WO2005010009A1 - Thienopyridine and furopyridine kinase inhibitors - Google Patents

Thienopyridine and furopyridine kinase inhibitors Download PDF

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Publication number
WO2005010009A1
WO2005010009A1 PCT/US2004/024003 US2004024003W WO2005010009A1 WO 2005010009 A1 WO2005010009 A1 WO 2005010009A1 US 2004024003 W US2004024003 W US 2004024003W WO 2005010009 A1 WO2005010009 A1 WO 2005010009A1
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Prior art keywords
group
aryl
alkyl
amino
heteroaryl
Prior art date
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PCT/US2004/024003
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English (en)
French (fr)
Inventor
Patrick Betschmann
Andrew F. Burchat
David J. Calderwood
Michael L. Curtin
Steven K. Davidsen
Heather M. Davis
Robin R. Frey
Howard R. Heyman
Gavin C. Hirst
Peter Hrnciar
Michael R. Michaelides
Melanie A. Muckey
Paul Rafferty
Carol K. Wada
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Abbott Laboratories
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Abbott Laboratories
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Priority claimed from US10/626,092 external-priority patent/US20050020619A1/en
Priority to AU2004259765A priority Critical patent/AU2004259765B2/en
Priority to PL04779180T priority patent/PL1648905T3/pl
Priority to BRPI0412894-0A priority patent/BRPI0412894A/pt
Priority to DK04779180T priority patent/DK1648905T3/da
Priority to CA2532982A priority patent/CA2532982C/en
Priority to JP2006521305A priority patent/JP4707192B2/ja
Priority to NZ544712A priority patent/NZ544712A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to KR1020067001692A priority patent/KR101120936B1/ko
Priority to MXPA06000919A priority patent/MXPA06000919A/es
Priority to DE602004018780T priority patent/DE602004018780D1/de
Priority to EP04779180A priority patent/EP1648905B1/en
Priority to SI200431056T priority patent/SI1648905T1/sl
Publication of WO2005010009A1 publication Critical patent/WO2005010009A1/en
Priority to IL173348A priority patent/IL173348A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Definitions

  • the present invention relates to compounds which are useful for inhibiting protein tyrosine kinases, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
  • PTKs Protem tyrosine kinases
  • Aberrant or excessive PTK activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting -from inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft vs. host disease.
  • Endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, and infantile hemangiomas).
  • the non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences.
  • non-receptor tyrosine kinases comprising eleven subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIJVIK) have been identified.
  • the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • the Src subfamily of enzymes has been linked to oncogenesis and immune responses.
  • the present invention provides a compound of formula (I)
  • X is selected from the group consisting of O and S; Z is selected from the group consisting of C and N; R 1 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkoxycarbonylalkynyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, aryloxyalkyl, aryloxyalkynyl, arylsulfanylalkyl, arylsulfanylalkynyl, arylsulfonyloxyalkenyl, carboxy, carboxyalkenyl, carboxyalkyl, carboxyalkynyl, cyano, cyanoalkenyl, cyanoalkyl, cyanoalkynyl, cyclo, cyanoalkenyl,
  • R 2 is absent or selected from the group consisting of hydrogen and alkyl
  • R 3 is selected from the group consisting of halo, aryl, heteroaryl, and heterocyclyl, wherein the aryl, the heteroaryl, and the heterocyclyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, heteroaryl, hetero
  • R 4 is selected from the group consisting of aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
  • R 5 and R 6 are independently selected from the group consisting of hydrogen and alkyl;
  • R a and R b are independently selected from the group consistmg of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylsulfanylalkyl, alky
  • the present invention provides compounds of formula (I) wherein R 2 is hydrogen and R 1 , R 3 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is selected from the group consisting of halo, heteroaryl, and heterocyclyl; and R 1 , R 2 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl and R 1 , R 2 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; and R a , R b , R 1 , R 2 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR R b ; and R a , R b , R ! , R 2 , R 4 , L, Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; L is O; and and R a , R b , R 1 , R 2 , R 4 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR R b ; L is O; R 1 is selected from the group consisting of heterocyclylalkenyl, heterocyclylcarbonylalkenyl, (NR a R b )alkenyl, and (NR a R b )carbonylalkenyl; and R a , R ⁇ R 2 , R 4 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; L is O; R 1 is selected from the group consisting of hydrogen, alkoxycarbonylalkenyl, carboxyalkenyl, heteroaryl, and hydroxyalkenyl; and R a , R b , R 2 , R 4 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherem the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; L is selected from the group consisting of NR 5 C(O)(CH 2 ) m and NR 5 SO 2 ; and m, R a , R b , R 1 , R 2 , R 4 , R 5 , Z, and X are as defined in formula (I).
  • the present invention provides the compound of formula (I) wherein R 3 is aryl, wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; L is selected from the group consisting of NR 5 C(O)(CH 2 ) m and NR 5 SO 2 ; R 1 is (NR a R b )alkenyl; and m, R a , R b , R 2 , R 4 , R 5 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; L is selected from the group consisting of NR s C(O)(CH 2 ) m and NR 5 SO 2 ; R 1 is selected from the group consisting of heterocyclylalkenyl, heterocyclylalkyl, and (NR a R )carbonylalkenyl; and m, R a , R b , R 2 , R 4 , R 5 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; L is selected from the group consisting of NR 5 C(O)(CH 2 ) m and NR 5 SO 2 ; R 1 is selected from the group consisting of hydrogen, alkoxycarbonylalkenyl, carboxyalkenyl, formylalkenyl, and heteroaryl; and m, R a , R b , R 2 , R 4 , R 5 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ;
  • L is selected from the group consisting of NR 5 C(O)(CH 2 ) m and NR 5 SO 2 ;
  • R 1 is selected from the group consisting of alkoxyalkynyl, arylalkynyl, carboxyalkynyl, cycloalkylalkynyl, halo, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkynyl, hydroxyalkynyl, and (NR a R b )alkynyl; and m, R a , R , R 2 ,
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ; and m, n, R a , R b , R 1 , R 2 , R 4 , R 5 , R 6 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R ;
  • L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ;
  • R 1 is selected from the group consisting of alkynyl, arylalkynyl, aryloxyalkynyl, arylsulfanylalkynyl, cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, and (NR a R b )alkynyl; and m, n, R a , R , R 2 , R 4 , R 5 ,
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ;
  • L is (CH 2 ) m N(R s )C(O)N(R 6 )(CH 2 ) n ;
  • R 1 is selected from the group consisting of alkoxycarbonylalkenyl, carboxyalkenyl, heteroarylcarbonylalkenyl, heterocyclylcarbonylalkenyl, and (NR a R b )carbonylalkenyl; and m, n, R a , R b , R 2 , R 4 , R 5 , R 6 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; L is (CH 2 ) m N(R 5 )C(O)N(R 6 XCH 2 ) n ; R 1 is selected from the group consisting of aryl and heteroaryl; and m, n, R a , R b , R 2 , R 4 , R 5 , R 6 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ;
  • L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ;
  • R 1 is selected from the group consisting of alkoxycarbonylalkyl, carboxyalkyl, heterocyclylalkyl, hydroxyalkyl, (NR a R b )alkyl, and
  • R 3 is aryl wherein the aryl is substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; L is
  • R 1 is selected from the group consisting of hydrogen, halo, nitro, and NR a R b ; and m, n, R a , R b , R 2 , R 4 , R 5 , R 6 , Z, and X are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of alkynyl, arylalkynyl, aryloxyalkynyl, arylsulfanylalkynyl, cyanoalkynyl, cycloalkylalkoxyal ynyl, heteroarylalkynyl, hydroxyalkynyl, and (NR a R b )alkynyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 and optionally with one or two additional substituents independently selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, hydroxyalkyl, and NR a R b ; R 4 is aryl; L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of alkynyl, arylalkynyl, aryloxyalkynyl, arylsulfanylalkynyl, cyanoalkynyl, cycloalkylalkoxyalkynyl, heteroarylalkynyl, hydroxyalkynyl, and (NR a R b )alkynyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein the preferred groups are chloro, fluoro, methyl, and trifluoromethyl; L is (CH 2 ) m N(R 5 )C(O
  • the present invention provides compoxmds of formula (I) wherein R 1 is (NR a R b )alkynyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein the preferred groups are chloro, fluoro, methyl, and trifluoromethyl; L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ; R 5 and R 6 are hydrogen; m is 0; n is 0; X is S; Z is C; and R a and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )alkynyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein preferred groups are chloro, fluoro, methyl, and trifluoromethyl; L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ; R 5 and R 6 are hydrogen; m is 0; n is 0; X is S; Z is C; R a is selected from the group consisting of hydrogen and alkyl; and R is heteroarylcarbonyl.
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )alkynyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein preferred groups are chloro, fluoro, methyl, and trifluoromethyl; L is (CH 2 ) ra N(R 5 )C(O)N(R 6 )(CH 2 ) n ; R 5 and R 6 are hydrogen; m is 0; n is 0; X is S; Z is C; R a is selected from the group consisting of hydrogen and alkyl; and R b is heteroarylcarbonyl wherein the heteroaryl is pyridinyl.
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of alkynyl, arylalkynyl, aryloxyalkynyl, arylsulfanylalkynyl, cyanoalkynyl, cycloalkylalkoxyalkynyl, heteroarylalkynyl, hydroxyalkynyl, and (NR a R b )alkynyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 and optionally substituted with 1 alkoxy group; R 4 is heteroaryl; L is N(R 5 )C(O)(CH 2 ) m wherein the nitrogen is attached to R 3 and the carbonyl is attached to R 4 ; R 5 is hydrogen; m is 0; X is S; Z is C; and R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkyl
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of alkynyl, arylalkynyl, aryloxyalkynyl, arylsulfanylalkynyl, cyanoalkynyl, cycloalkylalkoxyalkynyl, heteroarylalkynyl, hydroxyalkynyl, and (NR R )alkynyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 and optionally substituted with 1 alkoxy group; R 4 is heteroaryl wherein the heteroaryl is selected from the group consisting of indolyl and thienyl wherein the heteroaryl is optionally substituted with 1 alkyl group wherein the preferred heteoaryl is 1- methyl-lH-indol-2-yl; L is N(R 5 )C(O)(CH 2 ) m wherein
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of alkenyl, arylalkenyl, heterocyclylalkenyl, hydroxyalkenyl, (NR a R b )carbonylalkenyl, and (NR a R b )alkenyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ;
  • R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein the preferred groups are chloro, fluoro, methyl, and trifluoromethyl;
  • R 5 and R 6 are hydrogen;
  • L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ;
  • m
  • the present invention provides compounds of formula (I) wherein R 1 is heterocyclylalkenyl wherein the heterocycle is selected from the group consisting of piperazinyl and piperidinyl wherein the heterocycle is optionally substituted with 1 substituent selected from the group consisting of carboxy, hydroxy, hydroxyalkyl, oxo, NR a R b , and (NR a R b )alkyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ;
  • R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein the preferred groups are chloro, fluoro, methyl, and trifluoromethyl;
  • R 5 and R 6 are hydrogen;
  • L is (CH 2 ) m N(R 5
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )carbonylalkenyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein the preferred groups are chloro, fluoro, methyl, and trifluoromethyl; R 5 and R 6 are hydrogen; L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ; m is 0; n is 0; X is S; Z is C; and R a and R b are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl wherein the cycloalkyl is
  • the present invention provides compounds of formula (I) wherein R 1 is heterocyclylalkenyl wherein the heterocycle is selected from the group consisting of piperazinyl and piperidinyl wherein the heterocycle is optionally substituted with 1 substituent selected from the group consisting of carboxy, hydroxy, hydroxyalkyl, oxo, NR a R b , and (NR a R b )alkyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with LR 4 and optionally substituted with 1 alkoxy group;
  • R 4 is heteroaryl wherein the heteroaryl is selected from the group consisting of indolyl and thienyl wherein the heteroaryl is optionally substituted with 1 alkyl group wherein the preferred heteoaryl is 1- methyl-lH-indol-2-yl;
  • L is N(R 5 )C(O)(CH 2 ) m wherein the
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )alkenyl; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 and optionally substituted with 1 alkoxy group; R 4 is heteroaryl wherein the heteroaryl is selected from the group consisting of indolyl and thienyl wherein the heteroaryl is optionally substituted with 1 alkyl group wherein the preferred heteoaryl is l-methyl-lH-indol-2-yl; L is N(R 5 )C(O)(CH 2 ) m wherein the nitrogen is attached to R 3 and the carbonyl is attached to R 4 ; R 5 is hydrogen; m is 0; X is S; Z is C; and R a and R b are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl wherein the cycloalkyl is cyclohexyl optionally substitute
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is aryl; L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ; R 5 and R 6 are hydrogen; m is 0; n is 0; Z is C; and X is S.
  • the present invention provides compounds of formula (I) .
  • R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzothiazolyl, benzothienyl, benzoxazolyl, furyl, indolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and thienyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, formyl, halogen, and haloalkyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ;
  • R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein the preferred groups are chloro,
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of indolyl, pyridinyl, and pyrimidinyl, wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, halogen, and haloalkyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ;
  • R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein the preferred groups are chloro, fluoro, methyl, and trifluoromethyl;
  • L is (CH 2 ) m N(R 5 )C(O)N(R 0 )(CH 2 ) n
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is heteroaryl; L is N(R 5 )C(O)(CH 2 ) m wherein the nitrogen is attached to R 3 and the carbonyl is attached to R 4 ; R 5 is hydrogen; m is 0; Z is C; and X is S.
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzothiazolyl, benzothienyl, benzoxazolyl, furyl, indolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and thienyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, formyl, halogen, and haloalkyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ;
  • R 4 is heteroaryl wherein the heteroaryl is selected from the group consisting of indolyl and thienyl wherein the heteroaryl is optionally substituted with 1 alkyl group wherein the preferred heteoaryl
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of indolyl, pyridinyl, and pyrimidinyl, wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, halogen, and haloalkyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is heteroaryl wherein the heteroaryl is selected from the group consisting of indolyl and thienyl wherein the heteroaryl is optionally substituted with 1 alkyl group wherein the preferred heteoaryl is 1 -methyl- lH-indol-2-yl; L is N(R 5 )C(O)(CH 2 ) m wherein the nitrogen is attached to R 3 and the carbonyl is attached to R 4 ; R s is hydrogen
  • the present invention provides compounds of formula (I) wherein R 2 is hydrogen; R 3 is heteroaryl; Z is C; X is S; and R 1 is as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of alkenyl, arylalkenyl, heterocyclylalkenyl, hydroxyalkenyl, (NR a R b )carbonylalkenyl, and (NR a R b )alkenyl; R 2 is hydrogen; R 3 is • heteroaryl; Z is C; X is S; and R and R b are as defined in formula (I):
  • the present invention provides compounds of formula (I) wherein R 1 is heterocyclylalkenyl wherein the heterocycle is selected from the group consisting of piperazinyl and piperidinyl wherein the heterocycle is optionally substituted with 1 substituent selected from the group consisting of carboxy, hydroxy, hydroxyalkyl
  • the present invention provides compounds of formula (I) wherein R 1 is heterocyclylalkenyl wherein the heterocycle is selected from the group consisting of piperazinyl and piperidinyl wherein the heterocycle is optionally substituted with 1 substituent selected from the group consisting of carboxy, hydroxy, hydroxyalkyl, oxo, NR a R b , and (NR a R b )alkyl;
  • R 2 is hydrogen;
  • R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzofuranyl, benzothienyl, and indolyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )carbonylalkenyl; R 2 is hydrogen; R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, indolyl, isoquinolinyl, and quinolinyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and nitro; X is S; Z is C; and R a and R b are independently selected from
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )carbonylalkenyl; R 2 is hydrogen; R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzofuranyl, benzothienyl, and indolyl, wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and nitro;
  • X is S;
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )alkenyl; R 2 is hydrogen; R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, indolyl, isoquinolinyl, and quinolinyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and nitro; X is S; Z is C; and R a and R b are independently selected from the group consisting of
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )alkenyl; R 2 is hydrogen; R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzofuranyl, benzothienyl, and indolyl, wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and nitro; X is S; Z is C; and R and R b are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl wherein the cycloalkyl is cyclohexyl optionally substituted with NH 2 .
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of alkynyl, arylalkynyl, aryloxyalkynyl, arylsulfanylalkynyl, cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, and (NR a R b )alkynyl; R 2 is hydrogen; R 3 is heteroaryl; X is S; Z is C; and R a and R are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )alkynyl; R 2 is hydrogen; R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, indolyl, isoquinolinyl, and quinolinyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and nitro; X is S; Z is C; and R a and R b are independently selected from the group
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )alkynyl; R 2 is hydrogen; R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzofuranyl, benzothienyl, and indolyl, wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and nitro;
  • X is S;
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl; R 2 is hydrogen; R 3 is heteroaryl; X is S; Z is C; and R a and R b are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzothiazolyl, benzothienyl, benzoxazolyl, furyl, indolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and thienyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, formyl, halogen, and haloalkyl; R 2 is hydrogen; R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzisoxazoly
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of indolyl, pyridinyl, and pyrimidinyl wherein the heteroaryl is optionally substituted with 1 or .2 substituents selected from the group consisting of alkoxy, alkyl, formyl, halogen, and haloalkyl; R 2 is hydrogen; R 3 is heteroaryl wherein the heteroaryl is selected from the group consistmg of benzofuranyl, benzothienyl, and indolyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl; R 2 is hydrogen; R 3 is heterocyclyl; X is S; Z is C; and R a and R b are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzothiazolyl, benzothienyl, benzoxazolyl, furyl, indolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and thienyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, formyl, halogen, and haloalkyl; R 2 is hydrogen; R 3 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of dihydroin
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of indolyl, pyridinyl, and pyrimidinyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, formyl, halogen, and haloalkyl; R 2 is hydrogen; R 3 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of dihydroindolyl and dihydroisoindolyl wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of alkynyl, arylalkynyl, aryloxyalkynyl, arylsulfanylalkynyl, cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, and (NR a R b )alkynyl; R 2 is hydrogen; R 3 is heterocyclyl; Z is C; X is S; and R a and R b are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )alkynyl; R 2 is hydrogen; R 3 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of dihydroindolyl and dihydroisoindolyl wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and hydroxyalkyl; Z is C; X is S; and R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, and heterocyclylcarbonyl wherein the heterocyclyl is
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of alkenyl, arylalkenyl, heterocyclylalkenyl, hydroxyalkenyl, (NR a R b )carbonylalkenyl, and (NR a R b )alkenyl; R 2 is hydrogen; R 3 is heterocyclyl; Z is C; X is S; and R a and R b are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is heterocyclylalkenyl wherein the heterocycle is selected from the group consisting of piperazinyl and piperidinyl wherein the heterocycle is optionally substituted with 1 substituent selected from the group consisting of carboxy, hydroxy, hydroxyalkyl, oxo, NR a R b , and (NR a R b )alkyl;
  • R 2 is hydrogen;
  • R 3 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of dihydroindolyl and dihydroisoindolyl wherein the heterocyclyl is optionally substituted with 1 or 2 substitixents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, carboxy, cyano, halo, haloalkoxy,
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )carbonylalkenyl; R 2 is hydrogen; R 3 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of dihydroindolyl and dihydroisoindolyl wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and hydroxyalkyl; Z is C; X is S; and R and R b are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl wherein the cycloalkyl is cyclohexyl optionally substituted with NH 2
  • the present invention provides compounds of formula (I) wherein R 1 is (NR a R b )alkenyl; R 2 is hydrogen; R 3 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of dihydroindolyl and dihydroisoindolyl wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and hydroxyalkyl; Z is C; X is S; and R a and R b are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl wherein the cycloalkyl is cyclohexyl optionally substituted with NH 2 .
  • the present invention provides compounds of formula (I) wherein R 1 is aryl; and Z, X, R 2 , and R 3 are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is aryl wherein the aryl is phenyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkylsulfonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, methylenedioxy, 4-methylpiperazin-l-yl, phenoxy, (3-piperidin-l-ylpropanoyl)amino, pyrrolidin-1-ylmethyl, -NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl; R
  • the present invention provides compounds of formula (I) wherein R 1 is aryl wherein the aryl is phenyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkylsulfonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, methylenedioxy, 4-methylpiperazin-l-yl, phenoxy, (3-piperidin-l-ylpropanoyl)amino, pyrrolidin-1-ylmethyl, -NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with NH 2 ;
  • Z is C;
  • X is S; R
  • the present invention provides compounds of formula (I) wherein R 1 is aryl wherein the aryl is phenyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkylsulfonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, methylenedioxy, 4-methylpiperazin-l-yl, phenoxy, (3-piperidin-l-ylpropanoyl)amino, pyrrolidin-1-ylmethyl, -NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl;
  • R 2 is hydrogen;
  • R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzofuranyl, benzothienyl, and indolyl
  • the present invention provides compounds of formula (I) •wherein R 1 is aryl wherein the aryl is phenyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkylsulfonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, methylenedioxy, 4-methylpiperazin-l-yl, phenoxy, (3-piperidin-l-ylpropanoyl)amino, pyrrolidin-1-ylmethyl, -NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl;
  • R 2 is hydrogen;
  • R 3 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of dihydroindolyl and dihydroisoind
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, and (NR a R b )carbonyl; and Z, X, R a , R b , R 2 , and R 3 are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, and (NR a R b )carbonyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein the preferred groups are chloro, fluoro, methyl, and trifluoromethyl; L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ; R 5 and R 6 are hydrogen; m is 0; n is 0; Z is C; X is S; R a and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl; R
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, and (NR a R b )carbonyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with NH 2 ; Z is C; X is S; R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, heteroarylalkyl, and (NR c R d )alkylcarbonyl; and R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, and (NR R b )carbonyl; R 2 is hydrogen; R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzofuranyl, benzothienyl, and indolyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and nitro; Z is C; X is S; R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, heteroarylal
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, and (NR a R b )carbonyl; R 2 is hydrogen; R 3 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of dihydroindolyl and dihydroisoindolyl wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and hydroxyalkyl; Z is C; X is S; R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl;
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkynyl, heterocyclylcarbonyl, and heterocyclylalkyl; and X, R 2 , and R 3 are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkynyl, heterocyclylcarbonyl, and heterocyclylalkyl, wherein the heterocyclyl is selected from the group consisting of morpholinyl, piperazinyl, and piperidinyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, oxo, phenyl, pyrimidinyl, pyridinyl, and (NR a R b )alkyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ;
  • R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbon
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkynyl, heterocyclylcarbonyl, and heterocyclylalkyl, wherein the heterocyclyl is selected from the group consisting of morpholinyl, piperazinyl, and piperidinyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, oxo, phenyl, pyrimidinyl, pyridinyl, and (NR a R b )alkyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with NH 2 ;
  • Z is C;
  • X is S;
  • R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alky
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkynyl, heterocyclylcarbonyl, and heterocyclylalkyl, wherein the heterocyclyl is selected from the group consisting of morpholinyl, piperazinyl, and piperidinyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, oxo, phenyl, pyrimidinyl, pyridinyl, and (NR a R )alkyl;
  • R 2 is hydrogen;
  • R 3 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzofuranyl, benzothienyl, and indolyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy,
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkynyl, heterocyclylcarbonyl, and heterocyclylalkyl, wherein the heterocyclyl is selected from the group consisting of morpholinyl, piperazinyl, and piperidinyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, oxo, phenyl, pyrimidinyl, pyridinyl, and (NR a R b )alkyl;
  • R 2 is hydrogen;
  • R 3 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of dihydroindolyl and dihydroisoindolyl wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkenyl
  • the present invention provides compoxmds of formula (I) wherein R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, and carbonyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is heteroaryl wherein the heteroaryl is selected from the group consisting of indolyl and thienyl wherein the heteroaryl is optionally substituted with 1 alkyl group wherein the preferred heteoaryl is 1 -methyl- lH-indol-2-yl; L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ; R 5 and R 6 are hydrogen; m is 0; n is G, Z &- C; X is S; R and R b are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfony
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzothiazolyl, benzothienyl, benzoxazolyl, furyl, indolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and thienyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, formyl, halogen, and haloalkyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ;
  • R 4 is heteroaryl wherein the heteroaryl is selected from the group consisting of indo
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, and (NR a R b )carbonyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein the preferred groups are chloro, fluoro, methyl, and trifluoromethyl; L is (CH 2 ) m N(R 5 )C(O)N(R 6 )(CH 2 ) n ; R 5 and R 6 are hydrogen; m is 0; n is 0; Z is C; X is O; R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkyl
  • the present invention provides compounds of formula (I) wherein R 1 is aryl wherein the aryl is phenyl optionally substituted with 1, 2, or 3. substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkylsulfonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, methylenedioxy, 4-methylpiperazin-l-yl, phenoxy, (3-piperidin-l-ylpropanoyl)amino, pyrrolidin-1-ylmethyl, -NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ;
  • R 4 is aryl wherein the aryl
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzothiazolyl, benzothienyl, benzoxazolyl, furyl, indolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and thienyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, formyl, halogen, and haloalkyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ;
  • R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and halo
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of alkynyl, arylalkynyl, aryloxyalkynyl, arylsulfanylalkynyl, cyanoalkynyl, cycloalkylalkoxyalkynyl, heteroarylalkynyl, hydroxyalkynyl, and (NR a R b )alkynyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with LR 4 ; R 4 is aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkylcarbonyl, cyano, halogen, and haloalkyl wherein the preferred groups are chloro, fluoro, methyl, and trifluoromethyl; L is (CH 2 ) m N(R 5 )C(O
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkynyl, heterocyclylcarbonyl, and heterocyclylalkyl, wherein the heterocyclyl is selected from the group consisting of mo ⁇ holinyl, piperazinyl, and piperidinyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, oxo, phenyl, pyrimidinyl, pyridinyl, and (NR a R b )alkyl;
  • R 2 is hydrogen;
  • R 3 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of dihydroindolyl and dihydroisoindolyl wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkeny
  • the present invention provides compounds of formula (I) wherein R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with alkoxy and LR 4 ; R 4 is heteroaryl wherein the heteroaryl is indolyl optionally substituted with an alkyl group wherein the preferred alkyl group is methyl; L is NR 5 C(O)(CH 2 ) m ; R 5 and R 6 are hydrogen; m is 0; Z is C; X is S; and R 1 is as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is aryl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with alkoxy and LR 4 ; R 4 is heteroaryl wherein the heteroaryl is indolyl optionally substituted with an alkyl group wherein the preferred alkyl group is methyl; L is NR 5 C(O)(CH 2 ) m ; R 5 and R 6 are hydrogen; m is 0; Z is C; and X is S.
  • the present invention provides compounds of formula (I) , wherein R 1 is aryl wherein the aryl is phenyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkylsulfonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, methylenedioxy, 4-methylpiperazin-l-yl, phenoxy, (3-piperidin-l-ylpropanoyl)amino, pyrrolidin-1-ylmethyl, -NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with alkoxy and LR 4 ;
  • R 4 is heteroaryl
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, cyano, (NR a R b )alkenyl, and (NR R b )carbonyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with alkoxy and LR 4 ; R 4 is heteroaryl wherein the heteroaryl is indolyl .
  • R a and R b are as defined in formula (I).
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, cyano, (NR a R b )alkenyl, and (NR a R b )carbonyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with alkoxy and LR 4 ; R 4 is heteroaryl wherein the heteroaryl is indolyl optionally substituted with an alkyl group wherein the preferred alkyl group is methyl; L is NR 5 C(O)(CH 2 ) m ; R 5 and R 6 are hydrogen; m is 0; Z is C; X is S; R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and (NR c R d )al
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylcarbonyl, and heterocyclylalkyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with alkoxy and LR 4 ; R 4 is heteroaryl wherein the heteroaryl is indolyl optionally substituted with an alkyl group wherein the preferred alkyl group is methyl; L is NR 5 C(O)(CH 2 ) m ; R 5 and R 6 are hydrogen; m is 0; Z is C; and X is S.
  • R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylcarbonyl, and heterocyclylalkyl
  • R 2 is hydrogen
  • R 3 is aryl wherein the aryl is phen
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of heterocyclyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylcarbonyl, and heterocyclylalkyl, wherein the heterocyclyl is selected from the group consisting of morpholinyl, piperazinyl, and piperidinyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, oxo, phenyl, pyrimidinyl, pyridinyl, and (NR a R b )alkyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with alkoxy and LR 4 ;
  • R 4 is heteroaryl wherein the heteroaryl is indolyl optionally substituted with an alkyl group wherein the
  • the present invention provides compounds of formula (I) wherein R 1 is selected from the group consisting of heteroaryl, heteroarylalkyl, and heteroarylcarbonyl; R 2 is hydrogen; R 3 is aryl wherein the aryl is phenyl substituted with alkoxy and LR 4 ; R 4 is heteroaryl wherein the heteroaryl is indolyl optionally substituted with an alkyl group wherein the preferred alkyl group is methyl; L is NR 5 C(O)(CH 2 ) ra ; R 5 and R 6 are hydrogen; m is 0; Z is C; and X is S.
  • R 1 is selected from the group consisting of heteroaryl, heteroarylalkyl, and heteroarylcarbonyl
  • R 2 is hydrogen
  • R 3 is aryl wherein the aryl is phenyl substituted with alkoxy and LR 4
  • R 4 is heteroaryl wherein the heteroaryl is indolyl optionally substituted with an alkyl group where
  • the present invention provides compounds of formula (I) wherein R 1 is heteroaryl wherein the heteroaryl is selected from the group consisting of benzothiazolyl, benzothienyl, benzoxazolyl, furyl, indolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and thienyl wherein the heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, formyl, halogen, haloalkyl, NR R , and (NR a R b )carbonyl;
  • R 2 is hydrogen;
  • R 3 is aryl wherein the aryl is phenyl substituted with alkoxy and LR 4 ;
  • R 4 is heteroaryl wherein the heteroaryl is indolyl optionally substituted with an alkyl group wherein the preferred alkyl group is
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a method for inhibiting one or more protein kinases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
  • the protein kinases are selected from the group consisting of KDR, Ckit, CSF-1R, PDGFR ⁇ , PDGFR ⁇ , Flt-1, Flt-3, Flt-4, Tie-2, Lck, Src, Fyn, Lyn, Blk, Hck, Fgr, Cot, and Yes.
  • the protein kinases are selected from the group consisting of KDR and Lck.
  • the present invention provides a method for treating a condition in a patient comprising administering a therapeutically effective amount of a compound of formula (I), or a therapeutically acceptable salt thereof, to the patient, wherein the condition is selected from the group consisting of an ocular condition, a cardiovascular condition, a cancer, Crow-Fukase (POEMS) syndrome, a diabetic condition, sickle cell anemia, chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, osteoarthritis, " multiple sclerosis, graft rejection, lyme disease, sepsis, von Hippel Lindau disease, pemphigoid, psoriasis, Paget's disease, polycystic kidney disease, fibrosis, sarcoidosis, cirrhosis, thy
  • alkenyl refers to a straight or branched chain group of two to ten carbon atoms containing at least one carbon-carbon double bond. Preferred alkenyl groups of the present invention contain two to three carbon atoms.
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
  • alkoxyalkyl refers to an alkyl group substituted with at least one alkoxy group.
  • alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.
  • alkoxycarbonylalkenyl refers to an alkenyl group substituted with at least one alkoxycarbonyl group.
  • alkoxycarbonylalkyl refers to an alkyl group substituted with at least one alkoxycarbonyl group.
  • alkoxycarbonylalkynyl refers to an alkynyl group substituted with at least one alkoxycarbonyl group.
  • alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to ten carbon atoms. Preferred alkyl groups of the present invention contain one to four carbon atoms.
  • alkylcarbonyl refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkylsulfanyl refers to an alkyl group attached to the parent molecular moiety through a sulfur atom.
  • alkylsulfanylalkyl refers to an alkyl group substituted with at least one alkylsulfanyl group.
  • alkylsulfonyl refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.
  • alkynyl refers to a straight or branched chain hydrocarbon of two to ten carbon atoms containing at least one carbon-carbon triple bond. Preferred alkynyl groups of the present invention contain between two and six carbon atoms.
  • aryl refers to a phenyl group, or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings is a phenyl group.
  • Bicyclic fused ring systems are exemplified by a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • Representative examples of aryl groups include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • the aryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkylsulfonyl, alkynyl, a second aryl group, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, carboxy, carboxyalkenyl, carboxyalkyl, cyano, formyl, formylalkenyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, methylenedioxy, nitro, NR R b , (NR a R b )alkyl, (NR
  • arylalkenyl refers to an alkenyl group substituted with at least one aryl group.
  • arylalkoxy refers to an arylalkyl group attached to the parent molecular moiety through an oxygen atom.
  • arylalkoxycarbonyl refers to an arylalkoxy group attached to the parent molecular moiety through a carbonyl group.
  • arylalkoxycarbonylalkyl refers to an alkyl group substituted with at least one arylalkoxycarbonyl group.
  • arylalkyl refers to an alkyl group substituted with at least one aryl group.
  • arylalkynyl refers to an alkynyl group substituted with at least one aryl group.
  • arylcarbonyl refers to an aryl group attached to the parent molecular moiety through a carbonyl group.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxygen atom.
  • aryloxyalkyl refers to an alkyl group substituted with at least one aryloxy group.
  • aryloxyalkynyl refers to an alkynyl group substituted with at least one aryloxy group.
  • arylsulfanyl refers to an aryl group attached to the parent molecular moiety through a sulfur atom.
  • arylsulfanylalkyl refers to an alkyl group substituted with at least one arylsulfanyl group.
  • arylsulfanylalkynyl refers to an alkynyl group substituted with at least one arylsulfanyl group.
  • arylsulfonyl refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.
  • arylsulfonyloxy refers to an arylsulfonyl group attached to the parent molecular moiety through an oxygen atom.
  • arylsulfonyloxyalkenyl refers to an alkenyl group substituted with at least one arylsulfonyloxy group.
  • carbonyl refers to -C(O)-.
  • carboxy refers to -CO 2 H.
  • carboxyalkenyl refers to an alkenyl group substituted with at least one carboxy group.
  • carboxyalkyl refers to an alkyl group substituted with at least one carboxy group.
  • carboxyalkenyl refers to an alkenyl group substituted with at least one carboxy group.
  • carboxyalkynyl refers to an alkynyl group substituted with at least one carboxy group.
  • cyano refers to -CN.
  • cyanoalkynyl refers to an alkynyl group substituted with at least one cyano group.
  • cycloalkenyl refers to a non-aromatic cyclic or bicyclic ring system having three to ten carbon atoms and one to three rings, wherein each five- membered ring has one double bond, each six-membered ring has one or two double bonds, each seven- and eight-membered ring has one to three double bonds, and each nine-to ten- membered ring has one to four double bonds.
  • cycloalkenyl groups include, but are not limited to, cyclohexenyl, octahydronaphthalenyl, and norbornylenyl.
  • cycloalkyl refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms.
  • Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, bicyclo[3.1.1]heptyl, and adamantyl.
  • the cycloalkyl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, NR a R b , and spiroheterocyclyl.
  • a preferred cycloalkyl group of the present invention is cyclohexyl.
  • cycloalkylalkoxy refers to an alkoxy group substituted with at least one cycloalkyl group.
  • cycloalkylalkoxyalkynyl refers to an alkynyl group substituted with at least one cycloalkylalkoxy group.
  • cycloalkylalkenyl refers to an alkenyl group substituted with at least one cycloalkyl group.
  • cycloalkylalkyl refers to an alkyl group substituted with at least one cycloalkyl group.
  • formyl refers to -CHO.
  • formylalkenyl refers to an alkenyl group substituted with at least one formyl group.
  • haloalkyl refers to an alkyl group substituted with at least one formyl group.
  • halo and halogen refer to F, Cl, Br, or I.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl group substituted by one, two, three, or four halogen atoms.
  • a preferred haloalkyl group of the present invention is trfiluoromethyl.
  • heteroalkylene refers to a divalent group of two to eight atoms derived from a saturated straight or branched chain containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherem the remaining atoms are carbon.
  • the heteroalkylene groups of the present invention are attached to the parent molecular moiety through the carbon atoms or the heteroatoms in the chain.
  • heteroaryl refers to an aromatic five- or six-membered ring where at least one atom is selected from the group consisting of N, O, and S, and the remaining atoms are carbon.
  • heteroaryl also includes bicyclic systems where a heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, a monocyclic heterocyclyl group, as defined herein, or an additional monocyclic heteroaryl group; and tricyclic systems where a bicyclic system is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, a heterocyclyl group, as defined herein, or an additional monocyclic heteroaryl group.
  • heteroaryl groups include, but are not limited to, benzimidazolyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzisoxazolyl, benzothiazolyl, benzothienyl, cinnolinyl, dibenzofuranyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.
  • Preferred heteroaryl groups of the present invention are benzofuranyl, benzoxazolyl, fiiryl, imidazolyl, indolyl, isoquinolinyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, and thienyl.
  • heteroaryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, cyano, formyl, halo, haloalkoxy, haloalkyl, a second heteroaryl group, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, NR a R b , (NR a R b )alkyl, (NR a R b )carbonyl, and oxo; wherein the aryl, the aryl part of the arylalkenyl, the arylalkoxy, and the arylal
  • heteroarylalkenyl refers to an alkenyl group substituted with at least one heteroaryl group.
  • heteroarylalkyl refers to an alkyl group substituted with at least one heteroaryl group.
  • heteroarylalkynyl refers to an alkynyl group substituted with at least one heteroaryl group.
  • heteroarylcarbonyl refers to a heteroaryl group attached to the parent molecular moiety through a carbonyl group.
  • heteroarylcarbonylalkenyl refers to an alkenyl group substituted with at least one heteroarylcarbonyl group.
  • heteroarylcarbonylalkyl refers to an alkyl group substituted with at least one heteroarylcarbonyl group.
  • heteroarylsulfonyl refers to a heteroaryl group attached to the parent molecular moiety through a carbonyl group.
  • heterocyclyl refers to a non-aromatic four-, five-, six-, seven-, or eight-membered monocyclic or bicyclic ring where at least one atom is selected from the group consisting of oxygen, nitrogen, and sulfur.
  • the four- and five-membered rings have zero or one double bonds and the six- and seven-membered rings have zero, one, or two double bonds.
  • the heterocyclyl groups of the invention are connected to the parent molecular group through a substitutable carbon or nitrogen atom in the ring.
  • heterocyclyl also includes systems where a heterocyclyl ring is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocyclyl group; and tricyclic systems where a bicyclic system is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocyclyl group.
  • heterocyclyl groups include, but are not limited to, azetidinyl, benzodioxolyl, benzothiazolyl, diazepanyl, dihydroindolyl, dihydroisoindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, and thiomorpholinyl.
  • Preferred heterocyclyl groups of the present invention are benzodioxolyl, diazepinyl, imidazolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, and tetrahydropyranyl.
  • heterocyclyl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, alkylsulfonyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, NR a R b , (NR R b )alkyl, (NR a R b )alkylcarbonyl, (NR a R b
  • heterocyclylalkenyl refers to an alkenyl group substituted with at least one heterocyclyl group.
  • heterocyclylalkyl refers to an alkyl group substituted with at least one heterocyclyl group.
  • heterocyclylalkylcarbonyl refers to a heterocyclylalkyl group attached to the parent molecular moiety through a carbonyl group.
  • heterocyclylalkynyl refers to an alkynyl group substituted with at least one heterocyclyl group.
  • heterocyclylcarbonyl refers to a heterocyclyl group attached to the parent molecular moiety through a carbonyl group.
  • heterocyclylcarbonylalkenyl refers to an alkenyl group substituted with at least one heterocyclylcarbonyl group.
  • heterocyclylcarbonylalkyl refers to an alkyl group substituted with at least one heterocyclylcarbonyl group.
  • hydroxy refers to -OH.
  • hydroxy alkenyl refers to an alkenyl group substituted with at least one hydroxy group.
  • hydroxyalkoxy refers to a hydroxyalkyl group attached to the parent molecular moiety through an oxygen atom.
  • hydroxyalkoxyalkyl refers to an alkyl group substituted with at least one hydroxyalkoxy group.
  • hydroxyalkyl refers to an alkyl group substituted with at least one hydroxy group.
  • hydroxyalkynyl refers to an alkynyl group substituted with at least one hydroxy group.
  • methylenedioxy means a -OCH 2 O- group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms.
  • nitro refers to -NO 2 .
  • nitroalkenyl refers to an alkenyl group substituted with at least one nitro group.
  • nitroalkyl refers to an alkyl group substituted with at least one nitro group.
  • nitroalkynyl refers to an alkynyl group substituted with at least one nitro group.
  • NR a R b refers to two groups, R a and R b , which are attached to the parent molecular moiety through a nitrogen atom.
  • R a and R b are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylsulfanylalkyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylsulfonyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkyl, heterocycl
  • arylalkyl can be substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, nitro, and oxo.
  • (NR a R b )alkenyl refers to an alkenyl group substituted with at least one NR a R b group.
  • (NR a R b )alkyl refers to an alkyl group substituted with at least one NR a R b group.
  • (NR a R b )alkylcarbonyl refers to a (NR a R b )alkyl group attached to the parent molecular moiety through a carbonyl group.
  • (NR a R b )alkynyl refers to an alkynyl group substituted with at least one NR a R b group .
  • (NR a R b )carbonyl refers to an NR a R b group attached to the parent molecular moiety through a carbonyl group.
  • (NR a R b )carbonylalkenyl refers to an alkenyl group substituted with at least one (NR a R b )carbonyl group.
  • (NR a R b )carbonylalkyl refers to an alkyl group substituted with at least one (NR a R b )carbonyl group.
  • (NR a R b )carbonylalkynyl refers to an alkynyl group substituted with at least one (NR a R b )carbonyl group.
  • NR c R d refers to two groups, R c and R d , which are attached to the parent molecular moiety through a nitrogen atom.
  • R c and R d are independently selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, carboxyalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, hydroxyalkoxyalkyl, hydroxyalkyl, and RTl ⁇ alkyl, wherein the aryl, the heteroaryl, and the heterocyclyl can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, and nitro.
  • (NR°R d )alkyl refers to an alkyl group substituted with at least one NR c R d group.
  • (NR c R d )alkylcarbonyl refers to a (NR c R d )alkyl group attached to the parent molecular moiety through a carbonyl group.
  • (NR c R d )carbonyl refers to an NR c R d group attached to the parent molecular moiety through a carbonyl group.
  • (NR c R d )carbonylalkyl refers to an alkyl group substituted with at least one (NR c R d )carbonyl group.
  • NR e R f refers to two groups, R e and R f , which are attached to the parent molecular moiety through a nitrogen atom. R e and R f are independently selected from the group consisting of hydrogen and alkyl.
  • (NR'-R ⁇ alkyl refers to an alkyl group substituted with at least one NR e R f group.
  • spiroheterocyclyl refers to a heteroalkylene diradical, each end of which is attached to the same carbon atom of the parent molecular moiety.
  • spiroheterocyclyl groups include, but are not limited to, dioxanyl, dioxolanyl, tetrahydrofixranyl, and pyrrolidinyl.
  • the spiroheterocyclyl groups of the present invention can be optionally substituted with one, two, three, or four groups independently selected from the group consisting of alkoxy, alkyl, and halo.
  • sulfonyl refers to -SO 2 -.
  • the compounds of the present invention can exist as therapeutically acceptable salts.
  • therapeutically acceptable salt represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without xxndue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compoxmds or separately by reacting an NR a R b or NR c R d group with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate,trifluoroacetate, phosphate, glutamate, bi
  • NR a R b and NR c R d groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of therapeutically acceptable salts include lithium,, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine.
  • nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,
  • compositions useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • the present compounds can also exist as therapeutically acceptable prodrugs.
  • therapeutically acceptable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • prodrug refers to compounds which are rapidly transformed in vivo to parent compounds of formula (I) for example, by hydrolysis in blood. Asymmetric centers exist in the compounds of the present invention.
  • the invention contemplates various geometric isomers and mixtures thereof resulting from the arrangement of substituents around these carbon-carbon double bonds. It should be understood that the invention encompasses both isomeric forms, or mixtures thereof, which possess the ability to inhibit one or more protein kinases. These substituents are designated as being in the E or Z configuration wherein the term “E” represents higher order substituents on opposite sides of the carbon-carbon double bond, and the term “Z” represents higher order substituents on the same side of the carbon-carbon double bond. It should be understood that the terms "administering a” and “administering to,” refer to providing a compound of the present invention to a patient in need of treatment.
  • the patient to be treated can be any animal, and is preferably a mammal, such as a domesticated animal or a livestock animal. More preferably, the patient is a human.
  • therapeutically effective amounts of a compound of formula (I), as well as therapeutically acceptable salts thereof may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition.
  • the invention further provides pharmaceutical compositions, which include therapeutically effective amounts of compounds of formula (I), or therapeutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of formula (I) and therapeutically acceptable salts thereof are as described above.
  • the carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recepient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of formula (I), or a therapeutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Such a unit may contain, for example, 0.5mg to lg, preferably lmg to 700mg, more preferably 5mg to lOOmg of a compound of formula (I), depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of an active ingredient per dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art. Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical
  • compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical cerrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, wasces, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined ith a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided.
  • Dyestuffs can be added ot these coatings to distinguis different unit dosages.
  • Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or susain the release as for example by coating or embedding particulate material in polymers, wax, or the like.
  • the compoxmds of formula (I), and therapeutically acceptable salts thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • the compounds of formula (I), and therapeutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compoxmd molecules are coupled.
  • the compounds may also be coupled with sohxble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palitoyl residues.
  • the compoxmds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil- in-water cream base or a water-in oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles, and mouth washes.
  • Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
  • Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops include aqueous or oil solutions of the active ingredient.
  • Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insufflators.
  • Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and soutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • an effective amount of a compound of formula (I) for the treatment of a protein kinase-mediated condition will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I), or a therapeutically acceptable salt thereof, and the use of at least one other cancer treatment method.
  • combination therapies according to the present invention comprise the administration of at least one other pharmaceutically active agent, preferably an antineoplastic agent.
  • the compoxmd(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compounds of formula (I), or therapeutically acceptable salts thereof, and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies.
  • the other anti-cancer therapy is at least one additional chemotherapeutic therapy including administration of at least one anti-neoplastic agent.
  • a compoixnd of formula (I), or therapeutically acceptable salts thereof, with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • -Anti-neoplastic agents may include anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.
  • Anti-neoplastic agents useful in combination with the compounds and salts of formula (I) include the following: (1) cell cycle specific anti-neoplastic agents including, but not limited to, diterpenoids such as paclitaxel and its analog docetaxel; vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine; epipodophyllotoxins such as etoposide and teniposide; fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine; antimetabolites such as allopurinol, fludurabine, methotrexate, cladrabine, cytarabine, mercaptopurine, and thioguanine; and camptothecins such as 9-amino camptothecin, irinotecan, topotecan, CPT- 11, and the various optial forms of 7-(-4-methylpiperazino-methylene)-10,l 1-ethylenedioxy- 20-camp
  • ras inhibitors examples include the following: ras inhibitors, anti- IL1 agents, antihistamines, PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt/PTB inhibitors, IGF-IR inhibitors, PKC inhibitors, PI 3 kinase inhibitors, cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti- IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD 154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors,
  • the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the in vitro potency of compounds in inhibiting these protein kinases may be determined by the procedures detailed below.
  • the potency of compounds can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., synthetic peptide (Z. Songyang et al., Nature. 373:536-539) by a test compound relative to control.
  • KDR Tyrosine Kinase Production Using Baculovirus System The coding sequence for the human KDR intra-cellular domain (aa789-1354) was generated through PCR using cDNAs isolated from HUVEC cells. A poly-His6 sequence was introduced at the N-terminus of this protein as well. This fragment was cloned into transfection vector pNL1393 at the Xba 1 and Not 1 site. Recombinant baculovirus (BN) was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BN was plaque purified and verified through Western analysis. For protein production, SF-9 cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at 0.5 plaque forming units per cell (MOI). Cells were harvested at 48 hours post infection.
  • MOI plaque forming units per cell
  • KDR SF-9 cells expressing (His) 6 KDR(aa789-1354) were lysed by adding 50 ml of Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM ⁇ aCl, 10% glycerol, 1% Triton X-100, lmM PMSF, lO ⁇ g/ml aprotinin, 1 ⁇ g/ml leupeptin) to the cell pellet from IL of cell culture.
  • the lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4 °C.
  • the cell lysate was applied to a 5 ml ⁇ iCl- chelating sepharose colxxmn, equilibrated with 50 mM HEPES, pH7.5, 0.3 M ⁇ aCl.
  • KDR was eluted using the same buffer containing 0.25 M imidazole. Column fractions were analyzed using SDS-PAGE and an ELISA assay (below) which measures kinase activity.
  • the purified KDR was exchanged into 25mM HEPES, pH7.5, 25mM ⁇ aCl, 5 mM DTT buffer and stored at -80 °C.
  • Recombinant BN was plaque purified and verified through Western analysis.
  • SF-9 insect cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at MOI of 0.5. Purification of the His-tagged kinase used in screening was analogous to that described for KDR.
  • the baculoviral expression vector pNL1393 (Phar Mingen, Los -Angeles, CA) was used.
  • a nucleotide sequence encoding poly-His6 was placed 5' to the nucleotide region encoding the entire intracellular kinase domain of human Flt-1 (amino acids 786-1338).
  • the nucleotide sequence encoding the kinase domain was generated through PCR using cD ⁇ A libraries isolated from HUNEC cells.
  • the histidine residues enabled affinity purification of the protein as a manner analogous to that for KDR and ZAP70.
  • SF-9 insect cells were infected at a 0.5 multiplicity and harvested 48 hours post infection.
  • EGFR Tyrosine Kinase Source EGFR was purchased from Sigma (Cat # E-3641 ; 500 units/50 ⁇ L) and the EGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat # PF011-100).
  • the baculoviral expression vector used was pNLl 393. (Pharmingen, Los Angeles, Ca.)
  • the nucleotide sequence encoding amino acids M(H)6 LNPR 9 S was placed 5' to the region encoding the entirety of ZAP70 (amino acids 1-619).
  • the nucleotide sequence encoding the ZAP70 coding region was generated through PCR using cD ⁇ A libraries isolated from Jurkat immortalized T-cells. The histidine residues enabled affinity purification of the protein (vide infra).
  • the LNPRgS bridge constitutes a recognition seqxxence for proteolytic cleavage by thrombin, enabling removal of the affinity tag from the enzyme.
  • SF- 9 insect cells were infected at a multiplicity of infection of 0.5 and harvested 48 hours post infection.
  • Extraction and purification of ZAP70 SF-9 cells were lysed in a buffer consisting of 20 mM Tris, pH 8.0, 137 mM ⁇ aCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 ⁇ g/ml leupeptin, 10 ⁇ g/ml aprotinin and 1 mM sodium orthovanadate.
  • the soluble lysate was applied to a chelating sepharose HiTrap column (Pharmacia) equilibrated in 50 mM HEPES, pH 7.5, 0.3 M ⁇ aCl. Fusion protein was eluted with 250 mM imidazole.
  • the enzyme was stored in buffer containing 50 mM HEPES, pH 7.5, 50 mM ⁇ aCl and 5 mM DTT.
  • Protein kinase source Lck, Fyn, Src, Blk, Csk, and Lyn may be commercially obtained (e.g., from Upstate Biotechnology Inc. (Saranac Lake, ⁇ .Y) and Santa Cruz
  • Enzyme linked Immunosorbent Assay For PTKs Enzyme linked immunosorbent assays (ELISA) were used to detect and measure the presence of tyrosine kinase activity. The ELISA were conducted according to known protocols which are described in, for example, No Her, et al., 1980, "Enzyme-Linked Immunosorbent Assay," In: Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp 359-371 Am. Soc. of Microbiology, Washington, D.C. The disclosed protocol was adapted for determining activity with respect to a specific
  • PTK protein kinase
  • preferred protocols for conducting the ELISA experiments is provided below. Adaptation of these protocols for determining a compound's activity for other members of the receptor PTK family, as well as non-receptor tyrosine kinases, are well within the abilities of those in the art.
  • a universal PTK substrate e.g., random copolymer of poly(Glu 4 Tyr), 20,000-50,000 MW
  • ATP typically 5 ⁇ M
  • Reaction Buffer lOOmM Hepes, 20mM MgCl 2 , 4mM MnCl 2 , 5mM DTT, 0.02%BSA, 200 ⁇ M NaNO 4 , pH 7.10
  • ATP Store aliquots of 1 OOmM at -20 °C . Dilute to 20 ⁇ M in water
  • Washing Buffer PBS with 0.1% Tween 20
  • TMB Substrate mix TMB substrate and Peroxide solutions 9:1 just before use or use K-Blue Substrate from ⁇ eogen
  • Plate Preparation Dilute PGT stock (50mg/ml, frozen) in PBS to a 250 ⁇ g/ml. Add 125 ⁇ l per well of Corning modified flat bottom high affinity ELISA plates (Corning #25805-96). Add 125 ⁇ l PBS to blank wells. Cover with sealing tape and incubate overnight 37°C. Wash lx with 250 ⁇ l washing buffer and dry for about 2hrs in 37°C dry incubator.
  • Representative compounds of the present invention inhibited KDR at IC 50 values between about 0.002 ⁇ M and about 50 ⁇ M.
  • Preferred compounds inhibited KDR at IC 50 values between about 0.002 ⁇ M and about 1.5 ⁇ M.
  • Representative compounds of the present invention inhibited Lck at IC 50 values between about 0.03 ⁇ M and about 50 ⁇ M.
  • Compounds of the present invention may have therapeutic utility in the treatment of diseases involving both identified, including those mentioned and unmentioned herein, and as yet unidentified protein tyrosine kinases.
  • protein kinases include, but are not limited to, KDR, Ckit, CSF-IR, PDGFR ⁇ , PDGFR ⁇ , Flt-1, Flt-3, Flt-4, Tie-2, Lck, Src, Fyn, Lyn, Blk, Hck, Fgr, Cot, and Yes.
  • the human recombinant enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using conventional methods.
  • Cdc2 Assay A protocol that can be used is that provided with the purchased reagents with minor modifications.
  • the reaction is carried out in a buffer consisting of 50mM Tris pH 7.5, lOOmM NaCl, lmM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and lOmM MgCl 2 (commercial buffer) supplemented with fresh 300 ⁇ M ATP (31 ⁇ Ci/ml) and 30 ⁇ g/ml histone type IIIss final concentrations.
  • a reaction volume of 80 ⁇ L, containing units of enzyme is run for 20 minutes at 25 degrees C in the presence or absence of inhibitor.
  • the reaction is terminated by the addition of 120 ⁇ L of 10% acetic acid.
  • the substrate is separated from unincorporated label by spotting the mixture on phosphocellulose paper, followed by 3 washes of 5 minutes each with 75mM phosphoric acid. Counts are measured by a betacounter in the presence of liquid scintillant.
  • PKC kinase soxxrce The catalytic subunit of PKC may be obtained commercially (Calbiochem).
  • PKC kinase assay A radioactive kinase assay is employed following a published procedure (Yasuda, I., K-irshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 3:166, 1220-1227 (1990)). Briefly, all reactions are performed in a kinase buffer consisting of 50 mM Tris-HCl pH7.5, lOmM MgCl 2 , 2mM DTT, lmM EGTA, 100 ⁇ M ATP, 8 ⁇ M peptide, 5% DMSO and 33 P ATP (8Ci/mM).
  • the recombinant murine enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly MA. USA) or purified from known natural or recombinant sources using conventional methods.
  • Erk2 enzyme assay In brief, the reaction is carried out in a buffer consisting of 50 mM Tris pH 7.5, lmM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl 2 (commercial buffer) supplemented with fresh 100 ⁇ M ATP (31 ⁇ Ci/ml) and 30 ⁇ M myelin basic protein under conditions recommended by the supplier. Reaction volumes and method of assaying incorporated radioactivity are as described for the PKC assay (vide supra).
  • Cellular Receptor PTK Assays The following cellular assay was used to determine the level of activity and effect of the different compounds of the present invention on KDR/VEGFR2. Similar receptor PTK assays employing a specific ligand stimulus can be designed along the same lines for other tyrosine kinases using techniques well known in the art. VEGF-Induced KDR Phosphorylation in Human Umbilical Vein Endothelial Cells
  • HUNEC HUNEC as Measured by Western Blots: 1. HUNEC cells (from pooled donors) can be purchased from Clonetics (San Diego, CA) and cultured according to the manufacturer directions. Only early passages (3-8) are used for this assay. Cells are cultured in 100 mm dishes (Falcon for tissue cixlture; Becton Dickinson; Madison, England) using complete EBM media (Clonetics). 2. For evaluating a compound's inhibitory activity, cells are trypsinized and seeded at 0.5-1.0 x 10 5 cells/well in each well of 6-well cluster plates (Costar; Cambridge, MA). 3. 3-4 days after seeding, plates are typically 90-100% confluent. Medium is removed from all the wells, cells are rinsed with 5-10ml of PBS and incubated 18-24h with
  • EBM base media with no supplements added (i.e., serum starvation). 4. Serial dilutions of inhibitors are added in 1ml of EBM media (25 ⁇ M, 5 ⁇ M, or l ⁇ M final concentration to cells and incubated for one hour at 37 °C. Human recombinant NEGF- 65 ( R & D Systems) is then added to all the wells in 2 ml of EBM medium at a final concentration of 50ng/ml and incubated at 37 °C for 10 minutes. Control cells untreated or treated with VEGF only are used to assess background phosphorylation and phosphorylation induction by VEGF.
  • the lysate is spun at 14,000 rpm for 30min, to eliminate nuclei. Equal amounts of proteins are then precipitated by addition of cold (-20 °C) Ethanol (2 volumes) for a mimmum of 1 hour or a maximum of overnight. Pellets are reconstituted in Laemli sample buffer containing 5% -mercaptoethanol (BioRad; Hercules, CA) and boiled for 5min. The proteins are resolved by polyacrylamide gel electrophoresis (6%, 1.5mm Novex, San Deigo, ' CA) and transferred onto a nitrocellulose membrane using the Novex system.
  • the proteins After blocking with bovine serum albumin (3%), the proteins are probed overnight with anti-KDR polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or with anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid, NY) at 4 °C. After washing and incubating for 1 hour with HRP-conjugated F(ab), of goat anti-rabbit or goat-anti-mouse IgG the bands are visualized using the emission chemiluminescience (ECL) system (Amersham Life Sciences, Arlington Heights, IL).
  • ECL emission chemiluminescience
  • this system can serve as a model for in vivo inhibition of VEGF signalling and the associated hyperpermeability and edema.
  • Materials All hormones can be purchased from Sigma (St. Louis, MO) or Cal Biochem (La Jolla, CA) as lyophilized powders and prepared according to supplier instructions. Vehicle components (DMSO, Cremaphor EL) can be purchased from Sigma (St. Louis, MO). Mice (Balb/c, 8-12 weeks old) can be purchased from Taconic (Germantown, NY) and housed in a pathogen-free animal facility in accordance with institutional Animal Care and Use Committee Guidelines.
  • Day 1 Balb/c mice are given an intraperitoneal (i.p.) injection of 12.5 units of pregnant mare's serum gonadotropin (PMSG).
  • Day 3 Mice receive 15 units of human chorionic gonadotropin (hCG) i.p.
  • Day 4 Mice are randomized and divided into groups of 5-10. Test compounds are administered by i.p., i.v. or p.o. routes depending on solubility and vehicle at doses ranging from 1-100 mg/kg. Vehicle control group receive vehicle only and two groups are left untreated. Thirty minutes later, experimental, vehicle and 1 of the untreated groups are given an i.p. injection of 17 -estradiol (500 mg/kg).
  • each uterus was isolated and removed by cutting just below the cervix and at the junctions of the uterus and oviducts. Fat and connective tissue were removed with care not to disturb the integrity of the uterus prior to weighing (wet weight).
  • Uteri are blotted to remove fluid by pressing between two sheets of filter paper with a one liter glass bottle filled with water. Uteri are weighed following blotting (blotted weight). The difference between wet and blotted weights is taken as the fluid content of the uterus.
  • Mean fluid content of treated groups is compared to untreated or vehicle treated groups. Significance is determined by Student's test.
  • Non-stimulated control group is used to monitor estradiol response.
  • Certain compounds of this invention which are inhibitors of angiogenic receptor tyrosine kinases can also be shown active in a Matrigel implant model of neovascularization.
  • the Matrigel neovascularization model involves the formation of new blood vessels within a clear marble of extracellular matrix implanted subcutaneously which is induced by the presence of proangiogenic factor producing tumor cells (for examples see: Passaniti, A., et al, Lab. Investig. (1992), 67(4), 519-528; Anat. Rec. (1997), 249(1), 63-73; Int. J. Cancer (1995), 63(5), 694-701; Vase. Biol.
  • the model preferably runs over 3-4 days and endpoints include macroscopic visual/image scoring of neovascularization, microscopic microvessel density determinations, and hemoglobin quantitation (Drabkin method) following removal of the implant versus controls from animals untreated with inhibitors.
  • the model may alternatively employ bFGF or HGF as the stimulus.
  • the compounds of the present invention may be used in the treatment of protein kinase-mediated conditions, such as benign and neoplastic proliferative diseases and disorders of the immune system.
  • Such diseases include autoimmune diseases, such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis and systemic lupus erythematosus; psoriasis, organ transplant rejection (e.g,.
  • kidney rejection, graft versus host disease benign and neoplastic proliferative diseases
  • human cancers such as lung, breast, stomach, bladder, colon, pancreatic, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), glioblastoma, infantile hemangioma, and diseases involving inappropriate vascularization (for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings).
  • diseases vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings.
  • Such inhibitors may be useful in the treatment of disorders involving VEGF mediated edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury and adult respiratory distress syndrome (ARDS).
  • ARDS adult respiratory distress syndrome
  • the compounds of the invention may be useful in the treatment of pulmonary hypertension, particularly in patients with thromboembolic disease (J. Thorac. Cardiovasc. Surg. 2001, 122 (1), 65-73).
  • Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC), trimethylsilylethanesulfonamide (SES), benzyloxycarbonyl (CBZ) and benzyl (Bn) protecting groups.
  • the BOC protecting group may be removed by treatment with an acid such as trifluoroacetic acid or concentrated hydrochloric acid and the SES protecting group may be removed with a fluoride salt, such as cesium fluoride or tetrabutylammonium fluoride.
  • the CBZ and Bn protection groups may be removed by catalytic hydrogenation. Additional suitable protecting groups for hydroxy substituents include, but are not limited to, t-butyldimethylsilyl (TBDMS), tetra-hydropyranyl (THP), or isopropyl (i-Pr) protecting groups.
  • the TBDMS and THP protecting groups may be removed by treatment with an acid such as acetic acid or hydrochloric acid while the i-Pr protecting group may be removed by aluminum trichloride.
  • This invention is intended to encompass compounds having formula (I) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
  • the groups R',R 2 , R 3 , R 4 , and R 5 are as defined above unless otherwise noted below.
  • Scheme 1 shows the synthesis of compounds of formula (6).
  • Compounds of formula (3) can be reacted with ethyl (diethoxyphosphino)acetate in the presence of a base such as sodium hydride, LDA, or lithium hexamethyldisilazide to provide compounds of formula (4).
  • a base such as sodium hydride, LDA, or lithium hexamethyldisilazide
  • This reaction is typically conducted at about 0 to about 25 °C for about 1 to about 6 hours.
  • compounds of formula (3) can be treated with malonic acid in the presence of pyridine and piperidine to provide compounds of formula (4).
  • the reaction is typically conducted at about 90 to about 110 °C for abou 6 to about 18 hours.
  • Compounds of formula (4) can be converted to compounds of formula (5) by treatment with thionyl chloride and DMF followed by treatment with sodium azide and subsequent heating. The reaction is conducted at about 30 to about 260 °C for about 5 to about 10 hours. Conversion of compounds of formula (5) to compounds of formula (6) can be accomplished by treatment with POCl 3 at about 108 °C for about 1 to about 4 hours followed by treatment with ammonia under pressure at about 140 to about 160 °C.
  • transition metal catalysts used in these couplings include, but are not limited to, PdCl 2 (dppf), Pd(PPh 3 ) 4 , and Pd(PPh 3 ) 2 Cl 2 .
  • Representative bases include sodium carbonate, potassium carbonate, and cesium carbonate. The reaction is typically conducted at about 70 to aboxxt 90 °C for about 2 to about 24 hours.
  • Compounds of formula (8) can be converted to compounds of formula (la) (where L is selected from the group consisting of NR 5 C(O)(CH 2 ) m , NR 5 SO 2 , (CH 2 ) ra N(R 5 )C(O)N(R 6 )(CH 2 ) n ) by treatment with the appropriate acylating/sulfonylating reagent (i.e., a substituted acid chloride, sulfonyl chloride, or isocyanate) optionally in the presence of a base such as pyridine or triethylamine.
  • acylating/sulfonylating reagent i.e., a substituted acid chloride, sulfonyl chloride, or isocyanate
  • compounds of formula (6) can be reacted with compounds of formula (9) (where q is 1, 2, or 3 and each R y is selected from the group consisting of alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, heteroaryl, heterocyclyl, hydroxy, hydroxyalkyl, LR 4 , and NR R b ; provided that at least two of the three substituents are other than LR 4 ) in the presence of a transition metal catalyst and a base to provide compounds of formula (la).
  • transition metal catalysts used in these couplings include, but are not limited to, PdCl 2 (dppf), Pd(PPh 3 ) 4 , and Pd(PPh 3 ) 2 Cl 2 .
  • Representative bases include sodium carbonate, potassium carbonate, and cesium carbonate.
  • Compounds of formula (Ic) can be synthesized following the procedures shown in Scheme 4. Compounds of formula (la) or (lb) can be reacted with N-iodosuccinimide at about 20 to about 35 °C for about 1 to about 4 hours to provide compounds of formula (10).
  • Compounds of formula (Ic) can be prepared by coupling compounds of formula (10) with an appropriately substituted organometallic coupling partner (for example, an organoborane or an organostannane) in the presence of a transition metal catalyst. Examples of transition metal catalysts used in these couplings include, but are not limited to, PdCl 2 (dppf), Pd(PPh 3 ) 4 , and Pd(PPh 3 ) 2 Cl 2 .
  • a base When an organoborane is used in the coupling, a base is also required.
  • Representative bases include sodium carbonate, potassium carbonate, and cesium carbonate.
  • Compounds of formula (Ic) can be further functionalized at R 1 using methods known to those of ordinary skill in the art. For example, when R 1 contains an aldehyde (formed by coupling an alkenyl acetal with the compound of formula (10) and subsequent deprotection) reductive amination provides an alkenylamine. Similarly, when R 1 contains a primary amine, reaction with an aldehyde under reductive amination provides the secondary amine. In another example, when R 1 contains a carboxylic acid (prepared by hydrolysis of the corresponding ester) coupling with an amine provides an alkenylamide.
  • the unprotected amine can be further functionalized by reacting with an appropriately substituted acyl halide, sulfonyl chloride, or isocyanate to provide compounds of formula (13) where R v is the resulting functionality (i.e., alkylsulfonyl, alkylcarbonyl). Removal of the protecting group followed by coupling of the bromide as described in Scheme 2 or Scheme 3 provides compounds of formula (Id).
  • compounds of formula (14) can be converted to compounds of formula (15) by treatment with POCl 3 at about 108 °C for about 1 to about 4 hours.
  • Reaction of compounds of formula (15) with benzoyl peroxide and N- bromosuccinimide followed by treatment with sodium acetate provides compounds of formula (16). This reaction is typically conducted at about 70 to about 100 °C for about 24 to about 48 hours. Removal of the acetate group and displacement of the chloride can be accomplished by treating compounds of formula (16) with concentrated ammonium hydroxide at a temperature of about 120 to about 160 °C to provide compounds of formula (17).
  • Example IA 3 -bromo thieno ⁇ 3 ,2-c]pyridin-4(5H)-one A suspension of (2E)-3-(4-bromo-2-thienyl)acrylic acid (commercially available, 50.2g, 0.215 mol) in dichloromethane (150 mL) was treated with DMF (2 drops) and SOCl, (23 mL, 0.315 mol), stirred at room temperature for 48 hours, heated to reflux for 2 hours, and concentrated. The residue was dissolved in dioxane (100 mL) and added to a vigorously stirred solution of NaN 3 (25g, 0.384 mol) in water (100 mL) and dioxane (100 mL) over 10 minutes.
  • Example IB 3-bromothienor3 ,2-clpyridin-4-amine
  • a suspension of Example IA (35.91g, 0.156 mol) in POCl 3 (80 mL) was heated to reflux for 2.5 hours, cooled to room temperature, poured onto 800g of ice, and extracted repeatedly with dichloromethane. The combined extracts were washed with water and brine, dried (Na ⁇ O.,), filtered, and concentrated.
  • Example IC 3 (4-amino-3 -fluorophenyl)thieno [3 ,2-c1pyridin-4-amine
  • a solution of 4-bromo-2-fluoroaniline (1.83g, 9.6 mmol), bis(pinacolato)diboron (2.65g, 10.4 mmol) and potassium acetate (2.56g, 26.1 mmol) in DMF (50 mL) was purged with nitrogen, treated with PdCl 2 (dppf) (0.355g, 0.05 mmol), heated to 80 °C for 2.5 hours, cooled to room temperature, and treated with a solution of N- ⁇ CO;) (4.6 lg, 43.5 mmol) in water (20 mL), Example IB (2.02g, 8.8 mmol), and additional PdCl 2 (dppf) (0.355g, 0.05 mmol).
  • Example ID N-r4-(4-aminothienor3,2-clpyridin-3-yl)-2-fluorophenyll-N'-(3-methylphenyl)urea A solution of Example IC (125mg, 0.48 mmol) in dichloromethane (lmL) was treated with l-isocyanato-3-methylbenzene (0.065 mL, 0.5 mmol), stirred overnight at room temperature, and filtered.
  • the filter cake was purified by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7 ⁇ m particle size) using a solvent gradient of 10% to 100%) acetonitrile/ lOmM aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40mL/minute to provide 74 mg of the desired product.
  • Example 2 N-r4-(4-arninothienor3,2-c1pyridin-3-yl)-2-fluorophenyll-N'-(3-chlorophenyl)urea
  • the desired product was prepared by substituting l-isocyanato-3-chlorobenzene for 1- isocyanato-3-methylbenzene in Example 1.
  • Example 3 N-[4-(4-aminothienor3,2-c1pyridin-3-yl)-2-fluorophenyl1-N'-r3-(trifluoromethyl)phenyl]urea
  • the desired product was prepared by substituting l-isocyanato-3- trifluoromethylbenzene for l-isocyanato-3-methylbenzene in Example 1.
  • Example 5 N-r4-(4-aminothieno[3,2-c1pyridin-3-yl)-2-fluorophenyl1-N'-(3-bromophenyl)urea
  • the desired product was prepared by substituting l-bromo-3-isocyanatobenzene for 1- isocyanato-3-methylbenzene in Example 1.
  • Example 6 N- r4-(4-aminothieno [3 ,2-clpyridin-3 -yl)-3 -fluorophenyl] -N'-(3 -methylphenyl)urea
  • Example 6A 3 -(4-amino-2-fluorophenyl)thieno [3 ,2-clpyridin-4-amine
  • the desired product was prepared by substituting 4-bromo-3-fluoroaniline for 4- bromo-2-fluoroaniHne in Example IC.
  • MS (ESI(+)) m/e 260.0 (M+H) + .
  • Example 6B N-r4-(4-aminothienor3,2-clpyridin-3-yl)-3-fluorophenyll-N'-(3-methylphenyl)urea
  • the desired product was prepared by substituting Example 6 A for Example IC in Example ID.
  • Example 7 N-r4-(4-aminothieno
  • the desired product was prepared by substituting Example 6A and l-isocyanato-3- (trifluoromethyl)benzene for Example IC and l-isocyanato-3-methylbenzene, respectively, in Example ID.
  • Example 8 N- 4-(4-aminothieno ⁇ ,2-c]pyridin-3-yl)-3 -fluorophenyl! -N'-(3 -chlorophenyl)urea
  • the desired product was prepared by substituting Example 6A and l-chloro-3- isocyanatobenzene for Example IC and l-isocyanato-3-methylbenzene, respectively, in Example ID.
  • Example 9 N-r4-(4-ammothienor3,2-c]pyridin-3-yl)-3-chlorophenyll-N'-(3-methylphenyl)urea
  • Example 9A 3-(4-amino-2-chlorophenyl)thieno ⁇ 3 ,2-clpyridin-4-amine
  • the desired product was prepared by substituting 4-bromo-3-chloroaniline for 4- bromo-2-fluoroaniline in Example IC.
  • MS (ESI(+)) m/e 275.9, 278.1 (M+H) + .
  • Example 9B N- 4-(4-aminothienor3,2-clpyridin-3-yl)-3-chlorophenyll-N'-(3-methylphenyl)urea
  • the desired product was prepared by substituting Example 9A for Example IC in Example ID.
  • Example 10A 3 -(4-phenoxyphenyl)thieno ⁇ 3 ,2-clpyridin-4-amine
  • Example 10B 7-iodo-3 -(4-phenoxyphenyl)thieno 3 ,2-clpyridin-4-amine
  • a solution of Example 10A (1.69g, 5.3 mmol) in DMF (20 mL) was treated with NIS (1.26g, 5.6 mmol), stirred at room temperature for 3 hours, poured into water, and filtered.
  • the filter cake was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide 1.64g (70% yield) of the desired product.
  • MS (ESI(+)) m e 444.8 (M+H) + .
  • Example 10C 3-(4-phenoxyphenyl)-7-(4-pyridinyl)thieno 3,2-clpyridin-4-amine
  • the desired product was prepared by substituting Example 10B, 4-pyridylboronic acid, and PdCl 2 (dppf) for Example IB, 4-phenoxyphenylboronic acid, and Pd(PPh 3 ) 4 respectively, in Example 10A.
  • Example 11 A tert-butyl (2E)-3-r4-amino-3-(4-phenoxyphenyl)thienor3,2-clpyridin-7-yllacrylate
  • a mixture of Example 10B (0.417g, 0.94 mmol), tert-butyl acrylate (0.26 mL, 1.74 mol) and triethylamine (0.7 mL, 5 mmol) in DMF (3 mL) was degassed with nitrogen for 45 minutes, treated with PdCl 2 (o-tol 3 P) 2 (0.032g, 0.046 mmol), and heated to 80 °C overnight. The resulting mixture was cooled to room temperature, then partitioned between water and ethyl acetate.
  • Example 11B (2E)-3-r4-amino-3-(4-phenoxyphenyl)thieno 3,2-c1pyridin-7-yllacrylic acid
  • a solution of Example 11 A (0.25g, 0.57 mmol) in TFA (5 mL) was stirred at room temperature for 14 hours then concentrated under a stream of nitrogen to provide the desired product.
  • MS (ESI(+)) m/e 388.9 (M+H) + .
  • Example 11C 4- ⁇ (2E)-3-r4-amino-3-(4-phenoxyphenyl)thieno 3,2-c1pyridin-7-yll-2-propenoyl ⁇ -2- piperazinone
  • a mixture of Example 11B (0.09g, 0.23 mmol), 2-piperazinone (0.069g, 0.69 mmol), HOBT (0.095g, 0.7 mmol), N-methylmorpholine (0.22 mL, 0.92 mmol), and EDCI (0.136g, 0.71 mmol) in DMF (1 mL) was stirred at room temperature overnight, treated with water (20 mL), and filtered. The filter cake was dried to provide 1 lOmg of the desired product.
  • Example 12 tert-butyl (2E)-3-(4-amino-3-phenylthienor3,2-clpyridin-7-yl)acrylate
  • Example 12A 7-iodo-3-phenyltMeno[3,2-c]pyridin-4-amine
  • the desired product was prepared by sxxbstituting phenylboronic acid for 4- phenoxyphenylboronic acid in Example 10A and 10B.
  • Example 12B tert-butyl (2E)-3-(4-amino-3-phenylthienor3,2-clpyridin-7-yl)acrylate
  • the desired product was prepared by substituting Example 12A for Example 10B in Example 1 IA.
  • Example 13 (2E)-3-(4-amino-3-phenylthienof3 ,2-clpyridin-7-yl)acrylic acid
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 12B for Example 1 IA in Example 1 IB.
  • Example 14 (2E)-3-(4-amino-3-phenylthienor3,2-clpyridin-7-yl)-N-methylacrylamide
  • Example 15 3-(4-amino-3-phenylthienor3,2-clpyridin-7-yl)-N-methylpropanamide
  • a mixture of Example 14 (30mg, O.lmmol) and 10% Pd on carbon (30 mg) in 1:1 methanol/DMF (4 mL) was stirred xmder an atmosphere of hydrogen overnight.
  • the suspension was filtered through diatomaceous earth (Celite ® ).
  • the pad was washed with methanol and the filtrate was concentrated to half its original volume.
  • the residue was diluted with diethyl ether and filtered.
  • the filter cake was dried to provide 26 mg of the desired product.
  • Example 16 4-r(2E)-3-(4-amino-3-phenylthienor3,2-c]pyridin-7-yl)-2-propenoyll-2 -piperazinone
  • the desired product was prepared by substituting Example 13 for Example 1 IB in
  • Example 17 tert-butyl (2E)-3- ⁇ 3-[4-(acetylamino)phenyll-4-aminothienor3,2-c1pyridin-7-yl
  • Example 17A 3 -(4-aminophenyl)thieno [3 ,2-clpyridin-4-amine
  • the desired product was prepared by substituting 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline for 4-phenoxyphenylboronic acid in Example 10A.
  • Example 17C N- [4-(4-amino-7-iodothieno [3 ,2-c]pyridin-3 -yl)phenyl] acetamide
  • the desired product was prepared by substituting Example 17B for Example 10A in Example 10B.
  • Example 17D tert-butyl (2E)-3- ⁇ 3-r4-(acetylamino)phenyll-4-aminothienor3,2-clpyridin-7-yl) acrylate
  • the desired product was prepared by substituting Example 17C for Example 10B in Example 11 A.
  • Example 18 (2E)-3- ⁇ 3-r4-(ace1ylamino)phenyll-4-aminothienor3,2-clpyridin-7-yl ⁇ acrylic acid
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 17D for Example 11A in Example 11B.
  • Example 19 (2E)-3- ⁇ 3-[4-(ace1 lammo)phenyl1-4-annnothienor3,2-c1pyridiri-7-yl ⁇ -N-methylacrylamide The desired product was prepared by substituting Example 18 for Example 13 in Example 14.
  • Example 20 N-(4- ⁇ 4-amino-7-r(lE)-3-oxo-3-(3-oxo-l-piperazinyl)-l-propenyl1thienor3,2-clpyridin-3- yl
  • the desired product was prepared by substituting Example 18 for Example 1 IB in Example 1 IC.
  • Example 21 A 3-bromo-7-iodothieno[3,2-clpyridin-4-amine The desired product was prepared by substituting Example IB for Example 10A in Example 10B.
  • Example 2 IB (2E)-3-(4-anuno-3-bromotMeno[3,2-clpyridin-7-yl)-N-methylac ⁇ ylamide
  • the desired product was prepared by substituting Example 21 A for Example 10B and methylamine for piperazin-2-one in Examples 11 A-C.
  • MS (ESI(+)) m e 311.6,313.6 (M+H) + .
  • Example 21C (2E)-3 - r4-amino-3 -(4-chlorophenyl)thieno [3 ,2-clpyridin-7-yll -N-methylacrylamide
  • a mixture of Example 21B (150mg, 0.48 mmol), 4-chlorophenylboronic acid (75mg, 0.48 mmol), PdCl 2 (PPh 3 ) 2 (3mg) and Cs 2 CO 3 (188 mg) in DME/water/ethanol (70:30:20 mixture, 2 mL) was heated in a sealed vial to 160 °C for 7.5 minutes with stirring in a Smith Synthesizer microwave oven (at 300W).
  • the reaction was partinioned between water and dichloromethane and the organic layer was concentrated.
  • the residue collected was purified by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7 ⁇ m particle size) using a gradient of 10%o to 100%> acetonitrile: 5 mM aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40mL/min to provide 59 mg (36% yield) of the desired product.
  • Examples 22-35 were prepared by substituting the appropriate boronic acid (X) for 4- chloro-phenylboronic acid in Example 21C.
  • Example 36 (2E)-3 - r4-amino-3-(3 -phenoxy- 1 -propynyl)thieno [3 ,2-clpyridin-7-yll -N-methylacrylamide
  • Examples 37-65 were prepared by substituting Example 17A and the appropriate isocyanide (X) for Example IC and l-isocyanato-3-methylbenzene, respectively, in Example ID.
  • the crude product was purified either by trituration from dichloromethane by flash column chromatography on silica gel.
  • X l-isocyanato-3-methylbenzene.
  • Example 66A 3-bromo-2-methylthieno[3,2-c1pyridin-4(5H)-one
  • the desired product was prepared by substituting 3-(4-bromo-5-methyl-2- thienyl)acrylic acid for (2E)-3-(4-bromo-2-thienyl)acrylic acid in Example 1 A.
  • Example 66B 3-bromo-2-methyl-7-nitrothieno 3,2-c1pyridin-4(5H)-one
  • nitric acid (1.68 mL, 70%, 26. 8 mmol) in sulftxric acid (5 mL)
  • sulftxric acid 5 mL
  • the resulting mixture was stirred at 0 °C for 1 hour, warmed to room temperature overnight, and poured into ice water.
  • the resulting precipitate was collected by filtration, washed with water, and dried in a vacuum oven to provide 2.47g (64 %> yield) of the desired product.
  • MS (ESI(+)) m e 290 (M+H) + .
  • Example 66C 3-bromo-2-methyl-7-nitrothienor3,2-clpyridin-4-amine
  • Example 66D N-(3-methylphenyl)-N'-r4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea
  • a 0 °C mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (5.03g, 23 mmol) and l-isocyanato-3-methylbenzene (2.95 mL, 23 mmol) in THF (90 mL) was stirred at room temperature for 1 hour, concentrated, suspended in acetonitrile, and filtered. The filter cake was dried to provide 8.09g of the desired product.
  • Example 66E N-r4-(4-amino-2-methyl-7-nitrothieno[3,2-clpyridin-3-yl)phenyl1-N'-(3-methylphenyl)urea
  • the desired product was prepared by substituting Example 66C and Example 66D for Example IB and 4-phenoxyphenylboronic acid, respectively, in Example 10A.
  • Example 67A 3-bromo-2-methylthienor3,2-clpyridin-4-amine
  • the desired product was prepared by substituting Example 66A for Example 1 A in Example IB.
  • Example 67B N-r4-(4-amino-2-methylthieno[3,2-clpyridin-3-yl)phenyll-N'-(3-methylphenyl)urea
  • the desired product was prepared by substituting Example 67 A and Example 66D for Example IB and 4-phenoxyphenylboronic acid, respectively, in Example 10A.
  • Example 68 N-r4-(4-amino-2-methylthieno 3,2-clpyridin-3-yl)phenyll-N'-(3-chlorophenyl)urea
  • the desired product was prepared by substituting Example 67A and 4-( ⁇ [(3- chlorophenyl)amino]carbonyl ⁇ amino)phenylboronic acid (prepared by substituting 1- isocyanato-3-chlorobenzene for l-isocyanato-3-methylbenzene in Example 66D) for Example IB and 4-phenoxyphenylboronic acid, respectively, in Example 10A.
  • Example 69 N- 4-(4-amino-2-methylthieno[ ' 3,2-c]pyridin-3-yl)phenyl1-5,7-dimethyl-l,3-benzoxazol-2- amine
  • Example 69A 5,7-dimethyl-N-r4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl
  • a mixture of l-bromo-4-isothiocyanatobenzene (63.92g, 0.298 mol) and THF (1200 mL) was treated with 2-amino-4,6-dimethylphenol (41.8g, 0.304 mol), stirred at room temperature for 3 hours, treated with EDCI (68.46g, 0.358 mol), warmed to 40 °C for 16 hours, cooled to room temperature, and filtered.
  • the filtrate was concentrated at 50 °C to a final volume of about 300 mL, treated with acetonitrile (800 mL), concentrated to a volume of about 200 mL, treated with acetonitrile (800 mL), and again concentrated to a volume of about 200 mL.
  • the mixture was treated with acetonitrile (800 mL), cooled to room temperature, and filtered.
  • the filter cake was washed with acetonitrile (100 mL) and dried to constant weight in a vacuum oven at 45 °C over 24 hours to provide 85.8g (85%) of 5,7- dimethyl-l,3-benzoxazol-2-amine.
  • the concentrate was treated with heptane (800 mL), concentrated, treated with heptane (900 mL), stirred at 50 °C for 30 minutes, cooled to room temperature over 2 hours, and filtered.
  • the filter cake was washed with 100 mL heptane and dried to constant weight in a vacuum oven at 45 °C over 24 hours to provide 68.3g (77%) of the desired product.
  • Example 69B N-r4-(4-amino-2-methylthieno[3,2-clpyridin-3-yl)phenyl1-5,7-dimethyl-l,3-benzoxazol-2- amine
  • the desired product was prepared by substituting Example 67A and Example 69A for Example IB and 4-phenoxyphenylboronic acid, respectively, in Example 10 A.
  • Example 70 N-r4-(4-aminothienor3,2-clpyridin-3-yl)phenyll-5,7-dimethyl-l,3-benzoxazol-2-amine
  • the desired product was prepared by substituting Example 69A for 4-phenoxyphenylboronic acid in Example 10A.
  • Example 71 N-[4-(4,7-diamino-2-methylthieno ,2-c1pyridin-3-yl)phenyll-N'-(3-methylphenyl)urea
  • a suspension of Example 66E (0.44g, 1.01 mmol), NH 4 C1 (0.054g, 1.01 mmol), and iron powder (0.45g, 8.1 mmol) in ethanol (16 mL) and water (4 mL) was heated at 80 °C for 3 hours, cooled to room temperature, and filtered through diatomaceous earth (Celite ® ). The pad was washed with ethyl acetate and ethanol and the filtrate was extracted three times with ethyl acetate.
  • Example 72C tert-butyl 3-bromo-2-methyl-7-[(3-pyridinylcarbonyl)aminolthienor3,2-clpyridin-4- ylcarbamate
  • the desired product was prepared by substituting Example 72B and nicotinoyl chloride for Example 17A and acetyl chloride, respectively, in Example 17B.
  • Example 72D N- ⁇ 4-amino-2-methyl-3-r4-( ⁇ r(3-methylphenyl)aminolcarbonyl ⁇ amino)phenyllthienor3,2- clpyridin-7-yl) nicotinamide
  • the desired product was prepared by substituting Example 72C and Example 66D for
  • Example IB and 4-phenoxyphenylboronic acid, respectively, in Example 10A were prepared and 4-phenoxyphenylboronic acid, respectively, in Example 10A.
  • Example 73 N- ⁇ 4-amino-2-methyl-3-F4-( ⁇ (3-methylphenyl)aminolcarbonyl ⁇ amino)phenyPthieno 3,2- c1pyridin-7-yl
  • the desired product was prepared by substituting 2-fluoro-5-trifluromethylbenzoyl chloride for nicotinoyl chloride in Examples 72C-D.
  • Example 74 N- ⁇ 4-amino-2-methyl-3-r4-( ⁇ [(3-methylphenyl)amino]carbonyl ⁇ amino)phenyllthienor3,2- clpyridin-7-yl ⁇ -3-(dimethylamino)benzamide
  • the desired product was prepared by substituting 3-dimethylaminobenzoyl chloride for nicotinoyl chloride in Examples 72C-D.
  • Example 75 N- ⁇ 4-amino-2-methyl-3-r4-( ⁇ r(3-methylphenyl)aminolcarbonyl ⁇ amino)phenyllthienof3,2- clpyridin-7-yl) pentanamide
  • the desired product was prepared by substituting pentanoyl chloride for nicotinoyl chloride in Examples 72C-D.
  • Example 76 N-r4-(4-amino-7-bromothieno[3,2-c ⁇ pyridin-3- ⁇ l)phenyll-N'-(3-methylphenyl)urea
  • Example 76A tert-butyl 4-(4-aminothienoF3,2-clpyridin-3-yl)phenylcarbamate
  • MS (ESI(-)) m/e 340 (M-H) " .
  • Example 76B tert-butyl 4-(4-amino-7-bromothienor3,2-clpyridin-3-yl)phenylcarbamate
  • a solution of bromine (0.4 mL, 4.6 mmol) in dichloromethane (5 mL) was added dropwise to a -5 °C solution of Example 76A (1.57g, 4.6 mmol) in dichloromethane (30 mL). The mixture was stirred at -5 °C to 0 °C for 15 minutes and quenched with 1:1 saturated NaHCO 3 and saturated NaHSO 3 (10 mL).
  • Example 76C 3-(4-aminophenyl)-7-bromothienor3,2-clpyridin-4-amine A solution of Example 76B (0.5g, 1.1 mmol) in TFA (4 mL) and dichloromethane (5 mL) was stirred at 0 °C for 5 minutes, warmed to room temperature for 2 hours, then concentrated.
  • Example 76D N-r4-(4-amino-7-bromothieno[ " 3,2-c1pyridin-3-yl)phenyl1-N'-(3-methylphenyl)urea
  • the desired product was prepared by substituting Example 76C for Example IC in Example ID.
  • Example 77A tert-butyl 4-(4-amino-7-iodothienor3,2-c1pyridin-3-yl)phenylcarbamate
  • the desired product was prepared by substituting Example 76 A for Example 10A in Example 10B.
  • Example 77B 3 -(4-aminophenyl)-7-iodothieno f 3 ,2-clpyridin-4-amine The desired product was, prepared by substituting Example 77 A for Example 76B in Example 76C.
  • Example 77C tert-butyl (2E)-3- ⁇ 4-amino-3-r4-( ⁇ r(3- methylphenyl)amino ⁇
  • the desired product was prepared by substituting Example 77B for Example 10B in Example 11 A then substituting the product for Example 1 C in Example ID. !
  • Example 78 (2E)-3- ⁇ 4-amino-3-r4-( ⁇ r(3-methylphenyl)aminolcarbonyl ⁇ amino)phenyl]thienor3,2- clpyridin-7-yl) acrylic acid
  • the desired product was prepared by substituting Example 77C for Example 11 A in Example 1 IB.
  • Examples 79-103 were prepared by substituting the appropriate amine (X), Example 78, and TBTU for 2-piperazinone, Example 11B, and HOBT, respectively, in Example llC.
  • Example 79 (2E)-3- ⁇ 4-amino-3-[4-( ⁇ r(3-methylphenyl)aminolcarbonyl ⁇ amino)phenyllthienor3,2- clpyridin-7-yl ⁇ -N,N-dimethylacrylamide X dimethylamine hydrochloride.
  • the product was prepared as the trifluoroacetate salt by purifying the crude product as described in Example 82.
  • the product was prepared as the trifluoroacetate salt by preparative HPLC purification on a Waters Symmetry C8 column (25mm x 100mm, 7 ⁇ m particle size) using a gradient of 10%> to 100%> acetonitrile/0.1 % aqueous TFA over 8 minutes (10 minute rxm time) at a flow rate of 40mL/min.
  • Example 103 N-((2E)-3 - ⁇ 4-amino-3 - 4-( ⁇ ⁇ (3 -methylphenyl)aminolcarbonyl ⁇ amino)phenyl]thieno [3 ,2- clpyridin-7-yl)-2-propenoyP- ⁇ -alanine
  • the desired product was prepared by substituting Example 97 for Example 11 A in Example 1 IB.
  • Example 104 N-((2E)-3- ⁇ 4-amino-3-r4-( ⁇ r(3-methylphenypamino1carbonyl ⁇ amino)phenyl1thieno 3,2- clpyridin-7-yl)-2-propenoypglycine
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 102 for Example 11 A in Example 1 IB.
  • Example 105 tert-butyl 3- ⁇ 4-amino-3-F4-( ⁇ [ ' (3-methylphenypamino]carbonyl ⁇ amino)phenyl]thienor3 ,2- clpyridin-7-yl ⁇ propanoate
  • the desired product was prepared by substituting Example 77 for Example 14 in Example 15.
  • Example 106 3- ⁇ 4-amino-3-r4-( ⁇ r(3-methylphenyl)ammolcarbonyl ⁇ amino)phenyl]thienor3,2-c]pyridin-7- yljpropanoic acid
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 105 for 11 A in Example 1 IB.
  • Example 107 3- ⁇ 4-amino-3-r4-( ⁇ r(3-methylphenyl)aminolcarbonyl ⁇ amino)phenyllthienor3,2-clpyridin-7- yl ⁇ -N-r2-(4-mo ⁇ holinyl)ethyllpropanamide
  • the desired product was prepared by substituting 2-(4-mo ⁇ holinyl)ethanamine, Example 106, and TBTU for 2-piperazinone, Example 1 IB, and HOBT, respectively, in Example 1 IC.
  • Example 108 3- ⁇ 4-amino-3-r4-( ⁇ [(3-methylphenyl)aminolcarbonyl ⁇ amino)phenyllthienof3,2-clpyridin-7- yl ⁇ -N-methylpropanamide
  • the desired product was prepared by substituting methylamine, Example 106, and TBTU for 2-piperazinone, Example 1 IB, and HOBT, respectively, in Example 1 IC.
  • the desired product was prepared by substituting Example 100 for Example 14 in Example 15.
  • Example 110 ethyl (2E)-3- ⁇ 4-ammo-3-r4-( ⁇ r(3-methylphenyPaminolcarbonyl ⁇ amino) ⁇ henyllthienor3,2- c]pyridin-7-yl ⁇ acrylate
  • the desired product was prepared by substituting Example 76B and ethyl acrylate for Example 10B and tert-butyl acrylate, respectively, in Example 11 A, then substituting the product for Example 76B in Examples 76C-D.
  • Example 111 ethyl 3- ⁇ 4-amino-3-[4-( ⁇ [(3-methylphenyPaminolcarbonyl ⁇ amino)phenyl]thieno[3,2- clpyridin-7-yl ⁇ propanoate
  • the desired prodxxct was prepared by substituting Example 110 for Example 14 in
  • Example 112 (2E)-3-[4-a-mino-3-(4-aminophenyl)thieno[3,2-clpyridin-7-yll-N-methylacrylamide
  • Example 112A (2E)-3 -r4-amino-3 -(4-aminophenyPthieno [3 ,2-c1pyridin-7-yl]acrylic acid
  • the desired product was prepared by substituting Example 77 A for Example 10B in Examples 11A-B.
  • Example 112B (2E)-3-r4-amino-3-(4-aminophenyPthieno[3,2-clpyridin-7-yll-N-methylacrylamide
  • the desired product was prepared by substituting methylamine, Example 112 A, and TBTU for 2-piperazinone, Example 1 IB, and HOBT, respectively, in Example 1 IC.
  • Example 113 N-(4- ⁇ 4-amino-7-r(lE)-3-(methylamino)-3-oxo-l-propenyllthienor3,2-c]pyridin-3- yl ⁇ phenyl)-3-methylbenzamide
  • the desired product was prepared by substituting 3-methylbenzoyl chloride and Example 112 for acetyl chloride and Example 17A, respectively, in Example 17B.
  • Example 114 (2E)-3-r4-amino-3-(4- ⁇ [(3-methylphenyl)sulfonyllamino ⁇ phenyl)thienor3,2-clpyridin-7-yll- N-methylacrylamide
  • a solution of 3-methylbenzenesulfonyl chloride (70mg, 0.37 mmol) in DMF (1 mL) was added dropwise to a -30 °C solution of Example 112 (0.117g, 0.36 mmol) and N- methylmo ⁇ holine (0.057 mL, 0.54 mmol) in DMF (3 mL).
  • Example 115 N-(4- ⁇ 4-amino-7-r(lE)-3-(methylamino)-3-oxo-l-propenynthieno[ " 3,2-clpyridin-3- yl ⁇ phenypbenzamide
  • the desired product was prepared by substituting benzoyl chloride and Example 112 for acetyl chloride and Example 17 A, respectively, in Example 17B.
  • Example 116 (2E)-3-(4-amino-3-phenylthieno 3,2-clpyridin-7-yP-N,N-dimethylacrylamide
  • the desired product was prepared by substituting dimethylamine for methylamine hydrochloride in Example 14.
  • Example 117 (2E)-3-r4-amino-3-(4-aminophenvpthienor3,2-clpyridin-7-yll-N-r4- (dimethylamino)butyl] acrylamide
  • the desired product was prepared by substituting N,N-dimethyl-l,4-butanediamine, Example 112A, and TBTU for 2-piperazinone, Example 1 IB, and HOBT, respectively, in Example 1 IC.
  • Example 118 (2E)-3-r4-amino-3-(4-aminophenyPthieno 3,2-clpyridin-7-yll-N-(3- pyridinylmethypacrylamide
  • the desired product was prepared by substituting l-(3-pyridinyl)methanamine, Example 112A, and TBTU for 2-piperazinone, Example 1 IB, and HOBT, respectively, in Example l lC.
  • Example 119 3-(4-aminophenyl)-7-r(lE)-3-oxo-3-(l-piperazinyP-l-propenyl1thienof3,2-c1pyridin-4-amine
  • the desired product was prepared as the bis-trifluoroacetate salt by substituting tert- butyl 1-piperazinecarboxylate and Example 112A for piperazin-2-one and Example 1 IB, respectively, in Example 1 IC, then by removing the protecting group following the procedure of Example 1 IB.
  • Example 120 3-r4-amino-3-(4-aminophenypthienor3,2-c ⁇ pyridin-7-yl]propanoic acid
  • the desired product was prepared by substituting Example 112A for Example 14 in Example 15.
  • Example 121 A tert-butyl 4-f4-amino-7-(4-pyridinyl)thienor3,2-c1pyridin-3-yllphenylcarbamate
  • Example 121B 3-(4-aminophenyl)-7-(4-pyridinyPthieno [3 ,2-clpyridin-4-amine
  • Example 122 N- ⁇ 4-r4-amino-7-(4-pyridinypthieno[ ' 3,2-clpyridin-3-yl1phenyl ⁇ -N'-r2-fluoro-5- (trifluoromethyPphenyllurea
  • a -20 °C solution of Example 121B (0.18g, 0.57 mmol) in DMF (3 mL) and THF (3 mL) was treated dropwise with l-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.085 mL, 0.57 mmol) and warmed to room temperature over 1.5 hours. The resulting mixture was diluted with water and extracted twice with ethyl acetate.
  • Example 123 N- ⁇ 4-r4-amino-7-(4-pyridinypthienor3,2-c]pyridin-3-yllphenyl ⁇ -N'-(2-fluoro-5- methylphenyl)urea
  • the desired product was prepared by substituting l-fluoro-2-isocyanato-4- methylbenzene for l-fluoro-2-isocyanato-4-(trifluoromethyl)benzene in Example 122.
  • J H NMR 300 MHz, DMSO-d 6 ) ⁇ 2.29 (s, 3H), 5.74 (s, 2H), 6.80-6.85 (m, IH), 7.12 (dd,
  • Example 124 3 -(4-aminophenyl)-7-(3 -pyridinypthieno [3 ,2-clpyridin-4-amine
  • the desired product was prepared by substituting 3-pyridylboronic acid for 4- pyridylboronic acid in Examples 121 A-B.
  • Example 126 3-(4-aminophenyP-7-(3-thienyPthieno[3,2-clpyridin-4-amine
  • the desired product was prepared by substituting Example 77B and 3-thienylboronic acid for Example 77A and 4-pyridylboronic acid, respectively, in Example 121A. !
  • Example 127 N- ⁇ 4-r4-amino-7-(3-thienyl)thienor3,2-clpyridin-3-yllphenyl ⁇ -N'-(3-methylphenyPurea
  • the desired product was prepared by substituting for l-isocyanato-3-methylbenzene and Example 126 for l-fluoro-2-isocyanato-4-(trifluoromethyl)benzene and Example 121B, respectively, in Example 122.
  • Example 128A 3-(4-aminophenyp-7-(6-methoxy-3-pyridinypthieno 3,2-clpyridin-4-amine
  • the desired product was prepared by substituting Example 77B and 6-methoxy-3- pyridinylboronic acid for Example 77A and 4-pyridylboronic acid, respectively, in Example 121A.
  • MS (ESI(+)) m/e 349 (M+H) + .
  • Example 128B N- ⁇ 4-r4-amino-7-(6-methoxy-3-pyridinyl)thieno[3,2-clpyridin-3-yl1phenyl ⁇ -N'-F2-fluoro-5- (trifluoromethyPphenyllurea
  • the desired product was prepared by substituting Example 128A for Example 121B in Example 122.
  • Example 129 N- ⁇ 4-r4-amino-7-(6-methoxy-3-pyridinypthienor3,2-c1pyridin-3-yllphenyl ⁇ -N'-(2-fluoro-5- methylphenyPurea
  • the desired product was prepared by substituting for l-fluoro-2-isocyanato-4- methylbenzene and Example 128A for l-fluoro-2-isocyanato-4-(trifluoromethyl)benzene and Example 121B, respectively, in Example 122.
  • Example 130 N- ⁇ 4-r4-amino-7-(6-methoxy-3-pyridinypthienor3,2-clpyridin-3-yllphenyl ⁇ -N'-r3- (trifluoromethypphenyllurea
  • the desired product was prepared by substituting for l-isocyanato-3- (trifluoromethyl)benzene and Example 128A for l-fluoro-2-isocyanato-4- (trifluoromethyl)benzene and Example 121B, respectively, in Example 122.
  • Example 131 N- ⁇ 4- 4-amino-7-(4-cyanophenypthienor3,2-clpyridin-3-yllphenyl ⁇ -N'-r2-fluoro-5- (trifluoromethyl)phenyllurea
  • Example 131 A 4-r4-Amino-3-(4-amino-phenyP-thieno 3,2-clpyridin-7-yll-benzonitrile
  • the desired product was prepared by substituting Example 77B and 4- cyanophenylboronic acid for Example 77A and 4-pyridylboronic acid, respectively, in Example 121A.
  • MS (ESI(+)) m/e 343 (M+H) + .
  • Example 13 IB N- ⁇ 4- 4-amino-7-(4-cyanophenyPthieno[3,2-c1pyridin-3-yl ⁇ phenyl ⁇ -N'-r2-fluoro-5- (trifluoromethypphenyllurea
  • the desired product was prepared by substituting Example 131 A for Example 121B in Example 122.
  • Example 132 N- ⁇ 4-r4-amino-7-(4-cyanophenypthieno[3,2-clpyridin-3-yl1phenyl ⁇ -N'-(2-fluoro-5- methylphenypurea
  • the desired product was prepared by substituting for l-fluoro-2-isocyanato-4- methylbenzene and Example 131 A for l-fluoro-2-isocyanato-4-(trifluoromethyl)benzene and Example 121B, respectively, in Example 122.
  • Example 133 A 3-(4-aminophenyP-7-(2-methoxy-5-pyrimidinypthieno 3,2-clpyridin-4-amine The desired product was prepared by substituting 2-methoxy-5-pyrimidinylboronic acid for 4-pyridylboronic acid in Examples 121A-B. MS (ESI(+)) m/e 350 (M+H) + .
  • Example 133B N- ⁇ 4-r4-amino-7-(2-methoxy-5-pyrimidinyPthieno[3,2-clpyridin-3-yllphenyl ⁇ -N'-r2-fluoro- 5 -(trifluoromethypphenyllxxrea The desired prodxxct was prepared by substituting Example 131A for Example 121B in Example 122.
  • Example 134 N- ⁇ 4-r4-amino-7-(2-methoxy-5-pyrimidinypthieno[3,2-clpyridin-3-yllphenyl ⁇ -N'-f3- (trifluoromethypphenyllurea
  • the desired product was prepared by substituting l-isocyanato-3- (trifluoromethyl)benzene and Example 131 A for l-fluoro-2-isocyanato-4- (trifluoromethypbenzene and Example 121B, respectively, in Example 122.
  • Example 135 A 3-(4-an ⁇ mophenyp-7-(2,6-dimethyl-3-pyridinypthienor3,2-clpyridin-4-amine The desired product was prepared by substituting 2,6-dimethyl-3-pyridinylboronic acid for 4-pyridylboronic acid in Examples 121A-B. MS (ESI(+)) m/e 347 (M+H) + .
  • Example 135B N- ⁇ 4-r4-anuno-7-(2,6-dimethyl-3-pyridinyl)thienor3,2-clpyridin-3-yllphenyl ⁇ -N'-r2-fluoro- 5-(trifluoromethyl)phenyl1urea
  • the desired product was prepared by substituting Example 135A for Example 121B in Example 122.
  • Example 136 A 3-(4-aminophenyp-7-(5-pyrimidinyl)thieno[3,2-clpyridin-4-amine The desired product was prepared by substituting 5-pyrimidinylboronic acid for 4- pyridylboronic acid in Examples 121A-B. MS (ESI(+)) m e 320 (M+H) + .
  • Example 136B N- ⁇ 4- 4-amino-7-(5-pyrimidinyPthienof3,2-clpyridin-3-yllphenyl ⁇ -N'-(3-methylphenyPurea
  • the desired product was prepared by substituting l-isocyanato-3-methylbenzene and Example 136A for l-fluoro-2-isocyanato-4-(trifluoromethyl)benzene and Example 121B, respectively, in Example 122.
  • Example 137 N- ⁇ 4-F4-ammo-7-(5-pyrirnidinyl)thienor3,2-c1pyridin-3-yllphenyl ⁇ -N'-r2-fluoro-5- (trifluoromethyPphenyllurea
  • the desired product was prepared by substituting Example 136A for Example 121B in Example 122.
  • Example 138 3-(4-aminophenyp-7-r4-(benzylox ⁇ )phenyl1tMenor3,2-c]pyridin-4-amine
  • the desired product was prepared by substituting Example 77B and 4- benzyloxyphenylboronic acid for Example 77A and 4-pyridylboronic acid, respectively, in Example 121A.
  • Example 139 4-r4-amino-3-(4-aminophenyPthieno[3,2-c]pyridin-7-yllphenol A suspension of Example 138 (132 mg) in 48% HBr (2 L) and acetic acid (4 mL) was heated to 80 °C for 3 hours. The resxxlting homogeneous solution was concentrated and the residue was triturated from ethanol/diethyl ether to provide 130 mg of the desired product the dihydrobromide salt.
  • Example 140 N- ⁇ 4-r4-amino-7-(4-hydroxyphenyPthienor3,2-c1pyridin-3-yllphenyl ⁇ -N'-(3- methylphenyPurea
  • the desired product was prepared as the hydrobromide salt by substituting Example 138 for Example IC in Example ID, then substituting the product for Example 138 in Example 139.
  • Example 141 3 - ⁇ 4-amino-3 - ⁇ 4-( ⁇ f (3 -methylphenyPammoicarbonyl ⁇ amino)phenyll thieno ⁇ ,2-clpyridin-7- yl ⁇ -N-methylbenzamide
  • the desired product was prepared as the trifluoroacetate salt by substituting 3- [(methylamino)carbonyl]phenylboronic acid for 4-pyridylboronic acid in Examples 121 A-B, then substituting the product and l-isocyanato-3-methylbenzene for Example 121B and 1- fluoro-2-isocyanato-4-(trifluoromethyl)benzene, respectively, in Example 122.
  • Example 142 N-r4-(4-ammo-7-phenylthieno[3,2-clpyridin-3-yPphenyll-N'-(3-methylphenyl)urea
  • the desired product was prepared by substituting phenylboronic acid for 4- pyridylboronic acid in Examples 121 A-B, then substituting the product and l-isocyanato-3- methylbenzene for Example 12 IB and l-fluoro-2-isocyanato-4-(trifluoromethyl)benzene, respectively, in Example 122.
  • Example 143 N- ⁇ 4-[ " 4-amino-7-(4-pyridinypthienor3,2-clpyridm-3-yllphenyl ⁇ -N'-(3-methylphenyl)urea
  • the desired product was prepared by substituting l-isocyanato-3-methylbenzene for l-fluoro-2-isocyanato-4-(trifluoromethyl)benzene in Example 122. !
  • Example 144A N-[4-(4-amino-7-iodothieno[3,2-clpyridin-3-yPphenyll-N'-(3-methylphenyPurea The desired product was prepared by substituting Example 77B for Example IC in Example ID. MS (ESI(+)) m/e 501 (M+H) + .
  • Example 144B N- ⁇ 4-r4-amino-7-(4-hydroxy-l-butynyl)thienor3,2-clpyridin-3-yl1phenyl ⁇ -N'-(3- methylphenyPurea
  • a suspension of Example 144A (0.227g, 0.45 mmol) in piperidine (3 mL) was degassed by bubbling nitrogen through the suspension for 5 minutes, treated with 3-butyn-l- ol (0.069 mL, 0.91 mmol), Pd(PPh 3 ) 4 (26mg, 0.023 mmol), and Cul (5mg, 0.023 mmol), then heated to 80 °C in a sealed tube for 30 minutes.
  • the resulting homogeneous solution was cooled to room temperature and concentrated under a stream of nitrogen.
  • the residue was pxxrified by flash column chromatography on silica gel with 5% > methanol/dichloromethane to provide 164 mg (81%) of the desired product.
  • Examples 145-156 were prepared by substitxxting the appropriate al yne (X) for 3- butyn- 1 -ol in Example 144B .
  • the product was prepared as the trifluoroacetate salt by HPLC purification using the conditions described in Example 82.
  • the product was prepared as the trifluoroacetate salt by HPLC purification using the conditions described in Example 82.
  • the product was prepared as the trifluoroacetate salt by HPLC purification using the conditions described in Example 82.
  • the product was prepared as the trifluoroacetate salt by HPLC purification using the conditions described in Example 82.
  • the product was prepared as the trifluoroacetate salt by HPLC purification using the conditions described in Example 82.
  • the product was prepared as the bis(trifluoroacetate) salt by HPLC purification using the conditions described in Example 82.
  • Example 157 N- ⁇ 4- f 4-amino-7-(4-hydroxybxxtyPthieno ⁇ 3 ,2-c " lpyridin-3 -yllphenyl ⁇ -N'-(3 - methylphenypurea
  • the desired product was prepared by substituting Example 144B for Example 14 in Example 15.
  • Example 158 3-(4-aminophenyP-7-(4-isoquinolinyPthienor3,2-clpyridin-4-amine
  • the desired product was prepared by substituting 4-isoquinolinylboronic acid for 4- pyridylboronic acid in Examples 121 A-B.
  • Example 159 3-(4-aminophenyP-7-(2,6-difluoro-3-pyridinypthienor3,2-clpyridin-4-amine
  • the desired product was prepared by substituting 2,6-difluoro-3-pyridinylboronic acid for 4-pyridylboronic acid in Examples 121 A-B.
  • MS (ESI(+)) m/e 355 (M+H) + .
  • Example 160 3 -( 1 H-indol-6-yPthieno f 3 ,2-clpyridin-4-amine
  • the desired product was prepared by substituting lH-mdol-6-ylboronic acid for 4- phenoxyphenylboronic acid in Example 10A.
  • Example 161 N- ⁇ 4- 4-amino-7-(2,6-difluoro-3-pyridinyPthienoF3,2-clpyridin-3-yl1phenyl ⁇ -N'-(2-fluoro-5- methylphenypurea
  • the desired product was prepared by substituting Example 159 and l-fluoro-2- isocyanato-4-methylbenzene for Example 121 and l-fluoro-2-isocyanato-4- (trifluoromethypbenzene, respectively, in Example 122.
  • Example 162 N- ⁇ 4-r4-amino-7-(2,6-difluoro-3-pyridinyl)thienor3,2-clpyridin-3-yllphenyl ⁇ -N'-(3- methylphenyPurea
  • the desired product was prepared by sxxbstituting Example 159 and l-isocyanato-3- methylbenzene for Example 121 and l-fluoro-2-isocyanato-4-(trfluoromethy)benzene, respectively, in Example 122.
  • Example 163 N- ⁇ 4-r4-amino-7-(4-isoquinolinypthieno[3,2-clpyridin-3-yl1phenyl ⁇ -N'-r2-fluoro-5- (trifluoromethypphenyllurea
  • the desired product was prepared by substituting Example 158 for Example 121 in Example 122.
  • ⁇ NMR 300 MHz, DMSO-d 6 ) ⁇ 5.69 (s, 2H), 7.39-7.74 (m, IH), 7.46 (d,
  • Example 164 N- ⁇ 4-r4-amino-7-(4-isoquinolinyPthienor3,2-c1pyridin-3-yllphenyl ⁇ -N'-(3- methylphenyPurea
  • the desired product was prepared by substituting Example 158 and l-isocyanato-3- methylbenzene for Example 121 and l-fluoro-2-isocyanato-4-(trfluoromethy)benzene, respectively, in Example 122.
  • Example 165 N- ⁇ 4-r4-ammo-7-(3-pyridinyPthienor3,2-c1pyridin-3-yl]phenyl ⁇ -N'-[2-fluoro-5- (trifluoromethyl)phenyllurea
  • the desired product was prepared by substituting Example 124 for Example 121 in Example 122.
  • Example 166 N- (4- [4-amino-7-(3 -pyridinyPthieno [3 ,2-clpyridin-3 -yllphenyl ⁇ -N'-(2-fluoro-5- methylphenyPurea
  • the desired product was prepared by substituting Example 124 and l-fluoro-2- isocyanato-4-methylbenzene for Example 121 and l-fluoro-2-isocyanato-4- (trfluoromethy)benzene, respectively, in Example 122.
  • Examples 167-170 were prepared substituting the appropriate boronic acid (X) for 4- chlorophenylboronic acid in Example 21C.
  • Example 171 A (2E)-3-r4-amino-3-(4-bromophenyPthieno[3,2-clpyridin-7-yl1acrylic acid The desired compound was prepared by substituting Example IB for Example 10A in
  • Example 10B then substituting the product and methylamine for Example 11 A and piperazin-2-one, respectively, in Examples 11 A-B.
  • Example 17 IB (2E)-3-r4-amino-3-(4-bromophenyPthienor3,2-clpyridin-7-yl1-N-(4- pyridinylmethypacrylamide
  • the desired prodict was prepared as the bis(trifluoroacetate) salt substituting l-(4- pyridinypmethanamine and Example 171 A for methylamine and Example 13, respectively, in Example 14, then purifying the product by HPLC using the conditions described in Example 82.
  • Example 175 A 4-bromo-2-methoxyaniline A mixture of o-anisidine (27. Ig, 219 mmol) and dichloromethane (500 mL) was stirred under an atmosphere of nitrogen and treated with 2,4,4,6-tetrabromo-2,5- cyclohexadienone (90.0g, 219 mmol) in four roughly equal portions over the course of 20 minutes. The temperature of the reaction was maintained between 10 and 15 °C by cooling with a cold water bath during the addition of the 2,4,4,6-tetrabromo-2,5-cyclohexadienone.
  • Example 175B tert-butyl 4-bromo-2-methoxyphenylcarbamate
  • a mixture of Example 175A (36.4g, 180 mmol), and di-tert-butyl dicarbonate (47.2g, 216 mmol) in THF (500 mL) was heated to reflux for 20 hours and cooled to ambient temperature.
  • Example 175C tert-butyl 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yPphenylcarbamate
  • a mixture of Example 175B (61.3g, 203 mmol), 4,4,4',4',5,5,5 ' ,5'-octamethyl-2,2 ' -bi- 1,3,2-dioxaborolane (51.6g, 203 mmol), [l.T- bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (3.2g, 3.9 mmol), and potassium acetate (59.7g, 609 mmol) in DMF (1.0 L) was heated to 80 °C under
  • Example 175D tert-butyl 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenylcarbamate
  • dichloromethane 270 mL
  • a 1 : 1 solution of TFA/dichloromethane 500 mL
  • the reaction was warmed to ambient temperature and stirred for 2 hours.
  • the solvents were removed by evaporation at a pressure of 30 Torr and a bath temperature of ⁇ 30 °C.
  • Example 175E N- r2-methoxy-4-(4,4, 5 , 5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yPphenyl]- 1 -methyl- 1 H-indole-3 - carboxamide
  • a mixture of Example 175D (19.75g, 79.3 mmol) in dichloromethane (150 mL) was treated with N,N-diisopropylethylamine (12.3g, 95.2 mmol), cooled to ⁇ 5 °C with an ice bath, and treated slowly with a solution of 1 -methyl- lH-indole-2-carbonyl chloride (87.3 mmol) in dichloromethane (300 mL) while maintaining the reaction temperature below 5 °C.
  • the mixture was warmed to ambient temperature, stirred for 12 hours, extracted twice with water (150 mL, 100 mL), once with brine (100 mL), dried (MgSO 4 ), filtered, and concentrated.
  • the material was purified by flash chromatography using 400g of silica gel and 3 : 1 heptane/ethyl acetate to provide the desired product (30.3g, 94%).
  • Example 176A 3-bromo-7-r(lE)-3,3-diethoxy-l-propenyl1thienor3,2-c]pyridin-4-amine
  • a mixture Example 21A (200mg, 0.56 m ol), 2-[(lE)-3,3-diethoxy-l-propenyl]- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (175mg, 0.67 mmol), Pd(PPh 3 ) 4 (40mg, 0.03 mmol) and N-- 2 CO 3 (120mg, 1.13 mmol) in 1,2-dimethoxy ethane (10 mL) and water (5 mL) was heated in an 85 °C oil bath for 15 hours.
  • Example 176B N-(4- ⁇ 4-amino-7-[(lE)-3,3-diethoxy-l-propenyllthienor3,2-c]pyridin-3-yl ⁇ -2- methoxypheny I)- 1 -methyl- 1 H-indole-2-carboxamide
  • Example 176C N-(4- ⁇ 4-amino-7-r( 1 E)-3-oxo- 1 -propenyl]thieno [3 ,2-c]pyridin-3 -yl ⁇ -2-methoxyphenyl)- 1 - methyl-lH-indole-2-carboxamide
  • a mixture of Example 176B (90mg, 0.16 mmol) in acetone (9 mL) and water (1 mL) was treated with p-toluenesulfonic acid (5mg, 0.016 mmol) then stirred for 30 minutes. The solvent was evaporated under reduced pressure then the residue was partitioned between dichloromethane and water.
  • Example 176C (40mg, 0.083 mmol), sodium triacetoxyborohydride (35mg, 0.166 mmol) and the appropriate amine (0.166 mmol) in 1,2-dichloromethane (2 mL) were stirred for 2 to 72 hours at ambient temperature. The mixture was concentrated and the product was purified by normal or reverse phase chromatography.
  • Example 178 N-(4- ⁇ 4-amino-7-[(l E)-3-(ethylamino)- 1 -propenypthieno ⁇ ,2-c]pyridin-3 -yl ⁇ -2- methoxyphenyP- 1 -methyl- 1 H-indole-2-carboxamide amine ' : ethylamine.
  • Example 180 N- ⁇ 4-r4-amino-7-((lE)-3- ⁇ r3-(5-methyl-lH-pyrazol-4-yppropynamino ⁇ -l- propenypthienor3,2-c]pyridin-3-yl]-2-methoxyphenyl ⁇ -l-methyl-lH-indole-2-carboxamide amine: 3-(5-methyl-lH-pyrazol-4-yl)-l-propanamine.
  • Example 181 N- ⁇ 4-r4-ammo-7-((lE)-3- ⁇ r(5-methyl-2-pyrazinypmethyllamino ⁇ -l-propenyl)thieno[3,2- c]pyridin-3-yl]-2-methoxyphenyl ⁇ -l-methyl-lH " indole-2-carboxamide amine: (5-methyl-2-pyrazinyl)methylamine.
  • Example 182 N-(4- ⁇ 4-amino-7-r(lE)-3-(4-phenyl-l-piperazinyp-l-propenyl]thieno[3,2-c]pyridin-3-yl ⁇ -2- methoxyphenyl)- 1 -methyl- 1 H-indole-2-carboxamide amine: 1-phenylpiperazine.
  • Purification by reverse phase HPLC using ammonium acetate buffer followed by lyophilization provided the desired product as the diacetate salt.
  • Example 190 N- 4-(4-amino-7- ⁇ ( 1 E)-3- r4-(2-hydroxy ethyl)- 1 -piperidinyl] - 1 -propenyl ⁇ thieno 3 ,2- c]pyridin-3 -yp-2-methoxyphenyl]- 1 -methyl- 1 H-indole-2-carboxamide amine: 2-(4-piperidinyl)ethanol. Purification by reverse phase HPLC using ammonium acetate buffer followed by lyophilization provided the desired product as the diacetate salt.
  • Example 191 N-(4- ⁇ 7- ⁇ ( 1 E)-3-(4-acetyl- 1 -piperazinyl)- 1 -propenyl]-4-aminothieno [3 ,2-c]pyridin-3-yl ⁇ -2- methoxyphenyl)-l-methyl-lH-indole-2-carboxamide amine: 1-acetylpiperazine. Pxirification by reverse phase HPLC using ammonium acetate buffer followed by lyophilization provided the desired product as the acetate salt.
  • Example 192 N-(4- ⁇ 4-amino-7-r(lE)-3-(4-methyl-l-piperazinyP-l-propenyl]thieno[3,2-clpyridin-3-yl ⁇ -2- • methoxyphenyl)- 1 -methyl- 1 H-indole-2-carboxamide amine: 1-methylpiperazine.
  • Example 195 N- ⁇ 4-r4-amino-7-((lE)-3- ⁇ r2-(l-methyl-2-p ⁇ rrolidinyPethyllamino ⁇ -l-propenyl)thienor3,2- clpyridin-3 -yll -2-methoxyphenyl ⁇ - 1 -methyl- 1 H-indole-2-carboxamide amine: 2-(l-methyl-2-pyrrolidinyl)ethanamine. Purification by reverse phase HPLC using ammonium acetate buffer followed by lyophilization provided the desired product as the diacetate salt.
  • Example 196 N- 4-(4-amino-7- ⁇ (lE)-3-r(4-pyridinylmethyPammol-l-propenyl ⁇ thienor3,2-clpyridin-3-yP- 2-methoxyphenyl]-l-methyl-lH-indole-2-carboxamide amine: l-(4-pyridinyl)methanamine. Purification by reverse phase HPLC using ammonium acetate buffer followed by lyophilization provided the desired product as the diacetate salt.
  • Example 197 A tert-butyl (2E)-3-(4-amino-3-bromothienor3,2-clpyridin-7-yP-2-propenylcarbamate
  • Example 197B tert-butyl (2E)-3-r4-amino-3-(3-methoxy-4- ⁇ r(l-methyl-lH-indol-2- yl)carbonvnamino ⁇ phenyl)thieno[ ' 3,2-c1pyridin-7-yl]-2 -propenylcarbamate
  • Example 197C N-(4- ⁇ 4-amino-7-r(lE)-3-amino-l-propenyllthienor3,2-clpyridin-3-yl ⁇ -2-methoxyphenyl)-l- methyl- 1 H-indole-2-carboxamide
  • a mixture of Example 197B (250mg, 0.43 mmol), 6N HCI (2.5 mL), and acetone (5 mL) was stirred for 3 hours at ambient temperature and heated to 40 °C for 4 hours. The mixture was partitioned between 2N NaOH (10 mL) and dichloromethane (20 mL). The organic layer was separated and the aqueous layer was further extracted with dichloromethane (2 x 20 mL).
  • Example 197C General Procedure for the Preparation of Amides, Sulfonamides, Carbamates and Ureas from Example 197C
  • a mixture of Example 197C (30mg, 0.062 mmol) in dichloromethane (2 mL) and pyridine (0.1 mL) was treated with the appropriate acid chloride, sulfonyl chloride, or alkylchloroformate (1.2 eq) at ambient temperature.
  • Ureas were prepared in the same manner from Example 197C and the appropriate isocyanate, but pyridine was omitted from the reaction mixture. The mixtures were stirred for 2 hours at ambient temperature and concentrated. The products were purified by normal or reverse phase chromatography.
  • Example 200 methyl (2E)-3-r4-amino-3-(3-methoxy-4- ⁇ ⁇ (1 -methyl- lH-indol-2- yl)carbonyPamino ⁇ phenyPthienor3,2-c]pyridin-7-yl1-2 -propenylcarbamate starting reagent: methyl chloroformate.
  • Reverse phase HPLC (5%> to 95 % acetonitrile over 10 minutes, 1 mL/min, 254 nm, hypersil HS 100 A, C18, 5 ⁇ m, 250 x 4.6 column)
  • Example 202 N-r4-(4-ammo-7- ⁇ (lE)-3-r(3-pyridinylcarbonyl)aminol-l-propenyl ⁇ tMenor3,2-clpyridin-3- yl)-2-methoxyphenyll-l-methyl-lH-indole-2-carboxamide starting reagent: nicotinyl chloride.
  • Example 203 N-(4- ⁇ 4-amino-7-[(lE)-3-(isonicotinoylamino)-l-propenyllthienor3,2-clpyridin-3-yI ⁇ -2- methoxyphenyl)-l-methyl-lH-indole-2-carboxamide starting reagent: isonicotinyl chloride.
  • Example 205 N-r4-(4-amino-7- ⁇ (lE)-3-r(anilinocarbonyl)aminol-l-propenyl ⁇ thienor3,2-clpyridin-3-yP-2- -, methoxyphenyl]- 1 -methyl- 1 H-indole-2-carboxamide starting reagent: isocyanatobenzene.
  • Example 206 N-(4- ⁇ 4-ammo-7-r(lE)-3-(benzoylammo)-l-propenylltMenor3,2-c1pyridin-3-yl ⁇ -2- methoxyphenyp-l-methyl-lH-indole-2-carboxamide starting reagent: benzoyl chloride.
  • Example 21A (0.250g, 0.74 mmol) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was treated with the appropriate boronic acid (0.85 mmol), Na-,CO 3 (0.179g, 1.69 mmol) and Pd(PPh 3 ) 4 (0.081 g, 0.07 mmol) at 80 °C for 18 hours.
  • the organic solvent was removed in vacuo and the solid was isolated by filtration and purified by flash column chromatography on silica gel with 2% methanol/dichloromethane to provide the desired product in 40-88 % yield.
  • Example 210 3-bromo-7-(3-furyl)thienor3,2-clpyridin-4-amine boronic acid: 3-furylboronic acid.
  • Example 211 3-bromo-7-(4-pyridi ⁇ yPthienor3,2-cTpyridin-4-amine boronic acid: 4-pyridinylboronic acid.
  • Example 212 3-bromo-7-(3-pyridinyPthienor3,2-clpyridin-4-amine boronic acid: 3 -pyridinylboronic acid.
  • Example 214 3-bromo-7-(2-thienyl)thieno 3,2-c1pyridin-4-amine boronic acid: 2-thienylboronic acid.
  • the residue was purified by preparative reverse phase HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 40%> acetonitrile/O.lM ammonium acetate isocratic for 5 minutes, then 40-100% acetonitrile/O.lM ammonium acetate over 30 minutes, 21 mL/min).
  • the acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to provide the desired product.
  • Example 216 N- ⁇ 4-[4-amino-7-(4-pyridinypthienor3,2-clpyridin-3-yll-2-methoxyphenyl ⁇ -l-methyl-lH- indole-2-carboxamide bromide: Example 211.
  • Example 218 N- ⁇ 4- [4-amino-7-(3 -pyridinypthieno f3 ,2-c]p ⁇ ridin-3 -yl] -2 -methoxyphenyl ⁇ - 1 -methyl- 1 H- indole-2-carboxamide bromide: Example 212.
  • Example 219A 3-bromothieno[3,2-clpyridin-4-amine
  • a mixture of 3-bromo-4-chlorothieno[3,2-c]pyridine (prepared according to the procedure described in Bull. Soc. Chim. Beiges 1970, 79, 407-414, 3g, 12 mmol), concentrated aqueous NH 4 OH (100 mL), and p-dioxane (100 mL) was sealed in a stainless steel, high-pressure reactor and stirred for 18 hours at 150 °C. The mixture was concentrated to half its original volume, diluted with water, and extracted with ethyl acetate.
  • Example 219B 3-(4-phenoxyphenyPthienol3,2-c1pyridin-4-amine
  • a mixture of Example 219A (5.43g, 23.7 mmol), 4-phenoxyphenylboronic acid (6g, 28.03 mmol), Na ⁇ O, (3.7g, 34.9 mmol), Pd(PPh 3 ) 4 (5.4g, 4.7 mmol), DMF (96 mL), and water (24 mL) was stirred for 18 hours at 80 °C under nitrogen, poured into 10% aqueous NaCl (400 mL), and extracted with ethyl acetate (3 x 70 mL).
  • Example 220 N-[4-(4-aminothienor3,2-c1pyridin-3-yl)-2-methoxyphenyll-l-methyl-lH-indole-2- carboxamide
  • the desired product was prepared by substituting Example 175E for 4- phenoxyphenylboronic acid in Example 219B.
  • Example 221 tert-butyl (2E)-3-r4-amino-3-(4-phenoxyphenyl)thienor3,2-clpyridin-7-yl1acrylate
  • Example 221 A 7-iodo-3 -(4-phenoxyphenypthieno [3 ,2-clpyridin-4-amine
  • N- iodosuccinimide 4.23 g, 18.8 mmol
  • Example 22 IB tert-butyl (2E)-3 - 4-amino-3 -(4-phenoxyphenyl)thieno [3 ,2-c1pyridin-7-yl1acrylate A mixture of Example 221 A (2g, 4.5 mmol), tert-butyl acrylate (1.3 mL, 8.8 mmol),
  • the preabsorbed silica gel was subsequently- transferred to a silica gel (200 g) column and chromatographed with ethyl acetate/heptane (1 :6) to provide 1.52 g (76%.) of the desired product.
  • Example 222 butyl (2E)-3-r4-amino-3-(4-phenoxyphenyl)thienor3,2-clpyridin-7-yllacrylate
  • the desired product was prepared by substituting butyl acrylate for tert-butyl acrylate in Example 221.
  • Example 223 ethyl (2E)-3-r4-amino-3-(4-phenoxyphenyPthieno 3,2-clpyridin-7-yllacrylate
  • the desired product was prepared by substituting ethyl acrylate for tert-bxxtyl acrylate in Example 221.
  • Example 224 (2E)-3-r4-amino-3-(4-phenoxyphenyPthienor3,2-c1pyridin-7-yll-2-propen-l-ol
  • a solution of Example 223 (0.45g, 10.8 mmol) in THF at -78 °C was treated with 5.4 mL DIBAL-H solution (1.0M in toluene, 5.4 mmol) and methanol (1 mL), warmed to room temperature, and concentrated. The residue was dissolved in methanol (100 mL), treated with silica gel (5g), and concentrated.
  • Example 225 (2E)-3 - [4-amino-3 -(4-phenoxyphenyl)thieno [3 ,2-c1pyridin-7-yl1 acrylic acid
  • a solution of Example 22 IB (1.5g, 3.4 mmol) in dichloromethane and trifluoroacetic acid (10 mL) was stirred for 2 hours at ambient temperature, treated with toluene (200 mL), and concentrated to provide 1.7g (100%) of the desired product as the trifluoroacetate salt.
  • Example 226 (2E)-3 - r4-amino-3 -(4-phenoxyphenyl)thieno [3 ,2-clpyridin-7-yll acrylic acid
  • a solution of Example 225 (1.2g, 2.3 mmol) and p-dioxane (50 mL) was treated with 2.5M HCI. The mixture was stirred for 20 minutes at ambient temperature and concentrated. The process was repeated once more after which the residue was azeotropically dried with toluene (2 x 100 mL) to provide the desired product hydrochloride salt.
  • Example 228 (2E)-3-r4-amino-3-(4-phenoxyphenypthienor3,2-c1pyridin-7-yll-N-(3- pyrrolidinylmethyPacrylamide
  • the desired product was prepared by dissolving Example 227 in dichloromethane (8 mL) and adding TFA (2 mL). The mixture was stirred for 4 hours at room temperature and concentrated to provide the desired product.
  • Example 229A tert-butyU3R)-3-r( ⁇ (2E)-3-r4-amino-3-(4-phenoxyphenyPthienor3,2-clpyridin-7-yn-2- propenoyl ⁇ amino)methyll-l -pyrrolidinecarboxylate amine: tert-butyl (3R)-3-(aminomethyl)-l -pyrrolidinecarboxylate.
  • Example 229A was dissolved in dichloromethane (8 mL), treated with TFA (2 mL), stirred for 4 hours at room temperature, and concentrated to provide the desired product.
  • Example 230 A tert-butyl (3S)-3-r( ⁇ (2E)-3-r4-amino-3-(4-phenoxyphenyPthienor3,2-c1pyridin-7-yn-2- propenoyl ⁇ amino)methyll-l -pyrrolidinecarboxylate amine: tert-butyl (3S)-3-(aminomethyl)-l-pyrrolidinecarboxylate. !
  • Example 230B (2EV3-r4-amino-3-(4-phenoxyphenvPthienor3,2-clpyridin-7-yll-N-r(3R)-3- pyrrolidinylmethyl] acrylamide
  • Example 230A was dissolved in dichloromethane (8 mL), treated with TFA (2 mL), stirred for 4 hours at room temperature, and concentrated to provide the desired product.
  • Example 233 (2E)-3 - r4-amino-3 -(4-phenoxyphenyl)thieno f3 ,2-clpyridin-7-yl1 -N-(3 - pyrrolidinylmethypacrylamide
  • the desired product was prepared by substituting Example 232 for Example 229A in Example 229B.
  • Example 234 tert-butyl 4-( ⁇ (2E)-3-r4-amino-3-(4-phenoxyphenypthienor3,2-clpyridin-7-yl1-2- propenoyl ⁇ amino)- 1 -piperidihecarboxylate amine: tert-butyl 4-amino-l-piperidinecarboxylate.
  • Example 235 (2E)-3- 4-amino-3-(4-phenoxyphenyl)thieno 3,2-clpyridin-7-yl1-N-4-piperidinylacrylamide
  • the desired product was prepared by substituting Example 234 for Example 229A in Example 229B .
  • Example 236 tert-butyl 2- ⁇ 2-( ⁇ (2E)-3 - r4-amino-3 -(4-phenoxyphenyl)thieno [3 ,2-c1pyridin-7-yl1 -2- propenoyl ⁇ amino)ethyll- 1 -piperidinecarboxylate amine: tert-butyl 2-(2-aminoethyl)-l -piperidinecarboxylate.
  • Example 237 (2E -3-r4-amino-3-(4-phenoxyphenyPthieno[3,2-clpyridin-7-yll-N- 2-(2- piperidinypethyllacrylamide The desired product was prepared by substituting Example 236 for Example 229A in
  • Example 238 tert-butyl 3-r( ⁇ (2E)-3-r4-amino-3-(4-phenoxyphenyl)thienor3,2-c1pyridin-7-yll-2- propenoyl ⁇ amino)methyll- 1 -piperidinecarboxylate .
  • amine tert-butyl 3 -(aminomethyl)- 1 -piperidinecarboxylate.
  • Example 239 (2E)-3-r4-amino-3-(4-phenoxyphenyl)thienoP3,2-clpyridin-7-yll-N-(3- piperidinylmethyPacrylamide
  • the desired product was prepared by substituting Example 238 for Example 229A in Example 229B.
  • Example 240 tert-butyl 3-( ⁇ (2E)-3-r4-amino-3-(4-phenoxyphenyPthienor3,2-c1pyridin-7-yn-2- propenoyl ⁇ amino)- 1 -pyrrolidinecarboxylate amine: tert-butyl 3-amino-l-pyrrolidinecarboxylate.
  • Example 241 (2E)-3-[4-amino-3-(4-phenoxyphenyl)thienor3,2-clpyridin-7-yll-N-3-pyrrolidinylac ⁇ la-mide
  • the desired product was prepared by substituting Example 241 for Example 229A in Example 229B.
  • Example 242 ( ' 2EV3-r4-amino-3-(4-phenoxyphenypthienor3,2-c]pyridin-7-vn-N-r(3S)-3- pyrrolidinyll acrylamide
  • the desired product was prepared by substituting tert-butyl (3S)-3-amino-l- pyrrolidinecarboxylate into the general procedure for amide formation, then substituting the resulting amide for Example 229A in Example 229B.
  • Example 243 (2E)-3-r4-amino-3-(4-phenoxyphenyPthienor3,2-clpyridin-7-yll-N- (3R)-3- pyrrolidinyPacrylamide
  • the desired product was prepared by substituting tert-butyl (3S)-3-amino-l- pyrrolidinecarboxylate into the general procedure for amide formation, then substituting the resulting amide for Example 229A in Example 229B.
  • Example 244 ( ' 2E)-3-[4-amino-3-(4-phenoxyphenypthienor3,2-clpyridin-7-yll-N-F3-(4- morpholinyl)propyl1acrylamide amine: 3-(4-morpholinyl)-l-propanamine.
  • Example 245 (2E)-3-r4-amino-3-(4-phenoxyphenyl)thienor3,2-cl ⁇ yridin-7-yn-N-r2-(2- pyridinyPethyll acrylamide 1 amine: 2-(2-pyridinyl)ethanamme.
  • Example 246 (2E)-3-r4-amino-3-(4-phenoxyphen ⁇ pthienor3,2-clpyridin-7-yll-N-r2-(l-methyl-2- pyrrolidinypethyll acrylamide amine: 2-(l -methyl-2-pyrrolidinyl)ethanamine.
  • Example 247 (2E)-3-r4-amino-3-(4- ⁇ henoxyphenyl)thienor3,2-c1pyridin-7-yll-N-r3- (dimethy lamino)propy 11 acrylamide amine: N,N-dimethyl-l ,3-propanediamine.
  • Example 248 (2E)-3-r4-amino-3-(4- ⁇ henoxyphenypthienor3,2-clpyridin-7-yll-N-r3-(lH-imidazol-l- yppropyll acrylamide amine : 3 -( 1 H-imidazol- 1 -yl)- 1 -propanamine.
  • Example 249 (2E)-3-r4-amino-3-(4-phenoxyphenyPthienor3,2-c]pyridin-7-yll-N-r3-(l- piperidinyppropyl] acrylamide amine: 3-(l-piperidinyl)-l-propanamine.
  • Example 254 (2E -3-r4-amino-3-(4-phenoxyphenypthienor3,2-c1pyridin-7-yll-N-r2- (dimethylamino)ethyl]acrylamide airline: N,N-dimethyl-l,2-ethanediamine.
  • Example 256 (2E)-3-r4-amino-3-(4-phenoxyphenyPthienor3,2-c1pyridin-7-yll-N-(2- pyridinylmethyPacrylamide amine: l-(2-pyridinyl)methanamine.
  • Example 257 (2E)-3-r4-amino-3-(4-phenoxyphenyl)thienor3,2-clpyridin-7-yll-N-(4- pyridinylmethypacrylamide amine : 1 -(4-pyridinyl)methanamine .
  • Example 258 (2E)-3-r4-amino-3-(4-phenoxyphenyl)thienor3,2-clpyridin-7-yll-N-3-piperidinylacrylamide
  • the desired product was prepared by substituting tert-butyl 3-amino-l- piperidinecarboxylate into the general procedure for amide formation, then substituting the resulting amide for Example 229 A in Example 229B.
  • Example 259 (2E -3-r4-amino-3-(4-phenoxyphenyl)tl ⁇ ienor3,2-c1pyridin-7-yn-N-r(3R)-3- piperidinyllacrylamide
  • the desired product was prepared by substituting tert-butyl (3R)-3-(methylamino)-l- piperidinecarboxylate into the general procedure for amide formation, then substituting the resulting amide for Example 229 A in Example 229B.
  • Example 260 (2E -3-r4-amino-3-(4-phenoxyphenyPthienor3,2-clpyridin-7-yl1-N-(4- piperidinylmethyPacrylamide
  • the desired product was prepared by sxxbstituting tert-butyl 4-(aminomethyl)-l- piperidinecarboxylate into the general procedure for amide formation, then substituting the resulting amide for Example 229A in Example 229B.
  • the residue was dissolved in dichloromethane (100 mL), treated with 2.5g of silica gel, and concentrated.
  • the residue was transferred onto a silica gel column (10 g of silica) and eluted with ethyl acetate/heptane mixtures, typically 1:3, depending on the substrate.
  • Example 261 7-(2-furyP-3-(4-phenoxyphenyPthienoF3,2-clpyridin-4-amine boronic acid: 2-furylboronic acid. MS m e 385.3 (M+H) + .
  • Example 262 7-(3-furyl)-3 -(4-phenoxyphenyl)thieno 3 ,2-clpyridin-4-amine boronic acid: 3-fl ⁇ rylboronic acid. MS m/e 385.3 (M+H) + .
  • Example 263 7-(l-be- ⁇ zofuran-2-yl)-3-(4-phenoxyphenyl)thienor3,2-clpyridin-4-amine boronic acid: l-benzofuran-2-ylboronic acid. MS m/e 435.2 (M+H) + .
  • Example 264 5-r4-ammo-3-(4-phenoxyphenyl)thienor3,2-clpyridin-7-yP-2-furaldehyde boronic acid: 5-formyl-2-furylboronic acid. MS m/e 413.3 (M+H) + .
  • Example 265 3 (4-phenoxyphenyl)-7-( lH-pyrrol-3-ypthieno ⁇ 3 ,2-c]pyridin-4-amine
  • the desired product was prepared by substituting l-(tert-butoxycarbonyl)-lH-pyrrol- 3-ylboronic acid into the general procedure for Suzuki couplings, then substituting the resulting product for Example 229A in Example 229B.
  • Example 266 3-(4-phenoxyphenyl)-7-(lH-pyrrol-2-yl)thieno
  • the desired product was prepared by substituting l-(tert-butoxycarbonyl)-lH-pyrrol- 2-ylboronic acid into the general procedure for Suzuki couplings, then substituting the resulting product for Example 229 A in Example 229B.
  • Example 267 7-( lH-indol-2-yl)-3 -(4-phenoxyphenyl)thieno f3 ,2-clpyridin-4-amine
  • the desired product was prepared by substituting 1 -(tert-butoxycarbonyl)- lH-indol-2- ylboronic acid into the general procedure for Suzuki couplings, then substituting the resulting product for Example 229A in Example 229B.
  • Example 268 tert-butyl (2E)-3-(4-amino-3-bromothieno 3,2-clpyridin-7-yl)acrylate
  • a solution of Example 21 A (2.50g, 7.04 mmol), PPh 3 (0.370g, 1.41 mmol), and Na- j COs (1.49g, 14.1 mmol) in DMF (35 mL) was treated with tert-butyl acrylate (2.00 mL, 14.1 mmol) and palladium(II)acetate (0.158g, 0.704 mmol). The reaction was heated to 80 °C under an atmosphere of nitrogen for 16 hours.
  • the reaction was cooled to ambient temperatixre and partitioned between ethyl acetate (lOOmL) and brine.
  • the organic phase was washed with brine (2 x 100 mL), dried (NajSO.,), filtered, and concentrated.
  • the compound was purified by flash chromatography on silica gel using heptane/ethyl acetate (6:1) to (3:1) to provide the desired product (1.70g, 3.01 mmol).
  • Example 269 tert-butyl (2E)-3-r4-amino-3-(3-methoxy-4- ⁇ f(l-methyl-lH-indol-2- yl)carbonyllamino ⁇ phenyl)thienor3,2-clpyridin-7-yl1acrylate
  • a mixture of Example 268 (1.70g, 4.79 mmol), Example 175E (2.91g, 7.18 mmol), Na 2 CO 3 (l.Olg, 9.57 mmol), and Pd(PPh 3 ) 4 (0.332g, 0.287 mmol) was heated in a mixture of DME (60 mL) and water (30 mL) at 95 °C for 15 hours under an atmosphere of nitrogen.
  • Example 175E (0.97g, 2.39 mmol) and Pd(PPh 3 ) 4 (0.332g, 0.287 mmol), heated to 95 °C for another 5 hours, and cooled to ambient temperature.
  • the resulting precipitate was collected by Alteration and washed with diethyl ether (40mL).
  • the precipiate was dissolved in dichloromethane (200mL), dried (N- ⁇ SO.,), filtered, and concentrated to provide the desired product (1.98g, 3.57 mmol).
  • Example 271 (2E)-3-r4-amino-3-(3-methoxy-4- ⁇ r(l-methyl-lH-indol-2- yl)carbonyll amino ⁇ phenyl)thieno [3 ,2-clp ' yridin-7-yPacrylic acid
  • the desired product was prepared as the hydrochloride salt by substituting Example ' 70 for Example 225 in Example 226.
  • Example 273 N-(4- ⁇ 4-amino-7- (lZ)-3-oxo-3-(4-piperidinylamino)-l-propenynthieno 3,2-clpyridin-3-yl ⁇ - 2-methoxyphenyl)- 1 -methyl- lH-indole-2-carboxamide
  • Amixture of Example 272 50mg, 0.12 mmol
  • N,N-diisopropylethylamine 90 ⁇ L, 5.1 mmol
  • 4-piperidinamine (0.24 mmol)
  • DMF 2.5 mL
  • Example 274 N-r4-(4-amino-7- ⁇ (lZ)-3-oxo-3-r(3-piperidinylmethyl)aminol-l-propenyl ⁇ thienor3,2- clpyridin-3-yl)-2-methoxyphenyll-l-methyl-lH-indole-2-carboxamide
  • a mixture of Example 270 (llmg, 0.020 mmol), tert-butyl 3-(aminomethyl)-l- piperidinecarboxylate (5mg, 0.024 mmol), and Na ⁇ O- j (0.060 mmol, 6 mg) in dichloromethane (1 mL) and water (0.5 mL) was treated with a solution of tetramethylfluoroformadinium hexafluorophosphate (TFFH, 8mg, 0.030 mmol) in dichloromethane (0.5 mL), stirred for 3 days at ambient temparature, treated with additional
  • Example 275 (2E)-3-r4-amino-3-(4-bromophenyPthieno 3,2-clpyridin-7-yl1-N-3-pyridinylacrylamide
  • the desired product was prepared as the tris(trifluoroacetate) salt by substituting 3- pyridinamine for l-(4-pyridinyl)methanamine in Example 171B.
  • Example 276 3-(lH-indol-5-yl)thieno[3,2-clpyridin-4-amine
  • Example 277 N- ⁇ 4-r4-amino-7-(hydroxymethyl)thieno[3,2-c1pyridin-3-yl]phenyl ⁇ -N'-(3- methylphenyl)urea
  • Example 277 A 3-(4-bromo-2-thienyl)-2-butenoic acid
  • ethyl (diethoxyphosphino)acetate 34 mL, 171 mmol
  • THF 35 mL
  • a 0 °C suspension of NaH (6.9g, 60%> oil dispersion , 172 mmol)'in THF (200 mL).
  • Example 277C 3-bromo-4-chloro-7-methylthienor3,2-clpyridine
  • a solution of Example 277B (10,25g, 42.1 mmol) in POCl 3 (50 mL) was stirred at reflux for 2 hours, cooled to room temperature, diluted with ice water, and stirred vigorously resulting in a precipitate which was collected by filtration.
  • the filter cake was further purified by silica gel chromatography on silica gel with dichloromethane to provide 7.14g (64% yield) of the desired product.
  • MS (ESI(+)) m e 261.9, 263.9 (M+H) + .
  • Example 277D (3-bromo-4-chlorothieno [3 ,2-c]pyridin-7-yPmethyl acetate
  • MS (ESI(+)) m/e 339.5, 341.6, 343.4 (M+H) + .
  • Example 277E (4-amino-3-bromotMeno[3,2-c]pyridin-7-ypmethanol A mixture of Example 277D (3.1 g, 9.7 mmol), concentrated NH 4 OH (62 mL), and dioxane (62 mL) was heated to 150 °C in a sealed tube for 36 hours, filtered, and concentrated to provide a soid which was triturated with water (20 mL), collected and dried to give 2.1g (84% yield) of the desired product. MS (ESI(+)) m/e 258.9, 260.8 (M+H) + .
  • Example 277F N- ⁇ 4- 4-amino-7-(hydroxymethyl)thieno ⁇ 3 ,2-c]pyridin-3 -yllphenyl ⁇ -N'-(3 - methylphenypurea
  • the desired product was prepared by substituting Example 277E and Example 66D for Example IB and 4-phenoxyphenylboronic acid respectively, in Example 10A.
  • Example 278A 4-amino-3-bromothieno[3,2-clpyridine-7-carbaldehyde
  • a solution of Example 277E (lg, 3.86 mmol) in THF (100 mL) was treated with MnO 2 (2.66g, 42.1 mmol), stirred overnight at room temperature, and filtered through diatomaceous earth (Celite ® ). The pad was washed with THF and dichloromethane and the combined filtrates were concentrated to provide 0.88g (89%> yield ) of the desired product.
  • MS (ESI(+)) m/e 256.8, 258.8 (M+H) + .
  • Example 278B 3-bromo-7-(4-morpholinylmethyPthieno 3,2-c1pyridin-4-amine
  • a solution of Example 278A (0.048g, 0.187 mmol) in THF (15 mL) and dichloromethane (15 mL) was treated with acetic acid (0.012 mL, 0.21 mmol), morpholine (0.02 mL, 0.23 mmol), and sodium triacetoxyborohydride (0.063g, 0.3 mmol), stirred at room temperature overnight, treated with additional morpholine (0.08 mL), acetic acid (0.05 mL) and sodium triacetoxyborohydride (0.23g), and stirred an additional 8 hours.
  • Example 278C N- ⁇ 4- 4-amino-7-(4-morpholinylmethyl)thienor3,2-clp ⁇ ridin-3-yllphenyl ⁇ -N'-(3- methylphenypurea
  • the desired product was prepared by substituting Example 278B and Example 66D for Example IB and 4-phenoxyphenylboronic acid respectively, in Example 10A.
  • Example 279 N-(4- ⁇ 4-amino-7-r(3-oxo-l-piperazinyPmethyl]thienoF3,2-clpyridin-3-yl ⁇ phenyl)-N'-(3- methylphenypurea
  • the desired product was prepared substituting piperazin-2-one for morpholine in Examples 278B-C.
  • Example 280 N- [4-(4-amino-7- ⁇ [ " (2-methoxy ethyl)amino " lmethyl ⁇ thieno 3 ,2-c1pyridin-3 -yl)phenyll -N'-(3 - methylphenypurea
  • the desired product was prepared substituting 2-methoxyethylamine for morpholine in Examples 278B-C.
  • Example 281 N- ⁇ 4-f4-amino-7-(6-methoxy-3-p ⁇ ridinyl)thieno[ " 3,2-c1pyridin-3-yll-2-methoxyphenyl ⁇ -l- methyl-lH-indole-2-carboxamide
  • a mixture of Example 215 (1.0 eq) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was reacted with N-[2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l- methyl-lH-indole-2-carboxamide (1.2 eq), Na- ⁇ CO, (2.4 eq), and Pd(PPh 3 ) 4 (0.06 eq) at 95 °C c for 18 hours.
  • Example 282 Sf- ⁇ 4-[4-amino-7-(3-thienyPthienor3,2-c]pyridin-3-yl]-2-methoxyphenyl ⁇ -l-methyl-lH- indole-2-carboxamide
  • Example 175E 1.2 eq
  • Na-CO 3 2.4 eq
  • Pd(PPh 3 ) 4 0.06 eq
  • the -residue was purified by preparative reverse phase HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 40%) acetonitrile/O.lM ammonixim acetate isocratic for 5 minutes, then 40-100% acetonitrile/O.lM ammonium acetate over 3 minutes, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to provide the desired product.
  • Example 283 N- ⁇ 4- 4-amino-7-(2-thienyl)thienor3 ,2-clpyridin-3-yP-2-methoxyphenyl ⁇ - 1 -methyl- 1 H- indole-2-carboxamide
  • Example 175E 1.2 eq
  • N- ⁇ 2.4 eq
  • Pd(PPh 3 ) 4 0.06 eq
  • Example 284A 3 -(4-aminophenyl)-7-( 1 H-indol-5 -ypthieno 3 ,2-c]pyridin-4- amine
  • the desired product was prepared by substituting Example 77B and lH-indol-5- ylboronic acid for Example 77A and 4-pyridylboronic acid, respectively, in Example 121 A.
  • Example 284B N- ⁇ 4-r4-amino-7-(lH-indol-5-yPthienor3,2-c1pyridin-3-yl1 ⁇ henyl ⁇ -N'-f2-fluoro-5- (trifluoromethyPphenyllurea
  • the desired product was prepared by substituting Example 284A for Example 121B in Example 122.
  • Example 285 N- ⁇ 4-[4-amino-7-(lH-indol-5-yl)thienor3,2-clpyridin-3-yl1phenyl ⁇ -N'-(3-methylphenyPurea
  • the desired product was prepared by substituting Example 284A and l-isocyanato-3- methylbenzene for Example 12 IB and l-fluoro-2-isocyanato-4-(trifluoromethyl)benzene, respectively in Example 122.
  • Examples 286-288 were prepared by substituting the appropriate boronic acid (X) for 4-chloro-phenylboronic acid in Example 21C.
  • Example 289 4- ⁇ r4-amino-3-( 1 H-indol-5-yl)thieno ⁇ 3 ,2-clpyridin-7-yl]methyl ⁇ -2-piperazinone
  • the desired product was prepared by substituting piperazin-2-one for morpholine in Example 278B, then substituting the product for Example 21B in Example 29.
  • Example 290 N-(4- ⁇ 4-an ⁇ ino-7-f(3-oxo-l-piperazinyl)methyllthienor3,2-clpyridin-3-yl ⁇ phenyl)-N'-[3- (trifluoromethyl)phenyllurea
  • the desired product was prepared substituting piperazin-2-one for morpholine in Example 278B, then substituting the product and N-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea for Example IB and 4- phenoxyphenylboronic acid, respectively, in Example 10A.
  • Example 291 A (2E)-3-(4-amino-3-bromothienor3,2-clpyridin-7-yl)acrylic acid
  • the desired product was prepared sxxbstituting Example IB for Example lOA in Example 10B, then substituting the product for Example 10B in Examples 11 A-B.
  • MS (ESI(+)) m/e 298.8, 300.8 (M+H) + .
  • Example 29 IB ( ' 2E -3-r4-amino-3-(lH-indol-5-yl)thienor3,2-clpyridin-7-yll-N-(4- pyridinylmethyPacrylamide
  • the desired product was prepared substituting Example 291A for Example 78 in Example 90, then substituting the product for Example 2 IB in Example 29.
  • Example 292 (2E)-3-r4-amino-3-(lH-indol-5- ⁇ l)thienor3,2-c1pyridin-7-vn-N-r3-(lH-imidazol-l- yPpropyl] acrylamide
  • the desired product was prepared substituting Example 291 A for Example 78 in Example 96, then substituting the product for Example 2 IB in Example 29.
  • Example 293 (2E)-3-r4-amino-3-(lH-indol-5-yPthienor3,2-clpyridin-7-yl1-N-r2- (diethylamino)ethyllacrylamide
  • the desired product was prepared by substituting Example 291 A for Example 78 in
  • Example 86 then substituting the product for Example 21B in Example ' 29.
  • Example 294A tert-butyl 4-(4-aminothienoP,2-c1pyridin-3-yp-2-methoxyphenylcarbamate
  • a solution of Example IB (1.0g, 4.365 mmol) in ethyleneglycol dimethyl ether (20 mL) was treated with tert-butyl 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yPphenylcarbamate (1.83g, 5.238 mmol), Pd(PPh 3 ) 4 (0.303g, 0.262 mmol), and a solution of sodium carbonate (1.1 lg, 10.473 mmol) in water (10 mL), stirred at 85 °C for 16 hours under nitrogen, concentrated, and treated with dichloromethane.
  • Example 294B tert-butyl 4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenylcarbamate
  • a solution of Example 294A (1.49g, 4.01 mmol) in dimethylformamide (20 mL) was treated portionwise with N-iodosuccinimide (1.083g, 4.813 mmol), stirred at room temperature for 2 hours, treated with saturated sodium thiosulfate, stirred for 30 minutes, and filtered. The filter cake was washed with water and dried in a vacuum oven to provide 1.884g (94%) ofthe desired product.
  • Example 294C 3-(4-amino-3-methoxyphenyl)-7-iodothienor3,2-clpyridin-4-amine
  • a solution of Example 294B (8.641g, 17.374 mmol) in dichloromethane (100 mL) at 0 °C was treated dropwise with trifluoroacetic acid (30 mL) in dichloromethane (20 mL), stirred at 0 °C for 1 hour and at room temperature for 3 hours, concentrated, and dried under high vacuum. The residue was treated with dichloromethane and 6N HCI. The layers were partitioned and the organic layer was extracted with 6N HCI. The combined aqueous layers were cooled to 0 °C.
  • the aqueous layer was basified to pH 11 and the resulting precipitate was collected by filtration to provide 4.787g of the desired product.
  • the filtrate was extracted three times with ethyl acetate and the combined extracts were dried (MgSO 4 ), filtered, and concentrated to provide 2.41g of additional product.
  • Example 294D l-methyl-lH-indole-2-carbonyl chloride
  • a suspension of l-methyl-lH-2-indolecarboxylic acid (0.485g, 2.769 mmol) in dichloromethane (10 mL) at 0 °C was treated with oxalyl chloride (0.369g, 2.91 mmol) and one drop of dimethyl forrnamide.
  • the reaction mixture was stirred at 0 °C for 1 hour and at room temperature for 2 hours.
  • the solvent was removed under reduced pressure and dried on the high vacuum for 1 hour. The residue was used directly in the subsequent reaction without further purification or analysis.
  • Example 294E N- [4-(4-amino-7-iodothieno ⁇ 3 ,2-clpyridin-3 -yl)-2 -methoxyphenyl ⁇ - 1 -methyl- 1 H-indole-2- carboxamide
  • pyridine 10 mL
  • Example 294D 0.536g, 2.769 mmol
  • dichloromethane 5 mL
  • the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, dried (MgSO 4 ), filtered, and concentrated. The solid was dried on the high vacuum to remove residual pyridine to provide 0.906g (65%>) of the desired product.
  • Example 310 N- ⁇ 4-r4-amino-7-(3-amino-l-propynypthienor3,2-clpyridin-3-yll-2-methoxyphenyl ⁇ -l- methyl-lH-indole-2-carboxamide
  • a solution of Example 308 (0.095g, 0.163 mmol) in dichloromethane (10 mL) at 0 °C was treated with a solution of trifluoroacetic acid (4 mL) in dichloromethane (5 mL). The reaction mixtxxre was stirred at 0 °C for 35 minutes and at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was dried under high vacuum.
  • Example 311 N-(4- ⁇ 4-amino-7-r(6-amino-3-pyridinyl)ethynyl]thieno[3,2-c1pyridin-3-yl ⁇ -2- methoxyphenyl)- 1 -methyl- 1 H-indole-2-carboxamide
  • a solution of Example 309 (0.080g, 0.12 mmol) in dichloromethane (5 mL) at 0 °C . was treated with a solution of trifluoroacetic acid (2 mL) in dichloromethane (5 mL). The reaction mixture was stirred at 0 °C for 35 minutes and at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was dried under high vacuum.
  • Example 312 N-(4- ⁇ 4-amino-7-r6-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-l-hexynyllthieno[3,2- clpyridin-3 -yl ⁇ -2-methoxyphenyl)- 1 -methyl- 1 H-indole-2-carboxamide
  • Example 313 N- ⁇ 4-r4-amino-7-(3-formyl-2-flu ⁇ l)-l-benzothien-3-yl]-2-methoxyphenyl ⁇ -l-methyl-lH- indole-2-carboxamide
  • a mixture of Example 294E (0.120g, 0.217 mmol), 3-formyl-2-furylboronic acid (0.033g, 0.236 mmol), Pd(PPh 3 ) 4 (0.012g, 0.010 mmol), and sodium carbonate (0.057g, 0.538 mmol) in DMF (2 mL) and water (1 mL) was heated at 80 °C for 16 hours, cooled to ambient temperature, and concentrated.
  • the residue was partitioned between water (20 mL) and methanol/dichloromethane (1 :9, 20 mL). The layers were separated and the aqueous layer was extracted further with methanol/dichloromethane (1 :9, 2 x 20 mL). The organic layers were combined, dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel deactivated with triethylamine, using methanol/dichloromethane (1 :24) as the mobile phase to provide the desired product (0.017g, 0.032 mmol).
  • Example 314A tert-butyl allylcarbamate A solution of copper cyanide (1.15g, 12.9 mmol) in THF (30 mL) at -78 °C was treated slowly with n-butyllithium (16.9 mL, 27.1 mmol), stirred for 15 minutes at -78 °C, treated with tributyltin hydride (7.88g, 7.30 mL, 27.1 mmol) over a period of 5 minutes, stirred for 15 minutes, treated with tert-butyl 2-propynylcarbamate (2.00g, 12.9 mmol) in tetrahydrofuran (7 mL), stirred at -78 °C for 1 hour, and treated with a 9:1 aqueous solution of ammonium chloride: ammonium hydroxide (250 mL) and dichloromethane (200 mL).
  • the suspension was filtered through a short pad of diatomaceous earth (Celite ® ).
  • the organic phase of the filtrate was washed with brine and concentrated.
  • the residue was purified on silica gel using 1-2% ethyl acetate/heptane to provide the desired product (3.66g, 63%>).
  • Example 314B tert-butyl (2E)-3-r4-ammo-3-(3-methoxy-4- ⁇ f(l-methyl-lH-indol-2- yPcarbonyl1amino ⁇ phenyl)thienor3,2-c1pyridin-7-yl]-2-propenylcarbamate
  • Example 314A (2.62g,
  • Example 315 N-(4- ⁇ 4-amino-7-r(lE)-3-amino-l-propenyl]thieno[3,2-clpyridin-3-yl ⁇ -2-methoxyphenyl)-l- methyl- 1 H-indole-2-carboxamide
  • Example 315 A suspension of Example 315 (0.050g, 0.104 mmol) and the appropriate ketone/aldehyde (0.087 mmol) in dichloroethane (1.5 mL) was treated with sodium triacetoxyborohydride (0.036g, 0.173 mmol), stirred at room temperature for 2-12 hours, treated with 10% NaOH (3 mL) and dichloromethane (3 mL), stirred for 15 minutes, filtered through an Empore ® cartridge, and concentrated. The crude product was purified in one of three ways: Method A: Triturated in ethanol and collected by filtration.
  • Method B Purified by preparative reverse phase HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 40% acetonitrile - 0.1M ammonium acetate isocratic for 5 minutes, then 40-100% acetonitrile/O.lM ammonium acetate over 30 min, 21 mL/min) followed by lyophilization.
  • Method C Purified by reverse phase HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 40%> acetonitrile - 0.1M ammonium acetate isocratic for 5 minutes, then 5 -100%> acetonitrile/O.lM ammonium acetate over 30 min, 21 mL/min) then lyophilized..
  • LCMS Thermoquest AQA single-quad MS, Genesis C18 column, 3 ⁇ m particle size, 33 x 4.6mm; 70% 50 mM ammonium acetate in water to 95%) acetonitrile over 6 min, 0.8 to 0.5 mL/min).
  • the following examples were prepared by this procedure using the indicated ketone or aldehyde. Purification Methods and Spectral Data
  • Example 321 Purification Method: C; *H NMR too dilute for definitive analysis.
  • Example 176C A mixture of Example 176C (40 mg, 0.083 mmol), sodium triacetoxyborohydride (35 mg, 0.166 mmol) and the appropriate amine (0166 mmol) in 1,2-dichloromethane (2 mL) was stirred for 2 to 72 hours at ambient temperature. The mixture was concentrated and the residue was purified by normal or reverse phase chromatography. Where necessary a Boc- protected diamine was used for the reductive amination then the protecting group was removed by stirring the reaction mixture in a 2:1 mixture of acetone and 6N hydrochloric acid for 2 hours followed by concentration and purification of the residue. The following examples were prepared by this general method using the indicated amines:
  • Example 332 N-r4-(4-amino-7- ⁇ (lE)-3-r(4-aminocycl ⁇ hexypaminol-l-propenyl ⁇ thieno[3,2-clpyridin-3- yl)-2-methoxyphenyl1-l-methyl-lH-indole-2-carboxamide Prepared as the triacetate salt from tert-butyl 4-aminocyclohexylcarbamate and deprotected.
  • Example 333 N-[4-(4-amino-7- ⁇ (lE)-3-[methyl(l-methyl-4-piperidinyl)aminol-l-propenyl ⁇ thieno[3,2- c1pyridin-3-yp-2-methoxyphenyl ⁇ -l-methyl-lH-indole-2-carboxamide Prepared as the tetraacetate salt from N,l-dimethyl-4-piperidinamine.
  • Example 334 N-[4-(4-amino-7- ⁇ (lE)-3-r4-(6-oxo-l,6-dihydro-2-pyridinyl)-l-piperazinyn-l- propenyl ⁇ thieno ,2-c]pyridin-3-yl)-2-methoxyphenyl1- 1 -methyl- lH-indole-2-carboxamide Prepared as the acetate salt from 6-(l-piperazinyl)-2(lH)-pyridinone. !
  • Example 335 N-(4- ⁇ 4-amino-7-r(lE)-3-(4-methyl- 1 ,4-diazepan- 1 -yl)- 1 -propenyllthieno f3 ,2-clpyridin-3- yl ⁇ -2-methoxyphenyp- 1 -methyl- 1 H-indole-2-carboxamide Prepared as the acetate salt from 1 -methyl- 1,4-diazepane.
  • Example 336 N-[4-(4-amino-7- ⁇ (lE)-3-[4-(2-pyrazinyP-l-piperazinyl1-l-propenyl ⁇ thieno[3,2-clpyridin-3- vP-2-methoxyphenyll-l-methyl-lH-indole-2-carboxamide Prepared from 2-(l- ⁇ iperazinyl)pyrazine.
  • Example 337 N- ⁇ 4-r4-amino-7-((lE)-3- ⁇ r2-(2-hydroxyethoxy)ethyl1amino ⁇ -l-propenyPthienor3,2- clpyridin-3-yn-2-methoxyphenyl ⁇ -l-methyl-lH-indole-2-carboxamide Prepared as the diacetate salt from 2-(2-aminoethoxy)ethanol.
  • Example 340 N- ⁇ 4- 4-amino-7-(( 1 E)-3 - ⁇ [2-(4-pyridinyl) ethyl] amino ⁇ - 1 -propenypthieno [3 ,2-c]pyridin-3 - yl]-2-methoxyphenyl ⁇ -l-methyl-lH-indole-2-carboxamide Prepared as the acetate salt from 2-(4-pyridinyl)ethanamine.
  • Example 341 N- 4-(4-amino-7- ⁇ (lE)-3-r4-(2-cyanoethyl)-l-piperazinyl]-l-propenyl ⁇ thienor3,2-clpyridin- 3-yl)-2-methoxyphenyl]-l-methyl-lH-indole-2-carboxamide Prepared as the acetate salt from 3-(l-piperazinyl)propanenitrile.
  • Example 342 N-(4- ⁇ 4-amino-7-r(lE)-3-(4-amino-l-piperidinyl)-l-propenyl]thienoF3,2-c]pyridin-3-yl ⁇ -2- methoxyphenyl)- 1 -methyl- lH-indole-2-carboxamide ' Prepared as the diacetate salt from tert-butyl 4-piperidinylcarbamate and deprotected.
  • Example 343 N-[4-(4-amino-7- ⁇ (lE)-3-[4-(3-amino-3-oxopropyl)-l-piperazinyl]-l-propenyl ⁇ thieno[3,2- c]pyridin-3-yl)-2-methoxyphenyl1-l-methyl-lH-indole-2-carboxamide Prepared as the diacetate salt from 3-(l-piperazinyl)propanamide.
  • Example 345 N-[4-(4-amino-7- ⁇ (lE)-3-[(2-fijrylmethyl)(methyl)amino]-l-propenyl ⁇ thieno[3,2-c1pyridin- 3-yl)-2-methoxyphenyl]-l-methyl-lH-indole-2-carboxamide Prepared as the acetate salt from N-(2-furylmethyl)-N-methylamine. *H NMR (DMSO-d 6 , 400 MHz) ⁇ 9.52 (s, IH), 7.99-8.01 (m, 2H), 7.72 (d, IH), 7.58-7.63 (m, ' 2H),
  • Example 351 5 N- ⁇ 4-[4-amino-7-(( 1 E)-3- ⁇ 4- r2-(2-thienyl)ethyl] - 1 -piperazinyl ⁇ -1 -propenypthieno ⁇ 3 ,2- c]pyridin-3-yl]-2-methoxyphenyl ⁇ -l-methyl-lH-indole-2-carboxamide Prepared from l-[2-(2-thienyl)ethyl]piperazine.

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PCT/US2004/024003 2003-07-24 2004-07-26 Thienopyridine and furopyridine kinase inhibitors Ceased WO2005010009A1 (en)

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SI200431056T SI1648905T1 (sl) 2003-07-24 2004-07-26 Inhibitorji tienopiridin- in furopiridin kinaze
KR1020067001692A KR101120936B1 (ko) 2003-07-24 2004-07-26 티에노피리딘 및 푸로피리딘 키나제 억제제
BRPI0412894-0A BRPI0412894A (pt) 2003-07-24 2004-07-26 tienopiridina e furopiridina inibidores de quinases
DK04779180T DK1648905T3 (da) 2003-07-24 2004-07-26 Inhibitorer for thienopyridin- og furopyridinkinase
CA2532982A CA2532982C (en) 2003-07-24 2004-07-26 Thienopyridine and furopyridine kinase inhibitors
JP2006521305A JP4707192B2 (ja) 2003-07-24 2004-07-26 チエノピリジンおよびフロピリジン系キナーゼ阻害薬
NZ544712A NZ544712A (en) 2003-07-24 2004-07-26 Thienopyridine and furopyridine kinase inhibitors
AU2004259765A AU2004259765B2 (en) 2003-07-24 2004-07-26 Thienopyridine and furopyridine kinase inhibitors
DE602004018780T DE602004018780D1 (de) 2003-07-24 2004-07-26 Inhibitoren von thienopyridin- und furopyridinkinase
PL04779180T PL1648905T3 (pl) 2003-07-24 2004-07-26 Tienopirydynowe i furopirydynowe inhibitory kinazy
MXPA06000919A MXPA06000919A (es) 2003-07-24 2004-07-26 Inhibidores de quinasa de tienopiridina y furopiridina.
EP04779180A EP1648905B1 (en) 2003-07-24 2004-07-26 Thienopyridine and furopyridine kinase inhibitors
IL173348A IL173348A (en) 2003-07-24 2006-01-24 Thienopyridine compounds, pharmaceuticals containing them and their use in the preparation of drugs

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US10/626,092 2003-07-24
US10/626,092 US20050020619A1 (en) 2003-07-24 2003-07-24 Thienopyridine kinase inhibitors
US10/838,132 2004-05-03
US10/838,132 US20050026944A1 (en) 2003-07-24 2004-05-03 Thienopyridine and furopyridine kinase inhibitors

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WO2005116028A3 (en) * 2004-04-26 2006-03-30 Bristol Myers Squibb Co Bicyclic heterocycles as kinase inhibitors
WO2006135639A1 (en) * 2005-06-10 2006-12-21 Janssen Pharmaceutica N.V. Thiξnopyrimidine and thienopyridine derivatives as flt-3 kinase inhibitors
WO2007067781A3 (en) * 2005-12-08 2007-07-26 Abbott Lab 9-membered heterobicyclic compounds as inhibitors of protein kinases
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WO2008018881A1 (en) * 2006-08-10 2008-02-14 Osi Pharmaceuticals, Inc. 6,6-bicyclic ring substituted sulfur containing heterobicyclic protein kinase inhibitors
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JP2009504692A (ja) * 2005-08-16 2009-02-05 エフ．ホフマン−ラ ロシュ アーゲー 新規４−アミノ−チエノ［３，２−ｃ］ピリジン−７−カルボン酸アミド
JP2009507883A (ja) * 2005-09-15 2009-02-26 エフ．ホフマン−ラ ロシュ アーゲー ４−アミノ−チエノ［３，２−ｃ］ピリジン−７−カルボン酸誘導体
JP2009514899A (ja) * 2005-11-04 2009-04-09 スミスクライン ビーチャム コーポレーション チエノピリジンＢ−Ｒａｆキナーゼ阻害剤
JP2009528991A (ja) * 2006-02-14 2009-08-13 バーテックス ファーマシューティカルズ インコーポレイテッド プロテインキナーゼの阻害剤として有用なピロロ（３，２−ｃ）ピリジン
WO2010065825A3 (en) * 2008-12-05 2010-08-26 Abbott Laboratories Thieno [3, 2-c] pyridine derivatives as kinase inhibitors for use in the treatment of cancer
WO2012048222A1 (en) * 2010-10-08 2012-04-12 Abbott Laboratories FURO[3,2-d]PYRIMIDINE COMPOUNDS
WO2013012909A1 (en) 2011-07-20 2013-01-24 Abbott Laboratories Kinase inhibitor with improved aqueous solubility
CN103025741A (zh) * 2010-06-09 2013-04-03 Abbvie公司 激酶抑制剂的结晶形式
CN103038239A (zh) * 2010-06-09 2013-04-10 Abbvie公司 激酶抑制剂的晶体形式
JP2013528222A (ja) * 2010-06-09 2013-07-08 アボット・ラボラトリーズ キナーゼ阻害剤の結晶形態
WO2015157360A1 (en) 2014-04-08 2015-10-15 Abbvie Inc. Processes to make protein kinase inhibitors
US9951087B2 (en) 2009-10-22 2018-04-24 Fibrotech Therapeutics Pty Ltd Fused ring analogues of anti-fibrotic agents
US11014873B2 (en) 2017-02-03 2021-05-25 Certa Therapeutics Pty Ltd. Anti-fibrotic compounds

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US20050256154A1 (en) * 2004-05-04 2005-11-17 Kin-Chun Luk 4-Amino-thieno[3,2-c]pyridine-7-carboxylic acid amides
US7566721B2 (en) * 2005-08-08 2009-07-28 Osi Pharmaceuticals, Inc. Substituted thienol[2,3-d]pyrimidines as kinase inhibitors
GB0525164D0 (en) 2005-12-09 2006-01-18 Xention Discovery Ltd Compounds
US7932390B2 (en) * 2006-06-29 2011-04-26 Hoffman-La Roche Inc. Substituted thieno[3,2-C]pyridine carboxylic acid derivatives
MX2010001636A (es) * 2007-08-14 2010-03-15 Hoffmann La Roche Derivados de pirazolo[3,4-d]-pirimidina como agentes antiproliferativos.
AR070317A1 (es) * 2008-02-06 2010-03-31 Osi Pharm Inc Furo (3,2-c) piridina y tieno (3,2-c) piridinas
CA2723358A1 (en) * 2008-05-05 2009-11-12 Allison B. Reiss Method for improving cardiovascular risk profile of cox inhibitors
MX2012014487A (es) 2010-07-02 2013-02-21 Alcon Res Ltd Compuestos para el tratamiento de transtornos y enfermedades del segmento posterior.
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CN104945411B (zh) * 2014-03-27 2018-07-31 南京勇山生物科技有限公司 噻吩并[3,2-c]吡啶类化合物、其制备方法及应用
WO2016047678A1 (ja) * 2014-09-25 2016-03-31 武田薬品工業株式会社 複素環化合物
JP2023549540A (ja) 2020-11-18 2023-11-27 デシフェラ・ファーマシューティカルズ，エルエルシー Ｇｃｎ２およびｐｅｒｋキナーゼ阻害剤およびその使用方法

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WO2005116028A3 (en) * 2004-04-26 2006-03-30 Bristol Myers Squibb Co Bicyclic heterocycles as kinase inhibitors
US7566784B2 (en) 2004-04-26 2009-07-28 Bristol-Myers Squibb Company Bicyclic heterocycles as kinase inhibitors
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JP2009504692A (ja) * 2005-08-16 2009-02-05 エフ．ホフマン−ラ ロシュ アーゲー 新規４−アミノ−チエノ［３，２−ｃ］ピリジン−７−カルボン酸アミド
JP2009507883A (ja) * 2005-09-15 2009-02-26 エフ．ホフマン−ラ ロシュ アーゲー ４−アミノ−チエノ［３，２−ｃ］ピリジン−７−カルボン酸誘導体
JP2009514899A (ja) * 2005-11-04 2009-04-09 スミスクライン ビーチャム コーポレーション チエノピリジンＢ−Ｒａｆキナーゼ阻害剤
EP1951728A4 (en) * 2005-11-04 2011-04-20 Glaxosmithkline Llc THIENOPYRIDINES AS INHIBITORS OF B-RAF KINASE
JP2009518434A (ja) * 2005-12-08 2009-05-07 アボット・ラボラトリーズ タンパク質キナーゼ阻害薬としての９員ヘテロ二環式化合物
WO2007067781A3 (en) * 2005-12-08 2007-07-26 Abbott Lab 9-membered heterobicyclic compounds as inhibitors of protein kinases
JP2014088397A (ja) * 2005-12-29 2014-05-15 Abbvie Inc タンパク質キナーゼ阻害薬
WO2007079164A3 (en) * 2005-12-29 2007-09-27 Abbott Lab Protein kinase inhibitors
US7772231B2 (en) 2005-12-29 2010-08-10 Abbott Laboratories Substituted pyrazolo[3,4-d]pyrimidines as protein kinase inhibitors
JP2009528991A (ja) * 2006-02-14 2009-08-13 バーテックス ファーマシューティカルズ インコーポレイテッド プロテインキナーゼの阻害剤として有用なピロロ（３，２−ｃ）ピリジン
KR101101725B1 (ko) 2006-08-08 2012-01-05 에프. 호프만-라 로슈 아게 티에노[3,2-ｃ]피리딘-7-카르복실산 유도체
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US7994321B2 (en) 2006-08-08 2011-08-09 Hoffmann-La Roche Inc. Substituted thieno[3,2-C]pyridine-7-carboxylic acid derivatives
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WO2008018881A1 (en) * 2006-08-10 2008-02-14 Osi Pharmaceuticals, Inc. 6,6-bicyclic ring substituted sulfur containing heterobicyclic protein kinase inhibitors
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US8722890B2 (en) 2008-12-05 2014-05-13 Abbvie Inc. Thieno[3,2-C]pyridine kinase inhibitors with improved CYP safety profile
US9951087B2 (en) 2009-10-22 2018-04-24 Fibrotech Therapeutics Pty Ltd Fused ring analogues of anti-fibrotic agents
CN103025741A (zh) * 2010-06-09 2013-04-03 Abbvie公司 激酶抑制剂的结晶形式
CN103038239A (zh) * 2010-06-09 2013-04-10 Abbvie公司 激酶抑制剂的晶体形式
JP2013528220A (ja) * 2010-06-09 2013-07-08 アボット・ラボラトリーズ キナーゼ阻害剤の結晶形態
JP2013528221A (ja) * 2010-06-09 2013-07-08 アボット・ラボラトリーズ キナーゼ阻害剤の結晶形
JP2013528222A (ja) * 2010-06-09 2013-07-08 アボット・ラボラトリーズ キナーゼ阻害剤の結晶形態
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US8551981B2 (en) 2010-10-08 2013-10-08 Abbvie Inc. Furo[3,2-d]pyrimidine compounds
US8436179B2 (en) 2011-07-20 2013-05-07 Abbvie Inc. Kinase inhibitor with improved solubility profile
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DE602004018780D1 (de) 2009-02-12
CN103087078A (zh) 2013-05-08
CA2532982C (en) 2013-11-26
AU2004259765A1 (en) 2005-02-03
ATE419253T1 (de) 2009-01-15
AU2009251083A1 (en) 2010-01-21
KR101120936B1 (ko) 2012-03-29
PL1648905T3 (pl) 2009-07-31
JP2006528646A (ja) 2006-12-21
IL173348A (en) 2015-11-30
KR20060056344A (ko) 2006-05-24
PT1648905E (pt) 2009-04-08
CA2532982A1 (en) 2005-02-03
US20050026944A1 (en) 2005-02-03
AU2004259765B2 (en) 2009-10-22
CY1111599T1 (el) 2015-10-07
JP4707192B2 (ja) 2011-06-22
BRPI0412894A (pt) 2006-10-03
EP1648905A1 (en) 2006-04-26
NZ544712A (en) 2009-09-25
AU2009251083B2 (en) 2012-02-16
EP1648905B1 (en) 2008-12-31
DK1648905T3 (da) 2009-03-30
IL173348A0 (en) 2006-06-11
ES2319302T3 (es) 2009-05-06
KR20110123797A (ko) 2011-11-15
MXPA06000919A (es) 2006-05-04

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