EP1463505A2 - 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer - Google Patents

3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer

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Publication number
EP1463505A2
EP1463505A2 EP02790126A EP02790126A EP1463505A2 EP 1463505 A2 EP1463505 A2 EP 1463505A2 EP 02790126 A EP02790126 A EP 02790126A EP 02790126 A EP02790126 A EP 02790126A EP 1463505 A2 EP1463505 A2 EP 1463505A2
Authority
EP
European Patent Office
Prior art keywords
pyridin
indol
ethylamine
yloxy
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02790126A
Other languages
German (de)
English (en)
French (fr)
Inventor
Qun Li
Keith W. Woods
Gui-Dong Zhu
John P. Fischer
Jianchun Gong
Tongmei Li
Viraj Gandhi
Sheela A. Thomas
Garrick Packard
Xiaohong Song
Jason N. Abrams
Robert Diebold
Jurgen Dinges
Charles Hutchins
Vincent S. Stoll
Saul H. Rosenberg
Vincent L. Giranda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Inc
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/295,833 external-priority patent/US20030187026A1/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1463505A2 publication Critical patent/EP1463505A2/en
Withdrawn legal-status Critical Current

Links

Definitions

  • the present invention relates to compounds which are useful for inhibiting protein kinases, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
  • Protein kinases have been clearly shown to be important in the progression of many disease states that are induced by the inappropriate proliferation of cells. These kinases are often found to be up-regulated in many hyperproliferative states such as cancer. These kinases may be important in cell signaling, where their inappropriate activation induces cells to proliferate (e.g. EGFR, ERBB2, VEGFR, FGFR, PDGFR, c-Met, IGF-1R, RET, TIE2). Alternatively, they may be involved in signal transduction within cells (e.g. c-Src, PKC, Akt, PKA, c-Abl, PDK-1). Often these signal transduction genes are recognized proto-oncogenes.
  • kinases control cell cycle progression near the Gl-S transition (e.g. Cdk2, Cdk4), at the G2-M transition (e.g. Weel, Mytl, Chkl, Cdc2) or at the spindle checkpoint (Plk, Auroral or 2, Bubl or 3).
  • kinases are intimately linked to the DNA damage response (e.g. ATM, ATR, Chkl, Chk2). Disregulation of these cellular functions; cell signaling, signal transduction, cell cycle control, and DNA repair, are all hallmarks of hyperproliferative diseases, particularly cancer. It is therefore likely that pharmacological modulation of one or more kinases would be useful in slowing or stopping disease progression in these diseases.
  • X' is selected from the group consisting of C and N;
  • Y is selected from the group consisting of C and N; Y' is selected from the group consisting of C(R 9 ) and N; wherein R 9 is selected from, the group consisting of hydrogen and -L 2 -L 3 (R 3 )(R 6 );
  • Z is selected from the group consisting of C and N; provided that 0, 1, or 2 of X, X', Y, V, and Z are N;
  • L 1 is selected from the group consisting of a bond, -O-, -NR 5 -, alkenyl, alkynyl, -C(O)-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R 5 )-, -N(R 5 )S(O) 2 -, -C(R 12 ) 2 -, -C(R 12 ) 2 N(R 5 )-,
  • each group is drawn with its left end attached to R 1 and its right end attached to the aromatic ring;
  • L 2 is selected from the group consisting of a bond,-O-, -C(R 12 ) 2 -, -S-, -N(R 5 )-, -N(R 5 )C(O)-, and -C(O)N(R 5 )-;
  • L 3 is selected from the group consisting of a bond, alkylidene and alkylene, wherein the alkylidene and the alkylene are optionally substituted with one or two substituents independently selected from the group consisting of alkoxy, amino, cyano, and hydroxy;
  • R 1 is selected from the group consisting of aryl, heteroaryl, and heterocycle
  • R 2 and R 4 are independently absent or selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, arylalkynyl, cyano, cyanoalkenyl, halo, heteroaryl, heterocycle, hydroxyalkyl, and nitro; or
  • R 2 and L 1 together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle; or
  • R 4 and L 2 together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle; provided that when L 3 is alkylidene, R 4 and L 2 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle;
  • R 3 is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle;
  • R 6 is selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle; provided that when L 1 and L 2 are bonds, at least one of R 3 and R 6 is other than hydrogen;
  • R 5 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl;
  • R 7 is absent or selected from the group consisting of hydrogen, alkyl, cyanoalkenyl, and -L 2 -L 3 (R 3 )(R 6 ); or
  • R 7 and L 1 together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle; and each R 12 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle, and nitro.
  • the present invention provides a compound of formula (II)
  • L 1 is selected from the group consisting of a bond,-O-, -N(R 5 )-, alkenyl, alkynyl, -N(R 5 )C(O)-, and -C(O)N(R 5 )-;
  • L 2 is selected from the group consisting of a bond,-O-, -N(R 5 )-, -N(R 5 )C(O)-, and
  • L 3 is selected from the group consisting of a bond, alkylidene, and alkylene, wherein the alkylidene and the alkylene are optionally substituted with one or two substituents independently selected from the group consisting of amino, cyano, and hydroxy;
  • R 1 is selected from the group consisting of aryl, heteroaryl, and heterocycle;
  • R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl; wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; or R 2 and V, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of dihydropyrrolyl, pyrazolyl, and phenyl; or
  • R 4 and lb together with the carbon atoms to which they are attached, form a ring selected from the group consisting of dihydropyrrolyl, phenyl, pyridinyl, and pyrrolyl; wherein the ring can be optionally substituted with oxo; provided that when L 3 is alkylidene, R 4 and L 2 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting, of dihydropyrrolyl, phenyl, pyridinyl, and pyrrolyl; wherein the ring can be optionally substituted with oxo;
  • R 3 is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle;
  • R 6 are independently selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, and heteroarylalkoxy, heteroaryloxy, and heterocycle; provided that when L 1 and L 2 are bonds, at least one of R 3 and R 6 is other than hydrogen;
  • R 5 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl;
  • X is selected from the group consisting of C(R ⁇ and N; wherein R s is selected from the group consisting of hydrogen, amino, carboxy, cyano, and halo.
  • R s is selected from the group consisting of hydrogen, amino, carboxy, cyano, and halo.
  • the present invention provides a compound of formula (III)
  • L 1 is selected from the group consisting of a bond, -O-, -N(R 5 )-, alkenyl, alkynyl, and -N(R 5 )C(O)-;
  • L 2 is selected from the group consisting of a bond, -O-, -N(R 5 )-, -N(R 5 )C(O)-, and -C(O)N(R 5 )-;
  • L 3 is alkylene, wherein the alkylene is substituted with one or two substituents independently selected from the group consisting of amino and hydroxy;
  • R 1 is selected from the group consisting of aryl, heteroaryl, and heterocycle;
  • R 2 and R 4 are independently selected from the group consisting of hydrogen and halo;
  • R 3 and R 6 are independently selected from the group consisting of hydrogen, aryl, arylalkoxy, and heteroaryl; provided that when L 1 and L 2 are bonds, at least one of R 3 and R ⁇ is other than hydrogen; and
  • R 5 is selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is
  • L 1 is alkenyl
  • lb is selected from the group consisting of a bond,-O-, -C(R 12 ) 2 -, -S-, -N(R 5 )-, -N(R 5 )C(O)-, and -C(O)N(R 5 )-
  • L 3 is a bond or selected from the group consisting of alkylidene and alkylene, wherein the alkylidene and the alkylene are optionally substituted with one or two substituents independently selected from the group consisting of alkoxy, amino, cyano, and hydroxy
  • R 1 is selected from the group consisting of aryl, heteroaryl, and heterocycle
  • R 2 and R 4 are independently absent or selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, arylalkynyl, cyano, cyanoalken
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X'
  • Y 15 is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen,
  • R 3 is hydrogen;
  • R 6 is selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle; and
  • R 7 is absent or selected from the group
  • 25 consisting of hydrogen, alkyl, and cyanoalkenyl.
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is
  • L 1 is alkenyl
  • L 2 is -O-
  • L 1 is alkenyl
  • lb is -O-
  • L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy
  • R 1 is heteroaryl
  • R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the
  • R 3 is hydrogen
  • R 6 is selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle
  • R 7 is absent or selected from the group consisting of hydrogen, alkyl, and cyanoalkenyl.
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is C(R 9 j, wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; L 2 is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R' is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is heteroaryl; and R 7
  • the present invention provides a compound of formula (I) wherein X is N; and X' is C; Y is C; Y' is C(R°), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is aryl; and R 7
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; and X' is selected from the group consisting of C and N; Y is C; Y' is C(R), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; lb is -O-; L 3 is a bond; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazoly
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; lb is -O-; L 3 is a bond; R 1 is heteroaryl; R 2 and R 4 are hydrogen; R 3 is absent; R 6 is heterocycle; and R 7 is hydrogen.
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is alkenyl; lb is -N(R )C(O)-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkyn
  • the present invention provides a compound of formula (I) wherein X is N; and X' is C; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; V is alkenyl; lb is -N(R 5 )C(O)-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C;Y' is C(R 9 ), wherein R 9 is -Ib- L 3 (R 3 )(R 6 ); Z is C; L 1 is alkynyl; lb is selected from the group consisting of a bond,-O-, - C(R i2 ) 2 -, -S-, -N(R 5 )-, -N(R 5 )C(O)-, and -C(O)N(R 5 )-; L 3 is a bond or selected from the group consisting of alkylidene and alkylene, wherein the alkylidene and the alkylene are optional
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C;Y' is C(R 9 ), wherein R 9 is ⁇ lb- L 3 (R 3 )(R 6 ); Z is C; L 1 is alkynyl; lb is -O-; lb is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C;Y' is C(R 9 ), wherein R 9 is -Ib- L 3 (R )(R 6 ); Z is C; 1 is a bond; L 2 is selected from the group consisting of a bond,-O-, - C(R 12 ) 2 -, -S-, -N(R 5 )-, -N(R 5 )C(O)-, and -C(O)N(R 5 )-; L 3 is a bond or selected from the group consisting of alkylidene and alkylene, wherein the alkylidene and the alkylene are optionally substituted with one or two
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; and X' is selected from the group consisting of C and N; Y is C; Y' is C(R), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano,
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L l is a bond; L 2 is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is aryl; and R 7 is
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R )(R 6 ); Z is C; L 1 is a bond; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is heteroaryl; and R 7 is hydrogen
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is hydrogen; X' is N; Y is C; Y* is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 2 is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thi
  • the present invention provides a compound of formula (I) wherein X is N; X * is C; Y is N; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 is absent; R 4 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected. from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is aryl; and R
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is N; Y * is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyan ⁇ , and hydroxy; R 1 is heteroaryl; R 2 is absent; R 4 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is heteroaryl; and R 7
  • the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X' is C; Y is N; Y is R 9 ), wherein R 9 is -Ib- L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 is absent; R 4 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is hydrogen;
  • the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X is C; Y is N; Y' is C(R 9 ), wherein R 9 is -Ib- L 3 (R 3 )(R 6 ); Z is C L 1 is a bond; lb is -O-; lb is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R' is heteroaryl; R 2 is absent; R 4 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R
  • the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X' is C; Y is N; Y' is C(R 9 ), wherein R 9 is -Ib- L 3 (R 3 )(R 6 ); Z is N; L 1 is a bond; L 2 is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 4 is absent; R 2 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R
  • the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X' is C; Y is N; Y' is C(R wherein R 9 is -lb- L 3 (R 3 )(R 6 ); Z is N; L 1 is a bond; L 2 is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 4 is absent; R 2 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, aid heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is hetero
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is N; Y is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is N; V is a bond; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R is heteroaryl; R 4 is absent; R 2 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is aryl; and R 7 is hydrogen.
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is N; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is N; L 1 is a bond; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R' is heteroaryl; R 4 is absent; R 2 is selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is heteroaryl; and R 7
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is -C-; L 1 is a bond; L 2 is -N(R 5 )-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is CQ ⁇ wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L" is a bond; lb is -N(R 5 )-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 5 is selected from the group consisting
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is C(R 9 J, wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; lb is -N(R 5 )-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 5 is selected from the
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; lb is -N(R 5 )C(O)-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkyn
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is C(R wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L' is a bond; lb is -N(R 5 )C(O)-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is heteroary
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is C(R wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; lb is -N(R 5 )C(O)-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; R 3 is hydrogen; R 6 is ary
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is -N(R 5 )-; L 2 is selected from the group consisting of a bond, -O-, - C(R 12 ) 2 -, -S-, -N(R 5 )-, -N(R 5 )C(O)-, and -C(O)N(R 5 )-; L 3 is a bond or selected from the group consisting of alkylidene and alkylene, wherein the alkylidene and the.
  • alkylene are optionally substituted with one or two substituents independently selected from the group consisting of alkoxy, amino, cyano, and hydroxy
  • R 1 is selected from the group consisting of aryl, heteroaryl, and heterocycle
  • R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, arylalkynyl, cyano, cyanoalkenyl, halo, heteroaryl, heterocycle, hydroxyalkyl, and nitro
  • R 3 is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle
  • R 6 is selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is -N(R 5 )-; L 2 is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R' is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is C(R 9 ), wherein R 9 is ⁇ L 2 -L 3 (R 3 )(R 6 ); Z is C; L'.is -N(R 3 )-; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is -N(R 5 )-; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; lb is a bond; L 3 is a bond; R 2 and R 4 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl, wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is selected from the group consisting of a bond, -O-, -N ⁇ R 5 )-, alkenyl, alkynyl, -C(O)-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 N(R 5 )-, -N(R 5 )S(O) 2 -, -C(R ,2 ) 2 -, -C(R 12 -,
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N, wherein R 8 is hydrogen; X' is C; Y is C; Y is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; L 1 is a bond; L 3 is alkylidene, wherein the alkylidene is substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl wherein the heteroaryl is isoquinolinyl; R 4 and L 2 , together with the carbon atoms to which they are attached, form a heterocycle wherein the heterocycle is pyrrolidinyl substituted with oxo; R 3 is hydrogen; R 6 is heteroaryl, wherein the heteroaryl is indolyl; and R 7 is hydrogen.
  • X is selected from the group consisting of C(R 8
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; and X' is selected from the group consisting of C and N; Y is C;Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is aryl wherein the aryl ring is phenyl; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is absent; R ⁇ is heteroaryl; and R 7 is absent or selected
  • the present invention provides a compound of formula (I) wherein X is N; X' is C; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is aryl wherein the aryl ring is phenyl; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is absent; R 6 is heteroaryl; and R 7 is hydrogen.
  • the present invention provides a compound of formula (I) wherein X is N; X* is C; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is aryl wherein the aryl ring is phenyl; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is absent; R 6 is aryl; and R 7 is hydrogen.
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X' is selected from the group consisting of C and N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is heteroaryl wherein the heteroaryl is pyrazolyl; lb is a bond; lb is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 3 is hydrogen; R
  • the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X' is N; Y is C; Y' is C(R 9 ), wherein R 9 is -L -L 3 (R 3 )(R ⁇ ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is heteroaryl wherein the heteroaryl is pyrazolyl; L 2 is a bond; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is hydrogen; R 6 is aryl; and R 7 is absent.
  • X is C(R 8 ), wherein R 8 is hydrogen; X' is N; Y is C; Y' is C(R 9 ), wherein R 9 is -L -L 3 (R 3 )(R
  • the present invention provides a compound of formula (I) wherein X is C(R 8 ), wherein R 8 is hydrogen; X' is N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 2 and L 1 , together with the carbon atoms to which they are attached, form a ring that is heteroaryl wherein the heteroaryl is pyrazolyl; lb is a bond; lb is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is aryl; R 3 is hydrogen; R ⁇ is aryl; and R 7 is absent.
  • X is C(R 8 ), wherein R 8 is hydrogen; X' is N; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3
  • the present invention provides a compound of formula (I) wherein X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido; X is C; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R 6 ); Z is C; R 7 and L 1 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting aryl, heteroaryl and heterocycle; lb is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is selected from the group consisting of aryl, heterocycle, and heteroaryl; R 3 is hydrogen; and R 6 is selected from the group consisting of
  • the present invention provides a compound of formula (I) wherein X is N; and X' is C; Y is C; Y' is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R ⁇ ); Z is C; R 7 and L 1 , together with the carbon atoms to which they are attached, form a ring that is a heteroaryl wherein the heteroaryl is pyridinyl; L 2 is -O-; L 3 is alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is hydrogen; and R 6 is heteroaryl.
  • the present invention provides a compound of formula (I) wherein X is N; and X' is C; Y is C; Y* is C(R 9 ), wherein R 9 is -L 2 -L 3 (R 3 )(R ⁇ ); Z is C; R 7 and L 1 , together with the carbon atoms to which they are attached, form a ring that is a heteroaryl wherein the heteroaryl is pyridinyl; lb is -O-; L 3 is' alkylene, wherein the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano, and hydroxy; R 1 is heteroaryl; R 3 is hydrogen; and R 6 is aryl.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a therapeutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
  • the invention provides a method of inhibiting 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.
  • alkenyl refers to a group derived from a straight or branched chain hydrocarbon of up to six atoms containing at least one double bond.
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
  • alkoxyalkyl refers to an alkoxy group attached to the parent molecular moiety through an alkyl group.
  • alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through an alkyl group.
  • alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon of one to six atoms.
  • alkylene refers to a divalent group derived from a straight or branched chain saturated hydrocarbon of one to six atoms.
  • alkylcarbonyl refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkylidene refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
  • alkylsulfonyl refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.
  • alkynyl refers to agroup derived from a straight or branched chain hydrocarbon of two to six atoms containing at least one triple bond.
  • amino refers to an amino group attached to the parent molecular moiety through a carbonyl group.
  • amino refers to-NR a R b , wherein R ⁇ and R b are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, haloalkylcarbonyl, (NR L R d )alkylcarbonyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, (heterocycle)alkenyl, and (heterocycle)alkyl, wherein the aryl, the aryl part of the arylalkenyl, the arylalkyl, the heteroaryl, the heteroaryl part of the heteroarylalken
  • 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 cycloalkyl group, as defined herein, or another phenyl group.
  • Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a cycloalkyl group, as defined herein, or another phenyl group.
  • aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • arylalkenyl refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
  • arylalkoxy refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
  • arylalkyl refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • arylalkylamino refers to an arylalkyl group attached to the parent molecular moiety through a nitrogen atom, wherein the nitrogen atom is substituted with hydrogen.
  • arylalkyl idene refers to an aryl group attached to the parent molecular moiety through an alkylidene group
  • arylalkylthio refers to an arylalkyl group attached to the parent molecular moiety through a sulfur atom.
  • arylalkynyl refers to an aryl group attached to the parent molecular moiety through an alkynyl 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.
  • arylsulfonyl refers to an aryl group attached to the parent molecular moiety through an sulfonyl group.
  • arylthio refers to an aryl group attached to the parent molecular moiety through a sulfur atom.
  • carbonyl refers to a-C(O)- group.
  • cyano refers to -CN.
  • cyanoalkenyl refers to a cyano group attached to the parent molecular moiety through an alkenyl group
  • cycloalkyl refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms.
  • Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, bicyclo[3.1.1]heptyl, adamantyl, and the like.
  • (cycloalkyl)alkylidene refers to a cycloalkyl group attached to the parent molecular moiety through an alkylidene group.
  • halo or halogen, as used herein, refers 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.
  • haloalkylcarbonyl refers to an haloalkyl group attached to the parent molecular moiety through a carbonyl group.
  • 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.
  • the five-membered rings have two double bonds, and the six- membered rings have three double bonds.
  • the heteroaryl groups are connected to the parent molecular group through a substitutable carbon or nitrogen atom in the ring.
  • heteroaryl also includes systems where a heteroaryl ring is fused to an aryl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group.
  • Heteroaryls are exemplified by benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxadiazolyl, oxazolyl, purinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl,
  • 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, alkynyl, alkylcarbonyl, amino, aminoalkyl, aryl, arylalkoxy, arylalkyl, arylalkylthio, arylalkynyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heteroaryl group, heteroarylalkoxy, heteroarylalkyl, heterocycle, (heterocycle)alkoxy, (heterocycle)alkyl, hydroxy, hydroxyalkyl, nitro, and oxo, wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, the arylalky
  • aryloxy, the second heteroaryl group, the heteroaryl part of the heteroarylalkoxy and the heteroarylalkyl, the heterocycle, and the heterocycle part of the (heterocycle)alkoxy and the (heterocycle)alkyl can be further optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo.
  • heteroarylalkenyl refers to a heteroaryl group attached to the parent molecular moiety through an alkenyl group.
  • heteroarylalkoxy refers to a heteroaryl group attached to the parent molecular moiety through an alkoxy group.
  • heteroarylalkyl refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group.
  • heteroarylalkylidene refers to a heteroaryl group attached to the parent molecular moiety through an alkylidene group.
  • heteroaryloxy refers to a heteroaryl group attached to the parent molecular moiety through an oxygen atom.
  • heteroarylsulfonyl refers to a heteroaryl group attached to the parent molecular moiety through a sulfonyl group.
  • heterocycle refers to cyclic, non-aromatic, three-, four-, five-, six-, or seven-membered rings containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • the five-membered rings have zero or one double bonds and the six- and seven-membered rings have zero, one, or two double bonds.
  • the heterocycle groups of the invention are connected to the parent molecular group through a substitutable carbon or nitrogen atom in the ring.
  • the term 'heterocycle also includes systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
  • Heterocycle groups of the invention are exemplified by aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.
  • heterocycle 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, alkylidene, amino, aminoalkyl, aryl, arylalkoxy, arylalkyl, arylalkylidene, cyano, (cycloalkyl)alkylidene, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkoxy, heteroarylalkyl, heteroarylalkylidene, iminohydroxy, a second heterocycle, (heterocycle)alkoxy, (heterocycle)alkyl, (heterocycle)alkylidene, hydroxy, hydroxyalkyl, nitro, and oxo, wherein the aryl, the aryl part of the arylalkoxy and the
  • (heterocycle)alkenyl refers to a heterocycle group attached to the parent molecular moiety through an alkenyl group.
  • (heterocycle)alkoxy refers to a heterocycle group attached to the parent molecular group through an oxygen atom.
  • (heterocycle)alkyl refers to a heterocycle group attached to the parent molecular moiety through an alkyl group.
  • (heterocycle)alkylidene refers to a heterocycle group attached to the parent molecular moiety through an alkylidene group.
  • hydroxy refers to -OH.
  • hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl 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 each independently selected from hydrogen and alkyl.
  • (NR°R d )alkyl refers to a-NR c R d group attached to the parent molecular moiety through an alkyl group.
  • (NR°R d )alkylcarbonyl refers to a (NR°R d )alkyl group attached to the parent molecular moiety through a carbonyl group.
  • nitro refers to -NO 2 .
  • sulfonyl refers to -S(O) 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 withoutundue 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 compounds or separately by reacting an amino 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 (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3 -phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate,trifluoroacetate,
  • amino 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.
  • 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-dimefhylaniline, 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, diethyl
  • 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 transformed in vivo to parent compounds of formula (I) for example, by hydrolysis in blood.
  • the compounds can be administered alone or in combination with other anticancer agents.
  • the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used.
  • the compounds can be administered orally, parenterally, osmotically (nasal •sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof.
  • parenteral includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
  • Parenterally adminstered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents.
  • the injectable preparation can also be an injectable solution or suspension in a diluent or solvent.
  • acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
  • the anticancer effect of parenterally administered compounds can be prolonged by slowing their absorption.
  • injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound.
  • the rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state.
  • Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension.
  • Yet another way to slow absorption of a particular compound is administering injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled.
  • Transdermal patches can also provide controlled delivery of the compounds.
  • the rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers can be used to increase absorption.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose.
  • Capsules, tablets and pills can also comprise buffering agents, and tablets and pills can be prepared with enteric coatings or other release-controlling coatings.
  • Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefore.
  • Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
  • Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches.
  • the compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers.
  • These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg/kg body weight.
  • Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
  • the Aktl assay uses His-Aktl-S36, a truncated Aktl containing a His tag at the N- terminus, amino acid 139-460 of Aktl and the following point mutations: S378A, S381A, T450D and S473D.
  • the His-Aktl-S36 assay is run in 96 well plates by incubating InM His- Aktl-S36, 5 ⁇ M Biotin-BAD-peptide (Biotin) and 5 ⁇ M 33 P-ATP in 50 ⁇ L of reaction buffer (20 mM HEPES, pH 7.5, 10 mM MgCL, 0.009% Triton X-100) for 30 minutes at room temperature.
  • Akt2, Akt3, PKA, PKC, Erk2, Chkl, Cdc2, Src, CK2, MAPK AP kinase 2, and SGK are carried out similarly using their specific biotinylated peptide substrates and buffer conditions.
  • Compounds of the invention inhibited Akt by 0- 100% at a concentration of 1 ⁇ M.
  • Preferred compounds had percent inhibitions of between 77 and 100 at 1 ⁇ M and more preferred compounds had percent inhibitions of between 92 and 100 at 1 ⁇ M.
  • the compounds of the invention are useful in treating disorders which are caused or exacerbated by increased protein kinase levels.
  • 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.
  • Compounds of formula (4) can be converted to compounds of formula (la) by treatment with compounds of formula (5) (M is selected from B(OH) 2 ; Sn(R a ) 3 , where R a is an alkyl or aryl group; and hydrogen) in the presence of a palladium catalyst and an optional additive such as triethylamine.
  • a palladium catalyst include Pd(PPh. 4 , and Pd(OAc) 2 and P(o-tol) 3 .
  • Representative solvents include toluene, acetonitrile, and DME.
  • the reaction is typically conducted at temperatures between about 60 °C and about 110 °C and reaction times are typically about 4 to about 12 hours.
  • Scheme 2 shows that compounds of formula (6) (Z 1 and Z 2 are independently Cl, Br, I, or OTf) can be converted to compounds of formula (8) by treatment with compounds of formula (7) according to the procedure described in Scheme 1. These compounds can be converted to compounds of formula (9) by treatment with benzophenone imine, a palladium catalyst, and a base.
  • palladium catalysts include Pd 2 dba 3 and a ligand such as BINAP, dppf, or dppe.
  • Representative bases include sodium tert-butoxide and potassium tert-butoxide.
  • the reaction is conducted in a solvent such as toluene, acetonitrile, or DME; at temperatures from about 60 °C to about 90 °C; and at times from about 8 to about 24 hours.
  • Compounds of formula (9) can be treated with compounds of formula (10) in the presence of an acid such as acetic acid and then treated with sodium cyanoborohydride to provide compounds of formula (lb).
  • Representative solvents include methanol and ethanol. The reaction is typically conducted at about 20 °C to about 70 °C and reaction times are typically about 1 to about 4 hours.
  • Scheme 3 shows the preparation of compounds of formula (Ic).
  • Compounds of formula (11) (Z is Br) can be treated with a palladium catalyst under CO atmosphere to provide compounds of formula (12).
  • palladium catalysts include PdCVdppf, PdCl 2 and BINAP, and PdCl 2 -dppe.
  • Representative solvents include THF, water, DME, and mixtures thereof. The reaction is typically conducted at about 80 °C to about 100 °C and reaction times are typically between 12 and 24 hours.
  • Compounds of formula (12) can be converted to compounds of formula (Ic) by treatment with a substituted amine in the presence of a coupling agent.
  • Representative coupling agents include EDC, HOBt, DCC, DMAP, and mixtures thereof.
  • solvents used include dichloromethane, DMF, and DME. The reaction is typically conducted at about 0 °C to about 35 °C and reaction times are typically about 12 to about 24 hours.
  • Scheme 5 shows the synthesis of compounds of formula (le).
  • Compounds of formula (15) can be converted to compounds of formula (16) by treatment with a reducing agent.
  • reducing agents include Pd/C and ammonium formate, Pd/C and hydrogen, and PtO 2 and hydrogen.
  • Representative solvents include methanol and ethanol. The reaction is typically conducted at about 50 °C to about 70 °C for about 15 minutes to about 2 hours.
  • Compounds of formula (16) can be converted to compounds of formula (le) by treatment with an electrophile such as a halo-substituted heteroaryl group. Examples of solvents used in these reactions include ethanol and methanol. The reaction is typically conducted at about 50 °C to about 70 °C for about 6 to about 18 hours.
  • compounds of formula (8) can be converted to compounds of formula (If) (where L 2 is a bond) by treatment with compounds of formula (17) (M is B(OR z ) 2 , wherein R z is hydrogen or alkyl) in the presence of a palladium catalyst and a base such as cesium carbonate or sodium carbonate.
  • a palladium catalyst irclude PdCl 2 -dppf, Pd(PPh 3 ) 4 , and PdCl 2 (PPh 3 ) 2 .
  • solvents used in these reactions include DMF, DME, and NMP.
  • the reaction is typically conducted at about 30 °C to about 100 °C for about 4 to about 12 hours.
  • Example 1A N- ⁇ 2-[(5-bromopyridin-3-yl)oxy1ethyl ⁇ -N,N-dimethylamine
  • DMF dimethyl sulfoxide
  • sodium hydride 0.2 g, 8.4 mmol
  • 3,5-dibromopyridine 1.0 g, 4.2 mmol
  • the mixture was stirred at 90°C for 8 hours, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (TS ⁇ SO,,), filtered, and concentrated under vacuum.
  • Example 1A N,N-dimethyl-N- 2-( ⁇ 5-[(E)-2-pyridin-4-ylvinyllpyridin-3-y oxy)ethyllamine
  • 4-vinylpyridine (0.69 g, 5.53 mmol)
  • tri-o-tolylphosphine 0.6 g, 1.96 mmol
  • palladium acetate 0.16 g, 0.65 mmol
  • triethylamine 0.66 g, 6.53 mmol
  • the reaction solution was partitioned between ethyl acetate and water.
  • Example 2B tert-butyl ( 1 S)-2-( 1 H-indol-3-y 1)- 1 - ⁇ ( ⁇ 5-r(E)-2-pyridin-4-y lvinyllpyridin-3 - yl ⁇ oxy)methyllethylcarbamate
  • the desired product was prepared by substituting Example 2A for Example 1A in
  • Example 2C (lS)-2-(lH-indol-3-yl)-l-r( ⁇ 5-r(E)-2-pyridin-4-ylvinyl1pyridin-3-yUoxy)methy ⁇ ethylamine
  • a solution of Example 2B (603 mg, 1.28 mmol) in dichloromethane (20 mL) at room temperature was treated with 4N HCl in dioxane (5 mL), stirred for 2 hours, and concentrated. The residue was dissolved in water (1.5 mL) and freeze-dried to provide the desired product as the hydrochloride salt (610 mg, 99%).
  • Example 2D (lS)-2-(lH-indol-3-yl)-l-[( ⁇ 5-r(E)-2-pyridin-4-ylvinvnpyridin-3-yljoxy)methyllethylamine
  • dichloromethane 5 mL
  • trifluoroacetic acid 5 mL
  • the residue was dissolved in water (1.5 mL) and freeze-dried to provide the desired product.as the trifluoroacetate salt (643 mg, 85%).
  • the desired product was prepared as the hydrochloride salt by substituting D-Boc- tryptophanol for L-Boc-tryptophanol in Example 2A then proceeding as described for Examples 2B and 2C.
  • Example 4 l-(lH-indol-3-yl)-3-( ⁇ 5-[(E)-2-pyridin-4-ylviny ⁇ pyridin-3-yl ⁇ oxy)propan-2-ol
  • acetic acid 2.4 mL
  • NaNO 2 117 mg. 1.70 mmol
  • water 40 ⁇ L
  • stirred for an additional hour poured into 2N NaOH, and extracted with isopropanol/dichloromethane. The combined extracts were concentrated.
  • Example 6 (lS)-2,2-diphenyl-l-r( ⁇ 5-[(E)-2-pyridin-4-ylvinyllpyridin-3-yl)oxy)methynethylamine
  • the desired product was prepared as the hydrochloride salt by aibstituting L-Boc- diphenylalaninol for L-Boc-tryptophanol in Example 2A then proceeding as described for Examples 2B and 2C.
  • Example 7 (lS)-l- ⁇ 4-[(2,6-dichlorobenzyl)oxy1benzyl)-2-( ⁇ 5-r(E)-2-pyridin-4-ylvinvnpyridin-3- yl)oxy)ethylamine
  • the desired product was prepared as the hydrochloride salt by substituitng L-Boc-(4- (2,6-dichlorobenzyloxy)phenyl)alaninol for L-Boc-tryptophanol in Example 2A then proceeding as described for Examples 2B and 2C.
  • Example 8 (lS)-2-(benzyloxy)-l-[( ⁇ 5-[(E)-2-pyridin-4-ylvinyl1pyridin-3-yl ⁇ oxy)methyl1ethylamine
  • the desired product was prepared as the hydrochloride salt by substituting L-Boc-3- benzyloxyalaninol for L-Boc-tryptophanol in Example 2A then proceeding as described for Examples 2B and 2C.
  • Example 9 N,N-dimethyl-N-[(lS,2S)-l-methyl-2-phenyl-2-( ⁇ 5-r(E)-2-pyridin-4-ylvinyl1pyridin-3- yl)oxy)ethyl1amine
  • Example 9A 5-bromopyridin-3-yl acetate A mixture of 3-bromo-5-hydroxypyridine (9.00 g, 51.7 mmol), acetic anhydride (6.0 mL) and triethylamine (12.0 mL) in THF (50 mL) was heated to reflux overnight, cooled to room temperature, diluted with diethyl ether, washed with water, 5% NaHCO 3 , water, and brine, dried (MgSO 4 ), filtered, and concentrated to provide the desired product (9.37 g, 84%).
  • Example 9B 5-[(E)-2-pyridin-4-ylvinyllpyridin-3-ol
  • a mixture of Example 9A (9.37 g, 43,3 mmol), 4-vinylpyridine (14.0 mL, 130 mmol), tri-o-tolylphosphine (13.5 g, 44.4 mmol), palladium acetate (2.65 g, 11.8 mmol) and triethylamine (120 mL, 0.861 mol) in acetonitrile (40 mL) was heated to reflux overnight and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated under vacuum.
  • the desired product was prepared as the trifluoracetate salt by substituting L-Boc-(2- naphthyl)alaninol for L-Boc-tryptophanol in Example 2A then proceeding as described for Examples 2B and 2D.
  • the concentrate was purified by flash column chromatography on silica gel with 4% methanol/dichloromethane to provide the desired product (2.18 ,g, 36%).
  • Example 11A A mixture of Example 11A (1.88 g, 7.2 mmol), benzophenone imine (1.22 mL), Pd 2 (dba) 3 (66 mg), BINAP (125 mg), sodium tert-butoxide (0.97 g), and toluene (19 mL) was heated to 80 °C overnight and concentrated. The residue was purified by flash column chromatography on silica gel with ethyl acetate to provide a solid (2.44 g). This was stirred with 2N HCl (aq.) (5.0 mL) in THF (50 mL) at room temperature for.2 hours and concentrated.
  • 2N HCl aq.
  • Example 11C tert-butyl (lS)-2-(lH-indol-3-yl)-l-r( ⁇ 5-r(E)-2-pyridin-4-ylvinynpyridin-3- yl ⁇ amino)methyl "
  • ethylcarbamate A mixture of Example 1 IB (52 mg, 0.264 mmol), L-Boc-tryptophanal (J. Med.
  • Example I IP N-r(2S)-2-amino-3-(lH-indol-3-yl)propyl1-N- ⁇ 5-r(E)-2-pyridin-4-ylvinyl]pyridin-3-yl ⁇ amine
  • a solution of Example 1 IC (40 mg, 0.085 mmol) in dichloromethane (3.0 mL) at room temperature was treated with 4N HCl in dioxane (0.5 mL), stirred for 1 hour, and concentrated to provide the desired product as the hydrochloride salt (30 mg, 74%).
  • Example 12A 5-bromo-2-chloro-3-hydroxypyridine
  • HBr/HOAc 30%, 50 mL
  • the concentrate was partitioned between ethyl acetate and saturated Na ⁇ O-, (aq.).
  • the organic layer was washed with brine, dried (Na,SO 4 ), filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel with 30% ethyl acetate/hexane provided the desired product (0.51 g, 72%).
  • Example 12B The desired product was prepared by substituting Example 12B for 3-bromo-5- hydroxypyridine in Example 2A (0.78 g, 66%). MS (DCI/NH 3 ) m/e 481 (M+H) + .
  • Example 13 ( 1 S)-2-( ⁇ 6-chloro-5-r(E)-2-pyridin-4-ylvinvnpyridin-3-yl) oxy)- 1 -( 1 H-indol-3- ylmethyl)ethylamine
  • Example 13A tert-butyl (lS)-2-r(5-bromo-6-chloropyridin-3-yl)oxy1-l-(lH-indol-3- ylmethyQethylcarbamate
  • Example 13B tert-butyl (lS)-2-( ⁇ 6-chloro-5-r(E)-2-pyridin-4-ylvinyl1pyridin-3-yl)oxy)-l-(lH-indol-3- ylmethyQethylcarbamate
  • a solution Example 13A (1.50 g, 3.125 mmol), Pd 2 (dba) 3 (71 mg, 0.078 mmol) and tri-o-tolylphosphine (71 mg, 0.23 mmol) in DMF ( 30 mL) was treated with ⁇ vinylpyridine (492 mg, 4.68 mmol) and triethylamine (1.30 mL, 9.4 mmol), purged with nitrogen, and heated to 100 °C for 4 hours.
  • Example 14 ( 1 S)-2-( 1 H-indol-3 -y 1)- 1 -( ⁇ [5 -(pyr idin-4-y lethyny l)pyridin-3 -y lloxy ⁇ methyl)ethy lamine
  • Example 14A tert-butyl (lS)-2-(lH-indol-3-yl)-l-r( ⁇ 5-r(trimethylsilyl)ethynynpyridin-3- yl ⁇ oxy)methyl1ethylcarbamate
  • a mixture of Example 2A 500 mg, 1.12 mmol), Pd 2 Cl,(PPh 3 ) 2 (77 mg, 0.112 mmol), and Cul (52 mg, 0.27 mmol) was purged with nitrogen, treated with DMF (7 mL), trimethylsilylacetylene (475 ⁇ L, 3.36 mmol) and triethylamine (468 ⁇ L, 3.36 mmol) stirred at 50
  • Example 14B tert-butyl (lS)-2-r(5-ethynylpyridin-3-yl)oxyI-l-(lH-indol-3-ylmethyl)ethylcarbamate
  • THF 6 mL
  • tetrabutylammonium fluoride 1.0 M solution in THF, 1.12 mL, 1.12 mmol
  • ethyl acetate 50 mL
  • washed with brine dried (MgSO 4 ), filtered, and concentrated.
  • Example 14C tert-butyl ( 1 S)-2-( 1 H-indol-3 -yl)- 1 -( ⁇ [5 -(pyridin-4-ylethynyl)pyridin-3 - yl "
  • Example 14D A mixture of Example 14D (40 mg, 0.11 mmol), 5% Pd/BaSO 4 (8.1 mg) and quinoline (8-.1 ⁇ L) in methanol (3 mL) was stirred under hydrogen (20 psi) at room temperature for 12 minutes and filtered. The filtrate was concentrated and the residual oil was purified by HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA to provide the desired product (30 mg, 75%).
  • Example 16 (2S)-2-amino-4-phenyl-N- ⁇ 5-r(E)-2-pyridin-4-ylviny ⁇ pyridin-3-yl ⁇ butanamide
  • Example 16A tert-butyl (lS)-3-phenyl-l-[( ⁇ 5-[(E)-2-pyridin-4-ylvinyripyridin-3- yl)amino)carbony ⁇ propylcarbamate
  • HOBt 210 mg
  • EDC 290 mg
  • DMAP 25 mg
  • Boc-homophenylalanine was stirred at room temperature overnight and ' concentrated.
  • Example 17A 5- ⁇ r(2S)-2-r(tert-butoxycarbonyl)amino1-3-(lH-indol-3-yl)propyl1oxylnicotinic acid A solution of Example 2A (1.30 g, 3.02 mmol) and PdCl.dppf (123 mg) in
  • Example 17A A solution of Example 17A (410 mg, 1.0 mmol), 4-aminopyridine (100 mg, 1.0 mmol), EDC (960 mg), and HOBt (680 mg) in DMF (10 mL) was stirred at room temperature overnight, diluted with dichloromethane, washed with water, dried (MgSO ⁇ ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with ethyl acetate/methanol (8:1) to provide the desired product (87 mg, 18%). MS (DCI/NH,) m/e 488 (M+H) + .
  • Example 17C 5- ⁇ [(2S)-2-amino-3-(lH-indol-3-yl)propylloxy ⁇ -N-pyridin-4-ylnicotinamide
  • the desired product was prepared as the hydrochloride salt by substituting Example 17B for Example 2B in Example 2C (27 mg, 31%).
  • Example 18B 5-[(E)-2-pyridin-4-ylvinyllnicotinic acid A mixture of Example 18A (1.60 g, 6.3 mmol) and LiOHH 2 O (2.64 g) in THF/water (50 mL/50 mL) was stirred at room temperature for 2 hours. The THF was removed under vacuum and the aqueous layer was acidified with IN HCl (aq.). The solid was collected by filtration and dried to provide the desired product. MS (DCI/NH,) m/e 227 (M+H) + .
  • Example 18C N-(aminoethyl)-5-f(E)-2-pyridm-4-ylvinyl1nicotinamide
  • the desired product was prepared as the hydrochloride salt by substituting Example 18B and N-tert-butoxycarbonylaminoethylamine for Example 17A and 4-aminopyridine, respectively, in Examples 17B and 17C.
  • Example 19A (2E)-3 -(4-bromopheny l)prop-2-en- 1 -ol
  • ethyl 4-bromocinnamide (5.430 g, 22.07 mmol) in toluene (20 mL) at - 78 °C
  • DIBAL 1.5 M in toluene, 37.0 mL, 55.5 mmol
  • stirred for 30 minutes at -78 °C warmed to room temperature, stirred for 1 hour, quenched with 10% HCl (aq.), and extracted twice with diethyl ether.
  • Example 19A A mixture of Example 19A (2.0 g, 9.387 mmol) and SOCl 2 (3.5 mL, 47.9 mmol) in benzene (10 mL) was stirred at room temperature for 24 hours and concentrated to provide the desired product (2.167g, 99%).
  • the desired product was prepared as the hydrochloride salt by substituting Example 9B and N-tert-butoxylcarbonylaminoethanol (200 mg, 1.00 mmol) for 3-bromo-5- hydroxypyridine and L-Boc-tryptophanol, respectively, in Examples 2 A and 2C.
  • Example 19D N-r(2E)-3-(4-bromophenyl)prop-2-enyll-N-r2-( ⁇ 5-r(E)-2-pyridin-4-ylvinynpyridin-3- y 1 ⁇ oxy)ethy 11 amine
  • Example 20A tert-butyl (lS)-2-(lH-indol-3-yl)-l-r(3-nitrophenoxy)methyl1ethylcarbamate
  • the desired product was prepared by substituting 3-nitrophenol for 3-bromo-5- hydroxypyridine in Example 2A (257 mg, 61%).
  • MS (DCI/NH.) m/e 412 (M+H) + , 419 (M+18) + .
  • Example 20B tert-butyl (lS)-2-(3-aminophenoxy)-l-(lH-indol-3-ylmethyl)ethylcarbamate
  • a solution of Example 20A (247 mg, 0.600 mmol), ammonium formate (400 mg, 6.34 mmol) and 10% Pd/C (25 mg) in methanol (10 mL) was heated to reflux for 30 minutes, cooled to room temperature, filtered through diatomaceous earth (Celite ® ), and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate/hexanes (1 :1) to provide the desired product (200 mg, 87%). MS (DCI/NH) m/e 382 (M+H) + .
  • Example 20C tert-butyl (lS)-2- ⁇ 3-r(2-aminopyrimidin-4-yl)amino1phenoxy ⁇ -l-(lH-indol-3- ylmethyl)ethylcarbamate
  • a solution of Example 20B (41.2 mg, 0.108 mmol) and 2-amino-4-chloropyrimidine (14.0 mg, 0.108 mmol) in ethanol (0.5 mL) was heated to 80°C for 13 hours and purified by flash column chromatography on silica gel with dichloromethane/methanol/NH,OH (100:5:0.5) to provide the desired product (50 mg, 98%).
  • Example 20D N 4 -(3- ⁇
  • the desired product was prepared as the hydrochloride salt by substituting Example 20C for Example 2B in Example 2C (33 mg, 81%).
  • Example 21 (lR)-3- ⁇ 6-chloro-5-r(E)-2-pyridin-4-ylvinynpyridin-3-yU-l-(lH-indol-3- ylmethyl)propylamine
  • Example 21 A 6-chloro-5-r(E)-2-pyridin-4-ylvinyl]pyridin-3-amine
  • Example 21A A solution of Example 21A (1.0 g, 4.3 mmol) in 30% H 2 SO 4 (10 mL) at 0°C was treated with NaNO 2 (386 mg, 5.6 mmol), stirred for 5 hours, treated with a solution of Nal (2.1 g, 14 mmol) in H 2 O (2 mL), stirred for 2 hours, treated with additional Nal (2.1 g, 14 mmol), stirred for 2 hours, poured into 30% NaOH (aq.) (200 mL) at 0 °C and extracted three times with 10% methanol/ethyl acetate. The combined organic phases were dried (MgSO 4 ), filtered, and concentrated.
  • Example 2 ID tert-butyl ( 1 R)-3- ⁇ 6-chloro-5-r(E)-2-pyridin-4-y lviny npyridin-3 -y 1 ⁇ - 1 -( 1 H-indol-3 - ylmethyl)propylcarbamate
  • Example 22A tert-butyl (lS)-2- ⁇ r5-(4-cyanophenyl)pyridin-3-vnoxy
  • ethylene glycol dimethyl ether (20.0 mL) at room temperature was treated with tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol), stirred for 10 minutes, treated with a solution of (4-cyanophenyl)boronic acid (123 mg, 0.84 mmol) in ethanol (5.0 mL), stirred for 15 minutes, treated with 2M Na ⁇ O j (aq.) (1.4 mL), heated to reflux for 4 hours, cooled to room temperature, and concentrated.
  • Example 22B 4-(5- ⁇ r(2S)-2-amino-3-(lH-indol-3-yl)propyl1oxy)pyridin-3-yl)benzonitrile
  • a solution of Example 22A (20 mg, 0.043 mmol) in dichloromethane (2.0 mL) at 0 °C was treated dropwise with trifluoroacetic acid (0.5 mL) and stirred for 2 hours while warming to room temperature. The reaction mixture was concentrated to provide the desired product as the trifluoroacetate salt (27 mg, 88%).
  • Example 23A isoquinolin-5-yl trifluoromethanesulfonate
  • a mixture of 5-hydroxyisoquinoline (1.6 g; 11.0 mmol) and triethylamine (1.38 g; 13.6 mmol) in dichloromethane (25 mL) at 0 °C was treated slowly with triflic anhydride (3.35 g; 12.1 mmol), stirred overnight while warming to room temperature, diluted with dichloromethane, washed twice with water and saturated NH 4 C1 (aq.), once with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 7% ethyl acetate/dichloromethane to provide the desired product (1.54 g; 50%).
  • Example 23A 500 mg, 1.8 mmol
  • Example 23B 600 mg, 3.5 mmol
  • Pd 2 (dba) 3 42 mg; 0.045 mmol
  • BINAP 56 mg; 0.09 mmol
  • sodium tert-butoxide 350 mg; 3.6 mmol
  • the combined extracts were washed successively with saturated NaHCO 3 , water, and brine, dried (Na > SO 4 ), and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired product (97 mg, 18%).
  • Example 23C A mixture of Example 23C (175 mg, 0.58 mmol), benzophenone imine (150 mg, 0.83 mmol), Pd,(dba) 3 (54 mg, 0.06 mmol), BINAP (55 mg, 0.09 mmol), and sodium tert-biitoxide (80 mg, 0.82 mmol) in 3 mL toluene was heated to 75-80 °C for 4 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired product (150 mg, 64%).
  • Example 23E N-isoquinolin-5-ylpyridine-3,5-diamine
  • a mixture of Example 23D (145 mg; 0.36 mmol) in 3 mL THF at room temperature was treated with 10 drops of water and 3 drops of cone. HCl, stirred for 2 hours, and concentrated.
  • the residue was partitioned between ethyl acetate and concentrated NaHCO 3 • (aq).
  • the aqueous layer was extracted three times with ethyl acetate.
  • the combined extracts were washed with brine, dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 10% methanol/dichloromethane to provide the desired product (59 mg, 68%).
  • Example 23E A mixture of Example 23E (55 mg, 0.23 mmol) and L-Boc-tryptophanal (84 mg, 0.29 mmol) in 2 mL dichloromethane at room temperature was treated with Ti(iPrO) 4 (1 mL), stirred for 2 hours, and concentrated. The residue was dissolved in 2 mL ethanol, treated with NaBH 3 CN (30 mg; 0.46 mmol), stirred for 2 hours, diluted with water, and filtered. The filter cake was washed with methanol and the filtrate was concentrated. The residue was suspended in methanol/dichloromethane and filtered. The filtrate was concentrated and the concentrate was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide the desired product (28 mg, 24%).
  • Example 23F A solution of Example 23F (26 mg, 0.05 mmol) in 2 mL dichloromethane at room temperature was treated with 0.5 mL TFA, stirred for 3 hours, and concentrated. The concentrate was purifed by reverse phase HPLC on a C18 column with 0-100% CH 3 CN/H 2 O/0.1% TFA and the residue was dissolved in water and lyophilized to provide the desired product as the trifluoroacetate salt (27 mg, 70%).
  • a sealed tube was charged with 5-hydroxyisoquinoline (0.15 g, 1.03 mmol), 3,5- dibromopyridine (0.24 g, 1.03 mmol), potassium carbonate (0.27 g, 2.0 mmol) and DMF (4 mL).
  • the reaction was heated to 240 °C for 10 minutes in a personal chemistry microwave.
  • the reaction was partitioned between water and ethyl acetate.
  • the aqueous layer was extracted twice with ethyl acetate.
  • the combined extracts were concentrated and the residue was purified by flash column chromatography on silica gel with 2:1 ethyl acetate/hexanes to provide the desired product (0.071 g, 23%).
  • Example 24B N-r(2S)-2-amino-3-(lH-indol-3-yl)propyll-N-[5-(isoquinolin-5-yloxy)pyridin-3-yllamine
  • the desired product was prepared by substituting Example 24A for Example 23C in Examples 23D then proceeding as described for Examples 23E, 23F, and 23G.
  • Example 25A 2,2-dimethyl-N-pyridin-4-ylpropanamide
  • 4-aminopyridine 10 g, 106 mmol
  • pivaloyl chloride 12.9 g, 107 mmol
  • triethylamine 10.9 g, 108 mmol
  • the aqueous layer was extracted three times with dichloromethane and the combined extracts were washed with brine, dried (Na j SO ⁇ , filtered, and concentrated.
  • the product was recrystallized from toluene to provide the desired product (14 g, 74%).
  • Example 25B N-(3-formylpyridin-4-yl)-2,2-dimethylpropanamide A mixture of Example 25 A (11.4 g, 64 mmol) , in 200 mL THF was cooled to-78 °C, treated with 1.6 M nBuLi in hexanes (100 mL, 160 mmol), warmed to 0 °C, stirred for 1 hour, treated with a solution of DMF (22 g, 215 mmol) in 100 mL THF, warmed to room temperature, stirred for 1 hour, diluted with brine, and extracted three times with ethyl acetate.
  • DMF 22 g, 215 mmol
  • the combined extracts were washed with water, washed twice with brine, dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired - . product (9.1 g, 69%).
  • Example 25C 4-aminonicotinaldehyde -
  • a solution of Example 25B (870 mg, 4.2 mmol) in 3N HCl (aq.) (10 mL) was heated to reflux overnight, and extracted three times with diethyl ether. The aqueous layer was adjusted to pH >7 with solid K 2 CO 3 and extracted six times with 20% isopropanol/chloroform. The combined extracts were dried (Na 2 SO 4 ), filtered, and concentrated to provide the desired product (450 mg; 87%).
  • Example 25D 5-acetylnicotinamide A mixture of 5-bromonicotinamide (2.5 g, 12.4 mmol), tributyl(l -ethoxy vinyl)tin (5.0 g, 13.8 mmol) and dichlorobis(triphenylphosphine)palladium(II) (800 mg, 1.1 mmol) in 25 mL toluene was heated to reflux for 3 hours. The mixture was cooled to room temperature, treated with 25 mL 2N HCl (aq.), and stirred for 1 hour.
  • Example 25C 450 mg, 3.68 mmol
  • Example 25D 605 mg, 3.68 mmol
  • 20 mL ethanol and 1.2 mL of 10% NaOH (aq) was heated to reflux for 3 hours and concentrated.
  • the solid was collected and rinsed with ethyl acetate to provide the desired product (740 mg, 80%).
  • Example 25F 5-(l,6-naphthyridin-2-yl)pyridin-3-amine
  • the desired product was prepared by substituting Example 25E for 5- bromonicotinamide in Example 23B.
  • Example 25G tert-butyl (lS)-l-(lH-indol-3-ylmethyl)-2- ⁇ r5-(l,6-naphthyridin-2-yl)pyridin-3-yllamino ⁇ -2- oxoethylcarbamate
  • the desired product was prepared by substituting Example -25F (100 mg, 0.45 mmol) and L-Boc-tryptophan (150 mg, 0.49 mmol) for Example 1 IB and Boohomophenylalanine, respectively, in Example 16A.
  • Example 27B tert-butyl (lS)-2-(lH-indol-3-yl)-l- ⁇ r(5-isoquinolin-6-ylpyridin-3- y l)oxy]methyl
  • a solution of Example 27A (0.25 g, 0.86 mmol) and Example 2A (0.444 g, 1.00 mmol) in 6 mL of DMF was treated with Pd 2 (dba) 3 (0.08 g, 0.086 mmol), tri-o- tolylphosphine (0.02g, 0.04 mmol), and triethylamine (0.15 mL, 1.0 mmol), heated to 75 °C in a sealed tube for 8 hours, and concentrated. The residue was purified by flash column chromatography on silica gel with 2.5% methanol/dichloromethane to provide the desired product (0.125 g, 30%).
  • Example 27C tert-butyl (lS
  • the concentrate was azeotropically distilled with diethyl ether two times and the residue was purified by reverse phase HPLC on a C 18 column with 0-100% CH 3 CN/H 2 O/0.1 % TFA to provide the desired product as the di-trifluoroacetate salt (0.110 g, 70%).
  • the desired product was prepared by substituting D-Boc-tryptophanol for L-Boc tryptophanol in Example 2A.
  • Example 28B ( 1 R)-2-( lH-indol-3-yl)-l - ⁇ r(5-quinolin-6-ylpyridin-3-yl)oxy1methyl ) ethylamine
  • the desired product was prepared as the trifluoroacetate salt by substituting 28A for
  • Example 29 (lS)-2-r(6-chloro-5-isoquinolin-6-ylpyridin-3-yl)oxyl-l-(lH-indol-3-ylmethyl)ethylamine
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 13A for Example 2A in Example 27.
  • Example 30 (lS)-2-r(2-chloro-5-isoquinolin-6-ylpyridin-3-yl)oxyl-l-(lH-indol-3-ylmethyl)ethylamine
  • the desired product was prepared as the trifluoracetate salt by substituting Example 12C for Example 2A in Example 27 (0.02 g, 80%).
  • Example 32 5-(5- ⁇ r(2S)-2-amino-3-(lH-indol-3-yl)propyl1oxy ⁇ pyridin-3-yl)-lH-isoindole-l,3(2H)-dione
  • Example 32A tert-butyl (lS)-2-(lH-indol-3-yl)-l-( ⁇ r5-(trimethylstannyl)pyridin-3- ylloxy ⁇ methyl)ethylcarbamate
  • Example 2A A solution of Example 2A (1 g, 2.23 mmol) in DMA (15 mL) was treated with hexamethylditin (1.8 mL, 5.6 mmol) and Pd(PPh 3 ) 4 (0.4 g, 0.2 mmol), heated to 75 °C for 1.5 days, added to water, and extracted three times with ethyl acetate. The combined extracts were concentrated and the residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide the desired product (0.4 g, 34 %).
  • Example 32C A solution of Example 32A (0.2 g, 0.31 mmol) and 6-bromophthaIimide (0.084 g, 0.4 mmol) in DMF (2 mL) was treated with Pd 2 db% (0.04 g, 0.02 mmol), tri-o-tolylphosphine (0.02 g, 0.01 mmol), and triethylamine (0.06 mL, 0.4 mmol). The reaction was heated to 75 °C for 6 hours in a sealed tube and concentrated. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide the desired product (0.116 g, 55%).
  • Example 32C A solution of Example 32A (0.2 g, 0.31 mmol) and 6-bromophthaIimide (0.084 g, 0.4 mmol) in DMF (2 mL) was treated with Pd 2 db% (0.04 g, 0.02 mmol),
  • Example 33A methyl 4-bromo-2-methylbenzoate A solution of 4-bromo-2 -methyl benzoic acid (1.0 g, 4.7 mmol) in methanol (24 mL) was treated with 20 drops of HCl, heated at reflux for 6 hours, and concentrated to provide the desired product (1.07 g, . 100%).
  • Example 33B methyl 4-bromo-2-(bromomethyl)benzoate
  • a solution of Example 33A (1.02 g, 4.47 mmol) in C (22 mL) was treated with AIBN (0.065 g, 0.4 mmol) and NBS (0.955 g, 5.4 mmol), heated to reflux for 4 hours, washed with water, dried (Na,SO 4 ), filtered, and concentrated to provide the desired product (1 -1 g, 79%).
  • Example 33B A solution of Example 33B (1.1 g, 3.57 mmol) in THF (20 mL) at room temperature was treated with IN NH 3 in methanol (7.14 mL, 7.14 mmol), stirred for 24 hours, and filtered. The filter cake was washed with diethyl ether (100 mL) to provide the desired product (0.4 g, 52%).
  • Example 33D 5-(5- ⁇ r(2S)-2-amino-3-(lH-indol-3-yl)propynoxy ⁇ pyridin-3-yl)isoindolin-l-one
  • the desired product was prepared as the trifluoroacetate salt by substituitng Example
  • Example 34A N-(2-acetylphenyl)acetamide
  • 2'-aminoacetophenone 5.0 g, 37 mmol
  • dichloromethane 150 mL
  • acetyl chloride 3.2 mL, 45 mmol
  • the aqueous layer was extracted with ethyl acetate (2 x 20 mL) and the combined extracts were concentrated to provide the desired product (6.5 g, 100%).
  • Example 34B N-(2-acetyl-4-bromophenyl)acetamide A solution Example 34A (6.5 g, 37 mmol) in acetic acid (lOOmL) at room temperature was treated with Br 2 (4 mL, 84 mmol), stirred for 1 hour and 15 minutes, poured into water (200 mL), and filtered. The solid was washed with water (2 x 100 mL), and hexanes (2 x lOOmL), dissolved in diethyl ether, washed with brine (50 mL), and concentrated to provide the desired product (8.5 g, 89 %).
  • Example 34C N-(2-acetyl-4-bromophenyl)acetamide
  • Example 34B 6-bromocinnolin-4( 1 H)-one
  • THF tetrahydrofuran
  • Example 34D 6-bromocinnolin-4( 1 H)-one
  • a solution of Example 34B (6.28 g, 24.4 mmol) in THF (75 mL) was treated with concentrated HCl (aq.) (15 mL) and water (15 mL), heated to reflux for 1 hour, and concentrated to remove the THF.
  • the aqueous solution was treated with additional water (5mL) and concentrated HCl (5 mL), cooled to 0 °C, treated with a solution of NaNO 2 (1.85 g, 26.84 mmol) in water (10 mL) in 5 portions, warmed to room temperature gradually over a 2-hour period, and stirred overnight at room temperature.
  • the reaction was heated to reflux for 6 hours, and filtered.
  • the solid was washed with water (50 mL) and diethyl ether (50 mL) and
  • Example 34C 6-bromo-4-chlorocinnoline
  • POCl 3 2.5 mL
  • the aqueous layer was cooled to 0 °C and adjusted to pH 5-7 with 50% NaOH.
  • the aqueous layer was extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were concentrated. The residue was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product (0.190 g, 43%).
  • Example 34E 6-bromo-4-hydrazinocinnoline
  • ethanol 70 mL
  • hydrazine monohydrate 3 mL, 90% solution
  • the solid washed with water (50 mL) and diethyl ether (50 mL) and dried under vacuum to provide the desired product (2.5 g, 100%).
  • Example 34F 6-bromocinnoline A solution of Example 34E (3.5 g, 14 mmol) in water (50 mL) was heated to reflux, treated dropwise with a solution of CuSO 4 (2.8 g, 17.5 mmol) in water (20 mL), refluxed for 2 hours, cooled to room temperature, adjusted to pH 7 with saturated NaHCO 3 (aq), and extracted with ethyl acetate (2 x 25 mL). The combined extracts were concentrated and the residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide the desired product (0.7 g, 24%).
  • Example 34G 6-bromocinnoline
  • Example 35A 5 -bromo- 1 H-indazole A mixture of 5-bromo-2-fluorobenzaldehyde (10 g, 49.2 mmol) and 98% hydrazine (20 mL) was heated to reflux for 5 hours, poured over ice, and filtered. The solid was recrystallized from H 2 O/methanol to provide the desired product (3.7 g, 38%).
  • Example 35B ( 1 S)-2- ⁇ f5-( 1 H-indazol-5 -yl)pyridin-3 -ylloxy ) - 1 -( 1 H-indol-3 -y lmethyl)efhylamine
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 35A for 6-bromophthalimide in Example 32.
  • Example 36 5-(5- ⁇ r(2S)-2-amino-3-(lH-indol-3-yl)propylloxy ⁇ pyridin-3-yl)-l,3-dihydro-2H-indol-2-one
  • the desired product was prepared as the trifluoroacetate salt by substituting 5- bromooxindole for 6-bromophthalimide in Example 32.
  • the desired product was prepared by as the trifluoroacetate salt substituting 5-bromo- 3-(lH-pyrrol-2-ylmethylene)-l,3-dihydro-indol-2-one for 6-bromophthalimide (L. Sun, et al., J. Med. Chem., 1998, 41, 2588.) in Example 32.
  • Example 40 6-(5- ⁇ r(2R)-2-amino-3-(lH-indol-3-yl)propylloxy ⁇ pyridin-3-yl)-l,3-benzothiazol-2(3H)-one
  • the desired product was prepared by substituting 6-bromo-2-benzothiazolinone for 6- bromophthalimide in Example 32.
  • Example 41 A tert-butyl 3-(cyanomethy 1)- lH-indole- 1 -carboxylate
  • a solution of 3-cyanomethylindole (7.50 g, 48 mmol), di-tert-butyl dicarbonate (11.5 g, 52.8 mmol), and DMAP (300 mg) in dichloromethane (200 mL) was stirred at room temperature overnight.
  • the mixture was concentrated and the residue was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product (11.44 g, 93%).
  • Example 4 IB tert-butyl 3-r(5-bromopyridin-3-yl)(cyano)methyl "
  • Example 41C tert-butyl 3-[cyano(5-isoquinolin-6-ylpyridin-3-yl)methyll-lH-indole-l-carboxylate
  • the desired product was prepared by substituting Example 4 IB for Example 2A in
  • Example 41 D 2-(lH-indol-3-yl)-2-(5-isoquinolin-6-ylpyridin-3-yl)ethanamine
  • a mixture of Example 41C (159 mg, 0.345 mmol), RaNi 2800 (525 mg), ammonia (2 mL), and triethylamine (2 mL) in methanol (20 mL) was stirred under hydrogen (60 psi) at room temperature for 73 hours and concentrated. The residue was triturated with ethyl acetate and methanol. The resulting solid was dissolved in trifluoroacetic acid (1 mL), stirred for 5 minutes at room temperature, and concentrated.
  • Example 42A (2Z)-3-(5-bromopyridin-3-yl)-2-(lH-indol-3-yl)acrylonitrile
  • a solution of 3-cyanomethylindole (156 mg, 1.0 mmol) in anhydrous ethanol (1.5 mL) at room temperature was treated with 21% sodium ethoxide in ethanol (450 ⁇ L), stirred for 1 hour, treated with 3-bromopyridine-5-carboxaldehyde (J. Heterocycl. Chem., 1995, 32, 1801.) (187 mg, 1.0 mmol), stirred overnight, and concentrated.
  • the residue was purified by flash column chromatography on silica gel with 2% methanol/dichloromethane to provide the desired product (52 mg, 16%).
  • Example 42B 2-(lH-indol-3-yl)-3-(5-isoquinolin-6-ylpyridin-3-yl)propan-l-amine The desired product was prepared as the trifluoroacetate salt by substituting Example
  • Example 43A 6-bromo-3-hydroxyquinoline-4-carboxylic acid
  • a solution of 5-bromoisatin (2.26 g, 10 mmol) and potassium hydroxide (4.48 g, 80 mmol) in water (10 mL) was warmed until the materials were dissolved then cooled to room temperature, treated with bromopyruvic acid (2.3 g, 14 mmol), stirred for 6 days, adjusted to pH ⁇ 7 with concentrated HCl, and filtered. The solid was washed with water and ethanol and dried to provide the desired product (1.5 g, 58%).
  • Example 43B 6-bromo-3-hydroxyquinoline-4-carboxylic acid
  • Example 43 C tert-butyl (lS)-2-r(6-bromoquinolin-3-yl)oxy1-l-(lH-indol-3-ylmethyl)ethylcarbamate
  • the desired product was prepared by substituting Example 43B for 3-bromo-5- hydroxypyridine in Example 2A. Purification by flash column chromatography on silica gel with 100% ethyl acetate provided the desired product (0.89 g, 72%). MS (DCI/NH 3 ) m/e 497 (M+H) + .
  • Example 43D tert-butyl ( 1 S)-2-( 1 H-indol-3 -yl)- 1 - ⁇ r(6-pyridin-4-ylquinolin-3- yl)oxy1methyl ⁇ ethylcarbamate
  • a mixture of Example 43C (0.33 g, 0.67 mmol), pyridine-4-boronic acid (0.13 g, 0.99 mmol), cesium floride (0.2 g, 1.34 mmol) and tetrakistriphenylphosphine palladium (0.038 g,
  • Example 44B (3Z)-3-r(2S)-2-amino-3-(lH-indol-3-yl)propylidenel-5-isoquinolin-6-yl-l,3-dihydro-2H- pyrrolo f 2 , 3 -b] pyridin-2-one
  • the desired product was prepared by substituting Example 44A (260 mg) for Example 2A in Example 27.
  • Example 66 3-(6-(N,N-Dimathylamino)hexyloxyl)-5-r2-(4-pyridinyl)vinyllpyridine trifluoroacetic acid salt MS (DCI/NH 3 ) m/z 326 (M+H).
  • Example 70 3-(l-Pyridinyl-ethoxyl)-5-r2-(4-pyridinyl)vinyl1pyridine trifluoroacetic acid salt MS (DCI/NH,) m/z 304 (M+H). 'H NMR (DMS d 6 ) ⁇ 8.81 (d, 2H), 8.73 (d, 2H), 8.48 (s, IH), 8.34 (d, IH), 8.01 (d, IH), 7.85-7.81 (m, 2H), 7.74 (d, 2H), 7.57 (d, IH), 5.89 (q, IH), 1.65 (d, 3H).
  • Example 71 A 4- ⁇ 5-r(2S)-2-BOCamino-3-(lH-indol-3-yl)-propoxy1-pyridin-3-yl ⁇ -N-hydroxyl-benzamidine
  • hydroxylamine hydrochloride 33 mg, 0.48 mmol
  • potassium tert-butoxide 54 mg, 0.48 mmol
  • Example 71 A was prepared by substituting Example 71 A for Example 22 A in example 22B.
  • Example 72 A 4- ⁇ 5-r(2S)-2-BOC-amino-3-(lH-indol-3-yl)-propoxyl ⁇ pyridin-3-yl ⁇ -benzamidine
  • Example 71 To a solution of the product of Example 71 (110 mg, 0.22 mmol) in glacial acetic acid (5.0 ml) was added acetic anhydride (0.15 ml, 1.6 mmol) and the mixture was stirred for 2 h at ambient temperature. The acetic anhydride was hydrolyzed by addition of water (0.1 ml), 10 % palladium on charcoal (25 mg) was added and the mixture was stirred vigorously un ⁇ r a hydrogen atmosphere (1 atm.) for 4 h. The mixture was filtered through a pad of diatomaceous earth (Celite ® ) and the filtercake was washed with acetic acid.
  • acetic anhydride 0.1 ml
  • 10 % palladium on charcoal 25 mg
  • Example 72B 4- ⁇ 5-[(2S)-2-Amino-3-(lH-indol-3-yl)-propoxy]-pyridin-3-yl ⁇ -benzamidine trifluoroacetic acid salt
  • the desired product was prepared by substituting Example 72A for Example 22A in Example 22B.
  • Example 73 3-r(2S)-2-Amino-3-(lH-3-indolyl)-propyloxyl1-6-(3-pyridinyl)-quinoline
  • the desired product was prepared by substituting pyridine-3 -boronic acid for pyridine-4- boronic acid in Example 43.
  • MS DCI/NH ⁇ m/e 395 (M+1).
  • Example 74 3- (2S)-2-Amino-3-(lH-3-indolyl)-propyloxyll-6-(3-quinolinyl)-quinoline
  • the desired product was prepared by substituting quinoline-3-boronic acid for pyridine-4- boronic acid in Example 43.
  • Example 75A 2-Amino-4-iodopyridine
  • 2-floro-4-iodopyridine 3.0 g, 13.5 mmol
  • acetylamide 15.8 g, 269 mmol
  • potassium carbonate 9.2 g, 67 mmol
  • the concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexane to provide the title compound (1.1 g, 37%).
  • Example 75 C for 4-vinylpyridine in Example 2B.
  • Purification on silica gel eluting with 100% ethyl acetate provided the title compound (0.15 g, 49%).
  • Example 77 (lS)-l-(lH-Indol-3-ylmethyl)-2-(5-naphthalen-2-yl-pyridin-3-yloxy)-ethylamine
  • the desired product was prepared by substituting 2-bromonaphthalene for 6- bromoisoquinoline in Example 27.
  • Example 78B (lS)-l-(lH-Indol-3-ylmethyl)-2-(5-isoquinolin-5-yl-pyridin-3-yloxy)-ethylamine
  • the desired product was prepared by substituting Example 78A for 6-bromoisoquinoline in Example 27.
  • Example 80A 6-Bromo-indan-l,2-dione 1-oxime A solution of 5-bromo-l-indanone (1.8 g, 8.5 mmol) in ethanol (150 ml) was cooled to 0 "C, treated with t-butylnitrite (2.1 ml), stirred at room temperature for 2 hours, filtrated and washed the desired product with ether. The yield is 76%. MS (DC1/N ⁇ 3) m/e 242 (M+l) + .
  • Example 80B 6-Bromo-l,3-dichloro-isoquinoline
  • a suspension solution of Example 80A (1.5 g, 6.2 mmol) in POC1 3 (40 ml) was treated with PC1 5 (1.55 g, 7.4 mmol) and introduced HCl gas until solution was saturated.
  • the reaction was stirred at 60 °C for 6 hours and concentrated under vacumm.
  • the residue was slowly hydrolysed by adding water, treated with ethyl acetate (200 mL), washed with brine, dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexane to provide the title compound (1.7g, 100%).
  • Example 80C 6-Bromo-3-chloro-isoquinoline A mixture of Example 80B (1.8 g, 6.5 mmol), P (0.48g 15.5 mmol) and HI (3ml, 48%) in acetic acid (20 ml) was refluxed for 8 hours, filtrated under hot condition and concentrated under vacumm. The residue was basified by adding sodium hydroxide solution, treated with ethyl acetate (200 mL), washed with brine, dried (MgSQ , filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexane to provide the title compound (0.8 lg, 50%). MS (DCI/NH3) m/e 244
  • Example 80D 3-Chloro-6-trimethylstannanyl-isoquinoline
  • the desired product was prepared by substituting Example 80C for 6-bromoisoquinoline in Example 27A.
  • MS (DCI/NH3) m/e 327 (M+H) + .
  • Example 80E 3-Chloro-6-trimethylstannanyl-isoquinoline The desired product was prepared by substituting Example 80C for 6-bromoisoquinoline in Example 27A. MS (DCI/NH3) m/e 327 (M+H) + .
  • Example 80E 3-Chloro-6-trimethylstannanyl-isoquinoline
  • Example 81 (lS)-2-(r3,4'1Bipyridinyl-5-yloxy)-l-(lH-indol-3-ylmethyl)-ethylamine trifluoroacetic acid
  • the desired product was prepared by substituting 4-tributylstannylpyridine for Example 27A in Example 27.
  • Example 83 (lS)-l-(lH-Indol-3-ylmethyl)-2-(5-pyridin-3-ylethynyl-pyridin-3-yloxy)-ethylamine trifluoroacetic acid salt
  • the desired product was prepared by substituting 3 -bromopyridine for 4-bromopyridine in Example 14.
  • Example 84 (lS)-2-r5-(2-Fluoro-pyridin-4-ylethynyl)-pyridin-3-yloxyl-l-(lH-indol-3-ylmethyl)- ethylamine trifluoroacetic acid salt
  • the desired product was prepared by substituting 4-iodo-2-fluoropyridine for 4- bromopyridine in Example 14.
  • N ⁇ -r3-(2-Amino-ethoxy)-pheny ⁇ -pyrimidine-2,4-diamine hydrochloride The title compound was prepared by substituting N-Boc-aminoethanol for BOC-tryptophanol in Example 20.
  • Example 89A tr /7 -4-r(5-Bromo-pyridin-3-yl)-vinyll-2-amino-pyrimidine A solution of 5-bromo-pyridine-3-carbaldehyde (436 mg, 2.34 mmol) and 2-amino-4- methylpyrimidine (246 mg, 2.35 mmol) in formic acid (96%, 3 mL) was heated for 18 h. After cooling to rt, it was then diluted with water and basified to p ⁇ -13 with 1 N NaO ⁇ . The mixture was then extracted with methylene chloride. The combined extracts was washed with water (IX), dried over MgSO 4 and concentrated.
  • Example 89B tr ⁇ -4-r(5-Bromo-pyridin-3-yl)-vinyl]-2-[bis(tert-butoxycarbonyl)aminol-pyrimidine A suspension of Example 89A (439 mg, 1.58 mmol), (BOQO (1.040g, 4.77 mmol), DMAP (50 mg, 0.41 mmol), and triethylamine (670 ⁇ iL, 4.81 mmol) in THF (10 mL) was stirred at rt overnight. Reaction was concentrated and chromatographed on silica gel eluting with AcOEt:hexane (1:1) to give the title compound (511 mg, 68%). MS (DCI/NH) m/z 477, 479(M+1).
  • Example 89C ⁇ -[(S-amino-pyridin-S-yl -vinyll ⁇ - ⁇ ert-butoxycarbonvDamino-pyrimidine
  • Example 89B was converted to the title compound according to the procedures described for Example 51, Steps 4 and 5.
  • Example 89D trQ -[4-(2- ⁇ 5-[(2S)-2-Amino-3-(lH-indol-3-yl)-propylamino1-pyridin-3-yl ⁇ -vinyl)- pyrimidin-2-yll-carbamic acid ethyl ester trifluoroacetic acid salt
  • the title compound was prepared by substituting Example 89C for Example 1 IB in Example 11.
  • Example 90B 1 -Amino-6-bromoisoquinoline
  • a mixture of the chloride from Example 90A (264 mg, 1.09 mmol), acetamide (1.3 g) and K 2 CO 3 (0.45 g) was heated to 180 °C for 5 h. After cooling to rt, the mixture was dissolved in ethyl acetate, which was washed with water, brine, dried over MgSO 4 and concentrated. The residue was chromatographed on silica gel eluting with (100:5:0.5) to give the title compound (159 mg, 65%). MS (DCI/NH 3 ) m/z 223, 225 (M+l) + .
  • Example 90C l-r(Bis(tert-butoxycarbonyl)1amino-6-bromoisoquinoline
  • a solution of Example 90B (616 mg, 2.76 mmol), BOCp (1.81 g), DMAP (67 mg), and triethylamine (1.15 mL) in acetonitrile (15 mL) was stirred at rt for 2h. The reaction was concentrated and the residue was chromatographed on silica gel eluting with AcOEt : hexane (3:7) to give the title compound (1.18 g, 71%). MS (DC17NH 3 ) m/z 423 (M+l) + .
  • Example 90D l-Amino-6- ⁇ 5-[(2S)-2-amino-3-(lH-indol-3-yl)-propoxy1-pyridin-3-yl ⁇ -isoq ⁇ inoline trifluoroacetic acid salt
  • MS DCI/N ⁇ 3
  • 'H NMR DMSO-d6, 300 MHz
  • Example 91 6- ⁇ 5-r(2S)-2-amino-3-(lH-indol-3-yl)-propoxyI-pyridin-3-yl ⁇ -l-chloro-isoquinoline trifluoroacetic acid salt
  • the title compound was prepared by substituting Example 90A for 6-bromophthalimide in Example 32.
  • Example 93 (2S)-2-Amino-3-(naphtha-l-yl)-N-r5-(2-pyridin-4-yl-vinyl)-pyridin-3-yl1-propionamide hydrochloride
  • the title compound was prepared by substituting Boc-3-(l-naphthyl)alanine for Boc- homnophenyalanine in Example 16.
  • Example 94 (2S)-2-Amino-3-phenyl-N-r5-(2-pyridin-4-yl-vinyl)-pyridin-3-yll-propionamide hydrochloride The title compound was prepared by substituting Boc-phenylalanine for Boc- homnophenyalanine in Example 16.
  • Example 95 S-2-Amino-3-(imidazol-4-yl)-N-r5-(2-pyridin-4-yl-vinyl)-pyridin-3-yll-propionamide hydrochloride The title compound was prepared by substituting bis(Boc)-histidine for Boc- homnophenyalanine in Example 16.
  • the desired product was prepared by substituting 5-bromo-2-fluorobenzonitrile for 6- bromoisoquinoline in Example 27A.
  • Example 97B (lS)-r2-r5-(3-Cyano-4-fluoro-phenyl)-pyridin-3-yloxy1-l-(lH-indol-3-ylmethyl)-ethyl1- carbamic acid tert-butyl ester
  • the desired product was prepared by substituting Example 97A for in Example 27A in Example 27B.
  • Example 97D (lS)-5- ⁇ 5-r2-Amino-3-(lH-indol-3-yl)-propoxy1-pyridin-3-yl ⁇ -lH-indazol-3-ylamine
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 97C for Example 27B in Example 27C.
  • Example 99A ⁇ r(lS)-l-(lH-Indol-3-ylmethyl)-2-(5-isoquinolin-6-yl-pyridin-3-yloxy)-ethylcarbamoyll- methyU-carbamic acid tert-butyl ester
  • a solution of Example 27C (175 mg, 0.35 mmol),N-Boc-glycine (91 mg, 0.52 mmol), EDC (100 mg), iPr,Et ⁇ (0.30 mL) and DMAP (10 mg) in C ⁇ ,C1 2 (7 mL) was stirred at room temperature overnight, diluted with EtOAc, washed with water and brine, dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol/CH 2 Cl 2 to provide the desired product (112 mg, 58%).
  • Example 99B 2-Amino-N- (lS)-l-(lH-indol-3-ylmethyl)-2-(5-isoquinolin-6-yl-pyridin-3-yloxy)-ethyl1- acetamide
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 99A for Example 27B in Example 27C.
  • Example 101 2-Dimethylamino-N-r(lS)-l-(lH-indol-3-ylmethyl)-2-(5-isoquinolin-6-yl-pyridin-3-yloxy)- ethyll-acetamide
  • the desired product was prepared by substituting N,N-dimethylglycine for N-Boc-glycine in Example 99A.
  • Example 102A 0 A solution of 5-bromo-2-fluorobenzaldehyde (24.75 g; 122 mmol) in Et 2 O (125mL) at 0 °C was treated with 3.0 M MeMgBr in Et 2 O (43 mL, 129 mmol), stirred for 30 min., carefully diluted with water then acidified with 10% ⁇ C1 (aq). The aqueous was extracted with E O, rinsed successively with 10% ⁇ C1 (aq), water, and brine, dried (MgSO 4 ), and evaporated to give the desired product (26.6 g; 99%) of sufficient purity to carry on to the next step. D
  • Example 102B l-(5-Bromo-2-fluoro-phenyl)-ethanone
  • a solution of Example 102A (26.6 g; 121 mmol) and manganese(IV) oxide (53 g; 610 mmol) in j9-dioxane (500 mL) was heated at reflux for 4 hrs., cooled, filtered through Celite®, evaporated, and purified by flash chromatography (5-10% Et,O/hexane) to yield the desired product as a nearly colorless oil that solidified upon standing (20.5 g; 78%).
  • Example 102C 5-Bromo-3 -methyl- 1 H-indazole A mixture of 102B (10 g, 46 mmol) and 98% hydrazine (25 mL) was heated to reflux for 9 hours, and poured over ice. The precipitate was collected and purified by flash chromatography (1:1 Et 2 O:hexane) to give the desired product as a white solid (5.8 g, 60%).
  • Example 102D 3-Methyl-5-trimethylstannanyl-lH-indazole
  • a mixture of Example 102C (10.08 g, 47.8mmol), hexamethyl-d in 2 (18 g, 55mmol) and tetrakis(triphenylphosphine)palladium (5.5g, 4.8 mmol) in toluene (100ml) was stirred at 95 °C for 6h. The mixture was then evaporated and the residue was taken into ethyl acetate (300 ml), washed with saturated sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml).
  • Example 102E (lS)- ⁇ l-(lH-Indol-3-ylmethyl)-2-r5-(3-methyl-lH-indazol-5-yl)-pyridin-3-yloxy1-ethyU- carbamic acid tert-butyl ester
  • the desired product was prepared by substituting Example Example 102D for Example 27A in Example 27B.
  • Example 102F (lS)-l-(lH-Indol-3-ylmethyl)-2-r5-(3-methyl-lH-indazol-5-yl)-pyridin-3-yloxy1-ethylamine
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 102E for Example 27B in Example 27C.
  • MS (ESI) m/e 398 (M+ ⁇ ) + ; 'H NMR (DMSO-d & 300
  • 5-Bromo-2-fluoro-benzoic acid A mixture of 5-bromo-2-fluorobenzaldehyde (810 mg; 4.0 mmol), 15% NaO ⁇ (aq.) (3 mL), MeO ⁇ (5 mL), and 30% ⁇ 2 O 2 (5 mL) was stirred at r.t. for 2 hrs., then acidified with 10% HCl (aq.). The resulting white solid was collected, rinsed with water, and dried to give the desired product (670 mg; 77%).
  • Example 103B 5-Bromo-2-fluoro-benzoyl chloride
  • Example 103 A (665 mg; 3.0 mmol) in thionyl chloride (7 mL) was heated at reflux for 2 hrs., concentrated, and azeotroped with toluene to give a colorless oil that was carried on with no further purification.
  • Example 103C (5-Bromo-2-fluoro-phenyl)-(lH-pyrrol-2-yl)-methanone
  • a solution of 103B (720 mg; 3.0 mmol), and pyrrole (203 mg; 3.0 mmol) in 1,2- dichloroethane (10 mL) at 0 °C was treated portionwise with AICI 3 , stirred overnight while gradually warming to r.t., treated with ice and 1 N ⁇ C1, stirred for 1.5 hrs., and extracted with C ⁇ 2 C1 2 .
  • the extracts were rinsed with water and saturated NaHCQ (aq.), dried over Na ⁇ O ⁇ concentrated, and isolated by flash chromatography (10% EtOAc/hexane) to give the desired product as a purple solid (252 mg; 31%).
  • Example 103D 5-Bromo-3-(lH-pyrrol-2-yl)-lH-indazole The desired product was prepared by s ⁇ bstituting Example 103C for Example 102B in Example 102C.
  • Example 103E (lS)-l-(lH-Indol-3-ylmethyl)-2- ⁇ 5-r3-(lH-pyrrol-2-yl)-lH-indazol-5-yll-pyridin-3-yloxy ⁇ - ethylamine
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 103D for 6-bromoisoquinoline in Example 27.
  • Example 104 ( 1 S)- 1 -( lH-Indol-3 -ylmethyl)-2- 5-(3 -phenyl- lH-indazol-5 -y l)-pyridin-3 -yloxyl-ethylamine
  • the desired product was prepared as the trifluoroacetate salt by substituting phenyl magnesium bromide for methyl magnesium bromide in Example 102.
  • Example 106 (lS)-2-r5-(3-Ethyl-lH-indazol-5-yl)-pyridin-3-yloxyl-l-(lH-indol-3-ylmethyl)-ethylamine
  • the desired product was prepared as the trifluoroacetate salt by substituting ethyl magnesium bromide for methyl magnesium bromide in Example 102.
  • Example 108 (lS)-l-(lH-Indol-3-ylmethyl)-2-[5-(3-thiazol-2-yl-lH-indazol-5-yl)-pyridin-3-yloxy]- ethylamine
  • the desired product was prepared as the trifluoroacetate salt by substituting 2-thiozolyl lithium chloride for methyl magnesium bromide in Example 102.
  • Example 109A (40 mg; 0.06 mmol) in MeO ⁇ (4 mL) was treated with cone. ⁇ C1 (1 mL) and heated at reflux for 6 hrs., concentrated and purified by reverse phase ⁇ PLC on a C 18 column with 0- 100% C ⁇ 3 C ⁇ / ⁇ 2 O/0.1 % TFA to provide the desired product as the trifluoroacetate salt.
  • Example 11 IB (lS)-l-(lH-Indol-3-ylmethyl)-2-r5-(3-morpholin-4-yl-lH-indazol-5-yl)-pyridin-3-yloxyl- ethylamine
  • the desired product was prepared by substituting Example 111 A for 6-bromoisoquinoline in Example 27.
  • Example 112A 5-Bromo-l,3-dimethyl-lH-indazole
  • Example 102C (500 mg; 2.37 mmol) was added to a mixture of 60% Na ⁇ (115 mg; 2.84 mmol) in DMF (10 mL). After 15 min. at r.t. iodomethane (456 mg; 3.21 mmol) was added, the reaction was stirred for 2 hrs then diluted with water and extracted with EtOAc. The extracts were rinsed with water and brine, dried (MgSO 4 ), evaporated, and isolated by flash chromatography (1:1 Et 2 O:hexane) to give the desired product (360 mg; 67%).
  • Example 112B The desired product was prepared as the trifluoroacetate salt by substituting Example 112A for Example 6-bromoisoquinoline in Example 27.
  • Example 113 (lS)-l-(lH-Indol-3-ylmethyl)-2-r3-(3-methyl-lH-indazol-5-yl)-phenoxy1-ethylamine
  • the desired product was prepared as the trifluoroacetate salt by substituting 3-bromophenol for 3-bromo-5-hydroxypyridine in Example 102.
  • Example 114A 5-Bromo-3-(4-methyl-piperazin-l-yl)-lH-indazole
  • the reaction between Example 35A and N-methyl piperazine was carried out according to the procedure described by U. Wrstonono, K. Majewska, J. Dudzinska-Usarewicz, M. Bernas, Pharmzie, 1986, 41, 472-474.
  • Example 1 15 (lS)-(5- ⁇ 5-r2-Amino-3-(lH-indol-3-yl)-propoxyl-pyridin-3-yl ⁇ -lH-indazol-3-yl)-dimethyl- amine
  • Example 35A The reaction between Example 35A and dimethylamine was carried out according to the procedure described by U. Wrstonono, K. Majewska, J. Dudzinska-Usarewicz, M. Bernas, Pharmzie, 1986, 41, 472-474.
  • Example 115B (lS)-(5- ⁇ 5-r2-Amino-3-(lH-indol-3-yl)-propoxyl-pyridin-3-yl ⁇ -lH-indazol-3-yl)-dimethyl- amine
  • the desired product was prepared by substituting Example 1 15A for 6-bromoisoquinoline in Example 27.
  • Example 116B (lS)- ⁇ l-(lH-Indol-3-ylmethyl)-2-r5-(4-phenylaminomethyl-phenyl)-pyridin-3-yloxyI-ethyl ⁇ - carbamic acid tert-butyl ester
  • Example 116A (0.03 g, 0.06 mmol) was dissolved in 2 mL of MeOH and cooled to 0 °C, then treated with NaBH 4 (0.003 g, 0.08 mmol). The mixture was allowed to warm to room temperature over 2 h. The mixture was diluted with ethyl acetate (20 ml), washed with water (10 ml) and brine (10 ml). The ethyl acetate was evaporated off and the residue was used without further purification.
  • Example 117B (lS)-(4-(5-(2-Amino-3-(lH-indol-3-yl)-propoxy)-pyridin-3-yl)-phenyl)-methanol
  • the desired product was prepared by substituting Example 117A for Example 27B in Example 27C.
  • Example 118 (lS)-2-(5-(4-Fluoro-phenyl)- pyridin-3-yloxy)-l-(lH-indol-3-ylmethyl)-ethylamine
  • the desired product was prepared by substituting 4-fluorophenylboronic acid for 4- cyanophenylboronice acid in Example 22.
  • Example 120B (2S)-ri-(3-Bromo-5-isoquinolin-6-yl-phenoxymethyl)-2-(lH-indol-3-yl)-ethyll-carbamic acid tert-butyl ester
  • Example 120C (lS)-2-(3-Bromo-5-isoquinolin-6-yl-phenoxyoxy)-l-(lH-indol-3-ylmethyl)-ethylamine
  • the desired product was prepared by substituting Example 120B for Example 27B in Example 27C.
  • Example 121A (0.07 g, 0.153 mmol) and 4-chloro-2-pyrimidinylamine (0.021 g, 0.163 mmol) was dissolved in EtO ⁇ (ImL). The mixture was heated to 80°C overnight then cooled and evaporated. The product was used without further purification.
  • Example 122A (lS)-r2-r3-(Benzhydrylidene-amino)-5-isoquinolin-6-yl-phenoxy1rl-(lH-indol-3-ylmethyl)- ethyll-carbamic acid tert-butyl ester
  • a solution of Example 120B (0.165 g, 0.29 mmol) and benzophenone imine (0.1 mL, 0.6 ' mmol) in 5 mL oftoluene was treated with Pd 2 dba 3 (0.026 g, 0.028 mmol), BINAP (0.036 g, 0.058 mmol) and sodium tbutoxide (0.042 g, 0.44 mmol).
  • Example 122B (lS)-3-(2-Amino-3-(lH-indol-3-yl)-propoxy)-5-isoquinolin-6-yl-phenylamine
  • Example 123B 4-(5-Isoquinolin-6-yl-pyridin-3-yl)-piperazine-l -carboxylic acid tert-butyl ester The desired product was prepared by substituting Example 123 A for Example 27A in Example 123B.
  • Example 125 ((2S)-2-Amino-5-(5-(2-amino-3-(lH-indol-3-yl)-propoxy)-pyridin-3-yl)-phenyl-(3-chloro- phenyl-methanone
  • the title compound was prepared by substituting 2-amino-5-iodo-3 '-chloro benzophenone for Example 32A in Example 32.
  • Example 126 (lS)-N6-(3-(5-(2-Amino-3-(lH-indol-3-yl)-propoxy)-pyridin-3-yl)-phenyl)-9H-purine-2,6- diamine
  • the title compound was prepared by substituting 6-Chloro-9H-purin-2-ylamine for 4-chloro- 2-pyrimidinylamine in Example 121.
  • Example 127 (3-(5-((2S)-2-Amino-3-(lH-indol-3-yl)-propoxy)-pyridin-3-yl)-phenyl)-pyrimidin-2yl-amine
  • MS (ESI) m/z 437 (M + ⁇ ) + ; 'H ⁇ MR (500 MHz, .
  • Example 128 (3-(5-((2S)-2-Amino-3-(lH-indol-3-yl)-propoxy)-pyridin-3-yl)-phenyl)-thiazol-2yl-amine
  • the title compound was prepared by substituting 2-chlorothiazole for 4-chloro-2- pyrimidinylamine in Example 121.
  • MS (ESI) m/z 442 (M + ⁇ ) + ; 'H ⁇ MR (500 MHz,
  • Example 129B N-(3-(5-((2S)-2-Amino-3-(lH-indol-3-yl)-propoxy)-pyridin-3-yl)-phenyl)-acetamide The desired product was prepared by substituting Example 129A for Example 27B in Example 27C.
  • Example 120 A solution of Example 120 (0.2 g, 0.3 mmol) 6 mL of DMF was treated with Pd(dppf)Cl 2 (0.039 g, 0.07 mmol), Pd(OAc) 2 (0.016 g, 0.07 mmol), ammonium hydroxide (0.15 mL), and triethylamine (0.5 mL, 3.9 mmol).
  • the reaction was heated to 80°C after which CO was bubbled through for 30 minutes.
  • the mixture was heated to 80 °C overnight then cooled, neutralized with ⁇ C1 and washed with ethyl acetate.
  • the water was evaporated off to yield the product.
  • MS (ESI) m/z 538 (M + ⁇ ) + .
  • Example 13 IB 3-((2S)-2-Amino-3-(lH-indol-3-yl)-propoxy)-5-isoquinolin-6-yl-benzoic acid
  • the desired product was prepared by substituting Example 131 A for Example 27B in Example 27C.
  • Example 134 N6-(4-(5-((2S)-2-Amino-3-(lH-indol-3-yl)-propoxy)-pyridin-3-yl)-phenyl)-9H-purine-2,6- diamine
  • the title compound was prepared by substituting Example 132 for Example 121 A in Example 126.
  • Example 137A ( 1 S)-[2-(3 -Cyano-5 -isoquinolin-6-yl-phenoxy)- 1 -( lH-indol-3 -ylmethyl)-ethyll-carbamic acid tert-butyl ester
  • a solution of Example 120 (0.15 g, 0.3 mmol) 3 mL of dioxane and 1 mL of DMF was treated with Pd(PPh 3 ) 4 (0.030 g, 0.026 mmol), and zinc cyanide (0.037 g, 0.3 mmol). The reaction was heated to 95 °C for 3 days.
  • Example 137B 3-((2S)-2-Amino-3-(lH-indol-3-yl)-propoxy)-5-isoquinolin-6-yl-benzonitrile
  • the desired product was prepared by substituting Example 137A for Example 27B in Example 27C.
  • Example 138C 5'-Benzyloxy-5-isoquinolin-6-yl-(3,3')bipyridinyl
  • the title compound was prepared by substituting Example 138A for Example 2A, Example 138B for Example 27A in Example 27B.
  • Example 140B 2-Amino-6-chloro-nicotinamide To a mixture of Example 140A (11.9 g, 69.2 mmol) in 1,2-dichloroethane (100 mL) was added thionyl chloride (30 mL, 411 mmol) and DMF (catalytic). The mixture was refluxed for 4 h then evaporated. The residue was taken in ether (200 mL) and ammonia was bubbled through for 15 min. The mixture was stirred overnight at rt then washed with water (100 mL) and brine (100 ml). The ether was evaporated off to yield 9.2 g of product (78 %). MS (DCI/NH3) m/z 172 (M + 1) + .
  • Example 140B A mixture of Example 140B (1 g, 5.8 mmol) in triethylorthoformate (30 mL) was refluxed for
  • Example 140C 4,7-Dichloro-pyrido[2,3-d]pyrimidine
  • phosphorus oxychloride 40 mL
  • the residue was taken into ethyl acetate (75 ml), washed with saturated sodium bicarbonate (50 ml) water (50 ml) and brine (50 ml).
  • the ethyl acetate was evaporated to yield 0.8 g of product (73 %).
  • Example 140E (7-Chloro-pyrido[2,3-d]pyrimidin-4-yl)-phenyl-amine
  • Example 140F (7-(5-((2S)-2-Amino-3-(lH-indol-3-yl)-propoxy)-pyridin-3-yl)-pyrido(2,3-d)pyrimidin-4-yl)- phenyl-amine
  • the title compound was prepared by substituting Example 140E for 6-bromoisoquinoline in Example 27.
  • Example 141 (7-(5-((2S)-2-Amino-3-(lH-indol-3-yl) propoxy)-pyridin-3-yl)-pyrido(2,3-d)pyrimidin-4-yl)- ethyl-amine
  • the title compound was prepared by substimting ethylamine for aniline in Example 140.
  • Example 144A (lS)-[2-(5-Bromo-pyridin-3-yloxy)-l-phenyl-ethyl]-carbamic acid tert-butyl ester
  • 5-bromo-pyridin-3-ol 0.3 g, 1.7 mmol
  • (2-hydroxy-l-phenyl-ethyl)-carbamic acid tert-butyl ester 0.4 lg 1.7 mmol
  • triphenylphosphine 0.52 g, 2 mmol
  • Example 144B (lS)-2-(5-isoquinolin-6-yl-pyridin-3-yloxy)-l-phenyl-ethylamine The title compound was prepared by substituting Example 144A for Example 2A in Example 27.
  • Example 202A (lS)-[l-Benzyloxymethyl-2-(5-bromo-pyridin-3-yloxy)-ethyl]-carbamic acid tert-butyl ester
  • the product was prepared by substituting Boc-serinol(Bn) for Boc-tryptophanol in Example 2A.
  • Example 202B (lS)-[l-Benzyloxymethyl-2-(5-isoquinolin-6-yl-pyridin-3-yloxy)-ethyl]-carbamic acid tert- butyl ester
  • the desired product was prepared by substituting 202A for Example 2A in Example 27B.
  • Example 202C ( 1 S)- 1 -B enzy loxymethy l-2-(5 -isoquino 1 in-6-y l-pyridin-3 -y loxy)-ethy lamine
  • the desired product was prepared by substituting Example 202B for Example 27A in Example 202. in Example 27C.
  • Example 203A 5-Bromo-3-methyl-indazole-l -carboxylic acid tert-butyl ester
  • Example 203B 3 Methyl-5-trimethylstannanyl-indazole-l -carboxylic acid tert-butyl ester
  • a solution of Example 203A (1.35 g; 4.3 mmol), hexamethylditin (1.56 g; 4.8 mmol), and Pd(PPh 3 ) 4 (250 mg, 0.22 mmol) in toluene (15 mL) was stirred overnight at 85 °C, evaporated and purified by flash chromatography (20% Et 2 O/hexane) to provide the desired product
  • Example 203C (2S)-5-[5-(3-Benzyloxy-2-tert-butoxycarbonylamino-propoxy)-pyridin-3-yl]-3-methyl- indazole-1 -carboxylic acid tert-butyl ester
  • the desired product was prepared by substituting 203 B for Example 27A in Example 202B.
  • Example 203D (lS)-l-Benzyloxymethyl-2-[5-(3-methyl-lH-indazol-5-yl)-pyridin-3-yloxy]-ethylamine
  • the desired product was prepared by substituting 203C for Example 27B in Example 27C.
  • Example 204A (lS)-[l-Hydroxymethyl-2-(5-isoquinolin-6-yl-pyridin-3-yloxy)-ethyl]-carbamic acid tert- butyl ester
  • ammonium formate (377 mg, 5.97 mmol)
  • MeOH MeOH
  • Pd/C 320 mg
  • the resulting black reaction mixture was warmed to 70 °C for 6 d and then cooled to room temperature and filtered through Celite.
  • K 2 CO 3 50 mg
  • silica gel were added and the volatiles removed on a rotary evaporator.
  • Example 204B (lS)-[2-(5-Isoquinolin-6-yl-pyridin-3-yloxy)-l-(naphthalen-2-yloxymethyl)-ethyl]-carbamic acid tert-butyl ester 2-Napthol (15 mg, 101 ⁇ mol), Example 204A (20 mg, 51 ⁇ mol), DBAD (17 mg, 76 ⁇ mol), and PPh 3 -polymer (3 mmol/g) (34 mg, 101 ⁇ mol) were combined in a 10 mL round bottom flask. THF (2 mL) was added and the reaction mixture stirred 2 d at 23 °C and then rotavapped with silica gel.
  • Example 204B was prepared by substituting Example 204B for Example 27B in Example 27C.
  • Example 206 (lS)-2-(5-Isoquinolin-6-yl-pyridin-3-yloxy)-l-(quinolin-7-yloxymethyl)-ethylamine
  • the desired product was prepared as trifluoroacedic acid salt by substituting 7- hydroxyquinoline for 2-naphthol in Example 204.
  • Example 207 (2S)-4-r2-Amino-3-(5-isoquinolin-6-yl-pyridin-3-yloxy)-propoxy1-benzonitrile
  • the desired product was prepared as trifluoroacedic acid salt by substituting 4-cyanophenol for 2-naphthol in Example 204.
  • Example 208A (2S)- ⁇ l-[(5-Bromo-pyridin-3-ylamino)-methyll-2-phenyl-ethyl ⁇ -carbamic acid tert-butyl ester
  • a solution of Example 23B (0.4 g, 2.3 mmol), (l-formyl-2-phenyl-ethy)-carbamic acid tert- butyl ester (0.7g, 2.8 mmol), and Ti(iPrO) 4 (10 ml) in CHC1 2 (15 mL) was stirred at room temperature for 2 h. The solvent was evaporated off and the residue was dissolved in 15 ml of EtOH.
  • Example 208B (2S)-5-r5-(2-tert-Butoxycarbonylamino-3-phenyl-propylamino)-pyridin-3-yl1-3-methyl- indazole-1 -carboxylic acid tert-butyl ester
  • the desired product was prepared by substituting Example 208 A for Example 202A in Example 203C.
  • Example 208C (2S)-N'-(5-(3-methyl-lH-indazol-5-yl)-pyridin-3-yl)-3-phenyl-propane-l,2-diamine
  • the desired product was prepared by substituting Example 208B for Example 27B in Example 27C.
  • Example 211 (2S)-N-(2-Amino-3-phenyl-propyl)-N-[5-(3-methyl-lH-indazol-5-yl)-pyridin-3-yll- benzamide
  • the desired product was prepared as trifluoroacetic acid salt by substituting benzoyl chloride for methanesulfonyl chloride in Example 209.
  • Example 212 (2S)-N-(2-Amino-3-phenyl-propyl)-N-[5-(3-methyl-lH-indazol-5-yl -pyridin-3-yl1-acetamide
  • the desired product was prepared as trifluoroacetic acid salt by substituting acetyl Chloride for methanesulfonyl chloride in Example 209.
  • Example 214 (lS)-2-(5-Isoquinolin-6-yl-pyridin-3-yloxy)-l-(l-methyl-lH-indol-3-ylmethyl)-ethylamine
  • the title compound was prepared as trifluoroacetic acid salt by substituting 5-bromo-7- azaindole (D. Mazeas, et al., Heterocycles 1990, 50, 1065) for 6-bromophthalimide in Example 32.
  • Example 215A (lS)-N- ⁇ -(lH-Indol-3-ylmethyl)-2-(5-isoquinolin-6-yl-pyridin-3-yloxy)-ethyll-2-nitro- benzenesulfonamide
  • Example 27 400mg, 1.Olmmol
  • DIEA 1.06mL, 6.06mmol
  • 2-nitrobenzylsulfonyl chloride 896mg, 4.04mmol

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EP02790126A 2001-12-13 2002-12-12 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer Withdrawn EP1463505A2 (en)

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US295833 2002-11-18
PCT/US2002/039915 WO2003051366A2 (en) 2001-12-13 2002-12-12 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer

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CA2470214A1 (en) 2003-06-26
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AU2002353147A1 (en) 2003-06-30
TW200301122A (en) 2003-07-01

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