to remove excess thionyl chloride. The resulting oil was dissolved in dichloromethane (10 mL) and added dropwise to a solution of aniline (0.93 g, 10 mmol) (Aldrich), 4-dimethylamino-pyridine (0.1 g, 0.08 mmol) (Fluka) and KN-diisopropylethylamine (1,6 g, 12.4 mmol) (Aldrich) in dichloromethane (10 mL) with magnetic stirring. When addition was complete, mixture was stirred at room temperature for

an additional 2 hours. Reaction mixture was then partitioned between water (50 mL) and dichloromethane (2 X 50 mL). Organic layers were combined, and concentrated to dryness. Residue was dissolved in THF (10 mL), methanol (10 mL) and 1 N aqueous sodium hydroxide (10 mL) and stirred at room temperature for 16 hours. The yellow solution was diluted with water (100 mL) and acetic acid (5 mL) and extracted with ethyl acetate (2 X 100 mL). Ethyl acetate layers were washed with brine (100 mL), combined, dried (MgS04), and concentrated to give crude 3-hydroxy-N-phenyl-benzamide which was used in the next step without further purification. (Yield 2.20 g, 103%).
Lithium aluminum hydride solution (19 mL, 1M in tetrahydrofuran) (Aldrich) was added slowly to a suspension of the crude 3-hydroxy-N-phenyl-benzamide (2.0 g, 6.3 mmol) in dry tetrahydrofuran (30 mL) under an argon atmosphere with magnetic stirring with cooling in an ice - water bath (exothermic reaction). When addition was complete, mixture was heated at reflux for 1 hour. Reaction mixture was allowed to cool to room temperature and was quenched by pouring slowly into 15% aqueous ammonium chloride solution (100 mL) and ether (100 mL). After stirring thoroughly, mixture was diluted with ethyl acetate (100 mL) and µLtered through Celite. µLtercake was washed thoroughly with ethyl acetate. Combined µLtrate and washing was concentrated under reduced pressure. The resulting oil was purified by flash chromatography (Biotage 40M silica gel, 20% ethyl acetate in hexanes as solvent) to give 3-phenylaminomethyl-phenol an a colorless oil. (Yield L48 g, 73.5%). A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-phenylaminomethyl-phenol (0.21 g, 1.07 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:1,18 mL) was heated at 70 °C for 3 hours. 3"Bromomethyl"4-chloro-thieno[3,2-c]pyridme-7-carboxylic acid ethyl ester (034 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 4-chloro-3-(3-phenylaminomethyl-phenoxymethyl)-thieno[372-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.15g, 33%).
Ammonia gas was bubbled into a solution of 4-chloro-3-(3-phenylaminomethyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.15 g, 0.33 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a

sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The crude material was purified by HPLC eluting with acetonitrile / water to give to 4-amino-3-(3-phenylaminomethyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.030 g, 21%).
A solution of 4-amijio-3"(3-phenylaminomethyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.03 g, 0.07 mmol) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by HPLC eluting with acetonitrile / water to give to 4"amino-3-(3-phenylaininomethyl-phenoxymethyl)-thieno [3,2-c]pyridine~7-carboxylic acid (2-hydroxy~ethyl)-amide as a white solid. (Yield 13.0 mg, 33%). HRMS (ES+) m/z Calcd for C24H24N4O3S + H [(M+H)+]: 449.1642. Found: 449.1645.
Example 68 4-Amino-3 - {3 -[2~(4-chloro-phenyl)-ethoxy] -phenoxymethyl} -thieno [3,2-c]pyridine-7-

DEAD (2.0 g, 11.5 mmol) (Aldrich) was added to a stirred solution of triphenylphosphine (3.01 g, 11.5 mmol) (Aldrich) in tetrahydrofuran (80 mL) at room temperature. After stirring for 10 minutes, p-chlorophenethyl alcohol (L40 g, 8.9 mmol) (Aldrich) was added. After stirring for 10 minutes resorcinol (2.92 g, 26.55 mmol) (Aldrich) in tetrahydrofuran (20 mL) was added quickly and mixture stirred for another 18 hours. The reaction mixture was concentrate and the residue was purified by flash chromatography eluting with 20-40 % ethyl acetate in hexanes to give 3-[2-(4-chloro-phenyl)-ethoxy]-phenol. (Yield 1.44 g5 65%). A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-[2-(4-chloro-phenyl)-ethoxy}-phenol (0.27 g, 1.07 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:1,18 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, L02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic

phase was washed with water and brine, dried (MgSC>4) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 4-chloro-3-{3-[2-(4-cWoro-phenyl)-ethoxy]^ ethyl ester. (Yield 0.10 g5 20%).
Ammonia gas was bubbled into a solution of 4-chloro-3-{3-[2-(4-chloro-phenyl)-ethoxy]-phenoxy"methyl}-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.10 g, 0.20 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue Was washed with hot methanol, µLtered and dried to give 4-amino-3«{3-[2-(4-chloro-phenyl)-ethoxy]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.093 g, 96%). HRMS (ES+) mix Calcd for C25H23CIN2O4S + H [(M+H)+]: 483 J140. Found: 483.1143.

A solution of 4-amino-3-{3-[2-(4-chloro-phenyl)«ethoxy]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.04 g, 0.08 mmol) (from Example 68 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (L5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with ethyl acetate and methanol, dried to give 4"amino-3-{3-[2-(4»chloro^phenyl)-ethoxy]-phenoxy-methyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 28.0 mg, 70%). HRMS (ES+) m/z Calcd for C25H24CIN3O4S + H [(M+H)+]: 498.1249. Found: 498.1249.
Example 70

4-Amino-343-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3.2-c]pyri

A suspension of potassium carbonate (0.74 g, 5.39 mmol), 4-chloro-N-(3-hydroxy-phenyl)-benzamide (1.07 g, 4.30 mmol) (prepared by the reaction of excess 4-chlorobenzoyl chloride with 3-aminophenol and N?N-diisopropylethylamine followed by hydrolysis with 1 N sodium hydroxide) in tetrahydrofuran / N5N-dimethylformamide (5:2, 35 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (1.20 g5 3.59 mmol) (from Intermediate &supra) was added. Heating was continued for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was washed with hot dichloromethane and dried to give 4-chloro-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3?2-c]pyridine-7~carboxylic acid ethyl ester. (Yield 0.99 g, 55%). Ammonia gas was bubbled into a solution of 4-chloro-3"[3-(4-chloro-benzoylamino)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.28 g, 0.56 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyI]"thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.20 g, 74%). HRMS (ES+) m/z Calcd for C24H20CIN3O4S + H [(M+H)+]: 482.0936. Found: 482,0925.
Example 71
4-Amino-3-[3-(4-chloro-benzoylamino)-phenox^
acid (2-hydroxy-ethyl)-amide


A solution of 4"amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-tW 7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 70 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich)) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with ethyl acetate, dried to give 4"amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 21.0 mg, 40%). HRMS (ES+) mix Calcd for C24H21CIN4O4S + Na [(M+Na)*]: 519.0864. Found: 519.0858.
Example 72
4-Amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic
acid (3-hydroxy-propyl)-amide

A solution of 4-amino-3-[3«(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3 ?2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 70 supra) in dimethylsulfoxide (0.5 mL) was treated with 3-amino-l-propanol (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by CI 8 column chromatography eluting with acetonitrile / water to give 4-amino-3-[3-(4-chloro-benzoyl-amino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylicacid (3-hydroxy-propyl)-amide. (Yield 22.0 mg, 43%). HRMS (ES+) m/z Calcd for C25H23CIN4O4S + H [(M+H)+]: 511.1202. Found: 511.1195.

Example 72a
4-Amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[^

A solution of 4-amino-3-[3-(4-cUoro-beiizoyl-aixuno)-phenoxymethyl]-thieno[3;j2-c]pyridine-7-carboxylic acid (3-hydroxy-propyl)-amide (0.05 g, 0.10 mmol) (from Example 72 supra) in methanol (7.5 mL) was treated with 1M HC1 in diethyl ether (0.15 mL) and heated at 48 °C for 15 minutes. After cooling, diethyl ether (30 mL) was added. The solution was kept in a refrigerator overnight. The solid formed was µLtered and dried to give 4-amino-3-[3-(4-chloro-ben2oyl-amino)-phenoxymethyl]-thieno[3?2-c]pyridine-7«carboxylic acid (3-hydroxy-propyl)-amide hydrochloride. (Yield 52.0 mg, 96%). HRMS (ES+) m/z Calcd for C25H23CIN4O4S + H [(M+H)*]: 511.1202. Found: 511.1203.
Example 72b
4-Amino-3-[3-(4~cWoro-benzoylamino)-phenoxym
acid (3-hydroxy-propyl)-amide toluene-4-sulfonic acid salt

M.W. 511.003 + 172.204 C25H23CIN4O4S • C7Hg03S
A solution of 4-amino-3-[3"(4-chloro-benzoyl-amino)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (3-hydroxy-propyl)-amide (0.05 g, 0.10 mmol) (from Example 72 supra) in methanol (6 mL) was treated with toluene-4-sulfonic acid hydrate (18.6 mg,

0.10 mmol) (Aldrich) and heated at 40 °C for 30 minutes. The solution was concentrated.
The residue was washed with diethyl ether, dissolved in water and lyophilized to give 4-
amino-3-[3-(4-chloro-benzoyl-amino)-phenoxymeto^
acid (3-hydroxy-propyI)-amide, toluene-4-sulfonic acid salt (Yield 67.0 mg, 100%).
HRMS (ES+) m/z Calcd for C25H23CIN4O4S + H [(M+H)+]: 511.1202. Found: 511.1202.
Example 73
4-Amino-3-(2-oxo-1 -phenethyl-1 s2-dihydro-pyrimidin-4-yloxymethyl)-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra,
HRMS (ES+) m/z Calcd for C23H22N4O4S + H [(M+H)+]: 451.1435. Found: 451.1434.
Example 74
4-Amino-3-(2,6-dioxo-3-phenethyl-3,6-dihydro^^

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C^H^C^S + H [(M+H)*]: 451.1435. Found: 451.1434.



0.10 mmol) (Aldrich) and heated at 40 °C for 30 minutes. The solution was concentrated.
The residue was washed with diethyl ether, dissolved in water and lyophilized to give 4-
anuno-3-[3-(4-cMoro-benzoyl-amino)-ph
acid (3-hydroxy-propyI)-amide, toluene-4-sulfonic acid salt. (Yield 67.0 mg, 100%).
HRMS (ES4) m/z Calcd for C25H23CIN4O4S + H [(M+H)+]: 511.1202. Found: 511.1202.
Example 73
4-Amino-3-(2-oxo-1 -phenethyl-1,2-dihydro-pyrimidin-4-yloxymethyl)-thieno[3,2-
c]pyridine-7«carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C23H22N4O4S + H [(M+H)+]: 451.1435. Found: 451.1434.
Example 74
4-Amino-3-(2?6-dioxo-3-phene1hyl-3?6-dihydro-2H-pyriniidin-1 -ylmethyl>thieno[3.,2-
c]pyridine-7-carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C23H22N4O4S + H [(M+H)4]: 451.1435. Found: 451,1434.









Example 86
4-Amino-342-methyl-3-(5-m^
c]pyridine-7-carboxylic acid ethyl ester

This was prepared following General Procedure 4 supra.
Example 87
4-Anaino-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxymethyl}"thieno[3,2-c]pyridine-7-

To a solution of 3-[2-(4-chloro-phenyl)-vinyl]-phenol (035 g, 1.52 mmol) (from Example 56 supra) in methanol (20 mL) was treated with 10% Pd/C (0.04 g) (Aldrich). The reaction mixture was hydrogenated for 6 hours. The reaction mixture was passed through Celite and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 3-[2-(4-chlorophenyl)-ethyl]-phenol. (Yield 0.33 g5 94%).
A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-[2-(4-chlorophenyl)-ethyl]-phenol (0.25 g, 1.07 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:1, 18 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3?2"C]pyridine-7-carboxylic acid ethyl ester (0.34 g, L02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic

phase was washed with water and brine, dried (MgS04> and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 4-chloro-3 - {3 42-(4-chloro-pheny l)-e1hyl] ^
ethyl ester. (Yield 0.13 g, 26%).
Ammonia gas was bubbled into a solution of 4-chloro-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxy-methyl}"thieno[392'C]pyridine«7-carboxylic acid ethyl ester (0.13 g, 0.27 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-Amino-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.08 g, 67%). HRMS (ES+) m/z Calcd for C25H23CIN2O3S + H [(M+H)*]: 467.1191. Found: 467.1192.
Example 88
4-Amino-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxymethyl}-thieno[352-c]pyridine-7-

A solution of 4-amino-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxymethyl}-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.05 gs 0.11 mmol) (from Example 87 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot methanol and dried to give 4-amino-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxymethyl}-thieno[352-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 31.6 mg? 61%). HRMS (ES+) m/z Calcd for C25H24CIN3O3S + H [(M+H)4"]: 482.1300. Found: 482.1302.

Example 89
4-Amino-345-(4-cMoro-phenyk
7-carboxylic acid ethyl ester

A suspension of 3-hydroxy-4-methylbenzoic acid (10,73 g, 70.5 mmol) (Lancaster) in acetic anhydride (25 mL, 265 mmol) (Aldrich) was heated at reflux for 5 hours. After cooling to toom temperature, mixture was poured into ice - water mixture (600 mL) and stirred overnight. Solid clumps were broken up and collected by µLtration. Residue was washed with water and dried in vacuum oven to give 3-acetoxy-4-methyl-benzoic acid as a tan solid. (Yield 11.82 g, 86,3%).
3-Acetoxy-4-methyl-benzoic acid (1.94 g, 10 mmol) was suspended in thionylchloride (3 mL, 40 mmol) (Aldrich) and N,N-dimethyl-formamide (3 drops) and heated at reflux for 2 hours. After cooling to room temperature, mixture was diluted with toluene (30 mL) and concentrated under reduced pressure. Resulting oil was dissolved in dichloromethane (30 mL) and added dropwise to a solution of 4-chloroaniline (1.34 g,10,5 mmol) (Aldrich) and N5N-diisopropylethylamine (1.6 g312.5 mmol) in dichloromethane (50 mL). After stirring for another 2 hours, mixture was diluted with water (50 mL) and stirred for another 30 minutes. Layers were separated. Organic layer was washed with water (50 mL). Aqueous layers were back washed with dichloromethane (50 mL). Organic layers were then combined and concentrated. Residue was dissolved in mixture of tetrahydrofuran (25 mL), methanol (25 mL) and 1 N aqueous sodium hydroxide (10 mL, 10 mmol). After stirring for 16 hours, mixture was diluted with water (100 mL) and acetic acid (5 mL) and concnetrated under reduced pressure to remove most of the organic solvent. Precipitate formed was collected by µLtration and washed with water, and dried to give N-(4-chloro-phenyl)-3-hydroxy-4-methyl-benzamide as off-white crystals. (Yield 2.57 g, 98.2%).

A suspension of potassium carbonate (0.21 g, 1,53 mmol), N-(4-chloro-phenyl)-3-hydroxy-4-methyl-benzamide (0.32 g, 1.22 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:2, 21 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4"Chloro-thieno[3?2«c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was washed with hot dichloromethane and dried to give 4-chloro-3-[5-(4-chloro-phenylcarbamoyl)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.23 g, 43%).
Ammonia gas was bubbled into a solution of 4-cMoro-345-(4-cMoro-phenylcarbamoyl)-2-
methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-c^ acid ethyl ester (0.23 g, 0.45
mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was
heated in a sealed pressure vessel at 160 °C for lday. The reaction mixture was concentrated.
The residue was purified by CI8 column chromatography eluting with acetonitrile / water to
give4-amino~3-[5-(4-cMoro-phenylcarbam
c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.08 g, 36%). HRMS (ES4) m/z Calcd for CssH^ClNsC^S + H [(M+H)+]: 496.1093. Found: 496.1094.
Example 90
4-Amino-3-[5-(4-cMoro-phenylcarbamoyl)^

A solution of 4-amino-3-[5-(4-chloro-phenylcarbamoyl>2-methyl-phenoxymethyl]-thieno[3r2-c] pyridine-7~carboxylic acid ethyl ester (0.05 g, 0,10 mmol) (from Example 89 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and

heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by
CI 8 column chromatography eluting with acetonitrile / water to give 4-amino-3-[5-(4-chloro-
phenyl-carbamoyl)-2-methyl-phenoxymethyl]-tfo^
hydroxy-ethyl)-amide as a white powder. (Yield 25.0 mg, 48%).
HRMS (ES+) m/z Calcd for C25H23CIN4O4S + Na [(M+Na)+]: 533.1021. Found: 533.1025.
Example 91
4-Ammo-3-[5-(4-cWoro-benzoylamino)-2-m

A solution of p-chlorobenzoyl chloride (19.25 g, 110 mmol) (Aldrich) in tetrahydrofuran (50 mL) was added to a solution of 5-amino-o-cresol (6.16 g, 50 mmol) (Aldrich) and triethylamine (17.5 mLs 125 mmol) (Aldrich) and THF (100 mL) dropwise with magnetic stirring and cooling in an ice - water bath. When addition was complete, mixture was allowed to warm to room temperature and stirred for 16 hours. Reaction mixtrue was diluted with water (400 mL). After stirring for another 30 minutes, precipitate was collected to give crude 4-chloro-benzoic acid 5-(4-cWoro-benzoylamino)-2-methyl-phenyl ester as an off-white powder. (Yield 21.24 g, 106%).
4-Chloro-benzoic acid 5-(4-chloro-benzoylamino)-2-methyl-phenyl ester (4.04 g, 10 mmol) was dissolved in a mixture of tetrahydrofuran (25 mL, methanol (50 mL) and aqueous IN sodium hydroxide (10 mL, 10 mmol). Mixture was stirred at room temperature for 18 hours. Mixture was concentrated under reduced pressure to remove most of the organic solvent. Resulting suspension was diluted with water (100 mL) and saturated aqueous sodium bicarbonate solution (5 mL). After standing for 30 minutes, precipitate was collected and washer with water and dried to give 4-chloro-N-(3-hydroxy-4»methyl-phenyl)-benzamide as a white powder. (Yield 2.46 g, 93.1%).

A suspension of potassium carbonate (0.21 g, 1.53 mmoI)? 4-cWoro-N-(3-hydroxy-4-methyl-pheny])-benzamide (0.32 g, 1.22 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:2, 21 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine«7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was washed with hot dichloromethane and dried to give 4-chloro-3-[5-(4-chloro-benzoylamino)-2-methyl-phenoxymethyl]-tWeno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.1 Og, 19%).
Ammonia gas was bubbled into a solution of 4-chloro-3-[5-(4-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.10 g, 0.19 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3"[5-(4-cUorO"benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c] pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 95.0 mg, 99%), HRMS (ES+) m/z Calcd for C25H22CIN3O4S + H [(M+H)+]: 496.1093. Found: 496.1092.
Example 92
4-Ammo-345-(4-cWoro-benzoylamino)-2-mefo^

A solution of 4-amino-3-[5-(4-cUoro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3?2-c] pyridine-7-carboxylic acid ethyl ester (0.05 g; 0.10 mmol) (from Example 91 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) and heated at 160 °C for

2 hours in a microwave reactor. The reaction mixture was purified by CI8 column chromatography eluting with acetonitrile / water to give 4-amino-3-[5-(4~chloro-benzoyl-amino)-2-methyl-phenoxymethyl]-thieno[3?2-c]pyridine~7-carboxylic acid (2-hydroxy-ethyl)-amide. (Yield 34.0 mg, 65%). HRMS (ES+) m/z Calcd for C25H23CIN4O4S + H [(M+H)+]: 511.1202. Found: 511.1202.
Example^
4-Aimno-3-[3-(4-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-c^

This was prepared following the procedure found in Example 1 supra. HRMS (ES+) m/z Calcd for C24H20FN3O4S + H [(M+H)*]: 466.12322. Found: 466.1231.
Example 94 4-Amino-3-[5-(4-chloro-2-methyI-phenylcarbamoyl)-2-methoxy-phenoxymethyI]-

This was prepared following General Procedure 4 supra.
Example 95
4-Amino-3-[3-(5-chloro-2-methoxy-phenylcarbamoyl)-2-methyl-phenoxymethyl]-
thieno[3,2"C]pyridine-7-carboxyIic acid ethyl ester









HRMS (ES+) m/z Calcd for C23H2oClN504S + H [(M+H)+]: 498.0998. Found: 498.1000.
Example 103
4-Amiiio-3-(5-pheny]carbam^

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C23H21N5O4S + H [(M+H)+]: 464.1387. Found: 464.1390.
Example 104a
4-Amino-3-[3-(4-cMoro-benzoylammo
acid (4-pyrrolidin-l-yl-butyl)-amide trifluoro-acetic acid salt

MW. 578.138+114.024 C3oH32ClN503S-C2HF302
A mixture of 4-amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (0.15 g, 0.13 mmol) (from Example 151 infra), 1-hydroxybenzotriazole hydrate (71 mg5 0.56 mmol) (Aldrich) and l?3^diisopropylcarbodiimide (0.077 mL, 0.50 mmol) (Aldrich) were combined in tetrahydrofuran : N,N-dimethylformamide (9.0 mL, 5:1) with stirring. After 1 hour, 4-pyrroIidinobutylamine (0.14 g, 1.04 mmol) (Aldrich) was added. The mixture was stirred at room temperature for 3 days and then concentrated. The residue was purified by HPLC eluting with acetonitrile / water containing 0.1% trifluoroacetic acid to give 4-amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3.2-c]pyridine-7-carboxyIic acid (4-pyrrolidin-l-yl-butyl)-amide5 trifluoroacetic acid salt as a white powder. (Yield 0.16 g5 67%).

HRMS (ES+) m/z Calcd for C30H32CIN5O3S + H [(M+H)*]: 578.1987. Found: 578.1982.
Example 104b
4-Amino-3-[3-(4H±loro4>enzoylamino)-phenox
acid (4-pyrrolidin-l-yl-butyl)-amide toluene-4-sulfonic acid salt

To a solution of 4-amino-3-[3-(4-cMoro-benzoylamino)-phenoxymethyl]«thieno[3?2-c]pyridine-7-carboxylic acid (4-pyrrolidin-l-yl-butyl)-amide (0.047 g, 0.08 mmol) (from Example 104a supra) in methanol (6 mL) was treated with toluene-4-sulfonic acid hydrate (18.6 mg5 0.10 mmol) (Aldrich) and heated at 40 °C for 30 minutes. The solution was concentrated. The residue was washed with diethyl ether, dissolved in water and lyophilized togive4-amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (4-pyrrolidin-l-yl-butyl)-amide toluene-4-sulfonic acid salt as a white powder. (Yield 60.0 mg, 100%). HRMS (ES+) m/z Calcd for C30H32CIN5O3S + H [(M+H)+]: 578.1987. Found: 578.1984.
Example 105
4-Amino-3-[5-(4-cUoro-benzyloxy)-2-methyl»phenoxyme1hyl]-tMeno[3?2-c]pyridine-7-

A mixture of 2,4-dihydroxybenzaldehyde (6.62 g, 48 mmol) (Fluka), potassium fluoride (5.57 g, 96 mmol) (Aldrich) and 4-chlorobenzyl chloride (13.50 g, 84 mmol) (Aldrich) in

acetonitrile (50 mL) was heated at 90 °C for 24 hours. After cooling, mixture was partitioned between ether (2 X 100 mL) and water (2 X 100 mL). Organic layers were washed with brine (100 mL)5 combined, dried (MgS04)? µLtered and concentrated. Residue was purified by flash chromatography (Biotage 75S, hexanes, then hexanes - dichloromethane 1:1 as solvent) gave partial separation. Pure fractions of product were combined and concentrated and residue crystallized from hexanes with traces of dichloromethane to give 4-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde as white crystals. (Yield 4.74 g, 37.6%). Mother liquor and impure fractions were combined and further purified by flash chromatography (Biotage 40L, same solvent as before) and pure fractions combined and concentrated. Residue re-crystallized to give second crop of 4-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde. (Yield 3.03 g, 24.1%).
To a solution of 4-(4-chloro-benzyloxy)-2-hydroxybenzaldehyde (1.31 g, 5.0 mmol) and sodium cyanoborohydride (1.0 g, 15.9 mmol) (Aldrich) in tetrahydrofiiran (30 mL) was added methyl orange as an indictor, giving the solution a yellow color; IN aqueous HC1 solution (7.5 mL) was added slowly, keeping the solution orange. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate three times. The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with 0 - 40% ethyl acetate in hexanes to give 5-(4-chloro-benzyloxy)»2-methyl-phenol. (Yield 0.43 g,35%).
A suspension of potassium carbonate (0.33 g, 2.36 mmol), 5-(4-chloro-benzyloxy)-2-methyl-phenol (0.43 g, 1.73 mmol) in tetrahydrofiiran / N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.53 g, 1.57 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (MgS^) and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-chloro-3-[5-(4-chloro-benzyloxy)-2-methyl-phenoxymethyl]-tMeno[372-c]pyridine-7-carboxylicacid ethyl ester. (Yield 0.37 g, 47%).

Ammonia gas was bubbled into a solution of 4-chloro-3-[5-(4-chloro-benzyloxy)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.21 g, 0.29 mmol) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140 °C for 2 hours. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[5-(4-chloro-benzyloxy)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.18 g, 90%). HRMS (ES+) m/z Calcd for C25H23CIN2O4S + H [(M+H)+]: 483.1140. Found: 483.1143.
Example 106
4-Amino-3-[3-(4~fluoro-benzyloxy)-phenoxymeft^
ethyl ester

This was prepared following General Procedure 7 supra.
LRMS (ES*) m/z Calcd for C24H21FN2O4S + H [(M+H)+]: 453. Found: 453.
Example 107
4-Amino-3-[3-(4-methyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic
acid ethyl ester

This was prepared following General Procedure 7 supra. LRMS (ES+) m/z Calcd for C25H24N2O4 + H [(M+H)*]: 449. Found: 449.
Intermediate 47





LRMS (ES+) m/z Calcd for C24H20F2N2O4S + H [(M+H)*]: 471. Found: 471.
Example 110
4-Amino-3-[5-(4-chloro-benzyloxy)-2-m

A solution of 4-amino-3-[5-(4-cWoro-benzyloxy)-2-me1hyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 105 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by CI 8 column chromatography eluting with acetonitrile / water to give to 4-amino-3-[5-(4-chloro-benzyloxy)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 28 mg, 54%). HRMS (ES+) m/z Calcd for C25H24CIN3O4S + H [(M+H)*]: 498.1249. Found: 498.1248.
Example 111
4-Amino-3-(5-benzyloxy-2-methyl-phenoxymetiiyl)-lWeno[3?2-c]pyridine-7"Carboxylic acid

To a solution of 4-benzyloxy-2-hydroxybenzaldehyde (2.28 g, 10.0 mmol) (prepared by the method of Example 105 supra) and sodium cyanoborohydride (2.0 g, 15.9 mmol) in tetrahydrofuran (60 mL) was added methyl orange as an indictor, giving the solution a yellow color; IN aqueous HC1 solution (15 mL) was added slowly, keeping the solution orange. The mixture was stirred overnight at room temperature. Water was added, and the

mixture was extracted with ethyl acetate three times. The combined organic phase was washed with water and brine, dried (MgSC>4) and concentrated. The residue was purified by flash chromatography eluting with 0 - 40% ethyl acetate in hexanes to 5-benzyloxy-2-methyl-phenol (Yield 0.64 g, 30%),
A suspension of potassium carbonate (0.16 g, LI 7 mmol), 5-benzyloxy-2-methyl-phenol (0.23 g, 1.07 mmol) in tetrahydrofiiran / N,N-dimethylformamide (5:2; 14 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 3-(5-benzyloxy-2-methyl-phenoxymethyl)-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.17 g, 35%).
Ammonia gas was bubbled into a solution of 3-(5-benzyloxy-2-methyl-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.17 g, 0.36 mmol) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140 °C for 2 hours. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-(5-ben2yloxy-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0*07 g, 44%). HRMS (ES+) m/z Calcd for C25H24N2O4S + H [(M+H)+]: 449.1530. Found: 449.1529.
Example 112
4-Amino-3-(5-benzyloxy-2-me1hyLphenoxymethyl)"thieno[3,2-c]pyridine-7-carboxylic


A solution of 4-ammo-3-(5-benzyloxy-2-methyl^
carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 111 supra) in
dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at
160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by CI 8
column chromatography eluting with acetonitile / water to give to 4-amino-3-(5-benzyloxy-
2-methyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylicacid (2-hydroxy-ethyl)-amide
as a white powder. (Yield 27 mg, 52%).
HRMS (ES+) m/z Calcd for C25H25N3O4S + H [(M+H)*]: 464.1639. Found: 464.1642.
Example 113
4-Anuno-3-(5-benzoylamino-2-methyl-phenoxymethyl)-tlueno[3,2-c]pyridine"7-carboxylic

A solution of benzoyl chloride (7.75 g, 55 mmol) (Aldrich) in tetrahydrofuran (25 mL) was added to a solution of 5-amino-o-cresol (3.08 g, 25 mmol) (Aldrich) and triethylamine (8.8 mL, 62.5 mmol) (Aldrich) and THF (50 mL) dropwise with magnetic stirring. When addition was complete, mixture was allowed to warm to room temperature and stirred for 4 hours. Reaction mixtrue was diluted with water (400 mL). After stirring for another 30 minutes, precipitate was collected. This material was dissolved in a mixture of THF (120 mL), methanol (40 mL) and 1 N aqueous sodium hydroxide solution (25 mL, 25 mmol) and stirred at room temperature for 16 hours. Mixture was then diluted with water (100 mL) and concentrated under reduced pressure to remove organic solvent. Precipitate formed was collected and washed with water and dried to give N-(3-hydroxy-4-methyl-phenyl)-benzamide as an off white powder. (Yield 2.14 g, 37.7%). Further concentrating and on standing a second crop of N-(3-hydroxy«4-methyl-phenyl)-benzamide was formed. (Yield 3.66 g5 64.4%).

A suspension of potassium carbonate (0.16 g, 1.17 mmol), N-(3-hydroxy-4-methyl-phenyl)-benzamide (0.24 g, 1.07 mmol) in tetrahydrofuran / N?N»dimethylformamide (5:2, 14 mLl) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgSC>4) and concentrated. The residue was purified by flash chromatography eluting with 0 - 20% ethyl acetate in hexanes togive3«(5-benzoylamino-2-methyl-phenoxymethyl)^-chloro-tWeno[3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.12 g, 24%).
Ammonia gas was bubbled into a solution of 3-(5-benzoylamino-2«methyl-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.21 g, 0.44 mmol) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in microwave at 140 °C for 2 hours. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-(5-benzoylamino-2-methy]-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.12 g, 60%). HRMS (ES+) m/z Calcd for C25H23N3O4S + H [(M+H)4]: 462.1482. Found: 462.1483.
Example 114
4-Ajmno-3-(5-benzoylammo-2-methyl-pte
acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-(5-benzoylamino-2-methy]-phenoxyme11iyl)-thieno[3,2-c]pyridme-7-carboxylic acid ethyl ester (0.05 g? 0.11 mmol) (from Example 113 supra) in dimethylsulfoxide (0,5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by CI 8

column chromatography eluting with acetonitrile / water to give 4-amino«3-(5-benzoylamino-2-methyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 23.0 mg, 44%). HRMS (ES+) m/z Calcd for C25H24N4O4S + Na [(M+Na)4]: 499.1410. Found: 499.1411.
Intermediate 51
4-CWoro-3-[3-(3?5-difluoro-benzyloxy)-5-m^
carboxylic acid ethyl ester

This was prepared following General Procedure 6 supra.
LRMS (ES+) m/z Calcd for C25H20CIF2NO4S + H [(M+H)4]: 504. Found: 504.
Intermediate 52
4-CWoro-3-[3 carboxylic acid ethyl ester

This was prepared following General Procedure 6 supra.
LRMS (ES+) m/z Calcd for C25H2oClF2N04S + H [(M+H)*]: 504. Found: 504.























This was prepared following General Procedure 7 supra,
LRMS (ES+) m/z Calcd for C25H24N2O5S + H [(M+H)+]: 465. Found: 465.
Example 131
4-Amino-3- {3-[3
N,N-Diisopropylethylamine (15.51 g, 120 mmol) (Aldrich) was added to a suspension of 3-nitrophenol (13.91 g, 100 mmol) (Aldrich) in dichloromethane (50 mL) with cooling in an ice-water bath. Chloromethylmethyl ether (15.19 mL, 200 mmol) (Aldrich) was then added dropwise and the mixture stirred at room temperature for 3 hours. The mixture was then washed with mixture of brine (30 mL) and water (30 mL), followed by 0.1 N HC1 (3 X 20 mL) and brine (2 X 20 mL). Aqueous layers were back washed with dichloromethane (30 mL)t Organic solutions were combined, dried (MgS04), µLtered and concentrated. Residue was µLtered through silica gel (Biotage 40M) eluting with dichloromethnae. Fractions were combined and concentrated to give methoxymethoxy-3-nitro-benzene as pale yellow oil. (Yield 17,15 g, 93.6%).
To a solution of methoxymethoxy-3-nitro-benzene (5.06 g, 27.6 mmol) in methanol (50 mLl) was added 10% Pd/C (0.5 g) (Aldrich). The mixture was hydrogenated overnight. The mixture was passed through Celite and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 3-methoxymethoxy-phenylamine. (Yield 3.45 g, 15%).
To a solution of methyl-3-hydroxybenzoate (3.04 g, 20.0 mmol) in dimethylformamide (60mL) were added 4-(2-chloroethyl)morpholine (5.58 g, 30.0 mmol) (Aldrich) and potassium carbonate (8.30 g, 60.0 mmol). The mixture was heated at 80 °C for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and

brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with 10% methanol in dichloromethane to give 3-(2-morpholin-4-yl-ethoxy)-benzoic acid methyl ester. (Yield 5.63 g, 100%).
An aqueous solution of sodium hydroxide (IN, 32.0 mL, 32 mmol) was added to a solution 3-(2-moipholin-4-yl-ethoxy)-benzoic acid methyl ester (5.31 g, 20.0 mmol) in methanol (20 mL) and the mixture was heated at reflux for 18 hours. The reaction mixture was concentrated and azeotroped with toluene. The solid residue was washed with diethyl ether. The solid was dissolved in water and treated with hydrochloric acid (2.5N) to pH 2. The aqueous solution was concentrated, then dissolved in dichloromethane and µLtered. The solution was concentrated to give 3-(2-morpholin-4-yl-ethoxy)-benzoic acid. (Yield 1.05 g, 21%).
To a mixture of 3-(2-morpholin-4-yl-ethoxy)-benzoic acid (1.05 g, 4.18 mmol), HBTU (1.90 g, 5.01 mmol) (Oakwood) and diisopropylethylamine (1.82 mL, 10.45 mmol) inN,N-dimethylformamide (15.0 mL) was added 3-methoxymethoxy-phenylamine (0.77 g. 5.01 mmol). The mixture was stirred at room temperature for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate to give N-(3-methoxymethoxy-phenyl)-3«(2-morpholin-4-yl-ethoxy)-benzamide. (Yield 0.39 g, 24%).
To a solution of N-(3-methoxymethoxy-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide (0.39 g, 1.0 mmol) in tetrahydrofuran / 2-propanol (1:1,10 mL) was added 4M HC1 in dioxane (2 mL) (Aldrich). The reaction mixture was stirred at room temperature for 18 hours. The solution was concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried (MgSC^) and concentrated. The residue was purified by CI8 column chromatography eluting with acetonitrile / water to give N-(3-hydroxy-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide. (Yield 0.20 g, 57%). A suspension of cesium carbonate (0.20 g, 0.61 mmol), N-(3-hydroxy-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide (0.14 g, 0.41 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3?2'C]pyridine-7-carboxylic acid ethyl ester (0.14 g, 0.41 mmol) (from Intermediate 8 supra) was added. Heating was continued for 2 days. The reaction mixture

was partitioned between ethyl acetate and water. The aqueous phase was concentrated. The
residue was purified by CI 8 column chromatography eluting with acetonitrile / water to give
4-cWoro-3-{3-[3-(2-morpholm-^
c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.13 g, 54%).
Ammonia gas was bubbled into a solution of 4-chloro-3-{3-[3-(2-morpholin-4-yl-ethoxy)-
benzoylamino]»phenoxymethyl}-thieno[3T2-c]pyridine-7-carboxylic acid ethyl ester (0.13 g7
0,44 mmol) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in microwave at
140 °C for 4 hours. The reaction mixture was concentrated. The residue was washed with
hot methanol, µLtered and dried to give 4-amino-3-{3-[3-(2-morpholin-4-yl-ethoxy)-
benzoylamino]-phenoxymethyl}-thieno [3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield
0.05 g, 38%).
A solution of 4-amino-3- {3-[3-(2-morpholin-4-yl-ethoxy)-benzoylamino]-phenoxymethyl} -
thieno [3,2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.09 mmol) in dimethylsulfoxide
(0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich)) and heated at 160 °C for 2 hours
in a microwave reactor. The reaction mixture was purified by CI 8 column chromatography
eluting with acetonitrle / water to give 4-amino-3-{3-[3-(2-morpholin«4-yl-ethoxy)-
benzoylamino]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-
amide as a white powder. (Yield 20.0 mg, 39%).
HRMS (ES+) m/z Calcd for C3oH33N506S + H [(M+H)+j: 592.2225. Found: 592.2220,
Example 132
4-Amino-3-(3 -methylcarbamoyl-phenoxymethyl)-thieno[3 ,2-c]pyridine-7-carboxylic acid

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C19H19N3O4S + H [(M+H)+]: 386.1169, Found: 386.1170.
Example 133





This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C2]H22N404S + H [(M+H)+J: 427.1435. Found: 427.1437.
HRMS (ES+) m/z Calcd for C21H22N4O4S + Na [(M+Na)+]: 449.1254. Found: 449.1257.
Eumpfel39
4-Arnmo-3-(3-cyclopentylcarbamoyl-phenoxymethyl)-tWeno[3,2-c]pyridine-7-carboxylic

M.W. 454.552 C23H26N4O4S
This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C23H26N404S + H [(M+H)+]: 455.1748. Found: 455.1752.
Example 140
4-Amino-3-(5-memylcarbamoyl-pyridin-3-yloxymethyl)-thieno[3,2-c]pyridine-7-carboxylic

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for Ci8HlgN404S + H [(M+H)+]: 387.1122. Found: 387.1122.
Example 141








This was prepared following General Procedure 8 supra.
LRMS m/z Calcd for C25H23F2N3O4S + H [(M+H)4]: 500. Found: 500.
Example 150
4-Amino-3-[3-(23-difluoro-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7^

This was prepared following General Procedure 8 supra.
LRMS m/z Calcd for C24H21F2N3O4S + H [(M+H)"*]: 486. Found: 486.
Example 151
4-Amino-343-(4-chloro-benzoylamino)-phenoxymeft^
acid

An aqueous solution of sodium hydroxide (1 N, 1.0 mL, L0 mmol) was added to a solution of 4-ammo-3-[3-(4-cWoro-benzoylamino)-ph
carboxylic acid ethyl ester (0.16 g, 0.33 mmol) (from Example 70 supra) in tetrahydrofuran -methanol (8 mL, 3:1) and the mixture was heated at 40 °C for 2 days. The reaction mixture

was concentrated and azeotroped with toluene. The solid residue was washed with hot ethyl acetate. The solid was then suspended in water and treated with hydrochloric acid (1 N, 2 mL). After stirring 30 minutes, the solid was collected, washed with water and then diethyl ether and dried to give 4-amino-3-[3-(4-cUoro-benzoylamino)-phenox)'methyl]-thieno[3?2-c]pyridine-7-carboxylic acid. (Yield 0,15 g, 100%).
Example 152
4-Amino-3-[3-(pyrimidm-5-ylmethoxy)-phe
acid ethyl ester
RO5066450-000 37010-93,5 M.W. 436.493 C22H20N4O4S
This was prepared following the procedure found in Example 1 supra,
HRMS (ES+) m/z Calcd for C22H20N4O4S + H [(M+H)+]: 437.1278. Found: 437.1278.
Example 153
4-Amino-343-(pyrimidin-5-ylmetto

RO5066451-000 37010-95-1 M.W. 451.508 C22H21N5O4S
This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C22H21N5O4S + H [(M+H)+]: 452.1387. Found: 452.1385.
Intermediate 67
4-Chloro-3-(3-m1ro-phenoxyme1hyl)-thieno[3,2-c]pyridine«7-carboxylic acid ethyl ester


A mixture of 3-nitrophenol (457 mg, 3,29 mmol) (Aldrich) and potassium carbonate powder (498 mg, 3.60 mmol) in dry THF (10 mL) and DMF (5 mL) was stirred at 50 °C for 15 minutes before a solution of 3-bromomethyl-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (1.00 g? 2.99 mmol) (from Intermediate 8 supra) in THF (10 mL) was added. The reaction was stirred at 50 °C for 3 hours and the resulting mixture was concentrated to remove most of the solvent. The residue was dissolved in EtOAc (200 mL), washed with water (2 x 25 mL) and brine (25 mL), dried (Na2S04)9 µLtered and concentrated. The crude product was purified by column chromatography (CH2CI2 / MeOH, 98/2 to 90/10) to give 4-chloro-3-(3«nitro-phenoxymethyl)-thieno[3T!2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 911 mg, 78%). HRMS (ES+) m/z Calcd for C17H13CIN2O5S + H [(M+H)*]: 393.0307. Found: 393.0308.
Intermediate 68
3-(3-Amino-phenoxymethyl)-4-chloro-thieno[3,2»c]pyridine-7-carboxylic acid ethyl ester

RO5134429-000 37304-92A M.W. 362.838 C17H15CIN2O3S
To a solution of 4-chloro-3"(3-nitro-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (503.6 mg, L28 mmol) (from Intermediate 67 supra) in THF (175 mL) was added 10% Pd/C (253 mg) (Aldrich) and the mixture was stirred in an atmosphere of hydrogen (40 psi) for 4 hours. The Pd/C was µLtered off and the µLtrate was concentrated to give the crude product which was purified by column chromatography (hexanes / EtOAc, 80/20 to 50/50) to give 3-(3-amino-phenoxymethyl)-4-chloro-1iueno[3?2»c]pyridine-7-carboxylic acid ethyl ester as a white solid, (Yield 278 mg, 60%).

HRMS (ES+) m/z Calcd for CI7H15C1N203S + H [(M+H)+J: 363.0565. Found: 363.0565.

To a solution of 3-(3-amino-phenoxymethyl)^-chloro-tWeno[392-c]pyridine-7-carboxylic acid ethyl ester (96.9 mg, 0.267 mmol) (from Intermediate 68 supra) in THF (3 mL) were added diisopropylethylamine (78 mg, 0.603 mmol) and then 4-chlorobenzenesulfonyl chloride (64.7 mg, 0.297 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (50 mL), washed with aqueous IN NaOH (10 mL), brine (2 x 10 mL), dried (Na2S04), µLtered, and concentrated. The residue was purified by column chromatography (hexanes / EtOAc, 80/20 to 60/40) to give 4-chloro-3-[3-(4-chloro-benzenesulfonylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield
95.3 mg5 66%).
HRMS (ES+) m/z Calcd for C23H,8Cl2N205S2 + H t(M+H)+]: 537.0107. Found: 537.1015.
Example 154
4-Ainino-3-[3-(4-chloro-benzenesulfc^

RO5070056-000 37304-96A M.W. 518.014 C23H20CIN3O5S2

Ammonia gas was bubbled into a solution of 4-chloro-3«[3-(4-chloro-benzenesulfonylamino)«phenoxymethyl]-tWeno[3?2-c]pyridine-7-carboxylic acid ethyl ester (89.6 mg, 0.167 mmol) (from Intermediate 69 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a sealed vessel at 130 °C for 1.5 hours in a microwave reactor. The reaction mixture was concentrated and the residue was purifed by column chromatography (CH2C12 / MeOH, 98/2) to give 4-amino-3-[3-(4-chloro-benzenesulfonylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 76.5 mg, 88.6%). HRMS (ES+) m/z Calcd for C23H20CIN3O5S2 + H [(M+H)4]: 518.0606. Found: 518.0602.

A suspension of 4-amino-3-[3-(4-chloro-benzenesulfonylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxy!ic acid ethyl ester (54.4 mg, 0.105 mmol) (from Example 154 supra) in dimethylsulfoxide (1 mL) and ethanolamine (3 mL) (Aldrich) was heated at 135 °C for 2 hours in a microwave reactor. After cooling to room temperature, the precipitate was µLtered off, washed with MeOH and dried to give 3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)amide as a white solid (Yield 41.7 mg, 74.5%), HRMS (ES+) m/z Calcd for C23H2iClN405S2 + H [(M+H)+]: 533.0715. Found: 533.0710.
Intermediate 70
2-Chloro-5-(4-chloro-benzyloxy)-phenol


A mixture of 4-chlororesorcinol (2,89 g, 20 mmol) (Aldrich), potassium fluoride (2.32 g, 40 mmol) (Aldrich) and 4-chIorobenzyl chloride (4.83 g, 30 mmol) (Aldrich) in acetonitrile was heated at 90 °C for 24 hours. After cooling to room temperature, mixture was partitioned between ethyl acetate (2 X 100 mL) and water (2 X 100 mL). Organic layers were washed with brine (100 mL), combined, dried (MgS04), µLtered and concentrated. Residue was purified by flash chromatography (Biotage 40 L, ethyl acetate - hexanes as solvent). No good purification was achieved. Fractions were combined and concentrated. Residue was re-purified by flash chromatography (Biotage 40L, dichloromethane - hexanes 1:1 as solvent) to give product in two crops as white crystals. (Yield 1.93 g, 35.9%).

A suspension of cesium carbonate (0.50 g, 1.53 mmol), 2-chloro-5-(4-chloro-benzyloxy)-phenol (0.30 g, 1.12 mmol) (from Intermediate 70 supra) in tetrahydrofuran / N,N-dimethylformamide (5:2, 14 mL) was heated at 70 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl

acetate in hexanes to give 4-chloro«3-[2-chloro-5-(4-chloro-ben2yloxy)-phenoxymethyl]" tWeno[3,2-c]pyridine-7-carboxyIic acid ethyl ester. (Yield 0.12 g, 23%).

Ammonia gas was bubbled into a solution of 4-chloro-3-[2-chloro-5-(4«chloro-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.12 g, 0.23 mmol) (from Intermediate 71 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140 °C for 2 hours. After concentrating, the residue was purified by flash chromatography eluting with 2-5% ethyl acetate in dichloromethane to give 4-amino-3-[2-chloro-5-(4-chloro-beiizyloxy)-phenoxymethyl]-1iiienot3?2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0J0 g, 83%).

A solution of 4-amino-3-[2-chloro-5-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.04 g, 0.08 mmol) (from Example 156 supra) in dimethyl-sulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate was µLtered, washed with methanol and dried to give 4-amino-3-[2-chloro-5-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3?2-

c]pyridine-7-carboxyIic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 20 mg, 49%).
HRMS (ES+) m/z Calcd for C24H21CI2N3O4S + H [(M+H)+]: 518.0703. Found: 518.0706.

4-Chloro-3-{3-[(pyridme-2-carbonyl)^^
carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-4-chloro-
thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Intermediate 68 supra) and
picolinoyl chloride hydrochloride (TCI-US) following a similar procedure as described in
Intermediate 69 supra as off-white solid.
HRMS (ES+) m/z Calcd for C23H,8C1N304S + H [(M+H)4]: 468.0780. Found: 468,0779.
Example 158
4- Amino-3 - {3 - [(pyridine-2-carbonyl)-amino] -phenoxymethyl} -thieno[3,2-c]pyridine-7-

4-Amino-3-{3-[fcyridine-2-carbonyl)-a^
carboxylic acid ethyl ester was prepared from 4-chloro-3-{3"[(pyridine"2-carbonyl)-amino]-phenoxymethyl}-thieno[3,2-c]pyridine»7-carboxyiic acid ethyl ester (from Intermediate 72 supra) following a similar procedure as described in Example 154 supra as off-white solid.

HRMS (ES+) m/z Calcd for C23H20N4O4S + H f(M+H)+]: 449.1278. Found: 449.1279.
Example 159
4-Ammo-3-{3-[(pyridme-2-^^

4- Amino-3 - {3-[(pyridine-2-carbonyl)-amino] -phenoxymethyl} -thieno [3 ?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 4-amino-3-{3-[(pyridine-2-carbonyl)-amino]-phenoxymethyl}-tiiieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 158 supra) following a similar procedure as described in Example 155 supra as off-white solid. HRMS (ES+) m/z Calcd for C23H21N5O4S + H [(M+H)4]: 464.1387. Found: 464.1388.
Intermediate 73
4-CUoro-3-{3-[(6-methyl-pyridine-3"Carbonyl)-amino]-phenoxymethyl}-

4-Chloro-3-{3-[(6-methyl-pyridine-3-carbonyl)-amino]-phenoxymethyl}-thieno[3?2c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)»4-chloro-thieno[3?2-c]pyridine-7"Carboxylic acid ethyl ester (Intermediate 68 supra) and 6-methyl~nicotinoyl chloride which was made from 6-methyl-nicotinic acid

(from Aldrich) and oxalyl chloride (Aldrich), following a similar procedure as described in Intermediate 69 supra as off-white solid.
Example 160
4-Ammo-3 - {3 - [(6-methyl-pyri

4- Amino-3 - {3 - [(6-methyl-pyridine-3 -carbonyl)-amino] -phenoxymethyl} -thieno [3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 4-chloro-3-{3-[(6-methyl-pyridine-3-carbonyl)-amino]-phenoxymethyl}-thieno[3,2c]pyridine-7~carboxylic acid ethyl ester (from Intermediate 73 supra) following a similar procedure as described in Example 154 supra as off-white solid, HRMS (ES+) m/z Calcd for C24H22N4O4S + H [(M+H)4]: 463.1435. Found: 463.1430.

4-Amino-3-{3-[(6-methyl-pyridine-3-carbonyl)-amino]-phenoxymethyl}-thieno[3?2c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)~amide was prepared from 4-amino-3-{3-[(6~metiiyl-pyridine-3-carbonyl)-amino]-^^

carboxylic acid ethyl ester (from Example 160 supra) following a similar procedure as
described in Example 155 supra as off-white solid.
HRMS (ES+) m/z Calcd for C24H23N5O4S + H [(M+H)+j: 478.1544. Found: 478.1538.
Intermediate 74
4-Chloro-3-{3-[(pyridine-4-carbonyl)-am

4-CWoro-3-{3-[(pyridme-4-carbonyl)-am
carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyI)-4-chloro-
thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (Intermediate 68 supra) following a
similar procedure as described in Intermediate 69 supra as off-white solid.
HRMS (ES+) m/z Calcd for C23Hi8ClN304S + H [(M+H)+]: 468.0780. Found: 468.0777.

4-Amino-3-{3-[(^yridine-4-carbonyl)-amino]-phenoxymethyl}4hieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 4-chloro-3-{3-[(pyridine-4-carbonyl)-amino]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Intermediate 74 supra) following a similar procedure as described in Example 154 supra as off-white solid.

HRMS (ES+) m/z Calcd for C23H20N4O4S + H [(M+H)4]: 449.1278. Found: 449.1276.
Example 163
4-Amino-3- {3-[(pyridine-4-carbonyI)-amino]-phenoxyinethyl} -thieno[3 ,2-c]pyridine-7-

4- Amino-3 - {3 - [(pyridine-4-carbonyl)-amino] -phenoxymethyl} -thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 4-amino-3-{3-[(pyridine-4-carbonyl)«amino]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 162 supra) following a similar procedure as described in Example 155 supra as off-white solid. HRMS (ES+) m/z Calcd for C23H21N5O4S + H [(M+H)*]: 464.1387. Found: 464.1388.

A solution of 3-chlon>4-fluorobenzoyl chloride (21,23 g? 110 mmol) (Avocado) in tetrahydrofuran (50 mL) was added to a solution of 5-amino-o-cresol (6.16 g, 50 mmol) (Aldrich) and triethylamine (17.5 mL, 125 mmol) (Aldrich) and THF (50 mL) dropwise with magnetic stirring and cooling in an ice - water bath. When addition was complete, mixture was allowed to warm to room temperature and stirred for 16 hours. Reaction mixtrue was diluted with water (125 mL) and saturated aqueous sodium bicarbonate solution (125 mL).

After stirring for another 30 minutes, precipitate was collected to give crude 3-Chloro-4-fluoro-benzoic acid 5-(3-chloro-4-fluoro-benzoylamino)-2-methyl-phenyl ester as an off-white powder. (Yield 21.83 g, 101%).
3-Chloro-4-fluoro-benzoic acid 5-(3-chloro-4-fluoro-ben2oylamino)-2-methyl-phenyl ester (3.93 g, 9 mmol) was dissolved in a mixture of tetrahydrofuran (25 mL), methanol (50 mL) and aqueous IN sodium hydroxide (9 mL, 9 mmol). Mixture was stirred at room temperature for 18 hours. Mixture was concentrated under reduced pressure to remove most of the organic solvent. Resulting suspension was diluted with water (45 mL) and saturated aqueous sodium bicarbonate solution (5 mL). After standing for 30 minutes, precipitate was collected and washer with water and dried to give crude 3-cMoro-4-fiuoro-N-(3-hydroxy-4-methyl-phenyl)-benzamide as a white powder. (Yield 2.59 g, 103%).

A suspension of cesium carbonate (0.73 g, 2.24 mmol), 3-chloro-4-fluoro-N-(3-hydroxy-4-methyl-phenyl)-benzamide (0.46 g, 1.64 mmol) (from Intermediate 75 supra) in tetrahydrofuran / N,N-dimethylformamide (5:2, 21 mL) was heated at 70 °C for 3 hours. 3-BromomethyI-4-chloro«thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.50 g, 1.49 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was washed with hot dichloromethane / ethyl acetate and dried to give 4-chloro-3-[5-(3-chloro-4-fluoro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.14 g, 18%).


Ammonia gas was bubbled into a solution of 4-chloro-3-[5-(3-chloro-4-fluoro-
benzoylammo)-2-methyl-phenox acid ethyl ester
(0.14 g, 0.26 mmol) (from Intermediate 76 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140 °C for 2 hours. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[5-(3-chloro-4-fluoro-benzoylamino)-2-metiiyl-phenoxymethyl]-thieno[3s2-c]pyridine-7-carboxyiic acid ethyl ester as white powder. (Yield 0.09 g, 69%). HRMS (ES+) m/z Calcd for C25H2iClFN304S + H [(M+H)+]: 514.0998. Found: 514.0995.

A solution of 3-chlorobenzoyl chloride (32.81 g, 187.5 mmol) (Aldrich) in tetrahydrofuran (50 mL) was added to a solution of 5-amino-o-cresol (9.24 g, 75 mmol) (Aldrich) and triethylamine (31.43 mL, 225 mmol) (Aldrich) and THF (150 mL) dropwise with magnetic stirring and cooling in an ice - water bath. When addition was complete, mixture was allowed to warm to room temperature and stirred for 16 hours. Reaction mixtrue was diluted with water (200 mL) and saturated aqueous sodium bicarbonate solution (200 mL). After stirring for another 30 minutes, precipitate was collected to give crude 3-chlon>benzoic acid 5-(3-chloro-benzoylamino)"2-methyl-phenyl ester as an off-white powder. (Yield 31.74 g, 106%).

Crude 3-chloro-benzoic acid 5»(3-chloro-benzoylamino)-2-methyI-phenyl ester (11.42 g, 28.5 mmol) was dissolved in a mixture of tetrahydrofuran (70 mL), methanol (140 mL) and aqueous IN sodium hydroxide (28.5 mL, 28.5 mmol). Mixture was stirred at room temperature for 18 hours. Mixture was concentrated under reduced pressure to remove most of the organic solvent. Resulting suspension was diluted with water (90 mL) and saturated aqueous sodium bicarbonate solution (10 mL). After standing for 30 minutes, precipitate was collected and washer with water and dried to give 3-chloro-N-(3-hydroxy-4-methyl-phenyl)-benzamide as an off white powder. (Yield 6,06 g, 81.2%),

A suspension of cesium carbonate (0.73 g, 2.24 mmol), 3-chloro-N-(3-hydroxy-4-methyl-phenyl)-benzamide (0.43 g, 1.64 mmol) (from Intermediate 77 supra) in tetrahydrofuran / N,N-dimethylformamide (5:2, 21 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thienot3?2-c]pyridine-7-carboxylic acid ethyl ester (0.50 g, 1.49 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was washed with hot dichloromethane / ethyl acetate and dried to give 4-chlorO-3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.35 g, 45%).
Example 165
4-Amino-3-[5-(3-cMoro-4-benzoylamino)^
7-carboxylic acid ethyl ester


Ammonia gas was bubbled into a solution of 4-cMoro-3-[5-(3-chloro-4-benzoylamino)•-2-
methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-c^ acid ethyl ester (0.10 g, 0.19
mmol) (from Intermediate 78 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was >
heated in a microwave reactor at 140 °C for 2 hours. The reaction mixture was concentrated.
The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[5-(3-
cMoro-benzx)ylammo)-2-methyl-phenox
ethyl ester as white powder. (Yield 0.04 g, 43%).

A solution of 4-aminO"3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.04 g, 0.08 mmol) (from Example 165 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by Cl 8 column chromatography eluting with acetonitrile / water to give 4~amino-3-[5-(3-chloro-ben2oylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridme-7-carboxylic acid (2-hydroxy-ethyl)-amide as white powder. (Yield 8.0 mg, 20%). HRMS (ES+) m/z Calcd for C25H23CIN4O4S + H [(M+H)4]: 511.1202. Found: 511.1198.
Example 167

4-Amino-3-{5-[3-chloro-4-(2-hydroxy-ethyIamm^ phenoxymethyl]-thieno [3 ^

A solution of 4-amino-3-[5"(3-cUoro^"fluoro-benzoylamino)-2-metiiyl-phenoxymethyl]-
thieno[3,2«c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 164
supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and
heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by
CI 8 column chromatography eluting with acetonitrile / water to give 4-amino-3-{5-[3-
cWoro-4-(2-hydroxy-ethylammo)-benzoylam
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as white powder* (Yield 37.0 mg,
67%).
HRMS (ES+) m/z Calcd for C27H28C1N505S + H [(M+H)*]: 570.1573. Found: 570.1566.
Example 167a
4-Amino~3- {5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide toluene-4-

To solution of 4-amino-3-{5-[3»cUoro-4-(2-hydroxy-ethylamino)-benzoyIamino)--2-methyl-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide (51.6 mg, 0.09 mmol) (from Example 167 supra) in methanol (6 mL) was treated with toluene-4-sulfonic acid hydrate (18.9 mg, 0.10 mmol) (Aldrich) and heated at 40 °C for 30 minutes.

The solution was concentrated. The residue was washed with diethyl ether, dissolved in
water and lyophilized to give 4-amino-3-{5-[3-chloro-4-(24iydroxy-ethylamino>
benzoylamino)-2-methyl-phenoxy-m
hydroxy-ethyI)-amide, toluene-4-sulfonic acid salt. (Yield 56.0 mg5 86%).
HRMS (ES+) m/z CaJcd for C27H28CIN5O5S + H [(M+H)4]: 570.1573. Found: 570.1567.

A solution of 3-chloro-4-fluoro-N-(3"hydroxy-4-methyl"phenyl)-benzamide (1.0 g, 3.58 mmol) (from Intermediate 75 supra) in dimethylsulfoxide (5.0 mL) was treated with ethanolamine (10,0 mL) (Aldrich) and heated at 140 °C for 50 minutes in a microwave reactor. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was acidified with 2N hydrochloric acid. The precipitate was µLtered, washed with water and dried. The aqueous phase was extracted with ethyl acetate (2X), The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The two solid samples were combined and dried to give 3-chloro-4-(2-hydroxy-ethylamino)-N-(3-hydroxy-4-methyl-phenyl)-benzamide. (Yield 1.13 g, 98%).


A suspension of potassium carbonate (0.56 g, 4.05 mmol), 3-chloro-4-(2-hydroxy-ethylamino)-N-(3-hydroxy-4-methyl-phenyl)-benzamide (1.13 g, 4.30 mmol) (from Intermediate 19 supra) in N?N-dimethylformamide (15 mL) was stirred at room tempreature for 10 minutes. 3-Bromomethyl-4«chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (1.44 g, 4.30 mmol) (from Intermediate 8 supra) was added. Stirring was continued for 18 hours. The reaction mixture was partitioned between dichloromethane and water. The precipitate was µLtered, washed with water and dried. The aqueous phase was extracted with dichloromethane (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 40 -100% ethyl acetate in hexanes to give the second part of product. The combined solid was dried to give 4-chloro-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (Yield L68 g, 83%).

Ammonia gas was bubbled into a solution of 4-chloro-3-{5-[3-chloro-4-(2-hydroxy-
ethylamino)«benzoylamino]-2-metiiyl«phenoxymethyl}-thieno[3,2-c]pyrid
acid ethyl ester (0.96 g, 1.67 mmol) (from Intermediate 80 supra) in 2-propanol (70 mL) for
20 minutes. The mixture was heated in a microwave reactor at 140 °C for 2 hours. The
reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and
dried to give 4-amino-3-{5-[3»chloro-4-(2™hydroxy-ethylamino)-benzoylamino]-2-methyl-
phenoxymethyl}-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.83 g, 89%).


An aqueous solution of sodium hydroxide (2N, 11.0 mL, 5.5 mmol) was added to a solution of 4-amino-3- {5-[3-cWoro^-(2-hydroxy-ethylamino)-benzoylamino]-2-methy 1-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.83 g, 1.50 mmol) (from Example 168 supra) in tetrahydrofuran / methanol (3:1,28 mL) and the mixture was heated at 50 °C for 18 hours. The reaction mixture was concentrated and azeotroped with toluene. The solid was then suspended in water and treated with hydrochloric acid (2N). After stirring 30 minutes, the solid was collected, washed with water and dried to give 4-amino-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino]-2-methyl-phenoxy-methyl}-thieno[3,2-c]pyridine-7-carboxylic acid as white powder. (Yield 0.90 g, 95%).

To a mixture of 4-amino-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino]-2-methyl* phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (0.30 g, 0.57 mmol) (from Intermediate 81 supra), HBTU (0.27 g, 0.71 mmol) (Advanced ChemTech) and diisopropylethylamine (0.0.24 mL, 1.43 mmol) (Aldrich) in N,N-dimethylformamide (15 mL) was added ammonium chloride powder (39,0 mg, 0.73 mmol). The mixture was stirred

at room temperature for 1 day and then concentrated. The residue was purified by CI 8 colum chromatography eluting with acetonitrile / water to give 4-amino-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino]-2^
carboxylic acid amide as a powder. (Yield 0.17 g, 57%),
HRMS (ES+) m/z Calcd for C25H24CIN5O4S + H f(M+H)+]: 526.1311. Found: 526.1306.
Example 170
In vitro Kinase assay
In vitro enzyme activity was determined with c-Raf using a HTRF assay with 6H-MEK as substrate (Dose Response).
Assay Principle:
The assay utilizes 6H-MEK as the substrate. Upon c-Raf phosphorylation, phosphorylated 6H-MEK is detected with rabbit anti-phospho-MEKl/2, Eu-labeled anti-rabbit, and APC-labeled anti-6H antibodies.
Reagents and Instruments:
c-Raf enzyme was cloned human c-Raf with EE-tag and was phosphorylated (co-expressed
with v-src-FLAG in baculovirus Hi5 cells), 0.2 mg / mL (2.74 JJM assuming a molecular
weight of 73 kD) and stored at -15 °C. Wild-type full-length 6H-MEK was used as substrate,
4.94 mg / mL (154.4µM assuming a MW of 32 kD) and stored at -15 °C.
The following antibodies were used in the detection step: Rabbit a-P-(Ser 217/221 )-MEK-
1/2 Ab (from Cell Signaling, Cat # 9121S, Lot 4); Eu-a-rabbit IgG (from Wallac, Cat. #
AD0083, Lot 107557, labeling date 06/21/02, 8 Eu/protein, 580 µMg/mL, 3.63 µM); a-6H~
SureLight-APC (from Martek, Cat. #AD0059H, Lot E011AB01, 3.15 µM).
Assays were read with Envision from PerkinElmer, HTRF reading mode with 412 mirrors.
Assays were performed with Costar 384 all-black plates, 120 µL (Cat. #3710).
Test compounds were dispensed in Weidman 384 polypropylene plates (REMP).
Assay Procedure: i
Prepare Kinase Assay Buffer (KAB): 50 mM HEPES (HyClone) pH7, 10 mM MgCl2, 1 mM DTT, 0.1 mM Na3V2045 and 0.2 mg / mL BSA. Prepare 6H-MEK (150 nM) in KAB. Add 40 µL / well to a Weidman plate.

Prepare ATP (66 µM) in KAB.
Prepare c-Raf (60 nM) in KAB. Add 25 µL I well to a Weidman plate.
Dilute compounds to 2.4 mM in DMSO. Perform 10-point 3x dilution in DMSO. Withdraw
2.5 ul/well of DMSO solution and add to 27.5 µL / well ATP solution in (3).
Add 12 µL / well 6H-MEK to the assay plate on the Cybiwell, followed by 6 µL / well of
solution in (5) and 6 µL / well of solution in (4) for a DMSO concentration of 2.1% during
MEK phosphorylation.
Incubate at 37 °C for 30 minutes.
Prepare rabbit a-P-(Ser 217/221>MEK-l/2 Ab (1:225 from stock) in AB1: 50 mM HEPES
pH7, 0.2 mg / mL BSA, and 53 mM EDTA.
To stop reaction, add 6 µL / well of solution from (8) to the assay plate and incubate at 37 °C
for 30 minutes.
Prepare Eu-a-rabbit IgG (9 nM) and HEPES pH7 and 0.2 mg / mL BSA.
Add 6 µL / well of solution from (10) to the assay plate.
For determining the spectrum cross talk factor, prepare 2 samples following steps (6) to (9).
For the blank sample, add 6µLI well of AB2. For the cross talk factor sample, add 6 µL I
well of Eu-anti rabbit IgG (9 nM).
Incubate at 37 °C for 1 hour.
Read HTRF signals at 615 nm and 665 nm on the Envision. Normalize HTRF signals after
spectrum cross-talk correction.
The compounds of the present invention in the above assay exhibit C-Raf IC50 values of from 0.001 to 50 fiM. Representative IC50 values are, for example,:



The ras protein in its normal, unmutated form is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues. See J. Avruch et aL, TIBS (19), 279-283 (1994). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is activated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants, Magnuson et aL, Cancer Biology, 5, 247-253 (1994). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of antisense RNA or by small molecule Raf kinase inhibitors leads to the reversion of transformed cells to the normal growth phenotype, Sridhar et aL, Mol Cancer Ther 2005, 4(4), April 2005 and Bollag et aL, Current Opinion in Investigational Drugs, 4, vol 12, 2003.
The present invention provides 4-amino-thieno [3,2-c] pyridine-7-carboxylic acid derivatives which are small molecule inhibitors of Raf kinase. In addition to inhibiting Raf, these compounds may also inhibit some other important kinases including ABL, BRAF, BRAF(V600E) mutant, EPHA, EPHB, FGFR1, FGFR2, FGFR3, FLT3, FLT4, KIT, PDGFRA, PDGFRB, and VEFGR-2. These compounds can be potent and selective anticancer agents, especially agents for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.

Ring A is selected from the group consisting of aryl, heteroaryl or substituted heteroaryl, cycloalkyl and heterocycle; and
Ring B is selected from the group consisting of aryl, heteroaryl and substituted heteroaryl.

wherein
R1 is selected from the group consisting of hydrogen, lower alkyl, halogen, cyano, trifluoromethyi, lower alkoxy, -C(0)-NH-lower alkyl, -C(0)-NH-lower alkoxy, oxo and N02;
R3 is selected from the group consisting of hydrogen, lower alkyl, lower alky! substituted by -OR4 and -NR4R5;
R4 and R5 are selected from hydrogen; lower alkyl; lower alkyl substituted with OH or lower alkoxy; or
R4 and R5 together with the nitrogen atom to which they are attached form morpholinyl;

Q is hydrogen or a group ;
R2 may be the same or different lower alkenyl, lower aikynyl, methyl sulfonyl, sulfonamide, hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, lower alkoxy, NO2, sulfonyl urea, amide, ester, carbamoyl, carbamate, urea,
-NR4R5; and lower alkyl substituted with -OR4 or -NR4R5; the goup -X-Y- is selected from -OCH2-, -CH20-, -NHCO-, -CONH-, -0-,
-OCH2CH2-, -CH20CH2, -CH2CH20-, -CF=CH-,-CH=CF-, -NH-, -NHCH2-, -CH2NH-,
-SCH2-, -NHS02, -S02NH~, -CH2S-, -SOCH2-, -CH2SO-, -S02CH2-, -CH2S02-5 -S-,
-CH=CH- and lower alkyl;
W isOorNH;
n is 1 or 2;
Ring A is selected from the group consisting of aryl, heteroaryl or substituted heteroaryl, cycloalkyl and heterocycle; and
Ring B is selected from the group consisting of aryl, heteroaryl and substituted heteroaryl.

As a preferred embodiment there are provided 4-amino-thieno [3,2-c] pyridine-7-carboxylic acid derivatives of the formula (I)

or pharmaceutical^ acceptable salts thereof,
wherein
R1 is selected from the group consisting of hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, lower alkoxy and NO2;
R2 is selected from the group consisting of lower alkenyl, lower alkynyl, methyl sulfonyl, sulfonamide, hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, lower alkoxy, NO2; sulfonyl urea, amide, ester, carbamoyl, carbamate, urea, lower alkyl substituted with OR4, and NR4R5;
R3 is selected from the group consisting of hydrogen, lower alkyl, lower alkyl substituted by OR4 and NR4R5;
R4 and R5 are selected from hydrogen, lower alkyl, or lower alkyl substituted with OH or lower alkoxy;
X-Y are selected from the group consisting of -OCH2-, -CH20~, -NHCO-, -CONH-,
-0-, -OCH2CH2-, -CH2OCH2, -CH2CH20~, -CF=CH^-CH=CF-s -NH-, -NHCH2~,
-CH2NH-5 -SCH2-, -CH2S~, ~SOCH2-, -CH2SO-5 -S02CH2-5 -CH2S02-? -S-, -CH-CH- and lower alkyl;

W is -O- or -NH-;
Ring A is selected from the group consisting of aryl, heteroaryl or substituted heteroaryl, cycloalkyl and heterocycle; and
Ring B is selected from the group consisting of aryl, heteroaryl and substituted heteroaryl
Especially preferred are compounds of formula (I-A) or (I) wherein -X-Y- are selected from the group consisting of -OCH2-,-CH20-, -NHCO- and -CONH-.
Also preferred are compounds of formula (I-A) or (I) wherein R1 is selected from the group consisting of-CH3, -CI and -F.
Further preferred are compounds of formula (I-A) or (I) wherein R is selected from the group consisting of-CI, -F, -CF3, -CONH2, lower alkoxy, -NR4R5, and lower alkyl.
Still another preferred embodiment is the compound of formula (I-A) wherein Q is hydrogen, and the remaining substituents have the meanings given above.
Still another preferred embodiment is the compound of formula (I-A) wherein Q is hydrogen, and wherein
R1 is -O-CH3 or -C(0)-NH-CH3;
R3 is ethyl, which is unsubstituted or once substituted with -OH;
W is -O- or -NH-; and
Ring B is phenyl or pyridinyl.
Still another preferred embodiment is the compound of formula (I-A), wherein


the remaining substituents and n have the meanings given above. Still another preferred embodiment is the compound according to formula (I-A), wherein Q

the ring A is selected from pyrimidinyl, pyridinyl, piperidinyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydro-pyranyl, phenyl, pyrazolyl or thiophenyl; and
the ring B is pyrimidinyl, 2-oxo-pyrimidinyl or phenyl; and
the remaining substituents have the meanings given above.
Still another preferred embodiment is the compound of formula (I-A) or (I), wherein both rings A and B are phenyl.
Also preferred are compounds of formula (I-A) or (I) where Ring B is phenyl or pyridinyl.
More preferred are compounds of formula (I-A) or (I) where Ring B is 2,5-di-substituted phenyl.
Also more preferred are compounds of formula (I-A) or (I) where Ring B is 3-hydroxy~2,5-disubstituted pyridinyl.
Especially preferred are compounds

4-Amino-3 - [3 -(4-chloro-3 -trifluoromethyl-phenylcarbamoyl)"phenoxymethyl] -
thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(3-benzyloxy-phenoxymetiiyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl
ester;
4-Amiiio-3-(3-benzy]oxy-phenoxyme1hyl)-thieno[3T2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-cUoro-ben2yloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxyli
acid ethyl ester;
4^Amino-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-tWeno[3,2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3 - [3-(3-cWoro-benzy loxy )-phenoxy^
acid ethyl ester;
4-Amino-3-[3-(3-cWoro-benzyloxy)-phenoxymethyl]-lMeno[3,2-c]pyridin
acid (2-hydroxy-ethyl)-amide;
4- Amino-3 - [3 -(3 -trifluoromethy 1-benzy loxy)-phenoxymethyl] -thieno [3,2«c]pyridine-7-
carboxylic acid ethyl ester;
4-Amino-3-[3-(3-trifluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-(3-benzylsulfanyl-phenoxyme1hyl)-t^
ester;
4-Amino-3-(3-benzylsulfanyl-phenoxymethyl]-tWeno[3,2«c]pyridine-7-carboxyli
hydroxy-ethyl)-amide;
4-Ainino-3-(3-phenylmethaoesulfonyl-phenoxymethyl)"tMeno[3,2-c]pyridine-7-c
acid ethyl ester;
4-Amino-3-(3 phenylmetfaanesulfonyl-phenoxymethyl]-tMeno[3,2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Airuno-343-(3-methoxy-benzyloxy)-phenox^
acid ethyl ester;
4-Amino-3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]4Meno[3,2-c]pyridine«7-carboxylic
acid ethyl ester;

4-Amino-3^3-(4-methoxy-ben2yloxy)-phenoxyme acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-methoxy-3-1xifluoromethyl-benzyloxy)-phenoxymethyl]-tW
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3 - [3-(4-methoxy-3-trifluorom
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino^3"(3-phenoxy-phenoxymethyl)-1iiieno[3,2-c]pyridine-7-carboxylic acid ethyl ester;
4-Amino«3-(3-phenoxy-phenoxymethyl]-thieno[392-c]pyridine-7-carboxylic acid (2*
hydroxy-ethyl)-amide;
4-Amino-3-(3-phenylamino-phenoxyme1hyl)-thieno[3?2-c]pyridine-7-carboxyli
ester;
4-Amino-3-(3-phenylamino-phenoxymethyl]-thieno[3,2»c]pyridine-7-carboxylic acid (2-
hy droxy-ethyl)-amide;
4-Amino-3-(3-benzylamino-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl
este;r
4-Amino-3-(3-benzylamino«phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxyme
ethyl ester; 4-Amino-3-[3-(4-cyano-benzyloxy)"phenoxymethyl]-tMeno[3,2-c]pyridine-7-carboxylic acid;
4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxym^ acid
(2-hydroxy-ethyl)-amide;
4-Aimno-3-[3-(3-cyano-benzyloxy)^
ethyl ester;
4-Amino-3-[3«(3-cyano-benzyloxy)-phenoxymethyl]-tMeno[3,2-c]pyridine acid;
4-Amino-3-[3-(3-cyano-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine«7-carboxyU
(2-hydroxy-ethyl)-amide trifluoroacetic acid salt;
3 -(3 -beii2yloxy-phenoxymethyl)«4-(2-hydroxy-etiiylamino)-lMeno [3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Ammo-3-(3-methoxy-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(3-methoxy-phenoxymeth^
hydroxy-ethyl)-amide;

4-AmmoO-(3-benzoylaiimo^
ester;
4-Amino-3-(3-benzoylamino-phenoxy^
hydroxy-ethyI)-amide;
4-Amino~3-(3~benzoylamino-phenoxymeth^ acid (2-
hydroxy-ethyl)-amide hydrochloride;
4-Ainino-3»(3"beiizoylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide toluene-4-sulfonic acid salt;
4- Amino-3 - [3-(4-chloro-phenylcarbamoyl)-phenoxymethyl] -thieno [3,2-c]pyridine-7-
carboxylic acid ethyl ester;
4-Amino-3-[3-(4-cUoro-phenylcarbamoyl)-phenoxymethyl]-thieno[3,2-c]pyrid
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-fluoro-phenylcarbamoyl)-phenoxymethyl]-tWeno[3?2-c]pyridi^^
carboxylic acid ethyl ester;
4-Amino-3"[3-(4-fluoro-phenylcarbamoyl)-phenoxyme1hyl]-tWeno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic
acid trifluoro-acetic acid salt;
4-Amino-3-[3-(3-chloro-phenylcarbamoyl)-phenoxymethyl]-lMeno[3,2-c]pyridin^
carboxylic acid ethyl ester; 4-Amino-3-[3-(3-cUoro-phenylcarbamoyl)-phenoxymethyl]-tMeno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-cUoro-phenylcarbamoyl)-phenoxymethyl]-tMeno[3,2-c]pyridine-7-carboxylic acid (3-hydroxy-propyl)-amide; 4-Amino-3-[3-(4-cWoro-phenylcarbamoyl)-phenoxymethyl]-thieno[3,2«c]pyridine-7^
carboxylic acid propylamide;
4-Amino-3-[3-(4-chloro-phenylcarbamoyl)-phenoxyme1hyl]-thieno[3,2-c]pyrid
carboxylic acid ethylamide;
4-Amino-3-{3-[(4-chloro-phenyl)-methyl-carbamoyl]-phenoxyme1hyl}-lW
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[3-(l-methyl-piperidin-4^
carboxylic acid ethyl ester;

4-Ammo-3-[3-(5-methyl-pyrid^ carboxylic acid ethyl ester; 4-Amino-343-( 1-methanesulfo^ c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3- {3«[(4-chloro-phenyl)-me1hyl-carbamoyl]-phenoxymethyl} -thieno[3,2-c]pyridine~7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[5-(3-carbamoyl-phenylcarbamoyl)»2-methyl»phenoxymethyl]-tM
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(2-methyl-5-phenylcarbamoyl-phenox^
carboxylic acid ethyl ester;
4- Amino-3 - [3-(4-chloro-benzyloxy)-phenoxymethyl] -thieno [3,2-c]pyridine»7-carboxylic
acid (3»hydroxy-propyl)-amide trifluoro-acetic acid salt;
4-Amino-3-[3-(4-cWoro-phenoxymethyl)-pheM^
carboxylic acid ethyl ester;
4-Ammo-3-{3-[2-(4-cMoro-phenyl)-vm^
carboxylic acid ethyl ester;
4-Ammo-3-{3-[2-(4-chloro-phenyl)-^
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-cWoro-phenoxymethyl)-phenoxymethyl]-tWeno[3,2-c]pyri
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-chloro-phenylcarbamoy^
carboxylic acid (2-hydroxy-ethyl)-methyI-amide;
4-Ammo-3-[3-(4-cWoro-phenylcarbamo
carboxylic acid (2-methoxy-ethyl)»amide;
4*Amino-3-[3-(4-chlorO"phenylcarbamoyl)"phenoxymethyl]-thieno[3?2-c]py^
carboxylic acid methylamide;
3-[4-Amino-7-(morpholine-4«carbonyl)-thieno[3.2-c]pyridin»3-ylmethoxy]-N-(4-cWoro
pheny l)-benzamide;
4-Amino-3-(3-cyclohexylcarbamoyl-phenox
acid ethyl ester;
4-Amino-3 - [3-(tetrahy dro-pyran-4-yte
carboxylic acid ethyl ester;

4-Amino-3-[3-( 1-methanesulfonyl-pipOT
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-( 1 -methy]-piperidin"4"ylcarbamoyl)-phenoxymethyl]'thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyI)-amide;
4-Amino-3^3-phenylaminomethyl-phenoxymet^^ acid
(2-hydroxy-ethyl)-amide trifluoro-acetic acid salt;
4-Amino-3- {3-[2-(4-chloro-phenyl)-ethoxy]-phenoxymethyl} -thieno[3 ?2-c]pyridine»7-
carboxylic acid ethyl ester;
4-Ammo-3-{3-[2-(4-cMoro-phenyl)-efa
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-chloro-benzoylamino)^
acid ethyl ester;
4-Amino-3-[3-(4-cUoro-benzoylamino)-phenoxyme1hyl]-thieno[3?2«c]pyridiB^
acid (2~hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-chloro-benzoylamino)-phenoxy^^
acid (3-hydroxy-propyl)-amide;
4-Ajnino-3-[3«(4-cUoro-benzoylamino)-phenoxyme1hyl]-1hieno[3,2-c]pyri
acid (3-hydroxy-propyl)-amide hydrochloride;
4-Amino-343^4-cWoro4>enzoylamino)-phenoxyme&^
acid (3-hydroxy-propyl)-amide toluene-4-sulfonic acid salt;
4-Amino-3-(2-oxo-1 -phenethyl-1,2-dihydrO"pyrimidin«4-yloxymethyl)-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(2,6-dioxo-3-phenethyl-3 ,6-dihydro-2H-pyrimidin-1 -ylmethyl)-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(2,6-dioxo-3-phenethyl«3,6-dihydro-2H"pyrimidin-l-ylmethyl)4hieno[3?2-
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-342-methoxy-5-(3-metiioxy-phenylcarbam
c]pyridine-7-carboxylic acid ethyl este;
4-Ammo-3 - [ 5-(3,5-dimethoxy-phenylcarbam^
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[5-(4-cUoro-3-me1hyl-phenylcarbamoyl)-2-methoxy-phenoxymethyl]-
thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester;

4-Amino-3-(5-benzylcarbamoyl-2-mfr^
acid ethyl ester;
4-Ajruno-3-(2-methyl-3-phenylcarba^
carboxylic acid ethyl ester;
4-Amino-3-[3-(3?5-dimethoxy-phenylcarbamoyl)»2-methyl-phenoxymethyl]-tW
c]pyridine~7-carboxylic acid ethyl ester;
4-Amino-3«[2-nitro-5-(3-trifluoromethoxy-phenylcarbamoyl)-phenoxyme1hyl^
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[2-methyl-3-(3-trifluoromethox
c]pyridine-7-carboxylic acid ethyl ester;
4-AminO'3-[3-(3-methanesulfonyl-phenylcarbamoyl)»2-me1hyl-phenoxymethyl]-tW
c]pyridine-7-carboxylic acid ethyl ester;
4- Amino-3 - [3 -(3 -chloro-phenylcarbamoyl)-2-methyl-phenoxymethyl] -thieno [3 ,2-c]pyridine-
7-carboxylic acid ethyl ester;
4-Amino-3-[2-methyl-3-(5-methyl-1 H-pyrazol-3-ylcarbamoyl)-phenoxymethyl]-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[3-(3,5-difluoro-benzyloxy)-5-m
carboxylic acid ethyl ester;
4-Ammo-3-[3-(3,4-difluoro-benzyloxy)-5^
carboxylic acid ethyl ester;
4-Amino-3-[3-(5-cWoro-tWophen~2-ylmethoxy^
c]pyridine-7-carboxylic acid ethyl ester;
4-Ammo-3-[3-(3-methyl-benzyto^
acid ethyl ester;
4-Amino-3-[3-(5-chloro4hiophen-2-ylmethoxy)-phenoxymethyl]-tW
carboxylic acid ethyl ester;
4-Amino-3-[3-(2?5-difluoro-benzyloxy)-phenoxy^
acid ethyl ester;
4-Amino-3-[3-(4-fluoro-benzyloxy)-5-m
carboxylic acid ethyl ester;
4-Amino-3-[3-(2,4-difluoro-benzyloxy)-5-m
carboxylic acid ethyl ester;

4-Ammo-3-[3-(2?5-difluoro-benzylo
carboxylic acid ethyl ester;
4-Amino-3-[3-methyl-5-(4-methyl4>enzyloxy)-pte
carboxylic acid ethyl ester;
4-Aixiino-3-[3-methyl-5-(2-methyl-benzyloxy)-phenoxymethyl]-thieno[3,2^
carboxylic acid ethyl ester:
4-Amino-3-[3-(2-fluoro-benzyloxy)-5-me1h^
carboxylic acid ethyl ester;
4-Amino-3 - [3 -(2-methoxy-benzyloxy)-phenoxymethyl] -thieno [3 ?2-c]pyridine-7-carboxylic
acid ethyl ester;
4-Amino-3-{3-[3-(2-morpholin^-yl-ethoxy)-bera^
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino»3-(3-methylcarbamoyl-phenoxymethyl)-lMeno[3,2-c]pyrid
ethyl ester;
4-Amino-3-(3-cyclopropylcarbamoyl-phenoxymethyl)-lMeno[3,2-c]pyridine-7-carboxylic
acid ethyl ester;
4-Amno-3-(3-cyclopentylcarbamoyl-phen^
acid ethyl ester;
4-Ammo-3»(3-cyclohexylcarbamoyl^
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(tetrahydro-pyran-4-ylcarba^
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-(3-methylcarbamoyl-phenoxymethyl)-thieno[3 ,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide;
4-Amino-3-(3-cyclopropylcarbamoyl-phenoxymethyl)-tWeno[3?2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-(3-cyclopen1ylcarbamoyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-(5-methylcarbamoyl~pyridin-3-yto^
acid ethyl ester;
4-AminoT3-(5-methylcarbamoyl-pyridin"3-yloxymethyl)-tMeno[3,2«c]pyri
acid (2-hydroxy-ethyl)-amide?

4-Amino-3-[3-(2-fluoro-benzyloxy)-5-^
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-[3-(3,5-difluoro-benzyloxy)^^
carboxylic acid (2-hydroxy-ethyI)-amide,
4-Amino-3-[3-methyl-5-(2-methyl-benzyl
carboxylic acid (2~hydroxy-ethyl)-amide,
4-Amino-3-[3-(2?5-difluoro-benzyloxy)-phenoxy^^
acid (2-hydroxy-ethyl)«amide,
4-Amino-3-[3-(3-fluoro-benzyloxy)-5-m
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-343-(2,5-difluoro-benzyloxy)-5-m
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-343-methyl-5-(4-methyl-benzyloxy)-phenox
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-[3-(3,4-difluoro-benzyloxy)-5-me^
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-[3-(2,3-difluoro-benzyloxy)-phenoxym^
acid(2-hydroxy-ethyl)-amide,4-Amino-3-[3-(4-chloro^
thieno[3,2-c]pyridine-7-carboxylic acid,
4-Ammo-3-[3-(pyrimi^
acid ethyl ester,
4- Amino-3 - [3 -(pyrimidin-5 -y lmethoxy)-phenoxymethyl] -thieno[3,2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide,
4- Amino-3 - [3 -(4-chloro-benzenesulfonylamino)-phenoxymethyl] -thieno [3,2-c]pyridine-7-
carboxylic acid ethyl ester,
4- Amino-3 - [3-(4-chloro-benzenesulfony lamino)-phenoxymethyl] -thieno [3,2 -c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide5
4»Amino-3-[2-chloro-5-(4-cWoro-benzyloxy)-phenoxymethyl]-lMeno[3,2-c]p^
carboxylic acid ethyl ester,
4-Ammo-3-[2-cWoro-5-(4-cWoro-benz^
carboxylic acid (2-hydroxy-ethyl)-amide,

4-Ammo-3-{3-[(pyridme-2-carbonyl)-a
carboxylic acid ethyl ester,
4-Ammo-3-{3-[(pyridine-2-carbo
carboxylic acid (2-hydroxy-ethyI)-amide,
4-Amino-3-{3-[(6-metbyl-pyridine-3-carbonyI)-amino]-phenoxymethy
c]pyridine-7-carboxylic acid ethyl ester,
4-Amino-3-{3-[(6-methyl-pyridine-3-carbonyl)-amino]"phenoxymethyl}-
thieno[3,2c]pyridine»7-carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-{3-[(pyridine-4-carbonyl)-amino]-phen^
carboxylic acid ethyl ester,
4-Amino-3-{3-[(pyridine-4-carbonyl)-amino]^
carboxylic acid (2-hydroxy~ethyl)-amide,
4-Amino-3-[5-(3-chloro-4-fluoro-benzoylamino)^
cjpyridine-7-carboxylic acid ethyl ester,
4-Amino-3-[5-(3-chloro«4-benzoylaraino)-2-methyl-phenoxymethyl]-tiiieno[3,2-
7-carboxylic acid ethyl ester,
4- Amino-3 - [5 -(3 -chlorO"benzoylamino)-2-methyl-phenoxymethyl] -thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide5
4-Amino-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino)-2-methyl-
phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylicacid(2-hydroxy-ethyl)-amide,
4-Amino-3- {5-t3"Chloro-4-(2-hydroxy-ethylamino)-benzoylamino)-2-methyl-
phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide toluene-4-
sulfonic acid salt,
4-Amino-3- {5-[3-chloro-4-(2-hydroxy-ethylamino)-ben2oylamino]-2-methyl-
phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester; and
4-Amino«3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino]-2-methyl-
phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid amide.
As used herein, the following terms shall have the following definitions.

"Aryltf means a monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 membered aromatic ring system. Preferred aiyl groups include, but are not limited to, phenyl, naphthyl and tolyl.
"Heteroaryl" means an aromatic heterocyclic ring system containing up to two rings. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, pyrazolyl, benzofuran and tetrazolyl.
As used herein, in particular in R , the term
(a) "amide" means a substituent of the formula

(b) "ester" means a substituent of the formula

(c) "carbamoyl" means a substituent of the formula

(d) "carbamate" means a substituent of the formula


(e) "urea" means a substituent of the formula

R4 and R5 are selected from hydrogen; lower alkyl; lower alkyl substituted with OH or lower alkoxy.
"Effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
"Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"Hetero atom" means an atom selected from N, O and S.
"Lower alkyl" alone or in conjunction with another term, e.g. lower alkyl-heterocycle, denotes a straight-chain or branched, saturated aliphatic hydrocarbon having 1 to 6, preferably 1 to 4, carbon atoms. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl and the like.
The term "alkoxy" means a group -O-alkyl, preferably a group -O-lower alkyl, wherein "lower alkyl" has the meaning given above.
The term "alkenyl", alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 20, preferably up to 16 carbon atoms, more preferably up to 10 carbon atoms. Lower-alkenyl groups as described

below also are preferred alkenyl groups. The term "lower-alkenyl" refers to a straight-chain or branched hydrocarbon residue comprising an olefinic (double) bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propenyl. An alkenyl or lower-alkenyl group
may have a substitution pattern as described earlier in connection with the term "alky!".
The term "alkynyl"., alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 20, preferably up to 16 carbon atoms. The term "lower-aUcynyl" refers to a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propinyl. An alkynyl or lower-alkynyl group may have a substitution pattern as described earlier in connection with the term "alkyl".
The term "cycloalkyl" denotes a saturated mono- or bicyclic hydrocarbon with 3 to 10 carbon atoms. Preferred are monocyclic hydrocarbons with 3 to 6 carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexyl and the like.
The term "heterocycle" means a "cycloalkyl" as defined above, wherein one, two or three carbon atoms, preferably one or two carbon atoms, are replaced by a heteroatom selected from N, S or O. Especially preferred are 5- and 6-membered heterocycles. Examples of such heterocycles are piperidine, tetrahydro-pyran, piperazine, morpholine, pyrrolidine, pyrazolidine, tetrahydro-thiophene, imidazolidine and the like.
The term "Pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluene sulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium, lithium, magnesium, calcium and quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. The

chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
"Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
"Substituted" as used herein, for example in substituted alkyl or substituted heteroaryl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options.
"Therapeutically effective amount" means an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or ester thereof, that significantly inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines.
Medicaments containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of the present invention and/or pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert excipients/carriers.
In accordance with the invention the compounds of the present invention as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses, particularly proliferative disorders such as cancer, more particularly colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas. Based on their Raf kinase inhibition and their antiproliferative activity, said compounds are useful for the treatment of diseases such as cancer in humans or animals and for the production of corresponding medicaments. The

dosage depends on various factors such as manner of administration, species, age and/or individual state of health.
The compounds of the present invention can be prepared according to the following reaction schemes and general procedures, wherein unless explicitly otherwise stated all substituents and variables have the meanings given herein before. Unless explicitly described herein all reactions, reaction conditions, abbreviations such as "PG" for protecting group, and substances are known to the man of ordinary skill in the art.
Scheme 1:


Intermediate 1
4-Methyl-2-thiophenecarboxaldehyde

A solution of 3-methylthiophene (58.90 g, 0.60 mol) (Fluka) in anhydrous ether (600 mL) was stirred and cooled in an ice - water bath. This solution was treated dropwise over 15 minutes with n-butyllithium in pentane (2 M? 450 mL, 0.90 mol) (Aldrich). After stirring for 2 hours at room temperature the mixture was cooled in an ice - water bath and treated dropwise over 5 minutes with AyV-dimethylformamide (48.24 g, 0.66 mol) (Fisher) followed by stirring at room temperature over night. The mixture was diluted with ether (600 mL) and washed with water and brine. After drying (sodium sulfate) ether was evaporated on a rotary evaporator without vacuum to give 114 g of red liquid. This liquid was purified by chromatography over a pad of silica gel 60 (1 Kg, 70-230 mesh) eluting with 40% dichloromethane - hexanes. Evaporation without vacuum gave 4-methyl-2-thiophenecarboxaldehyde as a light red oil. (Yielded 56.62 g, 74.7%). This product contained small amounts of hexanes.
Intermediate 2
3-(4-Methyl-thiophen-2-yl)-acrylicacid

A solution of 4-methyl-2-thiophenecarboxaldehyde (56.62 g5 0.448 mol) (from Intermediate 1 supra), malonic acid (186.77 g, 1.79 mol) (Aldrich) and piperidine (1.90 g, 0.022 mol) (Fluka) in pyridine (550 mL) was heated at reflux with stirring over night. Reaction mixture was evaporated to dryness. The resulting residue was dissolve in dichloromethane and washed successively with 3 N hydrochloric acid, water and brine. The organic layer was

dried and evaporated to give 3-(4-methyl-thiophen-2-yl)-acrylic acid as a tan solid. (Yield 49.52 g, 65.7%).

To a solution of 3-(4-methyl-thiophen-2-yl)-acrylic acid (49.52 g, 0.294 mol) (from Intermediate 2 supra) and triethylamine (44.68 g, 0.441 mol) (Aldrich) in acetone (2000 mL) with stirring and cooling in an ice - water bath was added ethyl chloroformate (35.14 g3 0.323 mol) (Aldrich). After stirring at room temperature for 20 minutes, sodium azide (28.70 g, 0.441 mol) (Aldrich) was added and stirring continued for another 20 minutes at room temperature. Acetone was then evaporated off at reduced pressure and residue was diluted with water. This was extracted with dichloromethane. The organic extract was washed with brine, dried and concentrated to give 3-(4-methyl-thiophen-2-yl)-acryloyl azide as a brown solid. (Yield 48.51 g, 85.4%).

3-(4-Methyl-thiophen«2-yl)-acryloyl azide (1.54 g; 7.95 mmol) (from Intermediate 3 supra) was dissolved in meta-xylenes (16 mL). The solution was heated in an oil bath at 105 -115 °C for 30 minutes until nitrogen evolution ceased. At this point a few crystals of iodine were added to the reaction and the oil bath temperature was increased to 145 - 150 °C. The

reaction was heated at reflux for 6 hours. Upon cooling, solid precipitated out of solution. µLtration and drying yielded 3-methyl-5H4taeno[3.2-c]pyridine-4-one. (Yield 1.05 g; 80.1%).
HRMS(EI+) m/z Calcd for CgH7NOS [(M+)]: 165.0248. Found: 165.0250.

A solution of 3-methyl-5H-thieno[392-c]pyridin-4-one (24.27 g, 0.146 mol) (from Intermediate 4 supra) and AµModosuccinimide (34.70 g? 0.154 mol) (Avocado) in dimethylformamide (1000 mL) was stirred at room temperature over night. Reaction mixture was concentrated under reduced pressure and residue was stirred with ether (1000 mL) for 0.5 hour. Suspension was µLtered, washed with ether and sucked dry to give 7-iodo-3-methyl~5H-tWeno[3,2-c]pyridin-4-one as a brown solid. (Yield 41,88 g, 97.9%).

A stirred suspension of 7-iodo-3-methyl-5H-thieno[3,2-c]pyridin-4-one (1.14 g, 3.92 mmol) (from Intermediate 5 supra), triethylamine (2.5 mL, 17,94 mmol) (Aldrich) and bis(triphenylphosphine)palladium(II) chloride (0.14 g, 0.2 mmol) (Aldrich) in ethanol (50 mL) was degassed with argon and then saturated with carbon monoxide. The mixture was stirred with heating in a 75 °C oil bath over night under a blanket of carbon monoxide. After ,

cooling, reaction mixture was concentrated under reduced pressure to remove a portion of ethanol (about 20%). The solid formed was collected by µLtration, washed with ethanol -diethyl ether (1:1) and then diethyl ether and finally dried under vacuum to give 3-methyl-4-oxo-4.5-dihydro-thieno[352-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.78 g, 84.0%). HRMS(EI+) m/z Calcd for CnHnN03S [(M4)]: 237.0460. Found: 237.0451.

A mixture of 3-methyl-4-oxo-4,5-dihydro-thieno[3,2"C]pyridine-7-carboxylic acid ethyl ester (2.43 g, 10.24 mmol) (from Intermediate 6 supra) and AyV-diisopropylethylamine (2.4 mL, 13.87 mmol) (Fluka) was stirred with cooling in an ice - water bath. This mixture was slowly treated with phosphorous oxychloride (7.8 mL? 83.68 mmol) (Fluka) and then allowed to warm to room temperature. A^V-Dimethylformamide (1.0 mL, 12.86 mmol) was then added and the mixture stirred with heating at 70 °C for 30 minutes. A second portion of NJV-dimethylformamide (0.5 mL, 6.43 mmol) was added and the mixture was heated at 70 °C for another 30 minutes. After cooling, ice was added to the solution and the mixture was extracted with ethyl acetate. Organic extract was washed with water, saturated aqueous sodium bicarbonate solution, water and brine. The aqueous phases were back washed with ethyl acetate. The ethyl acetate solutions were combined, dried (sodium sulfate) and concentrated under reduced pressure. This residue was purified by flash chromatography over silica gel (Biotage 65M, 5 : 95 ethyl acetate - hexanes) to give 4-chloro-3-methyl-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 1.57 g? 60.0%). HRMS(EI+) m/z Calcd for CnHioClN02S [(M+)]: 255.0121. Found: 255.0119.


To a solution of 4-chloro-3-methyl-thieno[3,2-c]pyridine~7-carboxylic acid ethyl ester (14.65 g, 57.29 mmol) (from Intermediate 7 supra) in carbon tetrachloride (250 mL) was added N-bromosuccinimide (12.24 g, 68.75 mmol) and 2,2'-azobisisobutyronitrile (0.94 g? 5.73 mmol). The reaction mixture was heated at 80 °C for 24 hours. The mixture was then cooled and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate -hexanes to give 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as white crystals. (Yield 11.73 g). The mother liquid was concentrated and purified by flash chromatography (diethyl ether - hexanes, 1:4, V/V) to give second crop of 3-bromomethyl-4~ chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 4.39 g, 84% combined).












Compound XXDC (18 mmol) (Scheme 10) was dissolved in N,N'-dimethylformamide (10 vol). To this was added potassium carbonate (1.2 equivalents), potassium iodide (1.0 equivalent) and 3-bromomethyl-4-chloro-thieno[352-c]pyridine-7-carboxylic acid ethyl ester (1.0 equivalent) (from Intermediate 8 supra). The reaction was stirred at 70 °C for 16 hours. Water (100 mL) was added and the crude reaction mixture extracted with ethyl acetate (4 x 50 mL). The combined organic layers were dried (MgS04), µLtered and the solvent removed in vacuuo. The crude solid was suspended in ethyl acetate (50 mL). The resulting suspension was µLtered, and the solid washed with a further aliquot of ethyl acetate (20 mL) to give crude product XXX.

Compound XXX (8 mmol) (from General Procedure 1 supra) was dissolved in 2-propanol saturated with ammonia (10 vol). The solution was heat at 160 °C in a microwave reactor for 20 minutes. The reaction solvent was removed in vacuuo. Hot methanol was added and the resulting suspension µLtered. The solid (mainly unreacted starting material) was re-treated under microwave conditions (as above); dioxane (-5 mL) was added to aid solubility in some cases as required. The desired product was contained in the µLtrate, which was evaporated to dryness and analysed. This process was repeated until >90% conversion of starting material to desired product XXXI was achieved.
General Procedure 3 Synthesis of XXXII


Compound XXXI (6 mmol) (from General Procedure 2 supra) was dissolved in 20% trifluoroacetic acid in dichloromethane (10 vol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to dryness to give the product XXXn.

Compound XXXII (160 fimol) (from General Procedure 3 supra) was dissolved in dichloroethane (3 mL) and DMF (1 drop). Thionyl chloride (3 equivalents) was added and the reaction mixture agitated at room temperature until acid chloride formation was complete (monitored by LCMS; -16 hours). Triethylamine (6 equivalents) was added to the crude reaction mixture followed by aniline (3 equivalents). The reaction mixture was agitated at 40 °C for 16 hours during which time a precipitate formed. The reaction mixture was µLtered and the µLtrate washed with IN HC1 (2 mL). The organic layer was passed through a µLter of MgSC>4 and then combined with the precipitate from the reaction mixture. The solvent was removed under reduced pressure and the resulting solid was washed with THF. The collected solid was suspended in a mixture of 2-propanol / chloroform (1:1) and loaded onto a preparative TLC plate (run in 20% m ethanol - dichloromethane). The desired material was removed from the silica by washing with methanol and concentrating to give product XXXIII.
General Procedure 5
Synthesis of XVn


To substituted resorcinol (6.4 mmol) (Scheme 4) dissolved in N,N-dimethylformamide (5 vol.) was added cesium carbonate (1.2 equivalents) and benzyl halide (1 equivalent) (Scheme 4). The reaction was stirred overnight at room temperature. The crude reaction mixture was dissolved in dichloromethane (20 mL) and washed with IN HC1 (2 x 20 mL). The combined aqueous layers were extracted with dichloromethane (2 x 20 mL) and organic layers combined and washed with brine (20 mL), then dried (MgS04). The desired products were purified by chromatography, eluting with heptane then 20% EtOAc / heptane. Yields were typically 30 - 50%.

To alkylated resorcinol XVII (from General Procedure 5 supra) or other substituted phenol XXIV (Scheme 8) dissolved in N?N-dimethylformamide (5 vol) was added potassium carbonate (1.2 equivalents), potassium iodide (1 equivalent) and 3-bromomethyl-4-chloro-thieno[3?2-c]pyridine~7-carboxylic acid ethyl ester (1.0 equivalent) (from Intermediate 8 supra). The reaction was stirred overnight at 75 °C. The crude reaction mixture was dissolved in dichloromethane (20 mL) and washed with IN HC1 (20 mL). The organic layer was collected and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried (MgS04). The desired products were purified by

chromatography, eluting with heptane then 10% EtOAc / heptane, then recrystallisation from acetonitrile. Yields were typically 25 - 30%.
General Procedure 7
Synthesis of XXVI

Compound XXV (from General Procedure 6 supra) was dissolved in 2-propanol saturated with ammonia (10 vol.). The solution was heated at 140 °C in a microwave reactor for 3 x 30 minutes. Any precipitate formed was µLtered and washed with 2-propanol. In cases where no precipitate was formed, the solvent was removed under reduced pressure and the resulting solid was washed with 2-propanol. No further purification was necessary. Yields were typically 60 - 75%.
General Procedure 8
Synthesis of XXVII

To an oven dried vessel was added compound XXVI (from General Procedure 7 supra) dissolved in anhydrous dioxane (25 vol) under nitrogen. Trimethylaluminium (2.0 M in heptane; 4 equivalents) was added dropwise under nitrogen at room temperature, and then the reaction mixture stirred for 10 minutes. Ethanolamine (4 equivalents) was added dropwise and the reaction mixture stirred at room temperature for a further 10 minutes before heating to 95 °C and stirring overnight. Re-treatment using 2 equivalents of reagents may be

necessary, Rochelle's salt (1 vol. of a saturated solution) was added to the cooled reaction mixture and stirred for one hour. The mixture was diluted with dichloromethane (50 mL) and water (50 mL) was added. The organic layer was removed and the aqueous layer extracted with 1:1 CHCl3:2-propanol (3 x 20 mL). The combined organic washings were dried (Na2S04)? µLtered and the solvent removed under reduced pressure. Preparative HPLC was used to purify the final compounds,

A suspension of 3-hydroxybenzoic acid (16.2 g, 117.3 mmol) (Aldrich) in acetic anhydride (20 mL) (Aldrich) was heated at reflux for 5 hours. On heating a clear solution was formed. After cooling to room temperature, mixture was poured into ice -water (400 mL) and stirred. A white crystalline material was formed. This was collected by µLtration, washed with water and dried in vacuum oven to give 3-acetoxybenzoic acid as white crystals in two crops. (Yield 18,97 g5 89.8%).
A suspension of 3-acetoxybenzoic acid (1.80 g, 10 mmol) in a mixture of N,N-dimethyl-formamide (3 drops) and thionyl chloride (3 mL, 40 mmol) (Aldrich) was heated in an 90 °C bath for 2 hours. After cooling, mixture was diluted with toluene (20 mL) and concentrated under reduced pressure to remove excess thionyl chloride. The resulting oil was dissolved in dichloromethane (10 mL) and added dropwise to a solution of 4-chloro-3-(trifluoromethyl)aniiine (1.96 g, 10 mmol) (Aldrich), 4-dimethylamino-pyridine (0.1 g, 0.08 mmol) (Fluka) and N?N-diisopropylethylamine (L6 g, 12.4 mmol) (Aldrich) in dichloromethane (10 mL) with cooling in an ice - water bath and magnetic stirring. When addition was complete, cooling bath was removed and mixture stirred at room temperature for 2 hours. Reaction mixture was then partitioned between water (50 mL) and

dichloromethane (2 X 50 mL). Organic layers were combined, and concentrated to dryness. Residue was dissolved in THF (10 mL), methanol (10 mL) and 1 N aqueous sodium hydroxide (10 mL) and stirred at room temperature for 16 hours. The yellow solution was diluted with water (100 mL) and acetic acid (5 mL) and extracted with ethyl acetate (2 X 100 mL). Ethyl acetate layers were washed with saturated brine (100 mL), combined, dried (MgS04), µLtered, and concentrated. Residue was recrystallized from ethyl acetate - hexanes to give A^-(4-chloro-3-trifluoromethyl-phenyl)-3-hydroxy-benzamide as colorless plates. (Yield 2.54 g, 80.4%).

A suspension of 7V-(4-chloro-3«trifluoromethyl-phenyl)-3-hydroxy-benzamide (0.33 g, LOS mmol) (from Intermediate 9 supra) and potassium carbonate (0.16 g, 1.15 mmol) in N,N-dknethylformamide was heated at 65 °C for 2 hours with magnetic stirring. 3-Bromomethyl-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.33 g, 1 mmol) (from Intermediate 8 supra) was added and mixture heated for another 5 hours at the same temperature. After cooling, mixture was partitioned between ethyl acetate (2X50 mL) and water (2 X 50 mL). Organic layers were washed with brine (50 mL), combined, dried (MgS04), µLtered and concentrated. Residue was recrystallized from ethyl acetate -dichloromethane - hexanes to give 4-chloro-3-[3-(4-chloro-3-trifluoromethyl-phenylcarbamoyl)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester as a white crystalline material. (Yield 0,16 g, 28.5%).
Examples

The following examples are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims.
Example 1
4-Amino-3-[3-(4-chloro-3-trifluoromethyl«phenylcarbamoyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[4-(4-chloro-3-trifluoromethyl-phenyl-carbamoyl)«phenoxymethyl]-thieno[3,2-c]pyridine-7"Carboxylic acid ethyl ester (0.11 g, 0.19 mmol) (from Intermediate 10 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 165 °C for 1,5 days. After cooling, the reaction mixture was concentrated.- The residue was washed with hot methanol and the solid was µLtered. The solution was concentrated. The residue was purified by flash chromatography duting with (40 - 100%) ethyl acetate in hexanes to give 4-amino~3-[3-(4-chloro-3-trifluoromethyl-phenylcarbamoyl)-phenoxym ethyl ester. (Yield 0.05 g, 50%). HRMS (ES4) m/z Calcd for C25H19CIF3N3O4S + H [(M+H)*]: 550.0810. Found: 550.0811.
Intermediate 11 3-(3-Benzyloxy-phenoxymethyl)-4-chloro-1hieno[3?2-c]pyridine-7-carboxylic acid ethyl ester

A suspension of potassium carbonate (0.16g, 1.17 mmol), 3-(benzyloxy)phenol (0.21 g, 1.07 mmol) (TCI-US) and a catalytic amount of 18-crown-6 (Aldrich) in Ar,7^-dimethylformamide (15 mL) was heated at 65 °C for 2 hours. 3"Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was then added.

Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 3-(3-benzyloxy -phenoxymethyl)-4-chloro-thieno[352"C]pyridine-7-carboxylic acid ethyl ester. (Yield 0.14 g, 30%). HRMS (ES+) m/z Calcd for C24H20CINO4S + H [(M+H)*]: 454.0875. Found: 454.0876.
Example 2
4-Ammo-3-(3-benzyloxy-phenoxymethyl)-1^

Ammonia gas was bubbled into a solution of 3-(3-benzyloxy-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.14 g, 0.31 mmol) (from Intermediate 11 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was diluted with dichloromethane and washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 5% ethyl acetate in dichloromethane to give 4-amino-3-(3-benzyloxy-phenoxymethyl)-thieno [3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 80 mg, 62%). HRMS (ES+) m/z Calcd for C24H22N2O4S + H [(M+H)+]: 435.1373. Found: 435.1373.
Example 3
4-Amino-3-(3-ben2^1oxy-phenoxymethyl)-tMeno[3,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyI)-amide


M.W. 449.529 C24H23N3O4S
A solution of 4-amino-3-(3-benzyloxy-phenoxymethyl)-thieno [3,2-c]pyridine-7-carboxylic acid ethyl ester (0.07 g, 0.16 mmol) (from Example 2 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (2,0 mL, 33.24 mmol) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot ethyl acetate and dried to give 4-aminO"3-(3-ben2yloxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyI)-amide as a white solid. (Yield 56 mg, 80%). HRMS (ES+) m/z Calcd for C24H23N3O4S + H [(M+H)4]: 450.1482. Found: 450.1483.
Intermediate 12
3 -(4-Chloro-benzyloxy )-phenol

A suspension of potassium carbonate (2.02 g, 14.6 mmol) and resorcinol (16.08 g, 0.146 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 4-chlorobenzyl bromide (3.0 g, 14.6 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (IX). The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 3-(4-chloro-benzyloxy)-phenol. (Yield 2.62 g, 76%).
Intermediate 13
4-CWoro-3-[3-(4-cWorO"benzyloxy)-phenoxymethyl]4Weno[3?2-c]pyridine-7-carboxylic
acid ethyl ester


A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3~(4-chloro-benzyloxy)-phenol (0.25 g? 1.07 mmol) (from Intermediate 12 supra) and a catalytic amount of 18-crown-6 (Aldrich) in #, N-dimelhylformamide (15 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was.purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-chloro-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.14 g, 28%).
Example 4
4-Amino-3-[3-(4-cUoro-benzyloxy)-phenoxymethyl]-1hieno[3?2-c]pyridine-7-carboxylic
acid ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(4-chloro-benzyloxy)-phenoxy-methyl]-thieno[3s2-c]pyridine-7-carboxylic acid ethyl ester (0.14 g, 0.29 mmol) (from Intermediate 13 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 0.13 g5 100%).

HRMS (ES+) m/z Calcd for C24H21CIN2O4S + H [(M+H)4]: 469.0984. Found: 469.0983.
Example 5
4-Amino-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3?^
acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-[3-(4-cWoro-benzyloxy)^
carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 4 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot ethyl acetate and dried to give 4-amino-3-[3-(4-chloro-ben2yloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 40 mg, 77%). HRMS (ES+) m/z Calcd for C24H22CIN3O4S + H [(M+H)+]: 484.1093. Found: 484.1096.

A suspension of potassium carbonate (2.02 g, 14.6 mmol) and resorcinol (16.08 g, 0.146 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 3-chlorobenzyl bromide (3.0 g, 14.6 mmol) (Aldrich) in acetonitrile (60 mL) was added. Heating at reflux was continued for 2.5 days. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (IX). The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated.

The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 3-(3-chloro-benzyloxy)-phenol. (Yield 2.80 g, 82%).
Intermediate 15
4-Chloro-3-[3-(3n:hloro-benzyloxy)-phenoxymeth^
acid ethyl ester

A suspension of potassium carbonate (0.16 g? 1.17 mmol), 3-(3-chloro-benzyloxy)«phenol (0.25g? 1.07 mmol) (from Intermediate 14 supra) and a catalytic amount of 18-crown-6 in A^TV-dimethylformamide (15 mL) was heated at 65 °C for 2 hours, 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (034 g51.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-chloro-3-[3-(3-chloro-benzyloxy)-phenoxyrnethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester.
(Yield 0.13 g, 26%).
Example 6
4-Amino-3-[3-(3-cUoro-benzyloxy)-phenoxymethyl]4hieno[352-c]pyridine-7-carboxylic
acid ethyl ester


Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(3-chloro-benzyloxy)-phenoxy-methyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.13 g, 0.27 mmol) (from Intermediate 15 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a -sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was recrystallized from methanol to give 4-amino-3-[3-(3-chloro-benzyloxy)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.11 g, 92%). HRMS (ES+) m/z Calcd for C24H21CIN2O4S + H [(M+H)4]: 469.0984. Found: 469.0983.
Example 7
4-Amino-3-[3-(3-cWoro-benzyloxy)-phenoxymethyl]-lMeno[3,2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-[3^3-chloro-benzyloxy>^^
carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 6 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot ethyl acetate and dried to give 4-amino-3-[3-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3.2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 25 mg, 48%). HRMS (ES+) m/z Calcd for C24H22CIN3O4S + H [(M+H)+]: 484.1093. Found: 484.1095.
Intermediate 16
3-(3-Trifluoromethyl»benzyloxy)-phenol


A suspension of potassium carbonate (1.73 g, 12.6 mmol) and resorcinol (13.87 g, 0.126 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux firoor 1 hour. A solution of 1-bromomethyl-3-trifluoromethyl-benzene (2.3 g, 12.6 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (IX), The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to 3-(3-trifluoromethyl-benzyloxy)-phenol. (Yield 2.29 g, 68%).
Intermediate 17
4-CMoro-3-[3-(3-trifluoromethyl-benzylox
carboxylic acid ethyl ester

A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-(3-trifluoromethyl-benzyloxy)-phenol (0.29 g, 1.07 mmol) (from Intermediate 16 supra) and a catalytic amount of 18-crown-6 (Aldrich) in MA^-dimethylformamide (15 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl"4-chloro-thieno[372"C]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-chloro-3-[3-(3-Mfluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyri-dine-7-carboxylicacid ethyl ester. (Yield 0.13 g, 25%).

Example 8
4-Amino-3-[3 carboxylic acid ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(3-trifluoromethyl-benzyloxy)-phenoxy-methyl]-thieno[3,2"C]pyridine-7»carboxylic acid ethyl ester (0.13 g5 0.25 mmol)(firom Intermediate 17 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol to give 4-amino-3-[3-(3-trifluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7"Carboxylic acid ethyl ester as a white powder. (Yield 0.08 g, 64%). HRMS (ES+) m/z Calcd for C25H21F3N2O4S + H [(M+H)+]: 503.1247. Found: 503.1246.
Example 9
4-Ammo~3 - [3-(3-trifluoromethyl-benzy to
carboxylic acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3«[3-(3-trifluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g? 0.10 mmol) (from Example 8 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot ethyl acetate and dried to give 4-amino-3-[3-(3-trifluoromethyl-benzyloxy)-phenoxy-methyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyI)-amide as a white powder. (Yield 28 mg, 55%).

HRMS (ES+) m/z Calcd for C25H22F3N3O4S + H [(M+H)+]: 518.1356. Found: 518.1356,
Intermediate 18
3-Benzylsulfanyl-phenol

Benzyl bromide (7.61 g, 43.6 mmol) (Fluka) was added to a solution of 3-mercaptophenol (5.0 g, 39.6 mmol) (Aldrich) and sodium hydroxide (1.78 g, 43,6 mmol) in methanol (100 mL). Mixture was stirred at room temperature, overnight then diluted with water (200 mL) and acetic acid (10 mL) and concentrated to remove organic solvent. Resulting precipitate was collected and washed with water to give 3-benzylsulfanyl-phenol. (Yield 7.40 g, 86.3%).
Intermediate 19
3-(3-Benzylsulfanyl-phenoxymethyl)-4-^^
ester

A suspension of potassium carbonate (0.48 g? 3.44 mmol), 3-benzylsulfanyl-phenol (0.69 g9 3.17 mmol) (from Intermediate 18 supra) in tetrahydrofuran / A^jV-dimethylformamide (5:1, 30 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (1.0 g, 2.99 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in

hexanes to give 3-(3-ben2yl-sulfanyl-phenoxy^ carboxylic acid ethyl ester. (Yield 078 g, 56%).
Example 10
4-Amino-3-(3-benzylsulfanyl-pheM acid ethyl
ester

Ammonia gas was bubbled into a solution of 3-(3-benzylsulfanyl-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.78 g, 0.25 mmol) (from Intermediate 19 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was then concentrated. The residue was purified by flash chromatography eluting with 5% ethyl acetate in dichloromethane to give 4-. amino-3-(3-benzylsulfanyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxyH
ester as a white powder. (Yield 0.18 g, 50%).
HRMS (ES+) wt/z Calcd for C24H22N2O3S2 + H [(M+H)*]: 451.1145. Found: 451.1143.
Example 11
4-Amino-3-(3-benzylsulfanyl-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylicacid (2-
hydroxy-ethyl)-amide

A solution of 4-amino-3-(3-benzylsulfanyl-phenoxyme1hyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 10 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed

with hot ethyl acetate and dried to give 4-amino-3-(3-benzylsulfanyl-phenoxymethyl]-thieno[3.2-c]pyridine-7-carboxy-lic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield
23mg,37%).
HRMS (ES+) m/z Calcd for C24H23N3O3S2 + H [(M+H)4]: 466.1254. Found: 466.1255.
Example 12
4-Ammo-3-(3-phenylmethanesulfonyl-phenox
acid ethyl ester

To a solution of 4-amino-3^3-benzylsulfanyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.10 g, 0.22 mmol) (from Example 10 supra) in dichloromethane (10 mL) at -10 °C was added 3-chloro-peroxybenzoic acid (0.16 g, 0.55 mmol) (Aldrich). The reaction mixture was stirred at 0 °C for 3 hours. The mixture was concentrated. The residue was purified by CI8 column chromatography eluting with acetonitrile - water to give 4-amino-3-(3-phenylmetbanesulfonyl-phenoxy acid ethyl ester. (Yield 0.05 g, 45%). HRMS (ES+) m/z Calcd for C24H22N2O5S2 + H [(M+H)4]: 483.1043. Found: 483,1047.
Example 13
4-Amino-3-(3 phenylmethanesulfonyl-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide

M.W. 497.594 C24H23N305S2
A solution of 4-amino-3"(3-phenylmethanesulfonyl-phenoxymethyl)"thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.04 g, 0.08 mmol) (from Example 12 supra) in

dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at
130 °C for 2 hours in a microwave reactor. The crude material was purified by CI 8 column
chromatography eluting with acetonitrile - water to give 4-amino-3-(3-
phenyknethanesulfonyl-phenoxy-methyl]^
hydroxy-ethyl)-amide, (Yield 20 mg, 49%).
HRMS (ES+) m/z Calcd for Cz^NgO^ + H [(M+H)+]: 498.1152. Found: 498.1151.
3 -(3 -Methoxy-benzyloxy)-phenol

M.W. 230.27 C,4HI403
A suspension of potassium carbonate (2.02 g, 14.6 mmol) and resorcinol (16.08 g, 0.146 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 3-methoxybenzyl bromide (2.94 g, 14.6 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered, and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to 3-(3-methoxy-benzyloxy)-phenol. (Yield 2.43 g, 72%).
Intermediate 21
4-Chloro-3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]-thieno[3>2-c]pyridine-7-carboxylic
acid ethyl ester


A suspension of potassium carbonate (0.16 g, 1,17 mmol), 3-(3-methoxy-benzyloxy)-phenol (0.25 g, 1.07 mmol) (from Intermediate 20 supra) in tetrahydrofuran - N,N-dimethylformamide (5:1, 30 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered, and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes gradient to give 4-chloro-3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxyiic acid ethyl ester. (Yield 0.21 g, 43%).
Example 14
4-Amino-3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic
acid ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(3-methoxy-benzyloxy)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0*21 g, 0.43 mmol) (from Intermediate 21 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol to give 4-amino-3-[3-(3-methoxy-benzyl-oxy)-phenoxy-methyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.15 g, 75%). HRMS (ES+) m/z Calcd for C25H24N2O5S + H [(M+H)+]: 465.1479. Found: 465.1479.
Example 15
4-Amino-3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]4hieno[3,2«c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide


A solution of 4-amino-343-(3-methoxy-benzyloxy)-phenoxymethyl]^ 7-carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 14 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hpur in a microwave reactor. The precipitate was µLtered and washed with hot ethyl acetate and dried to give 4-amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 34 mg, 65%). HRMS (ES+) m/z Calcd for C25H25C1N305S + H [(M+H)+]: 480.1588. Found: 480.1587.
Intermediate 22
3-(4-Methoxy-benzy loxy)-phenol

A suspension of potassium carbonate (3,535 25.5 mmol) and resorcinol (28.12 g, 0.26 mol) (Aldriah) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 4-methoxybenzyl chloride (4.0 g, 25.5 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered, and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 3-(4-methoxy-benzyloxy)-phenol. (Yield 0.37 g, 6%).

Intermediate 23
4-Chloro-3 - [3 -(4-methoxy-benzyloxy)-phenoxymethyl] -thieno [3,2 -c]pyridine-7-carboxylic
acid ethyl ester

A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-(4-methoxy-benzyloxy)-phenol (0.25 g, 1.07 mmol) (from Intermediate 22 supra) in tetrahydrofuran - N,N-dimethylformamide (5:1,30 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (034 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X), The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered, and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes gradient to give 4-chloro-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.16 g, 33%).
Example 16
4-Amino-3-[3-(4-me1hoxy-benzyloxy)-phenoxy
acid ethyl ester

M.W. 464.54 C25H24N205S
Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(4-methoxy-benzyloxy)-phenoxy-methyl]-thieno[3r2-c]pyridine-7-carboxylic acid ethyl ester (0.16 g, 0.43 mmol) (from Intermediate 23 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The

residue was washed with hot methanol to give 4-amino-3-[3-(4-methoxy-benzyloxy)-phenoxy-methyl]-1iiieno[332-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.10 g, 67%). HRMS (ES+) m/z Calcd for C25H24N205S + H [(M+H)+j: 465.1479. Found: 465.1477.
Example 17
4-Amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethylH
acid (2-hydroxy-ethyI)-amide

A solution of 4-amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]-thieno[3?2«c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 16 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The reaction mixture was purified by CI 8 column chromatography eluting with acetonitrile - water to give 4-amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 34 mg, 65%). HRMS (ES+) m/z Calcd for C25H25CIN3O5S + H [(M+H)4]: 480.1588. Found: 480.1587.
Intermediate 24
3-(4-Methoxy-3"trifluoromethyl-benzyloxy)-phenol

M.W. 298.26 C15H13F3O3
A suspension of potassium carbonate (1.44 g, 10.4 mmol) and resorcinol (1L01 g, 0.10 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 4-methoxy-3-(trifluoromethyl)-benzyl bromide (2.8 g, 10.4 mmol) (Matrix) in acetonitrile (60 mL) was

added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 3-(4-methoxy-3-trifluoro-methyl-benzyloxy)-phenol. (Yield 0.99 g, 32%).
l«ter»e**e 25
4-Chloro-3™[3-(4-methoxy-3"trifluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester

A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenol (0.32 g, 1.07 mmol) (from Intermediate 24 supra) and a catalytic amount of 18-crown-6 (Aldrich) in 7^,iV-dimethylformamide (15 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3:)2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 10 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-chloro«3-[3-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenoxymethyl]-lMeno[3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.12 g, 21%).
Example 18
4-Amino-3-[3-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenoxymethyl]-1iiieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester


Ammonia gas was bubbled into a solution of 4-cMoro-3-[3-(4-methoxy-3-trifluoromethyl-
benzylH^xy)-phenoxymethyl]-thieno[3,2-c]pyridm^^ acid ethyl ester (0.12 g,
0.22 mmol) (from intermediate 25 supra) in dioxane (20 mL) for 20 minutes. The mixture
was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was
concentrated. The residue was purified by flash chromatography eluting with 5% ethyl
acetate in dichloromethane to give 4-amino-3-[3-(4-methoxy-3-trifluoromethyl™benzyl-oxy)-
phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder.
(Yield 0.065 g, 54%).
HRMS (ES+) m/z Calcd for C26H23F3N2O5S + H [(M+H)4]: 533.1353. Found: 533.1352.
Example 19
4-Amino-3-[3-(4-methoxy-3-1rifluorome
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-[3-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine«7-carboxylic acid ethyl ester (0.05 g? 0.10 mmol) (from Example 18 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The crude material was purified by CI 8 column chromatography eluting with acetonitrile - water to give 4-amino-3-[3-(4-methoxy-3-trifluoro-methyl-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylicacid(2-hydroxy-ethyl)-amide as a white powder. (Yield 20 mg, 39%). HRMS (ES+) m/z Calcd for C26H24F3N305S + H [(M+H)+j: 548.1462. Found: 548.1463.

Intermediate 26
4-Chloro-3-(3-phenoxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxyIic acid ethyl ester

A suspension of potassium carbonate (0,16 g, 1.17 mmol), 3-phenoxyphenol (0.20 g, 1.07 mmol) (Aldrich) in tetrahydrofuran - N^N-dimethylformamide (5:1, 30 mL) was heated at 70 °C for 3 hours. 3-Broraomethyl-4-chloro-thieno[3,2-c]pyridine-7"Carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-
chloro-3-(3-phenoxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.22 g, 49%).
Example 20
4-Amino-3-(3-phenoxy"phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-(3-phenoxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.22 g9 0.25 mmol) (from Intermediate 26 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue residue was recrystallized from ethyl acetate - hexanes to give 4-amino-3-(3-phenoxy -phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as white crystals. (Yield 0.10 g, 48%),

HRMS (ES+) m/z Calcd for C23H20N2O4S + H [(M+H)*]: 42L1217. Found: 421.1216,
Example 21
4-Ammo-3^3-phenoxy^^
hydroxy-etbyI)-amide

A solution of 4-amino-3-(3-phenoxy-phenoxymeth^
acid ethyl ester (0.05 g, 0.12 mmol) (from Example 20 supra) in dimethylsulfoxide (0.5 mL)
was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 130 °C for 2 hours in a
microwave reactor. The precipitate was µLtered and washed with hot methanol and dried to
give 4«amino-3-(3-phenoxy-phenoxymethyl]«thieno[3s2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide as a white powder. (Yield 40 mg, 77%).
HRMS (ES+) m/z Calcd for C23H21N3O4S + H [(M+H)+]: 436.1326. Found: 436.1326.
Intermediate 27
4-CUoro-3-(3-phenyIamino-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl
ester

A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-hydroxydiphenylamine (0,20 g, L07 mmol) (Alfa Aesar) in tetrahydrofuran - MA^-dimethylformamide (5:1, 30 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3.2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was

washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes
to give 4-cUoro-3-(3-phenylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxyIic acid ethyl ester. (Yield 0.16 g, 36%).
Example 22 4-Amino-3»(3-phenylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl

Ammonia gas was bubbled into a solution of 4-chloro-3-(3-phenylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.16 g, 0.36 mmol) (from Intermediate 27 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with methanol and dried to give 4-amino-3-(3-phenyiamino-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.10 g, 67%). HRMS (ES+) m/z Calcd for C23H21N3O3S + H [(M+H)"*]: 420.1377. Found: 420.1375.
Example 23
4-Amino-3-(3-phenylamino-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide

A solution of 4-amino-3-(3-phenylamino-phenoxymethyl]-thieno[372-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.12 mmol) (from Example 22 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at

130 °C for 2 hours in a microwave reactor. The crude material was purified by CI8 column chromatography eluting with acetonitrile - water to give 4-amino-3-(3-phenylamino-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white
powder. (Yield 30 mg, 58%).
HRMS (ES+) m/z Calcd for C23H22N4O3S + H [(M+H)*]: 435.1486. Found: 435.1485.

A solution of benzoyl chloride (3.0 g, 21.3 mmol) (J. T. Baker) in tetrahydrofuran (15 mL) was added dropwise at room temperature with magnetic stirring to a solution of m-aminophenol (L09 g, 10 mmol) (Eastman Organic), 4-dimethyl amino-pyridine (20 mg) (Fluka), and triethylamine (2.54 g, 25 mmol) (Aldrich) in tetrahydrofuran (30 mL). After stirring for 1 hour, precipitate was µLtered off and washed with ether* Combined µLtrate was comcentrated under reduced pressure and residue recrystallized from dichloromethnae -hexanes to give benzoic acid 3-benzoylamino-phenyl ester as a tan crystalline solid. (Yield 3.08 g, 97.1%).
Lithium aluminum hydride solution (19 mL, 1M in tetrahydrofuran) (Aldrich) was added slowly to a suspension of the benzoic acid 3-benzoylamino-phenyl ester (2.0 g, 6.3 mmol) (from Intermediate 28 supra) in anhydrous tetrahydrofuran (30 mL) under an argon

atmosphere with magnetic stirring at room temperature (exothermic reaction). When addition was complete, mixture was heated at reflux for 1 hour. Reaction mixture was allowed to cool to room temperature and was quenched by pouring slowly into 15% aqueous ammonium chloride solution (100 mL) and ether (100 mL). After stirring thoroughly, mixture was diluted with ethyl acetate (100 mL) and µLtered through Celite®. µLtercake was washed thoroughly with ethyl acetate. Combined µLtrate and washing was concentrated under reduced pressure. The resulting oil was purified by flash chromatography (Biotage 40M silica gel, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give crude product as a brown oil containing benzyl alcohol. This material was further purified by flash chromatography (Biotage 40L silica gel, 15% then 30% acetone in hexanes as solvent) to give 3-benzylamino-phenol as a colorless oil. (Yield 0.93 g5 74,1%).
Intermediate 30
3-(3-Benzylamino-phenoxymethyl)-4-cWoro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl
ester

A suspension of potassium carbonate (0.32 g, 2.31 mmol), 3-benzylamino-phenol (0.42 g5
2.11 mmol) (from Intermediate 29 supra) in tetrahydrofiiran - A^A^dimethylformamide (5:1,
30 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4«chloro-thieno[3,2-c]pyridine-7-
carboxylic acid ethyl ester (0.68 g, 2.03 mmol) (from Intermediate 8 supra) was added.
Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate
and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic
phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated.
The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes
to give 3-(3-benzyl-amino-phenoxymethyl)-4-c^ acid
ethyl ester. (Yield 0.51 g, 55%),

Example 24
4-Amino-3-(3-benzylammo-ph
ester

Ammonia gas was bubbled into a solution of 3-(3-benzylamino-phenoxymethyl)-4-chloro-tMeno[3,2-c]pyridine~7-carboxylic acid ethyl ester (0.51 g, 0.25 mmol) (from Intermediate 30 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was purified by CI 8 column chromatography eluting with acetonitrile - water to give 4-amin0'3»(3-benzylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.064 g, 13%) and recover starting material. HRMS (ES4) m/z Calcd for C24H23N3O3S + H [(M+H)*]: 434.1533. Found: 434.1532.
Example 25
4-Ammo-3-(3-benzylamino-phenoxym

A solution of 4-amino-3-(3-benzylamino-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 24 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (2.0 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The reaction mixture was puried by CI8 column chromatography eluting with acetonitrile - water to give 4-amino-3'(3-benzylamino-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 22 mg, 42%).

HRMS (ES+) m/z Calcd for C24H24N4O3S + H [(M+H)+]: 449.1642. Found: 449.1640.

A suspension of potassium carbonate (2.11 g, 15.3 mmol) and resorcinol (16.85 g, 0.153 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 4-bromomethyl-benzonitrile (3.0 g, 15.3 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (IX). The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated. The residue was washed with hot methylene chloride. The solid was µLtered and dried to give 4-(3-hydroxy-phenoxymethyl> benzonitrile. (Yield L77 g, 51%).
Intermediate 32
4-CMoro-3-[3-(4-cyano-benzyloxy)-pte
ethyl ester

A suspension of potassium carbonate (0.24 g, 1.71 mmol), 4-(3-hydroxy-phenoxymethyI)-benzonitrile (0.35 g, 1.56 mmol) (from Intermediate 31 supra) in tetrahydrofuran - NyN-dimethylformamide (5:1,18 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.50 g, 1.49 mmol) (from Intermediate 8

supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 0 - 5% ethyl acetate in dichloromethane to give 4-chloro-3«[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyri-dine-7-carboxylic acid ethyl ester. (Yield 0.38 g, 54%).
Example 26
4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid
ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0J6 g5 0,33 mmol) (from Intermediate 32 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.10 g, 67%). HRMS (ES+) m/z Calcd for C25H21N3O4S + H [(M+H)*]: 460.1326. Found: 460.1327.
Example 27
4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3.2-c]pyridine-7-carboxylic acid


An aqueous solution of sodium hydroxide (1.0 N, 0,63 mL, 0.63 mmol) was added to a solution of 4-amino-3-[3-(4-cyano«benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.17 g, 0.37 mmol) (from Example 26 supra) in tetrahydrofuran -methanol (8 mL, 3:1) and the mixture was heated at 40 °C for 1 day. The reaction mixture was concentrated and azeotroped with toluene. The solid residue was triturated with dichloromethane. The solid was then suspended in water and treated with hydrochloric acid (IN, 3 mL). After stirring for 30 minutes, the solid was collected, washed with water and then diethyl ether and dried to give 4»amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid as a white solid which was conteminated with a small amount of 4-amino-3"[3"(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid methyl ester. (Yield 0.086 g, 54%).
Exanple 28
4-Ajnino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-tMeno[3?2-c]pyridine-7*carboxylicacid
(2-hydroxy-ethyl)-amide

4-Amino-3«[3-(4-cyano-benzyloxy)-phenoxymethyl]"thieno[3,2-c]pyridine-7-carboxylicacid (86 mg, 0.13 mmol) (from Example 27 Supra), 1-hydroxybenzotriazole hydrate (43 mg, 0.32 mmol) (Aldrich) and 1,3-diisopropylcarbodiimide (0.044 mL, 0.29 mmol) (Aldrich) were combined in tetrahydrofuran - A^-dimethylformamide (3.6 mL, 5:1) with stirring. After 1 hour, ethanolamine (36 mg, 0.60 mmol) (Aldrich) was added. The mixture was stirred at room temperature for 18 hours and then concentrated. The residue was purified by HPLC eluting with acetonitrile - water to give 4-amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine~7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 65 mg, 68%). HRMS (ES+) m/z Calcd for C25H22N4O4S + Na [(M+Na)4]: 497.1254. Found: 497.1254.

Intermediate 33
3-(3-Hydroxy-phenoxymethyl)-benzonitrile

A suspension of potassium carbonate (2.11 g, 15.3 mmol) and resorcinol (16.85 g, 0.153 mol) (Aldrich) in acetonitrile (60 mL) was heated at reflux for 1 hour. A solution of 3-bromomethyl-benzonitrile (3.0 g, 15.3 mmol) (Aldrich) in acetonitrile (60 mL) was added. The reaction mixture was heated at reflux for 2.5 days. The solution was concentrated. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (IX). The combined organic phase was washed with brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 3-(3-hydroxy-phenoxymethyl)~benzonitrile, (Yield 2.89 g, 84%).
Intermediate 34
4-Chloro-3-[3-(3-cyanO'ben2yloxy)«phenoxymethyl]4Weno[3,2-c]pyridme-7-carboxylicacid
ethyl ester

A suspension of potassium carbonate (0.24 g, 1.71 mmol), 3-(3-hydroxy-phenoxymethyl)-benzo-nitrile (0.35 g? 1.56 mmol) (from Intermediate 33 supra) in tetrahydrofuran - N,N-dimethylformamide (5:1,18 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.50 g, 1.49 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried

(magnesium sulfate) µLtered and concentrated. The residue was purified by flash chromatography eluting with 0 - 5% ethyl acetate in dichloromethane to give 4-chloro-3-[3-
(3-cyano-ben2yloxy)-phenoxyme%l]4Weno[3,2-c]pyri-dine-7-carboxylic acid ethyl ester. (Yield 0.43 g, 61%).
Example 29
4-Amino-3-[3-(3-cyano»ben2yloxy)-phenoxymethyl]-tMeno[3,2-c]pyridine-7-carboxyli
ethyl ester

Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(3-cyano-benzyloxy)-phenoxy-methyl]-thieno[3,2-c]pyridine-7«carboxylic acid ethyl ester (0.14 g, 0.29 mmol) (from Intermediate 34 supra) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[3-(3-cyano-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.10 g, 77%). HRMS (ES+) m/z Calcd for C25H21N3O4S + H [(M+H)4]: 460.1326. Found: 460.1325.
Example 30
4-Amino-3-[3-(3-cyano-benzyloxy)-phenoxyme1hyl]-lWeno[3?2-c]pyridine-7-carboxylicacid

An aqueous solution of sodium hydroxide (1.0 N, 0.63 mL? 0.63 mmol) was added to a solution of 4-amino-3-[3-(3-cyano-benzyloxy)-phenoxymethyl]-1hieno[3,2«c]pyridine-7-carboxylic acid ethyl ester (0.17 g, 0.37 mmol) (from Example 29 supra) in tetrahydrofuran -

methanol (8 mL, 3:1) and the mixture was heated at 40 °C for 1 day. The reaction mixture was concentrated and azeotroped with toluene. The solid residue was triturated with dichloromethane. The solid was then suspended in water and treated with aqueous hydrochloric acid (1 N, 3 mL). After stirring for 30 minutes, the solid was collected, washed with water and then diethyl ether and dried to give 4-amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid as a white powder which was contaminated with a small amount of 4-amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid methyl ester. (Yield 86 mg, 54%).
Example 31
4-Ammo-3 - [3-(3-cyano-benzy loxy )^
(2-hydroxy-ethyl)-amide trifluoroacetic acid salt
4-amino-3-[3-(3-cyano-benzyloxy>phenoxym
(86 mg, 0.13 mmol) (from Example 30 supra), 1-hydroxybenzotriazole hydrate (43 mg? 0.32 mmol) (Aldrich) and 1,3-diisopropylcarbodiimide (0.044 mL, 0.29 mmol) (Aldrich) were combined in tetrahydrofuran - A^N-dimethylformamide (3.6 mL, 5:1) with stirring. After 1 hour, ethanolamine (0.036 g, 0.60 mmol) (Aldrich) was added. The mixture was stirred at room temperature for 18 hours and then concentrated, The residue was purified by HPLC eluting with acetonitrile - water containing trifluoroacetic acid to give 4-amino-3-[3-(3-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide trifluoroacetic acid salt as a white powder. (Yield 65 mg5 68%). HRMS(ES+)ff2/zCalcdforC25H22N404S + H[(M+H)+]: 475.1435. Found: 475.1434.
Example 32
3-(3-benzyloxy-phenoxymethyl)-4-(2-hydroxy-etnylamino)-thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide


A solution of 3-(3-benzyloxy"phenoxymethyl)-4-cWoro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.16 g, 0.35 mmol) (from Intermediate 11 supra) in dimethylsulfoxide (1.0 mL) was treated with ethanolamine (4.0 mL) (Aldrich) and heated at 130 °C for 2 hours in a microwave reactor. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was recrystallized from ethyl acetate - hexanes to give 3-(3-benzyloxy-phenoxymethyl)-4-(2-hydroxyetnyl-amino)-thieno[3,2-c]pyridine"7-carboxylic acid (2-hydroxy-ethyl)-amide as white crystals. (Yield 0.06 g, 35%). HRMS (ES+) m/z Calcd for C26H27N3O5S + H [(M+H)*]: 494.1744. Found: 494.1746

3-Hydroxybenzoic acid (5 g, 36.2 mmol) (Aldrich) was suspended in dry benzene (200 mL) and the mixture was heated to reflux. N, N-Dimethylformamide di-/-butyl acetal (34.7 mL, 0.14 mol) (Aldrich) was added dropwise and the mixture was heated at reflux for a further 1 hour. The cooled solution was washed with water, saturated sodium bicarbonate solution and brine. After drying (magnesium sulfate) and µLtering, the solvent was evaporated. The residue was purified by flash chromatography eluting with 25% hexanes in dichloromethane and 10% ethyl acetate in dichloromethane to give 3-hydroxy-benzoic acid ter/-butyl ester. (Yield 3.47 g, 49%).

Intermediate 36
3-(3-ter^Butoxycarbonyl-phenoxy
ethyl ester

A suspension of potassium carbonate (1.47 g, 10.65 mmol), 3-hydroxy-benzoic acid tert-butyl ester (1.89 g, 9.73 mmol) (from Intermediate 35 supra) and a catalytic amount of 18-crown-6 (Aldrich) in N, N-dimethylformamide (50 mL) was heated at 65 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (3.10 g5 9.26 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate), µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 3-(3-/er/-butoxycarbonyl-phenoxymethyl)-4»chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 2.5 g, 60%).
Intermediate 37
4-Amino-3-(3-tert-butoxycarbonyl-phenoxymethyl)-tMeno[3?2-c]pyridine-7-carboxylicacid
ethyl ester

Ammonia gas was bubbled into a solution of 3-(3-/er/t-butoxycarbonyI-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.62 g, 1.38 mmol) (from Intermediate 36 supra) in dioxane (20 mL) for 30 minutes. The mixture was heated in a

sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The
residue was washed with hot ethyl acetate, the solid was µLtered and dried to give 4-amino-3-
(3-^r/-butoxycarbonyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester
(0.46 g). The solution was concentrated. The residue was purified by flash chromatography
eluting with 40% ethyl acetate in hexanes to give the product (0.13 g). (Combined yield 0.59
g,100%).
HRMS (ES+) m/z Calcd for C22H24N205S + H [(M+H)+]: 429.1479. Found: 429.1480.
Intermediate 38
4-Amino-3-(3-carboxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester

4-Amino-3-(3-rer/-butoxycarbonyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylicaci^ ethyl ester (0.13 g, 0.30 mmol) (from Intermediate 37 supra) was dissolved in trifluoroacetic acid - dichloromethane (1:1,4 mL). The mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in saturate aqueous sodium carbonate solution and extracted with dichloromethane. The aqueous phase was acidified with 6 N hydrochloric acid. The solid formed was collected, washed with water and dried to give 4-amino-3-(3-carboxy-phenoxymethyl)-thieno[3,2-c]p3ridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.11 g, 100%). HRMS (ES+) m/z Calcd for C18H16N2O5S + H [(M+H)*]: 373.0853. Found: 373.0853,
Intermediate 39
4-Hydroxy-benzoic acid /er/-butyl ester


4-Hydroxybenzoic acid (5.29 g, 38 3 mmol) (Aldrich) was suspended in dry benzene (200 mL) and the mixture was heated to reflux. N,N -Dimethylformamide di-r-butyl acetal (36.7 mL, 0.15 mol) (Aldrich) was added dropwise and the mixture was heated at reflux for a further 1 hour. The cooled solution was washed with water, saturated aqueous sodium bicarbonate solution and brine. After drying (magnesium sulfate) and µLtering, the solvent was evaporated. The residue was purified by flash chromatography eluting with 25% hexanes in dichloromethane and 10% ethyl acetate in dichloromethane to give 4-hydroxy-benzoic acid tert-bxxtyl ester. (Yield 1.72 g, 23%).
Intermediate 40
3-(4-ter^Butoxycarbonyl-phenoxymethyty^

A suspension of potassium carbonate (1.34 g, 9.70 mmol), 4-hydroxy-benzoic acid ter/-butyl ester (1.72 g, 8.86 mmol) (from Intermediate 39 supra) and a catalytic amount of 18-crown-6 (Aldrich) in A^-dimethylformamide (50 mL) was heated at 65 °C for 2 hours. 3~ Bromomethyl-4«chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (2.82 g, 8.43 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X), The combined organic phase was washed with water and brine, dried (magnesium sulfate) µLtered and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 3-(4-terf-butoxycarbonyl-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 2.65 g, 70%),

Intermediate 41
4-Amino-3-(4-ter/-butoxycar^^
ethyl ester
Ammonia gas was bubbled into a solution of 3-(4-te^butoxycarbonyl-phenoxymethyl)-4-chloro4hieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (2.70 g, 6.03 mmol) (from Intermediate 40 supra) in dioxane (60 mL) for 30 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was recrystallized from ethyl acetate, the solid was µLtered and dried to give 4-amino-3-(4-/err-butoxycarbonyl-phenoxymethyl)-lMeno[3?2-c]pyridine-7-carboxylic acid ethyl ester (1.3 g). The mother liquid was concentrated. The residue was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to give the product (0.8 g). (Combined yield 2.1 g, 81%). HRMS (ES+) m/z Calcd for C22H24N2O5S + H [(M+H)*]: 429.1479. Found: 429.1480.
Intermediate 42
4-Amino-3-(4-carboxy-phenoxymethyl)-1hieno[3?2-c]pyridine-7-carboxylic acid ethyl ester

4-Ammo-3-(4-/er^butoxycarbonyl-phenoxymethyl)-thieno[3?2-c]pyµMdine-7-carboxylicacid ethyl ester (2.1 g, 4.9 mmol) (from Intermediate 40 supra) was dissolved in trifluoroacetic acid - dichloromethane (1:2, 60 mL). The mixture was stirred at room temperature for 3 hour then concentrated. The residue was dissolved in saturated aqueous sodium carbonate solution and extracted with dichloromethane. The aqueous phase was acidified with aqueous

6 N hydrochloric acid. The solid was collected, washed with water and dried to give 4-amino-3-(4-carboxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 1.83 g, 100%).
HRMS (ES+) m/z Calcd for CjgHi^OsS + H [(M+H)*]: 373.0853. Found: 373.0853.
Example 33
4-Amino-3-(3-methoxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester

This was prepared following the procedure found in Example 2 supra,
HRMS (ES+) m/z Calcd for C18H18N204S + H [(M+H)+]: 359.1060. Found: 359.1058.
Example 34
4-Ammo-3-(3-methoxy-phenoxymeth^
hydroxy-ethyl)-amide

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C18H19N3O4S + H [(M+H)+]: 374.1169. Found: 374.1169.
Example 35
4-Ammo-3-(3-benzoylamino-phenoxyme&^ ethyl
ester


This was prepared following the procedure found in Example 1 supra.
HRMS (ES*) m/z Calcd for C24H21N3O4S + H [(M+H)"*]: 448.1326. Found: 448.1325.
Example 36
4-Amino-3-(3-benzoylamino-phenoxyme1hyl)-thieno[3,2-c]pyridine-7-carboxyli acid (2-
hydroxy-ethyl)-amide

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C24H22N4O4S + H [(M+H)+]: 463.1435. Found: 463.1436.
Example 36a
4-Amino-3-(3-benzoylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide hydrochloride

This was prepared by treating 4-aminO"3-(3-benzoylamino-phenoxymethyl)-thienof3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide with 1 equivalent of hydrochloric acid. HRMS (ES+) m/z Calcd for C24H22N404S + H [(M+H)+]: 463.1435. Found: 463.1437. HRMS (ES+) m/z Calcd for C24H22N4O4S + Na [(M+Na)*]: 485.1254. Found: 485.1256.

Example 36b
4-Amino~3-(3-benzoylamino^
hydroxy-ethyl)-amide toluene-4-sulfonic acid salt

This was prepared by treating 4-anuno-3-(3-benzoylamino-phenoxymethyl)-thieno[3?2»
c]pyridine-7-carboxylic acid (24iydroxy-ethyl)-amide with 1 equivalent of toluene-4-sulfonic
acid,
HRMS (ES+) m/z Calcd for C24H22N4O4S + H [(M+H)4]: 463.1435. Found: 463.1437.
HRMS (ES+) m/z Calcd for C24H22N4O4S + Na [(M+Na)*]: 485.1254. Found: 485.1256.
Example 37
4-Amino-3-[3-(4-cWoro-phenylcarbamoyl)-phenoxymethyl]-tMeno[3,2-c]pyridine-7-
carboxylic acid ethyl ester

To a suspension of 4-amino-3-(3-carboxy-phenoxymethyl)-thieno[352-c]pyridine-7-carboxylic acid ethyl ester (49.2 mg, 0.132 mmol) (from Intermediate 38 supra) in DMF (5 mL) were added diisopropylethylamine (68 mg, 0.528 mmol), HOBt (26.7 mg, 0.198 mmol) (Aldrich) and HBTU (75.0 mg, 0.198 mmol) (Advanced ChemTech). After stirring for 30 minutes, 4-chloroaniline (20.0 mg, 0.158 mmol) (Aldrich) in DMF (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours before it was diluted with EtOAc (80 mL), washed with IN HC1 (10 mL), saturated aqueous Na2C03 solution (10 mL),

brine (2x10 mL), dried (Na2S04) and µLtered. Removal of the solvent followed by column chromatography (CH2C12 / MeOH, 98/2) gave 4-amino-3-[3-(4-chloro-phenylcarbamoyl)-phenoxymethyI]-thieno[3,2-c]pyridme-7-carboxylic acid ethyl ester as a white solid. (Yield
34.1 mg, 53.6%).
HRMS (ES+) m/z Calcd for C24H20CIN3O4S + H [(M+H)*]: 482.0936. Found: 482.0936.
Example 38
4-Amino-3-[3-(4^hloro-phenylcarbamoyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7'
carboxylic acid (2-hydroxy-ethyl)-amide

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C24H2iClN404S + H [(M+H)+]: 497.1045. Found: 497.1045.
Example 39
4-Amino-3-[3-(4«fluoro-phenylcarbamoyl)-phenoxyme1iiyl]-tMeno[352-c]pyridine-7-
carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C24H20FN3O4S + H [(M+H)*]: 466.1232. Found: 466.1230.
Example 40
4-Amino-3-[3-(4-fluorO"phenylcarbamoyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide


This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C24H21FN4O4S + Na [(M+Na)+]: 503.1160. Found: 503.1158.
Example 41
4-Amino-3-[3-(4-cMoro-benzyloxy)-phenoxymeft^
acid trifluoro-acetic acid salt

This was prepared by sodium hydroxide hydrolysis of 4-amino«3-[3-(4-chloro-benzyloxy)« phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) followed by purification with reverse phase chromatography using acetonitrile - water containing 0.1% trifluoroacetic acid as solvent.
Example 42
4-Amino-3-[3-(3-cWorO"phenylcarbamoyl)«phenoxymethyl]-1liieno[3?2-c]pyridine-7-
carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.

HRMS (ES+) m/z Calcd for C24H2oClN304S + H [(M+H)*]: 482.0936. Found: 482.0937.
Example 43
4-Ammo-3-[3-(3-cMoro-phenylcar^
carboxylic acid (2-hydroxy-ethyl)-amide

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for CsµMiClN^S + Na [(M+Na)4]: 519.064. Found: 519.0864.
Example 44
4-Amino-3-[3»(4-chloro-phenylcarbamoyl)-phenoxymethyl]-tWeno[3,2-c]pyridine-7-
carboxylic acid (3-hydroxy-propyl)-amide

This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with amino 1 -propanol. HRMS (ES+) m/z Calcd for C25H23CIN4O4S + Na [(M+Na)*]: 533.1021. Found: 533.1022.
Example 45
4-Amino-3-[3-(4-cUoro-phenylcarbamoyl)-phenoxyme1hyl]4hieno[3?2-c]pyridine-7-
carboxylic acid propylamide


This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with propylamine.
HRMS (ES+) m/z Calcd for C25H23CIN4O3S + Na [(M+Na)+]: 517.1071. Found: 517.1072.
Example 46 4-Amino-3-[3-(4-cMoro-phenylcarbamoyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-
carboxylic acid ethylamide

This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with ethylamine. HRMS (ES+) m/z Calcd for C24H21CIN4O3S + Na [(M+Na)+]: 503.0915. Found: 503.0917.
Example 47
4-Amino-3 - {3 - [(4-chloro-phenyl)-methyl-carbamoyl] -phenoxymethy 1} -thieno [3,2 -
c]pyridine-7-carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.

HRMS (ES+) m/z Calcd for C25H22CIN3O4S + H [(M+H)+]: 496.1093. Found: 496.1088.
Example 48
4-Amino-3-[3-( 1 -methyl-piperidin-4-ylcarbamoyI)-phenoxymethyl]-thieno[
carboxylic acid ethyl ester

This was prepared following the procedure found in Example 3 supra,
HRMS (ES+) m/z Calcd for C24H28N4O4S + H [(M+H)+]: 469.1904. Found: 469.1900.
Example 49
4-Amino-3-[3-(5-methyl-pyridin-2-ylcarbamoyl)-phenoxymethyl]-lWeno[3?2-c]pyri
carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C24H22N4O4S + H [(M+H)*]: 463.1435. Found: 463.1430.
Example 50
4-Amino-3-[3-(l-methanesulfonyl-piperidin-4-ylcarbamoyl)"phenoxymethyl]-thieno[3?2-
c]pyridine-7-carboxylic acid ethyl ester


This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C24H28N4O6S2 + Na [(M+Na)4]: 555.1342. Found: 555.1332.
Example 51
4-Amino-3- {3-[(4-chloro-phenyl)-methyl-carbamoyl]-phenoxymethyl} -thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C25H23CIN4O4S + Na [(M+Na)*]: 533.1021. Found: 533.1016.
Example 52
4-Amino-3-[5-(3-carbamoyl-phenylcarbamoyl)-2-methyl-phenoxymethyl]-thieno[3,2-

This was prepared following General Procedure 4 supra.
LRMS (ES+) m/z Calcd for C26H24N4O5S + H [(M+H)+]: 505. Found: 505.
Example 53
4-Amino-3-(2-methyl-5-phenylcarbamoyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-
carboxylic acid ethyl ester


This was prepared following General Procedure 4 supra.
Example 54
4-Ammo-3-[3-(4-cWoro-benzyloxy)-phen^
acid (3-hydroxy-propyl)~amide trifluoro-acetic acid salt

A solution of 4-ainino-3-[3-(4-cMoro-berizyloxy)-pte^
carboxylic acid ethyl ester (0.04 g, 0.09 mmol) (from Example 4 supra) in dimethylsulfoxide
(0*5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours
in a microwave reactor. The mixture was purified by HPLC eluting with acetonitrile/water
containing 0.1% trifluoroacetuic acid to give 4-amino-3-[3-(4-chloro-benzyloxy)-
phenoxymethyl]-thieno[3?2-c] pyridine-7-carboxylic acid (3-hydroxy-propyl)-amide
trifluoro-acetic acid salt. (Yield 9.0 mg5 17%).
HRMS (ES+) mfz Calcd for C25H24CIN3O4S + H [(M+H)4]: 498.1249. Found: 498.1248.
Example 55
4-Amino-3-[3-(4«chloro-phenoxymethyl)-phenoxymethyl]-thieno[3,2-c]pyridine"7-
carboxyiic acid ethyl ester


N?N-Diisopropylethylamine (19.2 mL, 110 mmol) (Aldrich) was added to a suspension of 3-hydroxybenzaldehyde (12.21 g, 100 mmol) (Aldrich) in dichloromethane (50 mL) with cooling in an ice-water bath. Chloromethylmethyl ether (15.19 mL, 200 mmol) (Aldrich) was then added dropwise and the mixture stirred at room temperature for 3 hours. The mixture was then washed with mixture of brine (30 mL) and water (30 mL), followed by 0.1 N HC1 (3 X 20 mL) and brine (2 X 20 mL). Aqueous layers were back washed with dichloromethane (30 mL). Organic solutions were combined, dried (MgSC>4), µLtered and concentrated. Residue was µLtered through silica gel (Biotage 40M) eluting with dichloromethane. Fractions were combined and concentrated to give 3-methoxymethoxy-benzaldehyde as pale yellow oil, (Yield 13.94 g, 83.9%).
Sodium borohydride (1.14 g, 30 mmol) (Aldrich) was added in small portions to a solution of 3-methoxymethyloxy-benzaldehyde (4.99 g, 30 mmol) in methanol (90 mL) and water (3 mL). Mixture was stirred for 3 hours at room temperature and then diluted with water (50 mL). Mixture was concentrated under reduced pressure and the resulting aqueous suspension extracted with ethyl acetate (2 X 75 mL). Organic layers were washed with water (50 mL) and brine (50 mL), and then combined, dried (MgS04), µLtered and concentrated to give crude (3-methoxymethoxy-phenyl)-methanol as a colorless oil. This was used in the next step without further purification. (Yield 5.04 gs 100%).
A neat mixture of (3-methoxymethoxy-phenyl)-methanol (1.68 g, 10 mmol), 4-chlorophenol (1.29 g, 10 mmol) (Aldrich) and N?N'-dicyclohexylcarbodiimide (2.06 g, 10 mmol) (Aldrich) was heated in a sealed tube at 100 °C for 24 hours. Sample was cooled to room temperature then triturated with ether. Dicyclohexylurea was removed by µLtration. µLtrate was washed with 1 N aqueous hydrochloric acid and brine. Aqueous layers were back washed with ether. Combined ether layers were dried (MgS04), µLtered and concentrated. Residue was µLtered through a Biotage flash cartridge (40S, eluting with dichloromethane) to give (4-chlorophenoxy-methyl)-3-methyloxymethoxy-benzene as a pale yellow oil (Yield 2.07 g, 74.3%).
To a solution of (4-chlorophenoxy-methyl)-3-methyloxymethoxy-ben2;ene (2.07 g, 7.43 mmol) in tetrahydrofuran / 2-propanol (1:1, 40 mL) was added 4M HC1 in dioxane (18.5 mL) (Aldrich). The reaction mixture was stirred at room temperature for 18 hours. The solution was concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous

sodium bicarbonate solution and brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to 3-(4-chloro-phenoxymethyl)-phenol. (Yield 1.72 g, 99%).
A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-(4-chloro-phenoxymethyI)-pbenol (0.25 g, 1.07 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:1.18 mL) was heated at 70 °C for 3 hours. 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, L02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgSO,*) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 4-chloro-3-[3-(4-cWoro-phenoxymethyl)-phenoxymethyl]-thieno[332-c]pyridine-7-carboxylicacid ethyl ester. (Yield 0.19 g, 38%).
Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(4-chloro-phenoxymethyl)-phenoxy-methyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.11 g, 0.23 mmol) in dioxane (20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[3-(4-chloro-phenoxymethyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield
0.087g, 79%).
HRMS (ES+) m/z Calcd for C24H21CIN2O4S + H [(M+H)+]: 469.0984. Found: 469.0984.
Example 56
4-Ammo-3-{3-[2-(4-cMoro-phenyl^

Sodium hydride (60% in oil, 1.0 g, 25 mmol) (Aldrich) was added in small portions to a solution of diethyl 4-chlorobenzylphosphonate (2.63 g, 1.0 mmol) (Alfa Aesar), catalytic

amount of 18-Crown-6 (Aldrich) and methanol (0.8 mL, 20 mmol) in dry DMF (15 mL). After stirring for 5 minutes, 3-methoxymethoxy-benzaldehyde (1.66 g, 10 mmol) in dry DMF (5 mL) was added and mixture was stirred at room temperature for 1 hour, then at 120 °C for 5 hours. After cooling to room temperature, mixture was diluted with water (100 mL) and extracted with ether (2 X 100 mL). Organic layers were washed with water and brine, dried (MgSC>4), µLtered and concentrated. Residue was purified by chromatography (Biotage 40M, 20%, then 40% dichloromethane in hexanes as solvent). Product was recrystallized from hexanes to give pure E-[2-(4-chloro»phenyl)-vinyl]-3-methyloxymethoxy-benzene as white crystalline plates. (Yield 2.74 g, 100%).
To a solution of E-[2-(4-chloro«phenyl)-vinyl]-3-methyloxymethoxy-benzene (2.22 g, 8.08 mmol) in tetrahydrofuran / 2-propanol (1:1, 40 mL) was added 4M HC1 in dioxane (15 mL) (Aldrich). The reaction mixture was stirred at room temperature for 18 hours. The solution was concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried (MgSO^O and concentrated. The residue was washed with hot dichloromethane and dried to give 3-[2-(4-chloro-phenyl)-vinyl]-phenol. (Yield 0.81 g, 44%).
A suspension of potassium carbonate (0.16 g, L17 mmol), 3-[2-(4-chloro-phenyl)-vinyl]-phenol (0.25 g, 1.07 mmol) in tetrahydrofuran / N,N»dimethylformamide (5:1, 18 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (034 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgSC>4) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 4-chloro-3-{3-[2-(4-cWoro-phenyl)-vmyl]-phenoxymethyl}-tWeno[3.2-c]pyridine-7-carboxy ethyl ester. (Yield 0.31 g, 63%).
Ammonia gas was bubbled into a solution of 4-chloro-3-{3-[2-(4-chloro-phenyl)-vinyl]-phenoxy-methyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.11 g, 0.23 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-{3-[(E)-2-(4-

cWoro-phenyI)-vmyl]-phenoxy^ acid ethyl ester.
(Yield 0.093 g, 96%).
HRMS (ES+) m/z Calcd for C25H2iClN203S + H [(M+H)*]: 465.1034, Found: 465.1034.
Example 57
4-Amino-3-{3-[2-(4-cMoro-phe^
carboxylic acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 56 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with ethyl acetate and dried to give 4-amino-3-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenoxy-methyl}-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)»amide as a white powder.
(Yield 36.0 mg, 69%).
HRMS (ES+) m/z Calcd for C25H22CIN3O3S + H [(M+H)*]: 480.1143. Found: 480.1144.
Example 58
4-Amino-3-[3-(4-cUoro-phenoxymelhyl)-phenoxymethyl]-1hieno[3?2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-[3-(4-cUoro-phenoxymethyl)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.11 mmol) (from Example 55 supra) in

dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot methanol and dried to give 4-amino-3-[3-(4-chloro-phenoxymethyl)-phenoxy-methyI]-thieno[3.2-c]pyridine-7-carboxylic acid (2~hydroxy-ethyI)-amide as a white solid. (Yield 25.8 mg, 50%). HRMS (ES+) m/z Calcd for C24H22CIN3O4S + H [(M+H)+]: 484.1093. Found: 484.1096.
Example 59
4-Amino-3-[3-(4-cWoro-phenylcarbamoyl)-phenoxymethyl]-tMeno[3?2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-methyl-amide
This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with 2-methylamino-ethanol. HRMS (ES+) m/z Calcd for C25H23CIN4O4S + Na [(M+Na)*]: 533.1021. Found: 533.1019,
Example 60
4-Amino-3-[3-(4-chloro-phepylcarbamoyl)-phenoxymethyl]-thieno[3?2»c]pyridine-7--
carboxylic acid (2-methoxy-ethyl)-amide


This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with 2-methoxy-ethylamine.
HRMS (ES+) m/z Calcd for C25H23CIN4O4S + Na [(M+Na)4]: 533.1021. Found: 533.1020.
Example 61
4-Ammo-3-[3-(4-cMoro-phenylcarba^
carboxylic acid methylamide

This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37 supra) following the procedure found in Example 27 supra and the resulting acid coupled with methylamine. HRMS (ES+) m/z Calcd for C23H19CIN4O3S + H [(M+H)*]: 467.0939. Found: 467.0941.
Example 62
3-[4-Amino-7-(morpholine-4-carbonyl)4hieno[3,2-c]pyridin-3-ylmethoxy]-N-(4-chloro-
phenyl)-benzamide

This was prepared by the hydrolysis of the corresponding ethyl ester (from Example 37
supra) following the procedure found in Example 27 supra and the resulting acid coupled
withmorpholine.
HRMS (ES+) m/z Calcd for C26H23CIN4O4S + H [(M+H)*]: 523.1202. Found: 523.1202.
HRMS (ES+) m/z Calcd for C26H23CIN4O4S + Na [(M+Na)*]: 545.1021. Found: 545.1022.

Example 63
4-Aimno-3 acid ethyl ester

This was prepared following the procedure found in Example 1 supra,
HRMS (ES+) m/z Calcd for C24H27N3O4S + H [(M+H)*]: 454.1795. Found: 454.1797.
Example 64
4- Amino-3 - [3 »(tetrahydro-pyran-4-ylcarbamoyl)-phenoxymethyl] -thieno [3,2-c]pyridine-7-

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C23H25N3O5S + H [(M+H)+]: 456.1588. Found: 456,1590.
Example 65
4-Amino-3-[3-(l-methanesulfonyl-piperidin-4-ylcarbamoyl)«phenoxymetiiyl]4hieno[3?2-


This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C24H29N506S2 + H [(M+H)*]: 548.1632. Found: 548.1636.
HRMS (ES+) m/z Calcd for C24H29N5O6S2 + Na [(M+Na)*]: 570.1451. Found: 570.1453.
Example 66
4-Amino-3-[3-( 1 -methyl-piperidin-4--ylcarbamoyl)-phenoxymethyl]-thieno[3 „2-c]pyridine-7-

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C24H29N5O4S + H [(M+H)+]: 484.2013. Found: 484.2012;
Example 67
4-Amino-3-(3-phenylaminomethyl-phenoxymethyl)-thieno[3?2-c]pyridine"7-carboxylic acid

A suspension of 3-acetoxybenzoic acid (1.80 g? 10 mmol) in a mixture of N5N-dimethylformamide (3 drops) and thionyl chloride (3 mL, 40 mmol) (Aldrich) was heated in a 90 °C bath for 2 hours. After cooling, mixture was diluted with toluene (20 mL) and concentrated under reduced pressure to remove excess thionyl chloride. The resulting oil was dissolved in dichloromethane (10 mL) and added dropwise to a solution of aniline (0.93 g, 10 mmol) (Aldrich), 4-dimethylamino-pyridine (0.1 g, 0.08 mmol) (Fluka) and KN-diisopropylethylamine (1,6 g, 12.4 mmol) (Aldrich) in dichloromethane (10 mL) with magnetic stirring. When addition was complete, mixture was stirred at room temperature for

an additional 2 hours. Reaction mixture was then partitioned between water (50 mL) and dichloromethane (2 X 50 mL). Organic layers were combined, and concentrated to dryness. Residue was dissolved in THF (10 mL), methanol (10 mL) and 1 N aqueous sodium hydroxide (10 mL) and stirred at room temperature for 16 hours. The yellow solution was diluted with water (100 mL) and acetic acid (5 mL) and extracted with ethyl acetate (2 X 100 mL). Ethyl acetate layers were washed with brine (100 mL), combined, dried (MgS04), and concentrated to give crude 3-hydroxy-N-phenyl-benzamide which was used in the next step without further purification. (Yield 2.20 g, 103%).
Lithium aluminum hydride solution (19 mL, 1M in tetrahydrofuran) (Aldrich) was added slowly to a suspension of the crude 3-hydroxy-N-phenyl-benzamide (2.0 g, 6.3 mmol) in dry tetrahydrofuran (30 mL) under an argon atmosphere with magnetic stirring with cooling in an ice - water bath (exothermic reaction). When addition was complete, mixture was heated at reflux for 1 hour. Reaction mixture was allowed to cool to room temperature and was quenched by pouring slowly into 15% aqueous ammonium chloride solution (100 mL) and ether (100 mL). After stirring thoroughly, mixture was diluted with ethyl acetate (100 mL) and µLtered through Celite. µLtercake was washed thoroughly with ethyl acetate. Combined µLtrate and washing was concentrated under reduced pressure. The resulting oil was purified by flash chromatography (Biotage 40M silica gel, 20% ethyl acetate in hexanes as solvent) to give 3-phenylaminomethyl-phenol an a colorless oil. (Yield L48 g, 73.5%). A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-phenylaminomethyl-phenol (0.21 g, 1.07 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:1,18 mL) was heated at 70 °C for 3 hours. 3"Bromomethyl"4-chloro-thieno[3,2-c]pyridme-7-carboxylic acid ethyl ester (034 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 4-chloro-3-(3-phenylaminomethyl-phenoxymethyl)-thieno[372-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.15g, 33%).
Ammonia gas was bubbled into a solution of 4-chloro-3-(3-phenylaminomethyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.15 g, 0.33 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a

sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The crude material was purified by HPLC eluting with acetonitrile / water to give to 4-amino-3-(3-phenylaminomethyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.030 g, 21%).
A solution of 4-amijio-3"(3-phenylaminomethyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.03 g, 0.07 mmol) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by HPLC eluting with acetonitrile / water to give to 4"amino-3-(3-phenylaininomethyl-phenoxymethyl)-thieno [3,2-c]pyridine~7-carboxylic acid (2-hydroxy~ethyl)-amide as a white solid. (Yield 13.0 mg, 33%). HRMS (ES+) m/z Calcd for C24H24N4O3S + H [(M+H)+]: 449.1642. Found: 449.1645.
Example 68 4-Amino-3 - {3 -[2~(4-chloro-phenyl)-ethoxy] -phenoxymethyl} -thieno [3,2-c]pyridine-7-

DEAD (2.0 g, 11.5 mmol) (Aldrich) was added to a stirred solution of triphenylphosphine (3.01 g, 11.5 mmol) (Aldrich) in tetrahydrofuran (80 mL) at room temperature. After stirring for 10 minutes, p-chlorophenethyl alcohol (L40 g, 8.9 mmol) (Aldrich) was added. After stirring for 10 minutes resorcinol (2.92 g, 26.55 mmol) (Aldrich) in tetrahydrofuran (20 mL) was added quickly and mixture stirred for another 18 hours. The reaction mixture was concentrate and the residue was purified by flash chromatography eluting with 20-40 % ethyl acetate in hexanes to give 3-[2-(4-chloro-phenyl)-ethoxy]-phenol. (Yield 1.44 g5 65%). A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-[2-(4-chloro-phenyl)-ethoxy}-phenol (0.27 g, 1.07 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:1,18 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, L02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic

phase was washed with water and brine, dried (MgSC>4) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 4-chloro-3-{3-[2-(4-cWoro-phenyl)-ethoxy]^ ethyl ester. (Yield 0.10 g5 20%).
Ammonia gas was bubbled into a solution of 4-chloro-3-{3-[2-(4-chloro-phenyl)-ethoxy]-phenoxy"methyl}-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.10 g, 0.20 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue Was washed with hot methanol, µLtered and dried to give 4-amino-3«{3-[2-(4-chloro-phenyl)-ethoxy]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.093 g, 96%). HRMS (ES+) mix Calcd for C25H23CIN2O4S + H [(M+H)+]: 483 J140. Found: 483.1143.

A solution of 4-amino-3-{3-[2-(4-chloro-phenyl)«ethoxy]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.04 g, 0.08 mmol) (from Example 68 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (L5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with ethyl acetate and methanol, dried to give 4"amino-3-{3-[2-(4»chloro^phenyl)-ethoxy]-phenoxy-methyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 28.0 mg, 70%). HRMS (ES+) m/z Calcd for C25H24CIN3O4S + H [(M+H)+]: 498.1249. Found: 498.1249.
Example 70

4-Amino-343-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3.2-c]pyri

A suspension of potassium carbonate (0.74 g, 5.39 mmol), 4-chloro-N-(3-hydroxy-phenyl)-benzamide (1.07 g, 4.30 mmol) (prepared by the reaction of excess 4-chlorobenzoyl chloride with 3-aminophenol and N?N-diisopropylethylamine followed by hydrolysis with 1 N sodium hydroxide) in tetrahydrofuran / N5N-dimethylformamide (5:2, 35 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (1.20 g5 3.59 mmol) (from Intermediate &supra) was added. Heating was continued for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was washed with hot dichloromethane and dried to give 4-chloro-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3?2-c]pyridine-7~carboxylic acid ethyl ester. (Yield 0.99 g, 55%). Ammonia gas was bubbled into a solution of 4-chloro-3"[3-(4-chloro-benzoylamino)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.28 g, 0.56 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyI]"thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.20 g, 74%). HRMS (ES+) m/z Calcd for C24H20CIN3O4S + H [(M+H)+]: 482.0936. Found: 482,0925.
Example 71
4-Amino-3-[3-(4-chloro-benzoylamino)-phenox^
acid (2-hydroxy-ethyl)-amide


A solution of 4"amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-tW 7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 70 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich)) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with ethyl acetate, dried to give 4"amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 21.0 mg, 40%). HRMS (ES+) mix Calcd for C24H21CIN4O4S + Na [(M+Na)*]: 519.0864. Found: 519.0858.
Example 72
4-Amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic
acid (3-hydroxy-propyl)-amide

A solution of 4-amino-3-[3«(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3 ?2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 70 supra) in dimethylsulfoxide (0.5 mL) was treated with 3-amino-l-propanol (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by CI 8 column chromatography eluting with acetonitrile / water to give 4-amino-3-[3-(4-chloro-benzoyl-amino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylicacid (3-hydroxy-propyl)-amide. (Yield 22.0 mg, 43%). HRMS (ES+) m/z Calcd for C25H23CIN4O4S + H [(M+H)+]: 511.1202. Found: 511.1195.

Example 72a
4-Amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[^

A solution of 4-amino-3-[3-(4-cUoro-beiizoyl-aixuno)-phenoxymethyl]-thieno[3;j2-c]pyridine-7-carboxylic acid (3-hydroxy-propyl)-amide (0.05 g, 0.10 mmol) (from Example 72 supra) in methanol (7.5 mL) was treated with 1M HC1 in diethyl ether (0.15 mL) and heated at 48 °C for 15 minutes. After cooling, diethyl ether (30 mL) was added. The solution was kept in a refrigerator overnight. The solid formed was µLtered and dried to give 4-amino-3-[3-(4-chloro-ben2oyl-amino)-phenoxymethyl]-thieno[3?2-c]pyridine-7«carboxylic acid (3-hydroxy-propyl)-amide hydrochloride. (Yield 52.0 mg, 96%). HRMS (ES+) m/z Calcd for C25H23CIN4O4S + H [(M+H)*]: 511.1202. Found: 511.1203.
Example 72b
4-Amino-3-[3-(4~cWoro-benzoylamino)-phenoxym
acid (3-hydroxy-propyl)-amide toluene-4-sulfonic acid salt

M.W. 511.003 + 172.204 C25H23CIN4O4S • C7Hg03S
A solution of 4-amino-3-[3"(4-chloro-benzoyl-amino)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (3-hydroxy-propyl)-amide (0.05 g, 0.10 mmol) (from Example 72 supra) in methanol (6 mL) was treated with toluene-4-sulfonic acid hydrate (18.6 mg,

0.10 mmol) (Aldrich) and heated at 40 °C for 30 minutes. The solution was concentrated.
The residue was washed with diethyl ether, dissolved in water and lyophilized to give 4-
amino-3-[3-(4-chloro-benzoyl-amino)-phenoxymeto^
acid (3-hydroxy-propyI)-amide, toluene-4-sulfonic acid salt (Yield 67.0 mg, 100%).
HRMS (ES+) m/z Calcd for C25H23CIN4O4S + H [(M+H)+]: 511.1202. Found: 511.1202.
Example 73
4-Amino-3-(2-oxo-1 -phenethyl-1 s2-dihydro-pyrimidin-4-yloxymethyl)-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra,
HRMS (ES+) m/z Calcd for C23H22N4O4S + H [(M+H)+]: 451.1435. Found: 451.1434.
Example 74
4-Amino-3-(2,6-dioxo-3-phenethyl-3,6-dihydro^^

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C^H^C^S + H [(M+H)*]: 451.1435. Found: 451.1434.



0.10 mmol) (Aldrich) and heated at 40 °C for 30 minutes. The solution was concentrated.
The residue was washed with diethyl ether, dissolved in water and lyophilized to give 4-
anuno-3-[3-(4-cMoro-benzoyl-amino)-ph
acid (3-hydroxy-propyI)-amide, toluene-4-sulfonic acid salt. (Yield 67.0 mg, 100%).
HRMS (ES4) m/z Calcd for C25H23CIN4O4S + H [(M+H)+]: 511.1202. Found: 511.1202.
Example 73
4-Amino-3-(2-oxo-1 -phenethyl-1,2-dihydro-pyrimidin-4-yloxymethyl)-thieno[3,2-
c]pyridine-7«carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C23H22N4O4S + H [(M+H)+]: 451.1435. Found: 451.1434.
Example 74
4-Amino-3-(2?6-dioxo-3-phene1hyl-3?6-dihydro-2H-pyriniidin-1 -ylmethyl>thieno[3.,2-
c]pyridine-7-carboxylic acid ethyl ester

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C23H22N4O4S + H [(M+H)4]: 451.1435. Found: 451,1434.









Example 86
4-Amino-342-methyl-3-(5-m^
c]pyridine-7-carboxylic acid ethyl ester

This was prepared following General Procedure 4 supra.
Example 87
4-Anaino-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxymethyl}"thieno[3,2-c]pyridine-7-

To a solution of 3-[2-(4-chloro-phenyl)-vinyl]-phenol (035 g, 1.52 mmol) (from Example 56 supra) in methanol (20 mL) was treated with 10% Pd/C (0.04 g) (Aldrich). The reaction mixture was hydrogenated for 6 hours. The reaction mixture was passed through Celite and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 3-[2-(4-chlorophenyl)-ethyl]-phenol. (Yield 0.33 g5 94%).
A suspension of potassium carbonate (0.16 g, 1.17 mmol), 3-[2-(4-chlorophenyl)-ethyl]-phenol (0.25 g, 1.07 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:1, 18 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3?2"C]pyridine-7-carboxylic acid ethyl ester (0.34 g, L02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic

phase was washed with water and brine, dried (MgS04> and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give 4-chloro-3 - {3 42-(4-chloro-pheny l)-e1hyl] ^
ethyl ester. (Yield 0.13 g, 26%).
Ammonia gas was bubbled into a solution of 4-chloro-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxy-methyl}"thieno[392'C]pyridine«7-carboxylic acid ethyl ester (0.13 g, 0.27 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-Amino-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.08 g, 67%). HRMS (ES+) m/z Calcd for C25H23CIN2O3S + H [(M+H)*]: 467.1191. Found: 467.1192.
Example 88
4-Amino-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxymethyl}-thieno[352-c]pyridine-7-

A solution of 4-amino-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxymethyl}-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.05 gs 0.11 mmol) (from Example 87 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate formed was µLtered and washed with hot methanol and dried to give 4-amino-3-{3-[2-(4-chloro-phenyl)-ethyl]-phenoxymethyl}-thieno[352-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 31.6 mg? 61%). HRMS (ES+) m/z Calcd for C25H24CIN3O3S + H [(M+H)4"]: 482.1300. Found: 482.1302.

Example 89
4-Amino-345-(4-cMoro-phenyk
7-carboxylic acid ethyl ester

A suspension of 3-hydroxy-4-methylbenzoic acid (10,73 g, 70.5 mmol) (Lancaster) in acetic anhydride (25 mL, 265 mmol) (Aldrich) was heated at reflux for 5 hours. After cooling to toom temperature, mixture was poured into ice - water mixture (600 mL) and stirred overnight. Solid clumps were broken up and collected by µLtration. Residue was washed with water and dried in vacuum oven to give 3-acetoxy-4-methyl-benzoic acid as a tan solid. (Yield 11.82 g, 86,3%).
3-Acetoxy-4-methyl-benzoic acid (1.94 g, 10 mmol) was suspended in thionylchloride (3 mL, 40 mmol) (Aldrich) and N,N-dimethyl-formamide (3 drops) and heated at reflux for 2 hours. After cooling to room temperature, mixture was diluted with toluene (30 mL) and concentrated under reduced pressure. Resulting oil was dissolved in dichloromethane (30 mL) and added dropwise to a solution of 4-chloroaniline (1.34 g,10,5 mmol) (Aldrich) and N5N-diisopropylethylamine (1.6 g312.5 mmol) in dichloromethane (50 mL). After stirring for another 2 hours, mixture was diluted with water (50 mL) and stirred for another 30 minutes. Layers were separated. Organic layer was washed with water (50 mL). Aqueous layers were back washed with dichloromethane (50 mL). Organic layers were then combined and concentrated. Residue was dissolved in mixture of tetrahydrofuran (25 mL), methanol (25 mL) and 1 N aqueous sodium hydroxide (10 mL, 10 mmol). After stirring for 16 hours, mixture was diluted with water (100 mL) and acetic acid (5 mL) and concnetrated under reduced pressure to remove most of the organic solvent. Precipitate formed was collected by µLtration and washed with water, and dried to give N-(4-chloro-phenyl)-3-hydroxy-4-methyl-benzamide as off-white crystals. (Yield 2.57 g, 98.2%).

A suspension of potassium carbonate (0.21 g, 1,53 mmol), N-(4-chloro-phenyl)-3-hydroxy-4-methyl-benzamide (0.32 g, 1.22 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:2, 21 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4"Chloro-thieno[3?2«c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was washed with hot dichloromethane and dried to give 4-chloro-3-[5-(4-chloro-phenylcarbamoyl)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.23 g, 43%).
Ammonia gas was bubbled into a solution of 4-cMoro-345-(4-cMoro-phenylcarbamoyl)-2-
methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-c^ acid ethyl ester (0.23 g, 0.45
mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was
heated in a sealed pressure vessel at 160 °C for lday. The reaction mixture was concentrated.
The residue was purified by CI8 column chromatography eluting with acetonitrile / water to
give4-amino~3-[5-(4-cMoro-phenylcarbam
c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.08 g, 36%). HRMS (ES4) m/z Calcd for CssH^ClNsC^S + H [(M+H)+]: 496.1093. Found: 496.1094.
Example 90
4-Amino-3-[5-(4-cMoro-phenylcarbamoyl)^

A solution of 4-amino-3-[5-(4-chloro-phenylcarbamoyl>2-methyl-phenoxymethyl]-thieno[3r2-c] pyridine-7~carboxylic acid ethyl ester (0.05 g, 0,10 mmol) (from Example 89 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and

heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by
CI 8 column chromatography eluting with acetonitrile / water to give 4-amino-3-[5-(4-chloro-
phenyl-carbamoyl)-2-methyl-phenoxymethyl]-tfo^
hydroxy-ethyl)-amide as a white powder. (Yield 25.0 mg, 48%).
HRMS (ES+) m/z Calcd for C25H23CIN4O4S + Na [(M+Na)+]: 533.1021. Found: 533.1025.
Example 91
4-Ammo-3-[5-(4-cWoro-benzoylamino)-2-m

A solution of p-chlorobenzoyl chloride (19.25 g, 110 mmol) (Aldrich) in tetrahydrofuran (50 mL) was added to a solution of 5-amino-o-cresol (6.16 g, 50 mmol) (Aldrich) and triethylamine (17.5 mLs 125 mmol) (Aldrich) and THF (100 mL) dropwise with magnetic stirring and cooling in an ice - water bath. When addition was complete, mixture was allowed to warm to room temperature and stirred for 16 hours. Reaction mixtrue was diluted with water (400 mL). After stirring for another 30 minutes, precipitate was collected to give crude 4-chloro-benzoic acid 5-(4-cWoro-benzoylamino)-2-methyl-phenyl ester as an off-white powder. (Yield 21.24 g, 106%).
4-Chloro-benzoic acid 5-(4-chloro-benzoylamino)-2-methyl-phenyl ester (4.04 g, 10 mmol) was dissolved in a mixture of tetrahydrofuran (25 mL, methanol (50 mL) and aqueous IN sodium hydroxide (10 mL, 10 mmol). Mixture was stirred at room temperature for 18 hours. Mixture was concentrated under reduced pressure to remove most of the organic solvent. Resulting suspension was diluted with water (100 mL) and saturated aqueous sodium bicarbonate solution (5 mL). After standing for 30 minutes, precipitate was collected and washer with water and dried to give 4-chloro-N-(3-hydroxy-4»methyl-phenyl)-benzamide as a white powder. (Yield 2.46 g, 93.1%).

A suspension of potassium carbonate (0.21 g, 1.53 mmoI)? 4-cWoro-N-(3-hydroxy-4-methyl-pheny])-benzamide (0.32 g, 1.22 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:2, 21 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine«7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was washed with hot dichloromethane and dried to give 4-chloro-3-[5-(4-chloro-benzoylamino)-2-methyl-phenoxymethyl]-tWeno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.1 Og, 19%).
Ammonia gas was bubbled into a solution of 4-chloro-3-[5-(4-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.10 g, 0.19 mmol) in a mixture of 2-propanol / dioxane (1:1, 20 mL) for 20 minutes. The mixture was heated in a sealed pressure vessel at 160 °C for 1 day. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3"[5-(4-cUorO"benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c] pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 95.0 mg, 99%), HRMS (ES+) m/z Calcd for C25H22CIN3O4S + H [(M+H)+]: 496.1093. Found: 496.1092.
Example 92
4-Ammo-345-(4-cWoro-benzoylamino)-2-mefo^

A solution of 4-amino-3-[5-(4-cUoro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3?2-c] pyridine-7-carboxylic acid ethyl ester (0.05 g; 0.10 mmol) (from Example 91 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) and heated at 160 °C for

2 hours in a microwave reactor. The reaction mixture was purified by CI8 column chromatography eluting with acetonitrile / water to give 4-amino-3-[5-(4~chloro-benzoyl-amino)-2-methyl-phenoxymethyl]-thieno[3?2-c]pyridine~7-carboxylic acid (2-hydroxy-ethyl)-amide. (Yield 34.0 mg, 65%). HRMS (ES+) m/z Calcd for C25H23CIN4O4S + H [(M+H)+]: 511.1202. Found: 511.1202.
Example^
4-Aimno-3-[3-(4-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-c^

This was prepared following the procedure found in Example 1 supra. HRMS (ES+) m/z Calcd for C24H20FN3O4S + H [(M+H)*]: 466.12322. Found: 466.1231.
Example 94 4-Amino-3-[5-(4-chloro-2-methyI-phenylcarbamoyl)-2-methoxy-phenoxymethyI]-

This was prepared following General Procedure 4 supra.
Example 95
4-Amino-3-[3-(5-chloro-2-methoxy-phenylcarbamoyl)-2-methyl-phenoxymethyl]-
thieno[3,2"C]pyridine-7-carboxyIic acid ethyl ester









HRMS (ES+) m/z Calcd for C23H2oClN504S + H [(M+H)+]: 498.0998. Found: 498.1000.
Example 103
4-Amiiio-3-(5-pheny]carbam^

This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C23H21N5O4S + H [(M+H)+]: 464.1387. Found: 464.1390.
Example 104a
4-Amino-3-[3-(4-cMoro-benzoylammo
acid (4-pyrrolidin-l-yl-butyl)-amide trifluoro-acetic acid salt

MW. 578.138+114.024 C3oH32ClN503S-C2HF302
A mixture of 4-amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (0.15 g, 0.13 mmol) (from Example 151 infra), 1-hydroxybenzotriazole hydrate (71 mg5 0.56 mmol) (Aldrich) and l?3^diisopropylcarbodiimide (0.077 mL, 0.50 mmol) (Aldrich) were combined in tetrahydrofuran : N,N-dimethylformamide (9.0 mL, 5:1) with stirring. After 1 hour, 4-pyrroIidinobutylamine (0.14 g, 1.04 mmol) (Aldrich) was added. The mixture was stirred at room temperature for 3 days and then concentrated. The residue was purified by HPLC eluting with acetonitrile / water containing 0.1% trifluoroacetic acid to give 4-amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3.2-c]pyridine-7-carboxyIic acid (4-pyrrolidin-l-yl-butyl)-amide5 trifluoroacetic acid salt as a white powder. (Yield 0.16 g5 67%).

HRMS (ES+) m/z Calcd for C30H32CIN5O3S + H [(M+H)*]: 578.1987. Found: 578.1982.
Example 104b
4-Amino-3-[3-(4H±loro4>enzoylamino)-phenox
acid (4-pyrrolidin-l-yl-butyl)-amide toluene-4-sulfonic acid salt

To a solution of 4-amino-3-[3-(4-cMoro-benzoylamino)-phenoxymethyl]«thieno[3?2-c]pyridine-7-carboxylic acid (4-pyrrolidin-l-yl-butyl)-amide (0.047 g, 0.08 mmol) (from Example 104a supra) in methanol (6 mL) was treated with toluene-4-sulfonic acid hydrate (18.6 mg5 0.10 mmol) (Aldrich) and heated at 40 °C for 30 minutes. The solution was concentrated. The residue was washed with diethyl ether, dissolved in water and lyophilized togive4-amino-3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (4-pyrrolidin-l-yl-butyl)-amide toluene-4-sulfonic acid salt as a white powder. (Yield 60.0 mg, 100%). HRMS (ES+) m/z Calcd for C30H32CIN5O3S + H [(M+H)+]: 578.1987. Found: 578.1984.
Example 105
4-Amino-3-[5-(4-cUoro-benzyloxy)-2-methyl»phenoxyme1hyl]-tMeno[3?2-c]pyridine-7-

A mixture of 2,4-dihydroxybenzaldehyde (6.62 g, 48 mmol) (Fluka), potassium fluoride (5.57 g, 96 mmol) (Aldrich) and 4-chlorobenzyl chloride (13.50 g, 84 mmol) (Aldrich) in

acetonitrile (50 mL) was heated at 90 °C for 24 hours. After cooling, mixture was partitioned between ether (2 X 100 mL) and water (2 X 100 mL). Organic layers were washed with brine (100 mL)5 combined, dried (MgS04)? µLtered and concentrated. Residue was purified by flash chromatography (Biotage 75S, hexanes, then hexanes - dichloromethane 1:1 as solvent) gave partial separation. Pure fractions of product were combined and concentrated and residue crystallized from hexanes with traces of dichloromethane to give 4-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde as white crystals. (Yield 4.74 g, 37.6%). Mother liquor and impure fractions were combined and further purified by flash chromatography (Biotage 40L, same solvent as before) and pure fractions combined and concentrated. Residue re-crystallized to give second crop of 4-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde. (Yield 3.03 g, 24.1%).
To a solution of 4-(4-chloro-benzyloxy)-2-hydroxybenzaldehyde (1.31 g, 5.0 mmol) and sodium cyanoborohydride (1.0 g, 15.9 mmol) (Aldrich) in tetrahydrofiiran (30 mL) was added methyl orange as an indictor, giving the solution a yellow color; IN aqueous HC1 solution (7.5 mL) was added slowly, keeping the solution orange. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate three times. The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with 0 - 40% ethyl acetate in hexanes to give 5-(4-chloro-benzyloxy)»2-methyl-phenol. (Yield 0.43 g,35%).
A suspension of potassium carbonate (0.33 g, 2.36 mmol), 5-(4-chloro-benzyloxy)-2-methyl-phenol (0.43 g, 1.73 mmol) in tetrahydrofiiran / N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.53 g, 1.57 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (MgS^) and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 4-chloro-3-[5-(4-chloro-benzyloxy)-2-methyl-phenoxymethyl]-tMeno[372-c]pyridine-7-carboxylicacid ethyl ester. (Yield 0.37 g, 47%).

Ammonia gas was bubbled into a solution of 4-chloro-3-[5-(4-chloro-benzyloxy)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.21 g, 0.29 mmol) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140 °C for 2 hours. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[5-(4-chloro-benzyloxy)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.18 g, 90%). HRMS (ES+) m/z Calcd for C25H23CIN2O4S + H [(M+H)+]: 483.1140. Found: 483.1143.
Example 106
4-Amino-3-[3-(4~fluoro-benzyloxy)-phenoxymeft^
ethyl ester

This was prepared following General Procedure 7 supra.
LRMS (ES*) m/z Calcd for C24H21FN2O4S + H [(M+H)+]: 453. Found: 453.
Example 107
4-Amino-3-[3-(4-methyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic
acid ethyl ester

This was prepared following General Procedure 7 supra. LRMS (ES+) m/z Calcd for C25H24N2O4 + H [(M+H)*]: 449. Found: 449.
Intermediate 47





LRMS (ES+) m/z Calcd for C24H20F2N2O4S + H [(M+H)*]: 471. Found: 471.
Example 110
4-Amino-3-[5-(4-chloro-benzyloxy)-2-m

A solution of 4-amino-3-[5-(4-cWoro-benzyloxy)-2-me1hyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 105 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by CI 8 column chromatography eluting with acetonitrile / water to give to 4-amino-3-[5-(4-chloro-benzyloxy)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 28 mg, 54%). HRMS (ES+) m/z Calcd for C25H24CIN3O4S + H [(M+H)*]: 498.1249. Found: 498.1248.
Example 111
4-Amino-3-(5-benzyloxy-2-methyl-phenoxymetiiyl)-lWeno[3?2-c]pyridine-7"Carboxylic acid

To a solution of 4-benzyloxy-2-hydroxybenzaldehyde (2.28 g, 10.0 mmol) (prepared by the method of Example 105 supra) and sodium cyanoborohydride (2.0 g, 15.9 mmol) in tetrahydrofuran (60 mL) was added methyl orange as an indictor, giving the solution a yellow color; IN aqueous HC1 solution (15 mL) was added slowly, keeping the solution orange. The mixture was stirred overnight at room temperature. Water was added, and the

mixture was extracted with ethyl acetate three times. The combined organic phase was washed with water and brine, dried (MgSC>4) and concentrated. The residue was purified by flash chromatography eluting with 0 - 40% ethyl acetate in hexanes to 5-benzyloxy-2-methyl-phenol (Yield 0.64 g, 30%),
A suspension of potassium carbonate (0.16 g, LI 7 mmol), 5-benzyloxy-2-methyl-phenol (0.23 g, 1.07 mmol) in tetrahydrofiiran / N,N-dimethylformamide (5:2; 14 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with 10 - 20% ethyl acetate in hexanes to give 3-(5-benzyloxy-2-methyl-phenoxymethyl)-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.17 g, 35%).
Ammonia gas was bubbled into a solution of 3-(5-benzyloxy-2-methyl-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.17 g, 0.36 mmol) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140 °C for 2 hours. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-(5-ben2yloxy-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0*07 g, 44%). HRMS (ES+) m/z Calcd for C25H24N2O4S + H [(M+H)+]: 449.1530. Found: 449.1529.
Example 112
4-Amino-3-(5-benzyloxy-2-me1hyLphenoxymethyl)"thieno[3,2-c]pyridine-7-carboxylic


A solution of 4-ammo-3-(5-benzyloxy-2-methyl^
carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 111 supra) in
dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at
160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by CI 8
column chromatography eluting with acetonitile / water to give to 4-amino-3-(5-benzyloxy-
2-methyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylicacid (2-hydroxy-ethyl)-amide
as a white powder. (Yield 27 mg, 52%).
HRMS (ES+) m/z Calcd for C25H25N3O4S + H [(M+H)*]: 464.1639. Found: 464.1642.
Example 113
4-Anuno-3-(5-benzoylamino-2-methyl-phenoxymethyl)-tlueno[3,2-c]pyridine"7-carboxylic

A solution of benzoyl chloride (7.75 g, 55 mmol) (Aldrich) in tetrahydrofuran (25 mL) was added to a solution of 5-amino-o-cresol (3.08 g, 25 mmol) (Aldrich) and triethylamine (8.8 mL, 62.5 mmol) (Aldrich) and THF (50 mL) dropwise with magnetic stirring. When addition was complete, mixture was allowed to warm to room temperature and stirred for 4 hours. Reaction mixtrue was diluted with water (400 mL). After stirring for another 30 minutes, precipitate was collected. This material was dissolved in a mixture of THF (120 mL), methanol (40 mL) and 1 N aqueous sodium hydroxide solution (25 mL, 25 mmol) and stirred at room temperature for 16 hours. Mixture was then diluted with water (100 mL) and concentrated under reduced pressure to remove organic solvent. Precipitate formed was collected and washed with water and dried to give N-(3-hydroxy-4-methyl-phenyl)-benzamide as an off white powder. (Yield 2.14 g, 37.7%). Further concentrating and on standing a second crop of N-(3-hydroxy«4-methyl-phenyl)-benzamide was formed. (Yield 3.66 g5 64.4%).

A suspension of potassium carbonate (0.16 g, 1.17 mmol), N-(3-hydroxy-4-methyl-phenyl)-benzamide (0.24 g, 1.07 mmol) in tetrahydrofuran / N?N»dimethylformamide (5:2, 14 mLl) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgSC>4) and concentrated. The residue was purified by flash chromatography eluting with 0 - 20% ethyl acetate in hexanes togive3«(5-benzoylamino-2-methyl-phenoxymethyl)^-chloro-tWeno[3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.12 g, 24%).
Ammonia gas was bubbled into a solution of 3-(5-benzoylamino-2«methyl-phenoxymethyl)-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.21 g, 0.44 mmol) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in microwave at 140 °C for 2 hours. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-(5-benzoylamino-2-methy]-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.12 g, 60%). HRMS (ES+) m/z Calcd for C25H23N3O4S + H [(M+H)4]: 462.1482. Found: 462.1483.
Example 114
4-Ajmno-3-(5-benzoylammo-2-methyl-pte
acid (2-hydroxy-ethyl)-amide

A solution of 4-amino-3-(5-benzoylamino-2-methy]-phenoxyme11iyl)-thieno[3,2-c]pyridme-7-carboxylic acid ethyl ester (0.05 g? 0.11 mmol) (from Example 113 supra) in dimethylsulfoxide (0,5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by CI 8

column chromatography eluting with acetonitrile / water to give 4-amino«3-(5-benzoylamino-2-methyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 23.0 mg, 44%). HRMS (ES+) m/z Calcd for C25H24N4O4S + Na [(M+Na)4]: 499.1410. Found: 499.1411.
Intermediate 51
4-CWoro-3-[3-(3?5-difluoro-benzyloxy)-5-m^
carboxylic acid ethyl ester

This was prepared following General Procedure 6 supra.
LRMS (ES+) m/z Calcd for C25H20CIF2NO4S + H [(M+H)4]: 504. Found: 504.
Intermediate 52
4-CWoro-3-[3 carboxylic acid ethyl ester

This was prepared following General Procedure 6 supra.
LRMS (ES+) m/z Calcd for C25H2oClF2N04S + H [(M+H)*]: 504. Found: 504.























This was prepared following General Procedure 7 supra,
LRMS (ES+) m/z Calcd for C25H24N2O5S + H [(M+H)+]: 465. Found: 465.
Example 131
4-Amino-3- {3-[3
N,N-Diisopropylethylamine (15.51 g, 120 mmol) (Aldrich) was added to a suspension of 3-nitrophenol (13.91 g, 100 mmol) (Aldrich) in dichloromethane (50 mL) with cooling in an ice-water bath. Chloromethylmethyl ether (15.19 mL, 200 mmol) (Aldrich) was then added dropwise and the mixture stirred at room temperature for 3 hours. The mixture was then washed with mixture of brine (30 mL) and water (30 mL), followed by 0.1 N HC1 (3 X 20 mL) and brine (2 X 20 mL). Aqueous layers were back washed with dichloromethane (30 mL)t Organic solutions were combined, dried (MgS04), µLtered and concentrated. Residue was µLtered through silica gel (Biotage 40M) eluting with dichloromethnae. Fractions were combined and concentrated to give methoxymethoxy-3-nitro-benzene as pale yellow oil. (Yield 17,15 g, 93.6%).
To a solution of methoxymethoxy-3-nitro-benzene (5.06 g, 27.6 mmol) in methanol (50 mLl) was added 10% Pd/C (0.5 g) (Aldrich). The mixture was hydrogenated overnight. The mixture was passed through Celite and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 3-methoxymethoxy-phenylamine. (Yield 3.45 g, 15%).
To a solution of methyl-3-hydroxybenzoate (3.04 g, 20.0 mmol) in dimethylformamide (60mL) were added 4-(2-chloroethyl)morpholine (5.58 g, 30.0 mmol) (Aldrich) and potassium carbonate (8.30 g, 60.0 mmol). The mixture was heated at 80 °C for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and

brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with 10% methanol in dichloromethane to give 3-(2-morpholin-4-yl-ethoxy)-benzoic acid methyl ester. (Yield 5.63 g, 100%).
An aqueous solution of sodium hydroxide (IN, 32.0 mL, 32 mmol) was added to a solution 3-(2-moipholin-4-yl-ethoxy)-benzoic acid methyl ester (5.31 g, 20.0 mmol) in methanol (20 mL) and the mixture was heated at reflux for 18 hours. The reaction mixture was concentrated and azeotroped with toluene. The solid residue was washed with diethyl ether. The solid was dissolved in water and treated with hydrochloric acid (2.5N) to pH 2. The aqueous solution was concentrated, then dissolved in dichloromethane and µLtered. The solution was concentrated to give 3-(2-morpholin-4-yl-ethoxy)-benzoic acid. (Yield 1.05 g, 21%).
To a mixture of 3-(2-morpholin-4-yl-ethoxy)-benzoic acid (1.05 g, 4.18 mmol), HBTU (1.90 g, 5.01 mmol) (Oakwood) and diisopropylethylamine (1.82 mL, 10.45 mmol) inN,N-dimethylformamide (15.0 mL) was added 3-methoxymethoxy-phenylamine (0.77 g. 5.01 mmol). The mixture was stirred at room temperature for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (MgS04) and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate to give N-(3-methoxymethoxy-phenyl)-3«(2-morpholin-4-yl-ethoxy)-benzamide. (Yield 0.39 g, 24%).
To a solution of N-(3-methoxymethoxy-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide (0.39 g, 1.0 mmol) in tetrahydrofuran / 2-propanol (1:1,10 mL) was added 4M HC1 in dioxane (2 mL) (Aldrich). The reaction mixture was stirred at room temperature for 18 hours. The solution was concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried (MgSC^) and concentrated. The residue was purified by CI8 column chromatography eluting with acetonitrile / water to give N-(3-hydroxy-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide. (Yield 0.20 g, 57%). A suspension of cesium carbonate (0.20 g, 0.61 mmol), N-(3-hydroxy-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide (0.14 g, 0.41 mmol) in tetrahydrofuran / N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thieno[3?2'C]pyridine-7-carboxylic acid ethyl ester (0.14 g, 0.41 mmol) (from Intermediate 8 supra) was added. Heating was continued for 2 days. The reaction mixture

was partitioned between ethyl acetate and water. The aqueous phase was concentrated. The
residue was purified by CI 8 column chromatography eluting with acetonitrile / water to give
4-cWoro-3-{3-[3-(2-morpholm-^
c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.13 g, 54%).
Ammonia gas was bubbled into a solution of 4-chloro-3-{3-[3-(2-morpholin-4-yl-ethoxy)-
benzoylamino]»phenoxymethyl}-thieno[3T2-c]pyridine-7-carboxylic acid ethyl ester (0.13 g7
0,44 mmol) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in microwave at
140 °C for 4 hours. The reaction mixture was concentrated. The residue was washed with
hot methanol, µLtered and dried to give 4-amino-3-{3-[3-(2-morpholin-4-yl-ethoxy)-
benzoylamino]-phenoxymethyl}-thieno [3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield
0.05 g, 38%).
A solution of 4-amino-3- {3-[3-(2-morpholin-4-yl-ethoxy)-benzoylamino]-phenoxymethyl} -
thieno [3,2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.09 mmol) in dimethylsulfoxide
(0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich)) and heated at 160 °C for 2 hours
in a microwave reactor. The reaction mixture was purified by CI 8 column chromatography
eluting with acetonitrle / water to give 4-amino-3-{3-[3-(2-morpholin«4-yl-ethoxy)-
benzoylamino]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-
amide as a white powder. (Yield 20.0 mg, 39%).
HRMS (ES+) m/z Calcd for C3oH33N506S + H [(M+H)+j: 592.2225. Found: 592.2220,
Example 132
4-Amino-3-(3 -methylcarbamoyl-phenoxymethyl)-thieno[3 ,2-c]pyridine-7-carboxylic acid

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for C19H19N3O4S + H [(M+H)+]: 386.1169, Found: 386.1170.
Example 133





This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C2]H22N404S + H [(M+H)+J: 427.1435. Found: 427.1437.
HRMS (ES+) m/z Calcd for C21H22N4O4S + Na [(M+Na)+]: 449.1254. Found: 449.1257.
Eumpfel39
4-Arnmo-3-(3-cyclopentylcarbamoyl-phenoxymethyl)-tWeno[3,2-c]pyridine-7-carboxylic

M.W. 454.552 C23H26N4O4S
This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C23H26N404S + H [(M+H)+]: 455.1748. Found: 455.1752.
Example 140
4-Amino-3-(5-memylcarbamoyl-pyridin-3-yloxymethyl)-thieno[3,2-c]pyridine-7-carboxylic

This was prepared following the procedure found in Example 1 supra.
HRMS (ES+) m/z Calcd for Ci8HlgN404S + H [(M+H)+]: 387.1122. Found: 387.1122.
Example 141








This was prepared following General Procedure 8 supra.
LRMS m/z Calcd for C25H23F2N3O4S + H [(M+H)4]: 500. Found: 500.
Example 150
4-Amino-3-[3-(23-difluoro-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7^

This was prepared following General Procedure 8 supra.
LRMS m/z Calcd for C24H21F2N3O4S + H [(M+H)"*]: 486. Found: 486.
Example 151
4-Amino-343-(4-chloro-benzoylamino)-phenoxymeft^
acid

An aqueous solution of sodium hydroxide (1 N, 1.0 mL, L0 mmol) was added to a solution of 4-ammo-3-[3-(4-cWoro-benzoylamino)-ph
carboxylic acid ethyl ester (0.16 g, 0.33 mmol) (from Example 70 supra) in tetrahydrofuran -methanol (8 mL, 3:1) and the mixture was heated at 40 °C for 2 days. The reaction mixture

was concentrated and azeotroped with toluene. The solid residue was washed with hot ethyl acetate. The solid was then suspended in water and treated with hydrochloric acid (1 N, 2 mL). After stirring 30 minutes, the solid was collected, washed with water and then diethyl ether and dried to give 4-amino-3-[3-(4-cUoro-benzoylamino)-phenox)'methyl]-thieno[3?2-c]pyridine-7-carboxylic acid. (Yield 0,15 g, 100%).
Example 152
4-Amino-3-[3-(pyrimidm-5-ylmethoxy)-phe
acid ethyl ester
RO5066450-000 37010-93,5 M.W. 436.493 C22H20N4O4S
This was prepared following the procedure found in Example 1 supra,
HRMS (ES+) m/z Calcd for C22H20N4O4S + H [(M+H)+]: 437.1278. Found: 437.1278.
Example 153
4-Amino-343-(pyrimidin-5-ylmetto

RO5066451-000 37010-95-1 M.W. 451.508 C22H21N5O4S
This was prepared following the procedure found in Example 3 supra.
HRMS (ES+) m/z Calcd for C22H21N5O4S + H [(M+H)+]: 452.1387. Found: 452.1385.
Intermediate 67
4-Chloro-3-(3-m1ro-phenoxyme1hyl)-thieno[3,2-c]pyridine«7-carboxylic acid ethyl ester


A mixture of 3-nitrophenol (457 mg, 3,29 mmol) (Aldrich) and potassium carbonate powder (498 mg, 3.60 mmol) in dry THF (10 mL) and DMF (5 mL) was stirred at 50 °C for 15 minutes before a solution of 3-bromomethyl-4-chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (1.00 g? 2.99 mmol) (from Intermediate 8 supra) in THF (10 mL) was added. The reaction was stirred at 50 °C for 3 hours and the resulting mixture was concentrated to remove most of the solvent. The residue was dissolved in EtOAc (200 mL), washed with water (2 x 25 mL) and brine (25 mL), dried (Na2S04)9 µLtered and concentrated. The crude product was purified by column chromatography (CH2CI2 / MeOH, 98/2 to 90/10) to give 4-chloro-3-(3«nitro-phenoxymethyl)-thieno[3T!2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 911 mg, 78%). HRMS (ES+) m/z Calcd for C17H13CIN2O5S + H [(M+H)*]: 393.0307. Found: 393.0308.
Intermediate 68
3-(3-Amino-phenoxymethyl)-4-chloro-thieno[3,2»c]pyridine-7-carboxylic acid ethyl ester

RO5134429-000 37304-92A M.W. 362.838 C17H15CIN2O3S
To a solution of 4-chloro-3"(3-nitro-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (503.6 mg, L28 mmol) (from Intermediate 67 supra) in THF (175 mL) was added 10% Pd/C (253 mg) (Aldrich) and the mixture was stirred in an atmosphere of hydrogen (40 psi) for 4 hours. The Pd/C was µLtered off and the µLtrate was concentrated to give the crude product which was purified by column chromatography (hexanes / EtOAc, 80/20 to 50/50) to give 3-(3-amino-phenoxymethyl)-4-chloro-1iueno[3?2»c]pyridine-7-carboxylic acid ethyl ester as a white solid, (Yield 278 mg, 60%).

HRMS (ES+) m/z Calcd for CI7H15C1N203S + H [(M+H)+J: 363.0565. Found: 363.0565.

To a solution of 3-(3-amino-phenoxymethyl)^-chloro-tWeno[392-c]pyridine-7-carboxylic acid ethyl ester (96.9 mg, 0.267 mmol) (from Intermediate 68 supra) in THF (3 mL) were added diisopropylethylamine (78 mg, 0.603 mmol) and then 4-chlorobenzenesulfonyl chloride (64.7 mg, 0.297 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (50 mL), washed with aqueous IN NaOH (10 mL), brine (2 x 10 mL), dried (Na2S04), µLtered, and concentrated. The residue was purified by column chromatography (hexanes / EtOAc, 80/20 to 60/40) to give 4-chloro-3-[3-(4-chloro-benzenesulfonylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield
95.3 mg5 66%).
HRMS (ES+) m/z Calcd for C23H,8Cl2N205S2 + H t(M+H)+]: 537.0107. Found: 537.1015.
Example 154
4-Ainino-3-[3-(4-chloro-benzenesulfc^

RO5070056-000 37304-96A M.W. 518.014 C23H20CIN3O5S2

Ammonia gas was bubbled into a solution of 4-chloro-3«[3-(4-chloro-benzenesulfonylamino)«phenoxymethyl]-tWeno[3?2-c]pyridine-7-carboxylic acid ethyl ester (89.6 mg, 0.167 mmol) (from Intermediate 69 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a sealed vessel at 130 °C for 1.5 hours in a microwave reactor. The reaction mixture was concentrated and the residue was purifed by column chromatography (CH2C12 / MeOH, 98/2) to give 4-amino-3-[3-(4-chloro-benzenesulfonylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 76.5 mg, 88.6%). HRMS (ES+) m/z Calcd for C23H20CIN3O5S2 + H [(M+H)4]: 518.0606. Found: 518.0602.

A suspension of 4-amino-3-[3-(4-chloro-benzenesulfonylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxy!ic acid ethyl ester (54.4 mg, 0.105 mmol) (from Example 154 supra) in dimethylsulfoxide (1 mL) and ethanolamine (3 mL) (Aldrich) was heated at 135 °C for 2 hours in a microwave reactor. After cooling to room temperature, the precipitate was µLtered off, washed with MeOH and dried to give 3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)amide as a white solid (Yield 41.7 mg, 74.5%), HRMS (ES+) m/z Calcd for C23H2iClN405S2 + H [(M+H)+]: 533.0715. Found: 533.0710.
Intermediate 70
2-Chloro-5-(4-chloro-benzyloxy)-phenol


A mixture of 4-chlororesorcinol (2,89 g, 20 mmol) (Aldrich), potassium fluoride (2.32 g, 40 mmol) (Aldrich) and 4-chIorobenzyl chloride (4.83 g, 30 mmol) (Aldrich) in acetonitrile was heated at 90 °C for 24 hours. After cooling to room temperature, mixture was partitioned between ethyl acetate (2 X 100 mL) and water (2 X 100 mL). Organic layers were washed with brine (100 mL), combined, dried (MgS04), µLtered and concentrated. Residue was purified by flash chromatography (Biotage 40 L, ethyl acetate - hexanes as solvent). No good purification was achieved. Fractions were combined and concentrated. Residue was re-purified by flash chromatography (Biotage 40L, dichloromethane - hexanes 1:1 as solvent) to give product in two crops as white crystals. (Yield 1.93 g, 35.9%).

A suspension of cesium carbonate (0.50 g, 1.53 mmol), 2-chloro-5-(4-chloro-benzyloxy)-phenol (0.30 g, 1.12 mmol) (from Intermediate 70 supra) in tetrahydrofuran / N,N-dimethylformamide (5:2, 14 mL) was heated at 70 °C for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.34 g, 1.02 mmol) (from Intermediate 8 supra) was added. Heating was continued for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl

acetate in hexanes to give 4-chloro«3-[2-chloro-5-(4-chloro-ben2yloxy)-phenoxymethyl]" tWeno[3,2-c]pyridine-7-carboxyIic acid ethyl ester. (Yield 0.12 g, 23%).

Ammonia gas was bubbled into a solution of 4-chloro-3-[2-chloro-5-(4«chloro-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (0.12 g, 0.23 mmol) (from Intermediate 71 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140 °C for 2 hours. After concentrating, the residue was purified by flash chromatography eluting with 2-5% ethyl acetate in dichloromethane to give 4-amino-3-[2-chloro-5-(4-chloro-beiizyloxy)-phenoxymethyl]-1iiienot3?2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0J0 g, 83%).

A solution of 4-amino-3-[2-chloro-5-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.04 g, 0.08 mmol) (from Example 156 supra) in dimethyl-sulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) and heated at 160 °C for 2 hours in a microwave reactor. The precipitate was µLtered, washed with methanol and dried to give 4-amino-3-[2-chloro-5-(4-chloro-benzyloxy)-phenoxymethyl]-thieno[3?2-

c]pyridine-7-carboxyIic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 20 mg, 49%).
HRMS (ES+) m/z Calcd for C24H21CI2N3O4S + H [(M+H)+]: 518.0703. Found: 518.0706.

4-Chloro-3-{3-[(pyridme-2-carbonyl)^^
carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-4-chloro-
thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Intermediate 68 supra) and
picolinoyl chloride hydrochloride (TCI-US) following a similar procedure as described in
Intermediate 69 supra as off-white solid.
HRMS (ES+) m/z Calcd for C23H,8C1N304S + H [(M+H)4]: 468.0780. Found: 468,0779.
Example 158
4- Amino-3 - {3 - [(pyridine-2-carbonyl)-amino] -phenoxymethyl} -thieno[3,2-c]pyridine-7-

4-Amino-3-{3-[fcyridine-2-carbonyl)-a^
carboxylic acid ethyl ester was prepared from 4-chloro-3-{3"[(pyridine"2-carbonyl)-amino]-phenoxymethyl}-thieno[3,2-c]pyridine»7-carboxyiic acid ethyl ester (from Intermediate 72 supra) following a similar procedure as described in Example 154 supra as off-white solid.

HRMS (ES+) m/z Calcd for C23H20N4O4S + H f(M+H)+]: 449.1278. Found: 449.1279.
Example 159
4-Ammo-3-{3-[(pyridme-2-^^

4- Amino-3 - {3-[(pyridine-2-carbonyl)-amino] -phenoxymethyl} -thieno [3 ?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 4-amino-3-{3-[(pyridine-2-carbonyl)-amino]-phenoxymethyl}-tiiieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 158 supra) following a similar procedure as described in Example 155 supra as off-white solid. HRMS (ES+) m/z Calcd for C23H21N5O4S + H [(M+H)4]: 464.1387. Found: 464.1388.
Intermediate 73
4-CUoro-3-{3-[(6-methyl-pyridine-3"Carbonyl)-amino]-phenoxymethyl}-

4-Chloro-3-{3-[(6-methyl-pyridine-3-carbonyl)-amino]-phenoxymethyl}-thieno[3?2c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)»4-chloro-thieno[3?2-c]pyridine-7"Carboxylic acid ethyl ester (Intermediate 68 supra) and 6-methyl~nicotinoyl chloride which was made from 6-methyl-nicotinic acid

(from Aldrich) and oxalyl chloride (Aldrich), following a similar procedure as described in Intermediate 69 supra as off-white solid.
Example 160
4-Ammo-3 - {3 - [(6-methyl-pyri

4- Amino-3 - {3 - [(6-methyl-pyridine-3 -carbonyl)-amino] -phenoxymethyl} -thieno [3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 4-chloro-3-{3-[(6-methyl-pyridine-3-carbonyl)-amino]-phenoxymethyl}-thieno[3,2c]pyridine-7~carboxylic acid ethyl ester (from Intermediate 73 supra) following a similar procedure as described in Example 154 supra as off-white solid, HRMS (ES+) m/z Calcd for C24H22N4O4S + H [(M+H)4]: 463.1435. Found: 463.1430.

4-Amino-3-{3-[(6-methyl-pyridine-3-carbonyl)-amino]-phenoxymethyl}-thieno[3?2c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)~amide was prepared from 4-amino-3-{3-[(6~metiiyl-pyridine-3-carbonyl)-amino]-^^

carboxylic acid ethyl ester (from Example 160 supra) following a similar procedure as
described in Example 155 supra as off-white solid.
HRMS (ES+) m/z Calcd for C24H23N5O4S + H [(M+H)+j: 478.1544. Found: 478.1538.
Intermediate 74
4-Chloro-3-{3-[(pyridine-4-carbonyl)-am

4-CWoro-3-{3-[(pyridme-4-carbonyl)-am
carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyI)-4-chloro-
thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (Intermediate 68 supra) following a
similar procedure as described in Intermediate 69 supra as off-white solid.
HRMS (ES+) m/z Calcd for C23Hi8ClN304S + H [(M+H)+]: 468.0780. Found: 468.0777.

4-Amino-3-{3-[(^yridine-4-carbonyl)-amino]-phenoxymethyl}4hieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 4-chloro-3-{3-[(pyridine-4-carbonyl)-amino]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Intermediate 74 supra) following a similar procedure as described in Example 154 supra as off-white solid.

HRMS (ES+) m/z Calcd for C23H20N4O4S + H [(M+H)4]: 449.1278. Found: 449.1276.
Example 163
4-Amino-3- {3-[(pyridine-4-carbonyI)-amino]-phenoxyinethyl} -thieno[3 ,2-c]pyridine-7-

4- Amino-3 - {3 - [(pyridine-4-carbonyl)-amino] -phenoxymethyl} -thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 4-amino-3-{3-[(pyridine-4-carbonyl)«amino]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 162 supra) following a similar procedure as described in Example 155 supra as off-white solid. HRMS (ES+) m/z Calcd for C23H21N5O4S + H [(M+H)*]: 464.1387. Found: 464.1388.

A solution of 3-chlon>4-fluorobenzoyl chloride (21,23 g? 110 mmol) (Avocado) in tetrahydrofuran (50 mL) was added to a solution of 5-amino-o-cresol (6.16 g, 50 mmol) (Aldrich) and triethylamine (17.5 mL, 125 mmol) (Aldrich) and THF (50 mL) dropwise with magnetic stirring and cooling in an ice - water bath. When addition was complete, mixture was allowed to warm to room temperature and stirred for 16 hours. Reaction mixtrue was diluted with water (125 mL) and saturated aqueous sodium bicarbonate solution (125 mL).

After stirring for another 30 minutes, precipitate was collected to give crude 3-Chloro-4-fluoro-benzoic acid 5-(3-chloro-4-fluoro-benzoylamino)-2-methyl-phenyl ester as an off-white powder. (Yield 21.83 g, 101%).
3-Chloro-4-fluoro-benzoic acid 5-(3-chloro-4-fluoro-ben2oylamino)-2-methyl-phenyl ester (3.93 g, 9 mmol) was dissolved in a mixture of tetrahydrofuran (25 mL), methanol (50 mL) and aqueous IN sodium hydroxide (9 mL, 9 mmol). Mixture was stirred at room temperature for 18 hours. Mixture was concentrated under reduced pressure to remove most of the organic solvent. Resulting suspension was diluted with water (45 mL) and saturated aqueous sodium bicarbonate solution (5 mL). After standing for 30 minutes, precipitate was collected and washer with water and dried to give crude 3-cMoro-4-fiuoro-N-(3-hydroxy-4-methyl-phenyl)-benzamide as a white powder. (Yield 2.59 g, 103%).

A suspension of cesium carbonate (0.73 g, 2.24 mmol), 3-chloro-4-fluoro-N-(3-hydroxy-4-methyl-phenyl)-benzamide (0.46 g, 1.64 mmol) (from Intermediate 75 supra) in tetrahydrofuran / N,N-dimethylformamide (5:2, 21 mL) was heated at 70 °C for 3 hours. 3-BromomethyI-4-chloro«thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.50 g, 1.49 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was washed with hot dichloromethane / ethyl acetate and dried to give 4-chloro-3-[5-(3-chloro-4-fluoro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.14 g, 18%).


Ammonia gas was bubbled into a solution of 4-chloro-3-[5-(3-chloro-4-fluoro-
benzoylammo)-2-methyl-phenox acid ethyl ester
(0.14 g, 0.26 mmol) (from Intermediate 76 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140 °C for 2 hours. The reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[5-(3-chloro-4-fluoro-benzoylamino)-2-metiiyl-phenoxymethyl]-thieno[3s2-c]pyridine-7-carboxyiic acid ethyl ester as white powder. (Yield 0.09 g, 69%). HRMS (ES+) m/z Calcd for C25H2iClFN304S + H [(M+H)+]: 514.0998. Found: 514.0995.

A solution of 3-chlorobenzoyl chloride (32.81 g, 187.5 mmol) (Aldrich) in tetrahydrofuran (50 mL) was added to a solution of 5-amino-o-cresol (9.24 g, 75 mmol) (Aldrich) and triethylamine (31.43 mL, 225 mmol) (Aldrich) and THF (150 mL) dropwise with magnetic stirring and cooling in an ice - water bath. When addition was complete, mixture was allowed to warm to room temperature and stirred for 16 hours. Reaction mixtrue was diluted with water (200 mL) and saturated aqueous sodium bicarbonate solution (200 mL). After stirring for another 30 minutes, precipitate was collected to give crude 3-chlon>benzoic acid 5-(3-chloro-benzoylamino)"2-methyl-phenyl ester as an off-white powder. (Yield 31.74 g, 106%).

Crude 3-chloro-benzoic acid 5»(3-chloro-benzoylamino)-2-methyI-phenyl ester (11.42 g, 28.5 mmol) was dissolved in a mixture of tetrahydrofuran (70 mL), methanol (140 mL) and aqueous IN sodium hydroxide (28.5 mL, 28.5 mmol). Mixture was stirred at room temperature for 18 hours. Mixture was concentrated under reduced pressure to remove most of the organic solvent. Resulting suspension was diluted with water (90 mL) and saturated aqueous sodium bicarbonate solution (10 mL). After standing for 30 minutes, precipitate was collected and washer with water and dried to give 3-chloro-N-(3-hydroxy-4-methyl-phenyl)-benzamide as an off white powder. (Yield 6,06 g, 81.2%),

A suspension of cesium carbonate (0.73 g, 2.24 mmol), 3-chloro-N-(3-hydroxy-4-methyl-phenyl)-benzamide (0.43 g, 1.64 mmol) (from Intermediate 77 supra) in tetrahydrofuran / N,N-dimethylformamide (5:2, 21 mL) was heated at 70 °C for 3 hours. 3-Bromomethyl-4-chloro-thienot3?2-c]pyridine-7-carboxylic acid ethyl ester (0.50 g, 1.49 mmol) (from Intermediate 8 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (IX). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was washed with hot dichloromethane / ethyl acetate and dried to give 4-chlorO-3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.35 g, 45%).
Example 165
4-Amino-3-[5-(3-cMoro-4-benzoylamino)^
7-carboxylic acid ethyl ester


Ammonia gas was bubbled into a solution of 4-cMoro-3-[5-(3-chloro-4-benzoylamino)•-2-
methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-c^ acid ethyl ester (0.10 g, 0.19
mmol) (from Intermediate 78 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was >
heated in a microwave reactor at 140 °C for 2 hours. The reaction mixture was concentrated.
The residue was washed with hot methanol, µLtered and dried to give 4-amino-3-[5-(3-
cMoro-benzx)ylammo)-2-methyl-phenox
ethyl ester as white powder. (Yield 0.04 g, 43%).

A solution of 4-aminO"3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.04 g, 0.08 mmol) (from Example 165 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by Cl 8 column chromatography eluting with acetonitrile / water to give 4~amino-3-[5-(3-chloro-ben2oylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridme-7-carboxylic acid (2-hydroxy-ethyl)-amide as white powder. (Yield 8.0 mg, 20%). HRMS (ES+) m/z Calcd for C25H23CIN4O4S + H [(M+H)4]: 511.1202. Found: 511.1198.
Example 167

4-Amino-3-{5-[3-chloro-4-(2-hydroxy-ethyIamm^ phenoxymethyl]-thieno [3 ^

A solution of 4-amino-3-[5"(3-cUoro^"fluoro-benzoylamino)-2-metiiyl-phenoxymethyl]-
thieno[3,2«c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.10 mmol) (from Example 164
supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and
heated at 160 °C for 2 hours in a microwave reactor. The reaction mixture was purified by
CI 8 column chromatography eluting with acetonitrile / water to give 4-amino-3-{5-[3-
cWoro-4-(2-hydroxy-ethylammo)-benzoylam
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as white powder* (Yield 37.0 mg,
67%).
HRMS (ES+) m/z Calcd for C27H28C1N505S + H [(M+H)*]: 570.1573. Found: 570.1566.
Example 167a
4-Amino~3- {5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide toluene-4-

To solution of 4-amino-3-{5-[3»cUoro-4-(2-hydroxy-ethylamino)-benzoyIamino)--2-methyl-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide (51.6 mg, 0.09 mmol) (from Example 167 supra) in methanol (6 mL) was treated with toluene-4-sulfonic acid hydrate (18.9 mg, 0.10 mmol) (Aldrich) and heated at 40 °C for 30 minutes.

The solution was concentrated. The residue was washed with diethyl ether, dissolved in
water and lyophilized to give 4-amino-3-{5-[3-chloro-4-(24iydroxy-ethylamino>
benzoylamino)-2-methyl-phenoxy-m
hydroxy-ethyI)-amide, toluene-4-sulfonic acid salt. (Yield 56.0 mg5 86%).
HRMS (ES+) m/z CaJcd for C27H28CIN5O5S + H [(M+H)4]: 570.1573. Found: 570.1567.

A solution of 3-chloro-4-fluoro-N-(3"hydroxy-4-methyl"phenyl)-benzamide (1.0 g, 3.58 mmol) (from Intermediate 75 supra) in dimethylsulfoxide (5.0 mL) was treated with ethanolamine (10,0 mL) (Aldrich) and heated at 140 °C for 50 minutes in a microwave reactor. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was acidified with 2N hydrochloric acid. The precipitate was µLtered, washed with water and dried. The aqueous phase was extracted with ethyl acetate (2X), The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The two solid samples were combined and dried to give 3-chloro-4-(2-hydroxy-ethylamino)-N-(3-hydroxy-4-methyl-phenyl)-benzamide. (Yield 1.13 g, 98%).


A suspension of potassium carbonate (0.56 g, 4.05 mmol), 3-chloro-4-(2-hydroxy-ethylamino)-N-(3-hydroxy-4-methyl-phenyl)-benzamide (1.13 g, 4.30 mmol) (from Intermediate 19 supra) in N?N-dimethylformamide (15 mL) was stirred at room tempreature for 10 minutes. 3-Bromomethyl-4«chloro-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester (1.44 g, 4.30 mmol) (from Intermediate 8 supra) was added. Stirring was continued for 18 hours. The reaction mixture was partitioned between dichloromethane and water. The precipitate was µLtered, washed with water and dried. The aqueous phase was extracted with dichloromethane (2X). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 40 -100% ethyl acetate in hexanes to give the second part of product. The combined solid was dried to give 4-chloro-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (Yield L68 g, 83%).

Ammonia gas was bubbled into a solution of 4-chloro-3-{5-[3-chloro-4-(2-hydroxy-
ethylamino)«benzoylamino]-2-metiiyl«phenoxymethyl}-thieno[3,2-c]pyrid
acid ethyl ester (0.96 g, 1.67 mmol) (from Intermediate 80 supra) in 2-propanol (70 mL) for
20 minutes. The mixture was heated in a microwave reactor at 140 °C for 2 hours. The
reaction mixture was concentrated. The residue was washed with hot methanol, µLtered and
dried to give 4-amino-3-{5-[3»chloro-4-(2™hydroxy-ethylamino)-benzoylamino]-2-methyl-
phenoxymethyl}-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.83 g, 89%).


An aqueous solution of sodium hydroxide (2N, 11.0 mL, 5.5 mmol) was added to a solution of 4-amino-3- {5-[3-cWoro^-(2-hydroxy-ethylamino)-benzoylamino]-2-methy 1-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.83 g, 1.50 mmol) (from Example 168 supra) in tetrahydrofuran / methanol (3:1,28 mL) and the mixture was heated at 50 °C for 18 hours. The reaction mixture was concentrated and azeotroped with toluene. The solid was then suspended in water and treated with hydrochloric acid (2N). After stirring 30 minutes, the solid was collected, washed with water and dried to give 4-amino-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino]-2-methyl-phenoxy-methyl}-thieno[3,2-c]pyridine-7-carboxylic acid as white powder. (Yield 0.90 g, 95%).

To a mixture of 4-amino-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino]-2-methyl* phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (0.30 g, 0.57 mmol) (from Intermediate 81 supra), HBTU (0.27 g, 0.71 mmol) (Advanced ChemTech) and diisopropylethylamine (0.0.24 mL, 1.43 mmol) (Aldrich) in N,N-dimethylformamide (15 mL) was added ammonium chloride powder (39,0 mg, 0.73 mmol). The mixture was stirred

at room temperature for 1 day and then concentrated. The residue was purified by CI 8 colum chromatography eluting with acetonitrile / water to give 4-amino-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino]-2^
carboxylic acid amide as a powder. (Yield 0.17 g, 57%),
HRMS (ES+) m/z Calcd for C25H24CIN5O4S + H f(M+H)+]: 526.1311. Found: 526.1306.
Example 170
In vitro Kinase assay
In vitro enzyme activity was determined with c-Raf using a HTRF assay with 6H-MEK as substrate (Dose Response).
Assay Principle:
The assay utilizes 6H-MEK as the substrate. Upon c-Raf phosphorylation, phosphorylated 6H-MEK is detected with rabbit anti-phospho-MEKl/2, Eu-labeled anti-rabbit, and APC-labeled anti-6H antibodies.
Reagents and Instruments:
c-Raf enzyme was cloned human c-Raf with EE-tag and was phosphorylated (co-expressed
with v-src-FLAG in baculovirus Hi5 cells), 0.2 mg / mL (2.74 JJM assuming a molecular
weight of 73 kD) and stored at -15 °C. Wild-type full-length 6H-MEK was used as substrate,
4.94 mg / mL (154.4µM assuming a MW of 32 kD) and stored at -15 °C.
The following antibodies were used in the detection step: Rabbit a-P-(Ser 217/221 )-MEK-
1/2 Ab (from Cell Signaling, Cat # 9121S, Lot 4); Eu-a-rabbit IgG (from Wallac, Cat. #
AD0083, Lot 107557, labeling date 06/21/02, 8 Eu/protein, 580 µMg/mL, 3.63 µM); a-6H~
SureLight-APC (from Martek, Cat. #AD0059H, Lot E011AB01, 3.15 µM).
Assays were read with Envision from PerkinElmer, HTRF reading mode with 412 mirrors.
Assays were performed with Costar 384 all-black plates, 120 µL (Cat. #3710).
Test compounds were dispensed in Weidman 384 polypropylene plates (REMP).
Assay Procedure: i
Prepare Kinase Assay Buffer (KAB): 50 mM HEPES (HyClone) pH7, 10 mM MgCl2, 1 mM DTT, 0.1 mM Na3V2045 and 0.2 mg / mL BSA. Prepare 6H-MEK (150 nM) in KAB. Add 40 µL / well to a Weidman plate.

Prepare ATP (66 µM) in KAB.
Prepare c-Raf (60 nM) in KAB. Add 25 µL I well to a Weidman plate.
Dilute compounds to 2.4 mM in DMSO. Perform 10-point 3x dilution in DMSO. Withdraw
2.5 ul/well of DMSO solution and add to 27.5 µL / well ATP solution in (3).
Add 12 µL / well 6H-MEK to the assay plate on the Cybiwell, followed by 6 µL / well of
solution in (5) and 6 µL / well of solution in (4) for a DMSO concentration of 2.1% during
MEK phosphorylation.
Incubate at 37 °C for 30 minutes.
Prepare rabbit a-P-(Ser 217/221>MEK-l/2 Ab (1:225 from stock) in AB1: 50 mM HEPES
pH7, 0.2 mg / mL BSA, and 53 mM EDTA.
To stop reaction, add 6 µL / well of solution from (8) to the assay plate and incubate at 37 °C
for 30 minutes.
Prepare Eu-a-rabbit IgG (9 nM) and HEPES pH7 and 0.2 mg / mL BSA.
Add 6 µL / well of solution from (10) to the assay plate.
For determining the spectrum cross talk factor, prepare 2 samples following steps (6) to (9).
For the blank sample, add 6µLI well of AB2. For the cross talk factor sample, add 6 µL I
well of Eu-anti rabbit IgG (9 nM).
Incubate at 37 °C for 1 hour.
Read HTRF signals at 615 nm and 665 nm on the Envision. Normalize HTRF signals after
spectrum cross-talk correction.
The compounds of the present invention in the above assay exhibit C-Raf IC50 values of from 0.001 to 50 fiM. Representative IC50 values are, for example,:









Claims

wherein
R1 is selected from the group consisting of hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, lower alkoxy, -C(0)-NH-lower alkyl, -C(0)-NH-lower alkoxy, oxo and NO2
R is selected from the group consisting of hydrogen, lower alkyl, lower alkyl substituted by -OR4 and -NR4R5;
R4 and R5 are selected from hydrogen; lower alkyl; lower alkyl substituted with OH or lower alkoxy; or
A 1
R and R together with the nitrogen atom to which they are attached form morpholinyl;
Q is hydrogen or a group
R" may be the same or different lower alkenyl, lower alkynyl, methyl sulfonyl, sulfonamide, hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, lower alkoxy, N02, sulfonyl urea, amide, ester, carbamoyl, carbamate, urea,
~NR4R5; and lower alkyl substituted with -OR4 or -NR4R5;

the goup -X-Y- is selected from -OCH2-, -CH20-, -NHCO-, -CONH-, -0-,
-OCH2CH2-, -CH2OCH2, -CH2CH20-, -CF=CH-,-CH=CF-, -NH-, -NHCH2-5 -CH2NH-,
-SCH2-, -NHS02, -S02NH-, -CH2S-, -SOCH2-, -CH2SO-, -S02CH2-, -CH2S02-, -S-,
»CH=CH- and lower alkyl;
W isOorNH;
n is 1 or 2;
Ring A is selected from the group consisting of aryl, heteroaryl or substituted heteroaryl, cycloalkyl and heterocycle; and
Ring B is selected from the group consisting of aryl, heteroaryl and substituted heteroaryl

or pharmaceutical^ acceptable salts thereof
wherein
R1 is selected from the group consisting of hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, lower alkoxy and N02;
R is selected from the group consisting of lower alkenyl, lower alkynyl, methyl sulfonyl, sulfonamide, hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, lower alkoxy, N02; sulfonyl urea, amide, ester, carbamoyl, carbamate, urea, and lower alkyl substituted with -OR4 or -NR4R5;

R" is selected from the group consisting of hydrogen, lower alkyl, lower alkyl substituted
by -OR4 and -NR4R5;
R4 and R5 are selected from hydrogen, lower alkyl, or lower alkyl substituted with
-OH or lower alkoxy;
X-Y are selected from the group consisting of -OCH2-, -CH20-, -NHCO-, -CONH-.
-0-, -OCH3CH2-, -CH2OCH2, -CH2CH2O-, -CF=CH-9-CH=CF-, -NH-, -NHCH2-,
-CH2NH-, -SCH2-, -CH2S-5 -SOCH2-, -CH2SO~, -SO2CH2-, -CH2SO2-, -S-, -CH=CH- and lower alkyl;
W is -O- or -NH-;
Ring A is selected from the group consisting of aryl, heteroaryl or substituted heteroaryl, cycloalkyl and heterocycle; and
Ring B is selected from the group consisting of aryl, heteroaryl and substituted heteroaryl.
3. The compound of claim 1 wherein Q is hydrogen, and the remaining substituents have the meanings given in claim 1.
4. The compound of claim 3, wherein
R1 is -O-CH3 or -C(0>NH-CH3;
R3 is ethyl, which is unsubstituted or once substituted with -OH;
W is -O- or -NH-; and
Ring B is phenyl or pyridinyl.

5. The compound of claim 1, wherein

the remaining substituents and n have the meanings given in claim 1.
6. The compound according to claim 5, wherein
the ring A is selected from pyrimidinyl, pyridinyl, piperidinyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydro-pyranyl, phenyl, pyrazolyl or thiophenyl; and
the ring B is pyrimidinyl, 2-oxo-pyrimidinyl or phenyl.
7. The compound of claim 5, wherein both rings A and B are phenyl.
8. The compound of claims 1 or 2 wherein the group -X-Y- is selected from -OCH2-> ~CH20-, -NHCO- and -CONH-.
9. The compound of claim 8 wherein R1 is selected from the group consisting of-CH3, -CI and -F.
10. The compound of claim 9 wherein R2 is selected from the group consisting of-Cl? -F, -CF3, ^CONH2, alkoxy, NR4R5, and lower alkyl.
11. A compound of claim 1 or 2 selected from the group consisting of
4-Amino-3-[3™(4-chloro-3«trifluoromethyl-phenylcarbamoyl)-phenoxymethyl]-thieno[3?2~c]pyridme-7-carboxylic acid ethyl ester;

4-Amino-3-(3-benzyloxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl
ester;
4-Amino-3-(3-benzyloxy-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxyIic acid (2-
hydroxy-ethyl)-amide;
4-Ammo-3-[3-(4-cMoro-benzyloxy)~p^
acid ethyl ester;
4-AniinO'3-[3-(4-chloro-benzyloxy)-phenoxymethyl]'tWeno[3,2-c]pyridine-7'carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(3-chloro-benzyloxy)-phenoxymethyl]-^
acid ethyl ester;
4-Amino-3-[3-(3-chloro-ben2yloxy)-phenoxym
acid (2-hydroxy-ethyl)-amide;
4- Amino-3- [3 -(3 -trifluoromethyl-benzyloxy)-phenoxymethyl] -thieno [3,2-c]pyridine-7-
carboxylic acid ethyl ester;
4-Amino-3 - [3-(3-trifluoromethyl-ben^
carboxylic acid (2-hydroxy-ethyI)-amide; and
4-Amino-3-(3-benzylsulfanyl-phenoxymethyl)-thieno [3 ?2-c]pyridine-7-carboxylic acid ethyl
ester.
12. A compound of claim 1 or 2 selected from the group consisting of
4-Ajmno-3-(3-benzylsulfanyl-phenoxym
hydroxy-ethyl)-amide;
4-Ammo-3-(3-pheny toethanesulfonyl-phenoxym
acid ethyl ester;
4-Amino-3-(3 phenylmethanesulfonyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3"(3-methoxy-benzyloxy)-phenoxymethyl]'thieno[3,2-c]pyridine-7-carboxylic
acid ethyl ester;
4-Amino«3-[3-(3-methoxy-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-methoxy-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxyli
acid ethyl ester;

4-Aminoo-[3-(4-methoxy-benzyloxy acid (2-hydroxy-ethyl)-amide;
4»Amino-3-[3-(4-methoxy-3-trifluoromelJiyl-benzyloxy)-phenoxymethyl]-1^ c]pyridine-7-carboxylic acid ethyl ester;
4-Ammo-3-[3-(4-methoxy-3-trifluorom c]pyridine-7-carboxyiic acid (2-hydroxy-ethyI)-amide and 4-Amino-3-(3-phenoxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester.
13. A compound of claim 1 or 2 selected from the group consisting of
4-Amino-3-(3-phenylamino-phenoxymethyl]-thieno[352-c]pyridine-7-carboxylicacid(2-
hydroxy-ethyl)-amide;
4-Amino-3-(3-benzylamino-phenoxyme1iiyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(3»benzylamino-phenoxymethyl]4hieno[3,2-c]pyridine«7-carboxylicacid(2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylicacid ethyl ester;
4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3s2-c]pyridine-7-carboxylic acid; 4-Amino-3-[3-(4-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2^c]pyridine-7-carboxylicacid (2-hydroxy-ethyl)-amide; 4-Amino-3-[3-(3-cyano-benzyloxy)-phenoxymethy1
ethyl ester;
4"Amino-3-[3-(3-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid; 4-Amino-3-f3-(3-cyano-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridine™7-carboxylicacid (2-hydroxy-ethyl)-amide trifluoroacetic acid salt;
3-(3-benzyloxy-phenoxymethyl)-4-(2 -hydroxy ™etnylamino)-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide; and 4-Amino-3-(3-methoxy-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester.
14. A compound of claim 1 or 2 selected from the group consisting of
4-Amino-3-(3-methoxy-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxyIic acid (2-
hydroxy-ethyl)-amide;

4-Ammo-3-(3-benzoylamino-phenoxyme
ester;
4-Amino-3-(3-benzoylamiriO"phenoxymethyl)-thieno[3 ?2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide;
4-AmiBO-3-(3-benzoylamino-phenoxymethyl)-thieno[3?2-c]pyridine-^
hydroxy-ethyl)-amide hydrochloride;
4-Amino-3-(3-benzoylamino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid (2-
hydroxy-ethyl)-amide toluene-4-sulfonic acid salt;
4-Amino-3-[3-(4-chloro-phenylcarbamoyl)-phenoxymeth^
carboxylic acid ethyl ester;
4-Amino-3-[3-(4-chloro-phenylcarbamoyl)-phenox^
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Aiiiino-3-[3-(4-fluoro-phenylcarbamoyl)-phenoxymethyl]-tMeno[352-c]pyridine
carboxylic acid ethyl ester;
4-Ammo-3 - [3-(4-fluoro-phenylcarbam^
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-chloro-benzyloxy)-phenoxymeth^
acid trifluoro-acetic acid salt; and
4~ Ammo-3 - [3-(3-cMoro-phenylcarba^
carboxylic acid ethyl ester.
15. A compound of claim 1 or 2 selected from the group consisting of
4-Amino-3-[3-(3-chloro-phenylcarbamoyl)"phenoxymethyl]-tMeno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-chloro-phenylcarbamoyl)-phenoxymethyl]-tWeno[3?2"c]pyridine-7-
carboxylic acid (3-hydroxy-propyl)-amide;
4-Amino-3-[3-(4-chloro-phenylcarbamoyl)-phenoxymethyl]"1hieno[3,2-c]pyridine-7-
carboxylic acid propylamide;
4-Amino-3-[3-(4-chloro-phenylcarbamo
carboxylic acid ethylamide;
4'Amino-3-{3-[(4-chloro-phenyl)-methyl-carbamoyl]-phenoxymethyl}-thieno[3,2-
c]pyridine-7-carboxylic acid ethyl ester;

4- Amino-3-[3-( 1 -methyl-piperidin-4-ylcarba^^ carboxylic acid ethyl ester;
4-Ammo-3-[3-(5-methyl-pyridin-2^ carboxylic acid ethyl ester;
4-Amino-3-[3^1-methanesulfonyl-piperto
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3- {3-[(4-chloro-phenyl)-methyl-carbamoyl]-phenoxymethyl} -thieno [3,2-
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino~3452-m
c]pyridine-7~carboxylic acid ethyl ester;
4-Ammo-3-(2-methyl-5-phenylcaA
carboxylic acid ethyl ester; and
4-Ajnino-3-[3-(4-chloro-benzyloxy)-phenoxymefo^
acid (3-hydroxy-propyl)-amide trifluoro-acetic acid salt.
16. A compound of claim 1 or 2 selected from the group consisting of
4"Amino-3-[3-(4-cUoro-phenoxymethyl)"phenoxymethyl]-thieno[3,2-c]pyridine-7-
carboxylic acid ethyl ester;
4-Amino-3-{3-[2»(4-cWoro-phenyl)-vinyI]-phenoxymethyl}-tWeno[3,2-c]pyridine-7-
carboxylic acid ethyl ester;
4-Amino«3-{3-[2-(4-cWorO"phenyl)-vinyl]-phenoxymetiiyl}-tWeno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4-cWoro-phenoxymethyl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy-ethyI)-amide;
4-Ammo-3-[3-(4-chloro-phenylcar^^
carboxylic acid (2-hydroxy-ethyl)-methyl-amide;
4-Amino-3-[3-(4-chloro-phenylcarbamoyl)-phenoxymethyl]-tWeno[3,2-c]pyridine-7-
carboxylic acid (2-methoxy~ethyl)~amide;
4-Amino-3-[3-(4-chloro-phenylcarbamoyl)-phenoxymethyl]4hieno[352-c]pyridine-7-
carboxylic acid methylamide;
3-[4-Amino-7-(morpholine-4-carbonyl)-thieno[3,2-c]pyridin-3-ylmethoxy]-N-(4-chloro-
phenyl)-benzamide;

4-Amino-3-(3-cyclohexylcarbamoyl-phenoxymethyl)-thieno[392-c]pyridine-7-carboxylic
acid ethyl ester;
4-Amino-3-[3 17. A compound of claim 1 or 2 selected from the group consisting of
4-Ammo-3-[3-(l-methyl-piperidin^-yb
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Ammo-3-(3-phenylammomethyl-phenox
(2-hydroxy-ethyl)-amide trifluoro-acetic acid salt;
4~Ammo~3-{3-[2-(4-cMoro-phenyl)-ethoxy]-^
carboxylic acid ethyl ester;
4-Amino-3-{3-[2-(4-chloro-ph^
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Ainino-3-[3-(4-cMoro-benzoylamino)-phenoxym
acid ethyl ester;
4-Amino-3-[3-(4-chloro-benzoylammo)-phenoxymethyl]-thienof3,2-c]pyridm^
acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[3-(4"Chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine«7-c^^
acid (3-hydroxy»propyl)-amide;
4-Amino-3-[3-(4-cWoro-benzoylamino)-phenoxymefo^
acid (3-hydroxy-propyl)-amide hydrochloride;
4-Amino-3-[3-(4-cUoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxyli^
acid (3-hydroxy-propyl)-amide toluene-4-sulfonic acid salt;
4-Amino-3-(2-oxo-l -phenethyl-1,2-dihydro-pyrimidin"4-yloxymethyl)-thieno[3?2-
c]pyridine-7-carboxylic acid ethyl ester; and
4-Ammo-3-(2,6-dioxo-3-phenethyl-3,6-dihydro-2H-pyrimidin-1 -ylmethyl)-thieno[3?2-
c]pyridine-7-carboxylic acid ethyl ester.
18, A compound of claim 1 or 2 selected from the group consisting of

4-Amino-3-(2,6-dioxo-3-phenethylO,6-dihydro-2H^
c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-[2-methoxy-5-(3-methoxy-phenylcar^
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[5^3,5 c]pyridine-7-carboxylic acid ethyl ester:
4-Amino-3-[5-(4-cWoro-3-metiiyl-phenylcarbamoyl)-2-methoxy-phenoxymethyl]-
thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-(5-benzylcarbamoyl-2-nifr^
acid ethyl ester;
4-Amino-3-(2-methyl-3-phenylcarbamoyl-phenoxymethyl)-thieno[3?2-c]pyri
carboxylic acid ethyl ester;
4-Amino-3-[3-(3,5-dimethoxy-phenylcarbamoyl)-2-m
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[2-nitro-5-(3-trifluoro^
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[2-methyl-3-(3-trifluorome1hoxy-phenylcarbamoyl)-phenoxymethyl]-tW
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[3-(3-methanesulfonyl^
c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[3-(3-chloro-phenylcarbamoyl)-2-m
7-carboxylic acid ethyl ester; and
4-Ammo-3-[2-methyl-3-(5-meth^
c]pyridine-7-carboxylic acid ethyl ester.

19. A compound of claim 1 or 2 selected from the group consisting of
4-Amino-3-[3-(3,5-difluoro-benzyloxy>5-^
carboxylic acid ethyl ester;
4-Ammo-3-[3^3,4-difluoro-ben^lox carboxylic acid ethyl ester;
4-Ajnino-3-[3-(5-chloro-thiophen-2-ylmethoxy)-5-methyl-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester;
4-Amino-3-[3-(3-me1hyl-benzyloxy)-phenoxymethyl]-thieno[3?2-c]pyridine-7-carboxylic acid ethyl ester;
4-Ammo-3 43-(5-cWoro-thiophen-2-ylm
carboxylic acid ethyl ester;
4-Amino-343-(2,5-difluoro-benzyloxy)-phenoxym
acid ethyl ester;
4-Amino-3-[3-(4-fluoro-benzyloxy)-5-methyl-phenoxymethyl]-thieno[3,2»c]pyridine-7-
carboxylic acid ethyl ester; and
4-Ammo-3-[3-(2,4-difluoro-benzyloxy)-5^
carboxylic acid ethyl ester.
20. A compound of claim 1 or 2 selected from the group consisting of
4-Ammo-3-[3 carboxylic acid ethyl ester;
4-Ammo-3-[3-methyl-5-(4-me1hyl-benzyloxy)
carboxylic acid ethyl ester;
4-Amino-3-[3-methyl-5-(2-methyl-benzyloxy)-phenoxymethyl]-lMenot3,2-c]pyridine-7-
carboxylic acid ethyl ester; 4-Amino-3-[3-(2-fluoro-benzyloxy)-5-me carboxylic acid ethyl ester; 4-Amino-3-[3-(2-methoxy-benzyloxy)-phen
acid ethyl ester;
4-Amino-3-{3-[3-(2-morpholin-4"yl-ethoxy)-benzoylamino]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;

4-Ammo-3-(3-methylcarbamoyl-pte^ ethyl ester;
4-Ammo-3-(3-cyclopropylcarbamoyl-phe^ acid ethyl ester;
4~AmiBO-3-(3-cyclopentylcarbamoyl^ acid ethyl ester; and
4-Amino-3-(3-cyclohexylcarbamoyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide,
21. A compound of claim 1 or 2 selected from the group consisting of
4-Amino-3-[3-(tetrahydro-pyran^-ylcarbamoyl)'phenoxymethyl]-1hieno[3,2-c]pyrid
carboxylic acid (2-hydroxy-ethyl)-amide;
4-Ainino-3-(3-methylcarbamoyl-phenoxymethyl)-thieno[3?2-c]pyridine-7-carboxylicacid(2^ hydroxy-ethyl)-amide;
4-Amino-3-(3-cyclopropylcarbamoyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide;
4-Amino-3-(3-cyclopentylcarbamoyl-phenoxymelhyl)-thieno[352-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide; 4-Amino-3-(5-methylcarbamoyl-pyridin-3^
acid ethyl ester; and
4~Amino-3-(5-methylcarbamoyl-pyridm-3^ acid (2-hydroxy-ethyl)-amide.
22. A compound of claim 1 or 2 selected from the group consisting of
4-Ajiiino-3-[3-(4-cWoro-benzoylammo)-ph
acid,
4-Aimno-3-[3-(pyrimidin-5-ylmetho
acid ethyl ester,
4-Amino-3~[3-(pyrimidm-5-ylm
acid (2-hydroxy-ethyl)~amide,
4-Amino-3-[3-(4-chloro-benzenesulfonylamino)-phenoxymethyl]"thieno[3?2-c]pyridine-7-
carboxylic acid ethyl ester,

4-Anuno-3-[3-(4-chloro-benzenesutf
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-[2-cMoro-5-(4-chloro4>enzyloxy)-phe
carboxylic acid ethyl ester,
4-Amino-3-[2-chloro-5-(4^Woro-benzyloxy)^
carboxylic acid (2-hydroxy-ethyI)-amide,
4-Aminoo-{34(pyridine«2-carbonyl)-amino]-phenoxymethyl}-thien^
carboxylic acid ethyl ester,
4-Amino-3-{3-[(pyridine-2-carbonyl)-amino]-pte
carboxylic acid (2-hydroxy-ethyI)-amide; and
4-Amino-3 - {3 - [(6-methy l-pyridine~3 -carbonyl)-amino] -phenoxymethyl} -thieno [3,2-
cjpyridine-7-carboxylic acid ethyl ester.
23. A compound of claim 1 or 2 selected from the group consisting of
4-Amino-3-{3-[(6*methyl-pyridine-3-carbonyl)-amino]-phenoxymethyl}-
thieno[3?2c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)~amide,
4-Amino-3-{3-[(pyridine-4-carbonyl)-amm^
carboxylic acid ethyl ester,
4-Amino-3-{3-[(jpyridine-4-carbonyI)-^
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-[5-(3-cMoro-4-fluoro«benzoylamino)-2-methyl-phenoxymethyl]-tin
c]pyridine-7-carboxylic acid ethyl ester,
4-Ammo-3-[5-(3-cWoro^-benzoylammo)-2-me&^
7-carboxylic acid ethyl ester,
4-Amino-3-[5^3-chloro-benzoylamino)-2-m
carboxylic acid (2»hydroxy-ethyl)-amide,
4-Amino-3-{5-[3-chloro-4-(2-hydroxy-ethylamino)-benzoylamino)-2-methyl-
phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylicacid(2-hydroxy-ethyl)-amide,
4-Amino-3-{5-[3-cWoro-4-(2-hydroxy"ethylamino)-benzoylamino)-2-methyl-
phenoxymethyl]-thieno[352-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide toluene-4-
sulfonic acid salt,

4«Amino-3-{5-[3-chloro-4"(2-hydroxy«ethylamino)«ben2oylamino]-2-metbyl^ phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester; and
4-Amino-3-{5-[3-chloro-4 24. A compound of claim 1 or 2 selected from the group consisting of
4-Amino-3-[3-(2-fluoro-benzyloxy)-5-methyl-pte
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Ammo-3-[3-(3,5-difluoro-benzyloxy)-5-meth^
carboxylic acid (2-hydroxy-ethyl)-amide,
4-Amino-3-[3-methyl-5-(2-methyl-benzyloxy)-phenoxymethyl]-thieno[3,2-c]pyridin^
carboxylic acid (2~hydroxy-ethyl)-amide,
4-Amino-3-[3-(2,5-difluoro-benzyloxy)-phenoxyme^
acid (2-hydroxy-ethyl)-amide,
4-Amino-3-[3-(3-fluoro-benzyloxy)-5-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-
carboxylic acid (2-hydroxy~ethyl)-amide,
4-Amino-3-[3-(2,5-difluoro-ben2yloxy)-5-me&^
carboxylic acid (2-hydroxy~ethyl)-amide,
4-Amino-3-[3-methyl-5-(4-methyl-benzyl^^
carboxylic acid (2-hydroxy-ethyl)-amide,
4~Amino-3-[3-(3,4-difluoro-benzyloxy)-5-m
carboxylic acid (2-hydroxy-ethyl)-amide; and
4-Amino-3-[3™(2,3-difluoro-benzyloxy)-phenox)^
acid (2-hydroxy-ethyl)-amide.
25. A compound according to any one of claims 1 to 24 for the treatment of cancer, in
particular colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma,
neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.
26. A pharmaceutical formulation comprising a compound according to any one of
& claims 1 to 24, together with pharmaceutically acceptable carriers or excipients.

27. The pharmaceutical formulation according to claim 26 for the treatment of cancer, in
particular colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma,
neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.
28. The use of a compound according to anyone of claims 1 to 24 for the manufacture of
medicaments for the treatment of cancer, in particular colorectal, breast, lung, prostate,
pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal
cancers, leukemias or lymphomas.

Documents:

1276-CHENP-2008 CORREPONDENCE OTHERS 24-11-2011.pdf

1276-CHENP-2008 EXAMINATION REPORT REPLY RECEIVED 26-10-2012.pdf

1276-CHENP-2008 CORRESPONDENCE OTHERS 26-12-2012.pdf

1276-CHENP-2008 CORRESPONDENCE OTHERS. 10-12-2012.pdf

1276-CHENP-2008 FORM-3 26-10-2012.pdf

1276-CHENP-2008 AMENDED CLAIMS 13-07-2012.pdf

1276-CHENP-2008 AMENDED PAGES OF SPECIFICATION 13-07-2012.pdf

1276-CHENP-2008 CORRESPONDENCE OTHERS 25-07-2012.pdf

1276-CHENP-2008 EXAMINATION REPORT REPLY RECEIVED 13-07-2012.pdf

1276-CHENP-2008 FORM-1 13-07-2012.pdf

1276-CHENP-2008 FORM-3 13-07-2012.pdf

1276-CHENP-2008 FORM-3 25-07-2012.pdf

1276-CHENP-2008 OTHER PATENT DOCUMENT 25-07-2012.pdf

1276-CHENP-2008 POWER OF ATTORNEY 13-07-2012.pdf

1276-CHENP-2008 AMENDED CLAIMS 22-10-2012.pdf

1276-CHENP-2008 EXAMINATION REPORT REPLY RECIEVED 22-10-2012.pdf

1276-chenp-2008-abstract.pdf

1276-chenp-2008-assignement.pdf

1276-chenp-2008-claims.pdf

1276-chenp-2008-correspondnece-others.pdf

1276-chenp-2008-description(complete).pdf

1276-chenp-2008-form 1.pdf

1276-chenp-2008-form 18.pdf

1276-chenp-2008-form 26.pdf

1276-chenp-2008-form 3.pdf

1276-chenp-2008-form 5.pdf


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Patent Number 255154
Indian Patent Application Number 1276/CHENP/2008
PG Journal Number 05/2013
Publication Date 01-Feb-2013
Grant Date 30-Jan-2013
Date of Filing 14-Mar-2008
Name of Patentee F. HOFFMANN-LA ROCHE AG
Applicant Address 124 GRENZACHERSTRASSE CH-4070 BASEL
Inventors:
# Inventor's Name Inventor's Address
1 BARTKOVITZ, DAVID, JOSEPH 21 POVERSHON ROAD NUTLEY, NJ 07110
2 CHEN, YI 2 COTTAGE PLACE NUTLEY, NEW JERSEY 07110
3 LUK, KIN-CHUN 66 EVERGREEN DRIVE NORTH CALDWELL NEW JERSEY 07006
4 ROSSMAN, PAMELA, LOREEN 82 OAKLEY TERRACE NUTLEY, NEW JERSEY 07110
5 SO, SUNG-SAU 6 WILMINGTON DRIVE NUTLEY, NJ 07110
6 CHU, XIN-JIE 21 RIKER HILL ROAD LIVINGSTON, NJ 07039
PCT International Classification Number C07D495/04
PCT International Application Number PCT/EP06/65986
PCT International Filing date 2006-09-05
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/832,460 2006-07-21 U.S.A.
2 60/717,271 2005-09-15 U.S.A.