Kinase inhibitors

Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.

TECHNICAL FIELD

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.

BACKGROUND OF THE INVENTION

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-Ab1, PDK-1). Often these signal transduction genes are recognized proto-oncogenes. Many of these kinases control cell cycle progression near the G1-S transition (e.g. Cdk2, Cdk4), at the G2-M transition (e.g. Wee1, Myt1, Chk1, Cdc2) or at the spindle checkpoint (Plk, Aurora1 or 2, Bub1 or 3). Furthermore, kinases are intimately linked to the DNA damage response (e.g. ATM, ATR, Chk1, 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.

SUMMARY OF THE INVENTION

In its principle embodiment the present invention provides a compound of formula (I)

or a therapeutically acceptable salt thereof, 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 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, Y , and Z are N;

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 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;

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 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

In another embodiment the present invention provides a compound of formula (II)

or a therapeutically acceptable salt thereof, wherein

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 L 1 , 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 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; 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;

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; and

X is selected from the group consisting of C(R 8 ) and N; wherein R 8 is selected from the group consisting of hydrogen, amino, carboxy, cyano, and halo.

In another embodiment the present invention provides a compound of formula (III)

or a therapeutically acceptable salt thereof, wherein

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 6 is other than hydrogen; and

R 5 is selected from the group consisting of hydrogen and alkyl.

In another embodiment, 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; 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 absent or 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, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle; 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, and cyanoalkenyl; and each R 12 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle, and nitro.

In another embodiment, 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; 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 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 thienyl; 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 consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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; L 2 is O ; 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 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 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 consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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; 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 heteroaryl; and R 7 is hydrogen.

In another embodiment, 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; 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 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 hydrogen.

In another embodiment, 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; L 1 is alkenyl; L 2 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, thiazolyl, and thienyl; R 3 is absent; R 6 is heterocycle; and R 7 is absent or selected from the group consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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; L 2 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.

In another embodiment, 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; L 2 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, 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 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 consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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; L 1 is alkenyl; L 2 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 heteroaryl; and R 7 is hydrogen.

In another embodiment, 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; L 2 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 aryl; and R 7 is hydrogen.

In another embodiment, 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 alkynyl; 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, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle; 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, and cyanoalkenyl; and each R 12 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle, and nitro.

In another embodiment, 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 alkynyl; 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 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 thienyl; 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 consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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 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, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle; 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, and cyanoalkenyl; and each R 12 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle, and nitro.

In another embodiment, 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; 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 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 thienyl; 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 consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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 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 hydrogen.

In another embodiment, 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 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 heteroaryl; and R 7 is hydrogen.

In another embodiment, 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 thienyl; R 3 is hydrogen; R 6 is heteroaryl; and R 7 is absent.

In another embodiment, 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; 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 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 7 is hydrogen.

In another embodiment, 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; 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 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 is hydrogen.

In another embodiment, 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 -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 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 7 is hydrogen.

In another embodiment, 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 -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 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 is hydrogen.

In another embodiment, 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 -L 2 -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 6 is aryl; and R 7 is hydrogen.

In another embodiment, 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 -L 2 -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 6 is heteroaryl; and R 7 is hydrogen.

In another embodiment, 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; 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 6 is aryl; and R 7 is hydrogen.

In another embodiment, 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; 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 6 is heteroaryl; and R 7 is hydrogen.

In another embodiment, 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, 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 of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl; 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 consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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 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 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 of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl; R 6 is heteroaryl; and R 7 is hydrogen.

In another embodiment, 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 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 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 of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl; R 6 is aryl; and R 7 is hydrogen.

In another embodiment, 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 )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, 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 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 consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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 a bond; L 2 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 heteroaryl; and R 7 is hydrogen.

In another embodiment, 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 a bond; L 2 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 aryl; and R 7 is hydrogen.

In another embodiment, 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, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle; 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, and cyanoalkenyl; and each R 12 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle, and nitro.

In another embodiment, 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 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 thienyl; R 3 is hydrogen; R 5 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl; 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 consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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 ) ; 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 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 thienyl; R 3 is hydrogen; R 5 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl; R 6 is heteroaryl; and R 7 is hydrogen.

In another embodiment, 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 ) ; 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 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 thienyl; R 3 is hydrogen; R 5 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl; R 6 is aryl; and R 7 is hydrogen.

In another embodiment, 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 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; R 3 is absent; R 6 is heterocycle; and R 7 is absent or selected from the group consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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 12 ) 2 , C(R 12 ) 2 N(R 5 ) , N(R 5 )C(O) , and C(O)N(R 5 ) , wherein each group is drawn with its left end attached to R 1 and its right end attached to the aromatic ring; L 3 is alkylidene, wherein the alkylidene is 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 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; 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, and cyanoalkenyl; and each R 12 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle, and nitro.

In another embodiment, 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.

In another embodiment, 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; 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 absent; R 6 is heteroaryl; and R 7 is absent or selected from the group consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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; 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 absent; R 6 is heteroaryl; and R 7 is hydrogen.

In another embodiment, 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; 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 absent; R 6 is aryl; and R 7 is hydrogen.

In another embodiment, 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; 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 selected from the group consisting of aryl, heterocycle, and heteroaryl; R 3 is hydrogen; R 6 is selected from the group consisting of aryl, heterocycle, and heteroaryl; and R 7 is absent or selected from the group consisting of hydrogen, alkyl, and cyanoalkenyl.

In another embodiment, 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; 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.

In another embodiment, 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; 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 aryl; R 3 is hydrogen; R 6 is aryl; and R 7 is absent.

In another embodiment, 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; 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 selected from the group consisting of aryl, heterocycle, and heteroaryl; R 3 is hydrogen; and R 6 is selected from the group consisting of aryl, heterocycle, and heteroaryl.

In another embodiment, 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; 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.

In another embodiment, 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; 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 aryl.

In another embodiment the invention provides a pharmaceutical composition comprising a compound of formula (I), or a therapeutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

In another embodiment 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.

DETAILED DESCRIPTION OF THE INVENTION

As used in the present specification the following terms have the meanings indicated:

The term alkenyl, as used herein, refers to a group derived from a straight or branched chain hydrocarbon of up to six atoms containing at least one double bond.

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

The term alkoxyalkyl, as used herein, refers to an alkoxy group attached to the parent molecular moiety through an alkyl group.

The term alkoxycarbonyl, as used herein, refers to an alkoxy group attached to the parent molecular moiety through an alkyl group.

The term alkyl, as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon of one to six atoms.

The term alkylene, as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon of one to six atoms.

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

The term alkylidene, as used herein, 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.

The term alkylsulfonyl, as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.

The term alkynyl, as used herein, refers to a group derived from a straight or branched chain hydrocarbon of two to six atoms containing at least one triple bond.

The term amido, as used herein, refers to an amino group attached to the parent molecular moiety through a carbonyl group.

The term amino, as used herein, refers to NR a R b , wherein R a and R b are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, haloalkylcarbonyl, (NR c 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 heteroarylalkenyl and the heteroarylalkyl, the heterocycle, and the heterocycle part of the (heterocycle)alkenyl and the (heterocycle)alkyl can be 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.

The term aminoalkyl, as used herein, refers to an amino group attached to the parent molecular moiety through an alkyl group.

The term aryl, as used herein, 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. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylthio, amino, aminoalkyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkoxy, heteroarylalkyl, heterocycle, (heterocycle)alkoxy, (heterocycle)alkyl, hydroxy, hydroxyalkyl, nitro, oxo, C( NOH)NH 2 , C( NH)NH 2 ; wherein the second aryl group, the aryl part of the arylalkoxy, the arylalkyl, and the arylcarbonyl, the heteroaryl, 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, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and nitro.

The term arylalkenyl, as used herein, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

The term arylalkoxy, as used herein, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

The term arylalkyl, as used herein, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

The term arylalkylamino, as used herein, refers to an arylalkyl group attached to the parent molecular moiety through a nitrogen atom, wherein the nitrogen atom is substituted with hydrogen.

The term arylalkylidene, as used herein, refers to an aryl group attached to the parent molecular moiety through an alkylidene group

The term arylalkylthio, as used herein, refers to an arylalkyl group attached to the parent molecular moiety through a sulfur atom.

The term arylalkynyl, as used herein, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

The term arylcarbonyl, as used herein, refers to an aryl group attached to the parent molecular moiety through a carbonyl group.

The term aryloxy, as used herein, refers to an aryl group attached to the parent molecular moiety through an oxygen atom.

The term arylsulfonyl, as used herein, refers to an aryl group attached to the parent molecular moiety through an sulfonyl group.

The term arylthio, as used herein, refers to an aryl group attached to the parent molecular moiety through a sulfur atom.

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

The term carboxy, as used herein, refers to C(O)OH.

The term cyano, as used herein, refers to CN.

The term cyanoalkenyl, as used herein, refers to a cyano group attached to the parent molecular moiety through an alkenyl group

The term cycloalkyl, as used herein, 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.

The term (cycloalkyl)alkylidene, as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through an alkylidene group.

The term halo, or halogen, as used herein, refers to F, Cl, Br, or I.

The term haloalkoxy, as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

The term haloalkyl, as used herein, refers to an alkyl group substituted by one, two, three, or four halogen atoms.

The term haloalkylcarbonyl, as used herein, refers to an haloalkyl group attached to the parent molecular moiety through a carbonyl group.

The term heteroaryl, as used herein, 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. The term 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, quinolinyl, thieno 2,3-c pyridinyl, tetrazolyl, triazinyl, and the like. The 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 arylalkylthio, the arylalkynyl, and the 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.

The term heteroarylalkenyl, as used herein, refers to a heteroaryl group attached to the parent molecular moiety through an alkenyl group.

The term heteroarylalkoxy, as used herein, refers to a heteroaryl group attached to the parent molecular moiety through an alkoxy group.

The term heteroarylalkyl, as used herein, refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group.

The term heteroarylalkylidene, as used herein, refers to a heteroaryl group attached to the parent molecular moiety through an alkylidene group.

The term heteroaryloxy, as used herein, refers to a heteroaryl group attached to the parent molecular moiety through an oxygen atom.

The term heteroarylsulfonyl, as used herein, refers to a heteroaryl group attached to the parent molecular moiety through a sulfonyl group.

The term heterocycle, as used herein, 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 1,3 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. The 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 arylalkyl, the heteroaryl, the heteroaryl part of the heteroarylalkoxy, the heteroarylalkyl, and the heteroarylalkylidene, the second heterocycle, and the heterocycle part of the (heterocycle)alkoxy, the (heterocycle)alkyl, and the (heterocycle)alkylidene 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.

The term (heterocycle)alkenyl, as used herein, refers to a heterocycle group attached to the parent molecular moiety through an alkenyl group.

The term (heterocycle)alkoxy, as used herein, refers to a heterocycle group attached to the parent molecular group through an oxygen atom.

The term (heterocycle)alkyl, as used herein, refers to a heterocycle group attached to the parent molecular moiety through an alkyl group.

The term (heterocycle)alkylidene, as used herein, refers to a heterocycle group attached to the parent molecular moiety through an alkylidene group.

The term hydroxy, as used herein, refers to OH.

The term hydroxyalkyl, as used herein, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

The term iminohydroxy, as used herein, refers to N(OH).

The term NR c R d , as used herein, 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.

The term (NR c R d )alkyl, as used herein, refers to a NR c R d group attached to the parent molecular moiety through an alkyl group.

The term (NR c R d )alkylcarbonyl, as used herein, refers to a (NR c R d )alkyl group attached to the parent molecular moiety through a carbonyl group.

The term nitro, as used herein, refers to NO 2 .

The term oxo, as used herein, refers to O.

The term sulfonyl, as used herein, refers to S(O) 2 .

The compounds of the present invention can exist as therapeutically acceptable salts.

The term therapeutically acceptable salt, as used herein, represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue 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, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, 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. Examples of 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.

The present compounds can also exist as therapeutically acceptable prodrugs. The term 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. The term prodrug, refers to compounds which are transformed in vivo to parent compounds of formula (I) for example, by hydrolysis in blood.

When any variable, substituent, or term (e.g. aryl, heterocycle, R 12 , etc.) occurs more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable combinations.

Because carbon-carbon double bonds exist in the present compounds, the invention contemplates various geometric isomers and mixtures thereof resulting from the arrangement of substituents around these carbon-carbon double bonds. It should be understood that the invention encompasses both isomeric forms, or mixtures thereof, which possess the ability to inhibit protein kinases. These substituents are designated as being in the E or Z configuration wherein the term E represents higher order substituents on opposite sides of the carbon-carbon double bond, and the term Z represents higher order substituents on the same side of the carbon-carbon double bond.

Asymmetric centers exist in the compounds of the present invention. These centers are designated by the symbols R or S, depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, or mixtures thereof, which possess the ability to inhibit protein kinases. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.

In accordance with methods of treatment and pharmaceutical compositions of the invention, the compounds can be administered alone or in combination with other anticancer agents. When using the compounds, 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. The term parenteral includes infusion as well as subcutaneous, intravenous, intramuscular, and intrastemal 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. Among the 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. One way to slow the absorption of a particular compound is administering 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. Conversely, absorption enhancers can be used to increase absorption.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, 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. 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.

Determination of Biological Activity

The Akt1 assay uses His-Akt1-S36, a truncated Akt1 containing a His tag at the N-terminus, amino acid 139-460 of Akt1 and the following point mutations: S378A, S381A, T450D and S473D. The His-Akt1-S36 assay is run in 96 well plates by incubating 1 nM His-Akt1-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 2 , 0.009% Triton X-100) for 30 minutes at room temperature. The reactions are stopped by adding 25 L of stopping buffer (4M NaCl and 0.1M EDTA). The samples are transferred to a Flash plate coated with streptavidin. The phosphorylation of BAD-peptide in the reactions is measured by counting the plate with the TopCount. Other kinase assays (Akt2, Akt3, PKA, PKC, Erk2, Chk1, 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. Thus, the compounds of the invention are useful in treating disorders which are caused or exacerbated by increased protein kinase levels.

Synthetic Methods

Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: DEAD for diethyl azodicarboxylate; THF for tetrahydrofuran; MTBE for methyl tert-butyl ether, PPh 3 for triphenylphosphine; OAc for acetate; P(o-tol) 3 for tri-o-tolylphoshphine; dba for dibenzylideneacetone; DME for 1,2-dimethoxyethane; BINAP for 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl; DMAP for 4-dimethylaminopyridine; dppf for diphenylphosphinoferrocene; dppe for diphenylphosphinoethane; EDC for 1-ethyl-3- 3-(dimethylamino)propyl carbodiimide hydrochloride; HOBt for 1-hydroxybenzotriazole; DCC for 1,3-dicyclohexylcarbodiimide; DMF for dimethylformamide; NMP for N-methylpyrrolidinone; DMSO for dimethylsulfoxide; Boc for tert-butoxycarbonyl; TFA for trifluoroacetic acid; DIBAL for diisobutylaluminum hydride; n-BuLi for n-butyllithium; 9-BBN for 9-borabicyclo 3.3.1 nonane; OiPr for isopropoxide; DMA for dimethylacetamide; AIBN for 2,2 -azobisisobutyronitrile; TEA for triethylamine; and NBS for N-bromosuccinimide.

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. The groups L 1 , L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 are as defined above unless otherwise noted below.

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.

As shown in Scheme 1, compounds of formula (2) (Z is Cl, Br, I, or OTf) can be converted to compounds of formula (4) by treatment with compounds of formula (3) in the presence of triphenylphosphine and an activating agent such as DEAD. The reaction can be carried out neat or in the presence of a solvent such as THF, diethyl ether, and MTBE. The reaction temperature is typically about 10 C. to about 35 C. and reaction times are typically about 8 to about 24 hours.

Compounds of formula (4) can be converted to compounds of formula (Ia) 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. Examples of palladium catalysts include Pd(PPh 3 ) 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. Examples of 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. Typically, 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 (Ib). 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). Examples of palladium catalysts include PdCl 2 .dppf, 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. Examples of 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.

As shown in Scheme 4, compounds of formula (13) can be hydrolyzed to provide compounds of formula (14) using methods known to those of ordinary skill in the art. Compounds of formula (14) can be converted to compounds of formula (Id) using the conditions described in Scheme 3.

Scheme 5 shows the synthesis of compounds of formula (Ie). Compounds of formula (15) can be converted to compounds of formula (16) by treatment with a reducing agent. Examples of 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 (Ie) 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.

As shown in Scheme 6, 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. Representative palladium catalysts include PdCl 2 .dppf, Pd(PPh 3 ) 4 , and PdCl 2 (PPh 3 ) 2 . Examples of 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.

As shown in Scheme 7, compounds of formula (9) can be reacted with compounds of formula (18) using the conditions described in Scheme 3 to provide compounds of formula (Ig).

The present invention will now be described in connection with certain preferred embodiments which are not intended to limit its scope. On the contrary, the present invention covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include preferred embodiments, will illustrate the preferred practice of the present invention, it being understood that the examples are for the purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.

A solution of N,N-dimethylethanolamine(0.5 mL) in DMF (10 mL) at room temperature was treated with sodium hydride (0.2 g, 8.4 mmol), stirred for 30 minutes, and treated with 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 (Na 2 SO 4 ), filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel with 50% ethyl acetate/hexane provided the desired product (0.8 g, 78%). MS (DCI/NH 3 ) m/e 246 (M H) .

The desired product was prepared by substituting Example 2A for Example 1A in Example 1B. MS (DCI/NH 3 ) m/e 471 (M H) .

A mixture of Example 12A in HBr/HOAc (30%, 50 mL) was stirred at 100 C. for 8 hours, cooled to room temperature and concentrated. The concentrate was partitioned between ethyl acetate and saturated Na 2 CO 3 (aq.). The organic layer was washed with brine, dried (Na 2 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%). MS (DCI/NH 3 ) m/e 209 (M H) .

A solution of Example 14A (400 mg, 0.86 mmol) in THF (6 mL) at room temperature was treated with tetrabutylammonium fluoride (1.0 M solution in THF, 1.12 mL, 1.12 mmol), stirred for 1 hour, treated with ethyl acetate (50 mL), washed with brine, dried (MgSO 4 ), filtered, and concentrated. The residual oil was purified by flash column chromatography on silica gel with 40% ethyl acetate/hexanes to provide the desired product (290 mg, 86%). MS (APCI) m/e 392 (M H) .

The desired product was prepared by substituting 3-bromo-5-ethoxycarbonylpyridine for Example 1A in Example 1B. MS (DCI/NH 3 ) m/e 355 (M H) .

A mixture of Example 18A (1.60 g, 6.3 mmol) and LiOH.H 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 1N HCl (aq.). The solid was collected by filtration and dried to provide the desired product. MS (DCI/NH 3 ) m/e 227 (M H) .

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 NaI (2.1 g, 14 mmol) in H 2 O (2 mL), stirred for 2 hours, treated with additional NaI (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. The residual solid was purified by flash column chromatography on silica gel with 70% ethyl acetate/hexanes to provide the desired product (1.03 g, 70%).

A solution of Example 21C (100 mg, 0.35 mmol) in THF (3 mL) at 0 C. was treated with 9-BBN (0.5 M solution in THF, 0.70 mL, 0.35 mmol), stirred overnight while gradually warming to room temperature, cannulated into a mixture of Example 21B (108 mg, 0.32 mmol), PdCl 2 (dppf) (26 mg, 0.032 mmol) and Cs 2 CO 3 (228 mg, 0.7 mmol) in DMF, purged with nitrogen, and stirred at 50 C. for 8 hours. The mixture was treated with ethyl acetate (50 mL), washed with brine, dried (MgSO 4 ), filtered, and concentrated. The residual oil was purified by flash column chromatography on silica gel with 80% ethyl acetate/hexanes to provide the desired product (69 mg, 40%).

A solution of Example 2A (250 mg, 0.56 mmol) in 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 2 CO 3 (aq.) (1.4 mL), heated to reflux for 4 hours, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel with hexanes/ethyl acetate (1:1) to provide the desired product (230 mg, 88%). MS (DCI/NH 3 ) m/e 469 (M H) .

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 Cl (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%).

A solution of 3M NaOH (250 mL) at room temperature was treated with bromine (25.9 g, 162 mmol), stirred for 15 minutes, treated with 5-bromonicotinamide (25 g, 124 mmol), stirred for 45 minutes, heated to 85-100 C. for 3 hours, cooled to room temperature, adjusted to pH 1 with 10% HCl (aq.) washed twice with diethyl ether. The aqueous layer was adjusted to pH 10-11 with solid NaOH, and extracted four times with diethyl ether and twice with dichloromethane. The combined extracts were dried (MgSO 4 ), filtered, and concentrated to provide the desired product (13.3 g, 62%).

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 conc. 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%).

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%).

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%).

A mixture of 4-aminopyridine (10 g, 106 mmol) and pivaloyl chloride (12.9 g, 107 mmol) in 200 mL dichloromethane was cooled to 0 C. and treated slowly with triethylamine (10.9 g, 108 mmol), warmed to room temperature, stirred overnight, and diluted with water. The aqueous layer was extracted three times with dichloromethane and the combined extracts were washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated. The product was recrystallized from toluene to provide the desired product (14 g, 74%).

A mixture of Example 25A (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. 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%).

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%).

A mixture of 5-bromonicotinamide (2.5 g, 12.4 mmol), tributyl(1-ethoxyvinyl)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. The aqueous layer was washed with ethyl acetate, adjusted to pH >7 with solid K 2 CO 3 , and extracted six times into 20% isopropanol/chloroform. The combined extracts were dried (Na 2 SO 4 ), filtered, and concentrated to provide the desired product (1.6 g, 78%).

A mixture of Example 25C (450 mg, 3.68 mmol) and Example 25D (605 mg, 3.68 mmol) in 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%).

The desired product was prepared by substituting Example 25E for 5-bromonicotinamide in Example 23B.

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 11B and Boc-homophenylalanine, respectively, in Example 16A.

A solution of 6-bromoisoquinoline (0.35 g, 1.7 mmol) in DMA (6 mL) was treated with hexamethylditin (0.55 mL, 1.9 mmol) and Pd(PPh 3 ) 4 (0.23 g, 0.2 mmol), stirred at 100 C. for 1 hour, diluted with 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 (0.247 g, 50%).

The desired product was prepared by substituting D-Boc-tryptophanol for L-Boc tryptophanol in 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%).

A solution of Example 32A (0.2 g, 0.31 mmol) and 6-bromophthalimide (0.084 g, 0.4 mmol) in DMF (2 mL) was treated with Pd 2 dba 3 (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%).

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%).

A solution of Example 33B (1.1 g, 3.57 mmol) in THF (20 mL) at room temperature was treated with 1N 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%).

A solution of 2 -aminoacetophenone (5.0 g, 37 mmol) in dichloromethane (150 mL) at room temperature was treated with triethylamine (5.3 mL, 40 mmol) and acetyl chloride (3.2 mL, 45 mmol), stirred for 3 hours, then washed with water. The aqueous layer was extracted with ethyl acetate (2 20 mL) and the combined extracts were concentrated to provide the desired product (6.5 g, 100%).

A solution Example 34A (6.5 g, 37 mmol) in acetic acid (100 mL) 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 (2 100 mL), and hexanes (2 100 mL), dissolved in diethyl ether, washed with brine (50 mL), and concentrated to provide the desired product (8.5 g, 89%).

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 (5 mL) 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 dried under vacuum to provide the desired product (3.0 g, 54%).

A solution of Example 34C (0.4 g, 1.8 mmol) in POCl 3 (2.5 mL) was heated to 100 C. for 2 hours, and poured slowly onto ice. 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 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%).

A solution of Example 34D (2.6 g, 10.6 mmol) in ethanol (70 mL) was treated with hydrazine monohydrate (3 mL, 90% solution), stirred at room temperature for 3 days, and filtered. 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%).

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 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%).

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%).

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%). MS (DCI/NH 3 ) m/e 257 (M H) .

A solution of Example 41A (5.46 g, 21.3 mmol) and 3,5-dibromopyridine (5.03 g, 21.3 mmol) in DMF (25 mL) at room temperature was treated with NaH (60% in mineral oil, 1.08 g, 25.6 mmol) in several portions. The reaction was stirred at room temperature for 20 minutes, heated to 60 C. for 2 hours, and poured into water. The aqueous layer was extracted with diethyl ether and the combined extracts were washed with water, dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with ethyl acetate/hexanes (1:7) to provide the desired product (336 mg, 4%). MS (DCI/NH 3 ) m/e 413 (M H) .

The desired product was prepared by substituting Example 41B for Example 2A in Example 27B. MS (DCI/NH 3 ) m/e 461 (M H) .

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%). MS (DCI/NH 3 ) m/e 269 (M H) .

A solution of Example 43A (1.5 g, 5.6 mmol) in nitrobenzene (10 mL) was refluxed for 5 minutes, filtered, cooled to room temperature and filtered again. The solid was washed with hexanes and dried to provide the desired product (0.68 g, 55%). MS (DCI/NH 3 ) m/e 225 (M H) .

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) .

Following the procedures described in Example 1, using the appropriate alcohols, the following compounds were made.

To a solution of Example 22 (200 mg, 0.43 mmol) in toluene (7.0 ml) and methanol (0.5 ml) were added hydroxylamine hydrochloride (33 mg, 0.48 mmol) and potassium tert-butoxide (54 mg, 0.48 mmol) and the mixture was stirred for 8 h at room temperature under a nitrogen atmosphere. Another portion of hydroxylamine hydrochloride (33 mg, 0.48 mmol) and potassium tert-butoxide (54 mg, 0.48 mmol) was added and the mixture was heated to 80 C. for 16 h. The mixture was concentrated and purified by column chromatography on silica gel using dichloromethane/methanol (15:1) as solvent system. Obtained were 130 mg (61%) of the product as a white powder.

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 under 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. The combined filtrates were evaporated in high vacuum and the residue was triturated with ethyl acetate to give 80 mg (39%) of the product as a beige powder.

A solution of the product from Example 75A above (1.0 g, 4.5 mmol) in THF (25 mL) was treated dropwise with 1.0M LiHMDS (9.0 mL, 9.0 mmol), stirred for 30 minutes, treated with di-t-butyl dicarbonate(1.96 g, 9.0 mmol) and stirred for 1 hour. The mixture was quenched with water (10 mL), warmed to room temperature and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was triturated with 1:1 hexanes/ethyl acetate to provide the desired product (1.0 g, 53%). MS (DCI/NH 3 ) m/z 421 (M H).

The desired product was prepared by substituting Example 75C for 4-vinylpyridine in Example 2B. Purification on silica gel eluting with 100% ethyl acetate provided the title compound (0.15 g, 49%). MS (DCI/NH 3 ) m/e 685 (M H).

The desired product was prepared by substituting Example 75D for Example 2B in Example 2C. Purification on HPLC provided the title compound (0.06 g, 70%).

To a solution of 5-aminoisoquinoline (2.0 g, 13.8 mmol) and 48% HBr (6 mL) in 20 mL water cooled to 0 C. was added a solution of sodium nitrite (0.95 g, 13.8 mmol) in 6 mL water. The solution was stirred at 0 C. for 20 minutes. The solution, while kept at 0 C., was added to a solution of CuBr (2.11 g, 15.9 mmol) in 48% HBr (4.77 mL) and water (10 mL). The reaction was stirred at room temperature for an additional 1 hr. The reaction was neutralized with NaOH (50%) and extracted with ethyl acetate (3 ). The combined organic layer was concentrated in vacuo and chromatographed using 1:1 hexanes/ethyl acetate to yield 1.4 g product (50%).

A suspension solution of Example 80A (1.5 g, 6.2 mmol) in POCl 3 (40 ml) was treated with PCl 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 (1.7 g, 100%). MS (DCI/NH 3 ) m/e 278 (M H) .

A mixture of Example 80B (1.8 g, 6.5 mmol), P (0.48 g, 15.5 mmol) and HI (3 ml, 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 (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexane to provide the title compound (0.81 g, 50%). MS (DCI/NH 3 ) m/e 244 (M H) .

The desired product was prepared by substituting Example 80C for 6-bromoisoquinoline in Example 27A. MS (DCI/NH 3 ) m/e 327 (M H) .

The desired product was prepared by substituting Example 80D for Example 27A in Example 27B. MS (DCI/NH 3 ) m/e 530 (M H) .

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 pH 13 with 1 N NaOH. The mixture was then extracted with methylene chloride. The combined extracts was washed with water (1 ), dried over MgSO 4 and concentrated. The residue was chromatographed on silica gel eluting with CH 2 Cl 2 :MeOH:NH 4 OH (100:5:0.5) to give the title compound (463 mg, 71%). MS (DCI/NH 3 ) m/z 277, 279 (M 1) .

Example 89B was converted to the title compound according to the procedures described for Example 51, Steps 4 and 5. MS (DCI/NH 3 ) m/z 314 (M 1) .

A solution of 6-bromo-1-hydroxylisoquinoline (9.205 g, 41.0 mmol) in POCl 3 (100 mL) was heated to 100 C. for 4 h. The reaction was concentrated to dryness. The residue was dissolved in ethyl acetate and the organic layer was washed with 5% NaHCO 3 , water, brine, dried over MgSO 4 and concentrated. The residue was was chromatographed on silica gel eluting with CH 2 Cl 2 :hexane (3:7) to give the title compound (6.176 g, 62%). MS (DCI/NH 3 ) m/z 241, 243 (M 1) .

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 CH 2 Cl 2 :MeOH:NH 4 OH (100:5:0.5) to give the title compound (159 mg, 65%). MS (DCI/NH 3 ) m/z 223, 225 (M 1) .

The desired product was prepared by substituting 5-bromo-2-fluorobenzonitrile for 6-bromoisoquinoline in Example 27A.

The desired product was prepared by substituting Example 97A for in Example 27A in Example 27B.

A solution of 5-bromo-2-fluorobenzaldehyde (24.75 g; 122 mmol) in Et 2 O (125 mL) 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% HCl (aq). The aqueous was extracted with Et 2 O, rinsed successively with 10% HCl (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.

A solution of Example 102A (26.6 g; 121 mmol) and manganese(IV) oxide (53 g; 610 mmol) in p-dioxane (500 mL) was heated at reflux for 4 hrs., cooled, filtered through Celite , evaporated, and purified by flash chromatography (5-10% Et 2 O/hexane) to yield the desired product as a nearly colorless oil that solidified upon standing (20.5 g; 78%).

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%).

A mixture of Example 102C (10.08 g, 47.8 mmol), hexamethyl-di-tin 2 (18 g, 55 mmol) and tetrakis(triphenylphosphine)palladium (5.5 g, 4.8 mmol) in toluene (100 ml) was stirred at 95 C. for 6 h. 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). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluting with 1:4 ethyl acetate/hexanes to give 11.2 g desired product (80%). MS: (ESI) m/z 409 (M H) .

The desired product was prepared by substituting Example Example 102D for Example 27A in Example 27B.

Example 103A (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.

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 AlCl 3 , stirred overnight while gradually warming to r.t., treated with ice and 1 N HCl, stirred for 1.5 hrs., and extracted with CH 2 Cl 2 . The extracts were rinsed with water and saturated NaHCO 3 (aq.), dried over Na 2 SO 4 , concentrated, and isolated by flash chromatography (10% EtOAc/hexane) to give the desired product as a purple solid (252 mg; 31%).

The desired product was prepared by substituting Example 103C for Example 102B in Example 102C.

The desired product was prepared as the trifluoroacetate salt by substituting N- 2-trimethylsilanyl)ethoxy methyl)-2-imidazolyl lithium chloride for methyl magnesium bromide in Example 102 without doing the last step.

The reaction between Example 35A and morpholine was carried out according to the procedure described by U. Wrzeciono, K. Majewska, J. Dudzinska-Usarewicz, M. Bernas, Pharmzie, 1986, 41, 472-474.

Example 102C (500 mg; 2.37 mmol) was added to a mixture of 60% NaH (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%).

The reaction between Example 35A and dimethylamine was carried out according to the procedure described by U. Wrzeciono, K. Majewska, J. Dudzinska-Usarewicz, M. Bernas, Pharmzie, 1986, 41, 472-474.

The desired product was prepared by substituting 4-formylphenylboronic acid for 4-cyanophenylboronice acid in Example 22. MS: (ESI) m/z 472 (M H) .

A solution of Example 116A (0.03 g, 0.06 mmol) in 2 mL of MeOH was cooled to 0 C. then treated with aniline (0.018 g 0.2 mmol), NaBH 3 CN (0.004 g, 0.06 mmol) and AcOH (1 ml). The mixture was allowed to warm to room temperature overnight. 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 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.

A solution of 3,5-dibromo-phenol (1 g, 4.1 mmol), (2-hydroxy-1-phenyl-ethyl)-carbamic acid tert-butyl ester (1.2 g, 4.1 mmol), and triphenylphosphine (1.6 g, 2 mmol) in THF (30 mL) was stirred at 0 C. for 30 min. To the mixture was added a solution of di-t-butyl azidodicarboxylate (1.45 g, 9.2 mmol) in 5 ml of THF. The mixture was allowed to warm to room temperature then stirred at room temperature for 20 h. The THF was evaporated off and 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 of and the residue was purified by flash column chromatography on silica gel, eluting with a solvent gradient of 1:4 to 1:1 ethyl acetate/hexane. Recovered 1.33 g of product (64%).

A solution of Example 120A above (0.6 g, 01.1 mmol) and 6-trimethylstannanyl-isoquinoline (0.26 g, 1 mmol) in 5 mL of DMF was treated with Pd 2 (dba) 3 (0.1 g, 0.1 mmol), P(o-tol) 3 (0.07 g, 0.2 mmol), and TEA (0.3 mL, 2.3 mmol). The reaction was heated to 95 C. for 6.5 h, then cooled and diluted with ethyl acetate (75 ml), washed with saturated sodium bicarbonate (50 ml) water (50 ml) and brine (50 ml). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluting with a solvent gradient of 1:4 to 1:1 ethyl acetate/hexane.

The desired product was prepared by substituting 3-aminophenylboronic acid for 4-cyanophenylboronice acid in Example 22.

A mixture of Example 121A (0.07 g, 0.153 mmol) and 4-chloro-2-pyrimidinylamine (0.021 g, 0.163 mmol) was dissolved in EtOH (1 mL). The mixture was heated to 80 C. overnight then cooled and evaporated. The product was used without further purification.

A solution of the 3,5-dibromo-pyridine (12.8 g, 68.8 mmol) and piperazine-1-carboxylic acid tert butyl ester (10 g, 42.4 mmol) in 200 mL of dioxane was treated with Pd 2 (dba) 3 (5 g, 5.5 mmol), 2-(di-tbutyl-phosphino)biphenyl (4 g, 13.4 mmol), and sodium t-butoxide (7.2 g, 75 mmol). The reaction was heated to 95 C. for 8 h then cooled and filtered through celite. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel, eluting with a solvent gradient of 1:4 ethyl acetate/hexane to 100% ethyl acetate. Recovered 2.9 g of product (20%). MS (ESI) m/z 344 (M H) .

Example 121A (0.05 g, 0.11 mmol) was taken in methylene chloride (1.5 mL) and treated with acetic anhydride (0.2 mL, 2.1 mmol) and triethylamine (0.1 mL, 0.77 mmol). The mixture was stirred overnight at room temperature then diluted with methylene chloride (25 mL) and washed with water (15 mL) and brine (15 mL). The mixture was evaporated and used without further purification.

A solution of Example 120 (0.2 g, 0.3 mmol) 6 mL of DMF was treated with Pd(dppf) 2 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 HCl and washed with ethyl acetate. The water was evaporated off to yield the product. MS (ESI) m/z 538 (M H) .

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. The mixture was diluted with ethyl acetate (25 mL) and washed with water (15 mL) and brine (15 mL). The mixture was evaporated and the residue was purified by flash column chromatography on silica gel, eluting 1:1 ethyl acetate/hexane. Recovered 0.108 g of product (79%). MS (ESI) m/z 519 (M H) .

The title compound was prepared by substituting 3,5-dibromopyridine for Example 2A in Example 27B.

The title compound was prepared by substituting 3-benzyloxy-5-bromopyridine for 6-bromoisoquinoline in Example 27A.

A mixture of 2,6-dichloro-nicotonic acid (17.77 g, 92.6 mmol) in concenterated aqueous ammonia (173 mL) at 200 psi, was heated to 130 C. for 24 h. The mixture evaporated and the residue was taken into water (200 mL) and neuteralized with conc HCl then extracted into ether (200 ml). The ether was evaporated off to yield 12 g of product (75%). MS (DCI/NH 3 ) m/z 173 (M 1) .

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/NH 3 ) m/z 172 (M 1) .

A mixture of Example 140B (1 g, 5.8 mmol) in triethylorthoformate (30 mL) was refluxed for 6 h then cooled. Hexane (150 mL) was added and the solid formed was filtered and washed with water and hexane to yield 0.27 g of product (26%). MS: (DCI/NH 3 ) m/z 182 (M 1)

A mixture of Example 140C (1 g, 5.5 mmol) in phosphorus oxychloride (40 mL) was refluxed for 2 h then cooled and evaporated. 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%).

A solution of Example 140D (0.5 g, 2.5 mmol), and aniline (0.23 mL, 2.5 mmol) in THF (25 mL) and 2-propanol (2.5 mL) was stirred at 0 C. for 1 h then at room temperature for 2 days. The THF was evaporated off and the residue was taken into ethyl acetate (75 ml), washed with water (50 ml) and brine (50 ml). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane. Recovered 0.15 g of product (23%). MS (ESI) m/z 390 (M H) .

A solution of 5-bromo-pyridin-3-ol (0.3 g, 1.7 mmol), (2-hydroxy-1-phenyl-ethyl)-carbamic acid tert-butyl ester (0.41 g 1.7 mmol), and triphenylphosphine (0.52 g, 2 mmol) in THF (15 mL) was stirred at 0 C. for 30 min. To the mixture was added a solution of di-t-butyl azidodicarboxylate (0.46 g, 2 mmol) in 5 ml of THF. The mixture was allowed to warm to room temperature then stirred at room temperature for 20 h. The THF was evaporated off and 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 off and the residue was purified by flash column chromatography on silica gel, eluting with a solvent gradient of 1:4 to 1:2 ethyl acetate/hexane. Recovered 0.82 g of a mixture of product and di-tert-butyl azidodicarboxylate. MS (ESI) m/z 395 (M H) .

The following compounds were made according the procedures used in Example 27 or 102, using the appropriate Boc protected N-Boc-aminoethanols.

A solution of Example 23B (0.4 g, 2.3 mmol), (1-formyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (0.7 g, 2.8 mmol), and Ti(iPrO) 4 (10 ml) in CH 2 Cl 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. The solution was treated with NaBH 3 CN (0.5 g, 4.9 mmol) then stirred overnight at room temperature. The mixture was diluted with ethyl acetate (50 ml), washed with water (25 ml) and brine (25 ml). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluting with a solvent gradient of 1:4 to 1:1 ethyl acetate/hexane to give 0.28 g of product (30%). MS: (ESI) m/z 408 (M H) .

The desired product was prepared by substituting Example 208A for Example 202A in Example 203C.

To a solution of Example 27 (400 mg, 1.01 mmol) and DIEA (1.06 mL, 6.06 mmol) in THF (30 mL) in ice-bath cooling was added 2-nitrobenzylsulfonyl chloride (896 mg, 4.04 mmol). The reaction was allowed to warm up to rt for 12 hrs. The reaction mixture was concentrated and the resulting crude oil was purified by flash column chromatography eluting with EtOAc/Hex (1:1), EtOAc, and EtOAc/MeOH (20:1) to give the title compound (267 mg, 46%). MS (DCI/NH 3 ) m/z 580 (M 1) .

A mixture of Example 216B (100 mg, 0.2 mmol), NaOMe (25% in MeOH) (1 mL) in MeOH (10 mL) was refluxed for 8 hrs. The mixture was concentrated to give the crude product.

To a stirred mixture of Example 227C (0.96 g, 4.48 mmol) in DMF (20 mL) at 35 C. was added benzyl cyanide (1.55 mL, 13.4 mmol) and then NaH (0.57 g of 95% NaH, 22.4 mmol). The resulting dark red mixture was stirred 15 min while being slowly warmed to 20 C. At this time most of the bubbling had stopped and the reaction mixture was then quickly warmed to room temperature and then to 100 C. overnight. The reaction mixture was cooled to room temperature and saturated aqueous NH 4 Cl was added. The mixture was extracted with EtOAc and the organic extracts washed twice with H 2 O and once with brine. Silica gel was added and the volatiles removed on a rotary evaporator. Flash chromatography (60-80-100% EtOAc-3% MeOH/EtOAc) gave 1.14 g (82%) of as an orange solid. R f 0.40 (5% MeOH/EtOAc); MS m/z 312 (M H) ; 1 H NMR (300 MHz, DMSO-D6) ppm 6.17 (s, 1 H) 7.40 (m, 4 H) 7.52 (m, 2 H) 8.00 (m, 2 H) 8.70 (m, 2 H) 8.74 (d, J 8.48 Hz, 1 H) 14.36 (s, 1 H); Anal Calcd for C 19 H 13 N 5 : C, 73.30; H, 4.21; N, 22.49. Found: C, 73.09; H, 4.10; N, 22.58.

A mixture of 2-fluoro-5-hydroxypyridine (1.00 g, 8.84 mmol) and BDCS reagent (0.5 TBSCl, 1.0 imidazole in DMF) (35.4 mL, 17.7 mmol) was stirred at rt for 1 h. The reaction was poured into satd. aqueous NaHCO 3 solution. The aqueous layer was extracted with ether. The combined extracts were washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% ethyl acetate/hexanes to give the title compound (1.96 g, 98%).

The desired product was prepared according to the procedures used for Example 227C by substituting Example 232A for 2,6-difluoropyridine in Example 227A.

The desired product was prepared by substituting Example 232B for Example 102C in Example 203A (75%).

A mixture of Example 232C (91 mg, 0.213 mmol) and TBAF (1 in THF, 213 L, 0.213 mmol) in THF (10 mL) was stirred at rt for 5 min. Reaction was concentrated. Flash column chromatography eluting with 5% methanol/CH 2 Cl 2 to give the dedired product purified the residue (75%).

The title compound was prepared by substituting Example 232D for Example 238A and Boc-phenylalaminol for Boc-4 -bromophenylalaminol in Example 238B.

Example 234A (16.15 g, 54.9 mmol), Pd 2 dba 3 (0.50 g, 0.55 mmol), rac-BINAP (1.03 g, 1.65 mmol), and sodium tert-butoxide (7.39 g, 76.9 mmol) were combined in a 500 mL round bottom flask with a stirbar. Benzophenone imine (11.1 mL, 65.9 mmol) was added followed by toluene (180 mL). The resulting reaction mixture was warmed to 80 C. for 3 h and then allowed to cool to room temperature, diluted with Et 2 O, and filtered through Celite. The volatiles were removed on a rotary evaporator. Flash chromatography (30-40-50% EtOAc/hexanes) yielded an impure orange oil which was dissolved in THF (180 mL) and 1 N HCl (60 mL). The resulting orange mixture was stirred 15 min and then partitioned between 30% EtOAc/hexanes and 0.5 M HCl. The layers were separated and the organic layer washed once with 0.5 M HCl. The combined HCl layers were washed once with 30% EtOAc/hexanes and then cooled to 0 C. 50% aqueous NaOH was added until the mixture was basic on litmus paper and then the mixture was extracted twice with CH 2 Cl 2 . The combined organic extracts were dried over Na 2 SO 4 and the volatiles removed on a rotary evaporator to yield 8.92 g (71%, two steps) of as a yellow solid. 1 H NMR (300 MHz, DMSO-D6) ppm 3.75 (s, 3 H) 4.97 (s, 2 H) 4.97 (s, 2 H) 5.29 (s, 2 H) 6.54 (t, J 2.37 Hz, 1 H) 7.35 (m, 2 H) 7.50 (d, J 2.37 Hz, 1 H) 7.54 (d, J 2.37 Hz, 1 H), 13 C NMR (100 MHz, DMSO-D6) ppm 55.0, 68.9, 105.6, 113.8, 125.3, 128.7, 129.3, 129.4, 145.7, 155.1, 159.0.

A mixture of Example 236A (1.43 g, 4.6 mmol), m-cresol (4.9 ml, 47 mmol) and TFA (4 ml) was refluxed for 24 hours. After cooled to room temperature, the solution was dried by vacuum. Purification on silica gel eluted with 5% ethyl acetate in hexanes to provide the crude title compound (contaminated with disulfide).

A 100 ml RBF was charged with Example 236B (0.620 mg, 3.26 mmol), 2-Hydroxy-1-(1H-indol-3-ylmethyl)-ethyl -carbamic acid tert-butyl ester (1.077 g, 3.71 mmol), Ph 3 P (1.23 g, 4.69 mmol) and DBAD (1.0968 g, 4.763 mmol). THF (10 ml) was added at 0 C. The reaction mixture was stirred at 0 C. for 1 h and at room temperature for 22 hours. The reaction mixture was concentrated and the residue was separated by flash chromatography (30% EtOAc in hexane) to provide 0.614 g product with DBAD.

The desired product was prepared by substituting 3-bromo-5-hydroxypyridine for Example 203B in Example 203C.

The desired product was prepared according to the procedures described for Example 2A, substituting Example 238A for 3-bromo-5-hydroxypyridine, and 3 -bromo-Boc-phenylalaminol for Boc-tryptophanol in Example 2A.

The 4-Bromo-2-fluoro-benzaldehyde (1 g, 4.9 mmol), acetamidine and DMA were mixed and heated to 140 C. for 5 hours. The mixture was cooled to room temperature and dried under vacuum. The mixture was purified by flash column afforded 47 mg product in 4% yield. MS (ESI) m/e 223 (M 1) .

The desired product was prepared by substituting 3-bromophenol for 3-bromo-5-hydroxypyridine and L-Boc-phenylalaminol for L-Boc-tryptophanol in Example 2A.

The desired product was prepared by substituting Example 243A for Example 2A in Example 102E.

The desired product was prepared by substituting Example 245A for L-Boc-tryptophanol in Example 2A.

The desired product was prepared by substituting Example 245C for Example 2A in Example 102E.

The desired product was prepared by substituting 2-chloro-4-hydroxybenzaldehyde for 3-bromo-5-hydroxypyridine and L-Boc-phenylalaminol for L-Boc-tryptophanol in Example 2A.

A solution of Example 247B (225 mg; 0.46 mmol) in EtOH (4 mL) was treated portionwise with NaBH 4 (26 mg; 0.70 mmol) and stirred for 30 min., diluted with water, and extracted into EtOAc. The extracts were rinsed with brine, dried (MgSO 4 ), concentrated, and purified by flash chromatography (60% EtOAc/hexane) to provide the desired product (150 mg; 66%).

A mixture of 4-bromo-2-nitroaniline (1 g; 4.6 mmol) and SnCl 2 .2H 2 O (6.2 g; 27.6 mmol) in MeOH (30 mL) with 5-6 drops of conc. HCl was heated at reflux for 5 hrs., concentrated, suspended in sat'd NaHCO 3 (aq.) and extracted with EtOAc. The extracts were rinsed with brine, dried (MgSO 4 ), and concentrated to provide the product of sufficient purity to carry on.

A mixture of Example 248A (262 mg; 1.4 mmol) in 10% H 2 SO 4 (4 mL) was treated with NaNO 2 (120 mg; 1.7 mmol) in water (1 mL), stirred for 30 min., diluted with water, and extracted with EtOAc. The extracts were rinsed with brine, dried (Na 2 SO 4 ), concentrated and purified by flash chromatography (5% MeOH/CH 2 Cl 2 ) to provide the desired product.

A solution of Example 248B (770 mg; 5 mmol) in THF (5 mL) was added to a solution of 20% phosgene in toluene (10 mL) at 20 C., stirred for 1 hr. at 20 C. then 2 hrs. at r.t., evaporated and dissolved in THF (4 mL). This solution was added to a solution of tBuOH (1 mL), and pyridine (426 mg; 5.4 mmol) in THF (3 mL) at 20 C. then stirred overnight at r.t. The solids were removed by filtration and rinsed with EtOAc. The filtrate was rinsed with water and brine, dried (MgSO 4 ), concentrated, and isolated by flash chromatography (1:1 Et 2 O:hexane) to provide the desired product (970 mg; 76%).

The desired product was prepared by substituting L-Boc-phenylalaminol for L-Boc-tryptophanol in Example 2A.

The desired product was prepared by substituting Example 249A for Example 2A in Example 32A.

The reaction between Example 35A and 4-(2-aminoethyl)morpholine was carried out according to the procedure described by U. Wrzeciono, K. Majewska, J. Dudzinska-Usarewicz, M. Bernas, Pharmzie, 1986, 41, 472-474.

The desired product was prepared by substituting 5-bromo-2-fluorobenzonitrile for 5-bromo-2-fluorobenzaldehyde in Example 35A.

A solution of 256A (2.5 g; 12 mmol) and trifluoroacetic anhydride (3.4 mL; 24 mmol) in pyridine (50 mL) was stirred at r.t. for 2 days, acidified with 10% HCl (aq), and extracted with EtOAc. The extracts were rinsed with water and brine, dried (MgSO 4 ), concentrated and purified by flash chromatography (1:1 EtOAc:hexane) to provide the desired product (3.0 g; 84%).

The desired product was prepared by substituting Example 203B for Example 27A and Example 23B for Example 2A in Example 27B.

The desired product was prepared by substituting Example 257A for Example 25E and L-Boc-phenylalanine for Boc-tryptophane in Example 25G.

The desired product was prepared by substituting Boc-alaminol for Boc-tryprophanol in Example 2A.

The desire product was prepared by substituting Example 260A for Example 249A in Example 249B.

A solution of Example 34D (500 mg; 2.5 mmol) and aniline (1.5 mL) in MeOH (11 mL) was stirred at r.t. for 2.5 hrs, the resulting precipitate was collected, rinsed with water and dried under vacuum to provide the desired product (400 mg; 62%).

A solution of 4-bromo-2-methyl benzoic acid (1.0 g; 4.7 mmol) in MeOH (24 mL) with 20 drops conc. HCl was heated at reflux for 6 hrs. the concentrated to provide the desired product (1.1 g; 100%).

A solution of Example 34C (200 mg; 0.8 mmol) in THF (10 mL) was treated with 3.0 phenylmagnesium bromide in Et 2 O (1.6 mL; 4.8 mmol), stirred at r.t. for 4 hrs., sat;d NH 4 Cl (aq) was added, and extracted with EtOAc. The extracts were rinsed with brine, dried (MgSO 4 ), concentrated and purified by flash chromatography (30% EtOAc/hexane) to provide the desired product (67 mg; 29%).

A solution of 34D (100 mg; 0.41 mmol) and benzylamine (0.5 mL) in MeOH (3 mL) was stirred at r.t. for 24 hrs., concentrated, suspended in Et 2 O, and the precipitate was collected to provide the desired product (100 mg; 78%).

A solution of 3-carboxyindazole (2.0 g; 12.3 mmol) and conc.HCl (2 mL) in MeOH (50 mL) was heated at reflux overnight, concentrated, diluted with 2N NaOH (aq), and extracted with EtOAc. The extracts were rinsed with brine, dried (MgSO 4 ), and concentrated to provide the desired product.

A solution of Example 271A (300 mg; 1.7 mmol), bis(trifluoroacetoxy)iodobenzene (800 mg; 1.9 mmol), and iodine (253 mg; 1.0 mmol) in CH 2 Cl 2 (10 mL) was stirred overnight at r.t., and treated with sodium bisulfite (aq). The precipitate was collected, rinsed with water and hexane, and dried under vacuum to provide the desired product (180 mg; 36%).

The desired product was prepared by substituting Example 271B for 6-bromophthalimide in Example 32B.

The desired product was prepared by substituting Example 271C for Example 27B in Example 27C.

A 100 mL RBF was charged with 3-bromo-5-hydroxypyridine (1.20 g, 6.87 mmol), (R)- 1-(tert-butyl-dimethyl-silanyloxymethyl)-2-hydroxy-ethyl -carbamic acid tert-butyl ester (2.1 g, 6.87 mmol) and Ph 3 P (2.34 g, 8.93 mmol), and was purged with nitrogen. THF (30 mL) was added at 0 C. After stirring at 0 C. for 10 min, DEAD (1.41 mL, 8.93 mmol) was added via syringe. The reaction mixture was stirred at 0 C. for 0.5 h and at rt for 2 h. The reaction mixture was concentrated and the residue was separated by flash chromatography (5-25% EtOAc in hexane) to provide the desired product (3.14 g, 99%). MS (DCI) m/z 461, 463 (M 1) .

To a solution of Example 273A (3.14 g, 6.8 mmol) in THF (40 mL) was added TBAF (7.14 mL, 7.14 mmol) at rt. The solution was stirred at rt for 1 h and was concentrated. The residual oil was purified by flash chromatography (40-80% EtOAc in hexane) to give the desired product (2.19 g, 93%). MS (DCI) m/z 347, 349 (M 1) .

Ph 3 P (1.13 g, 4.32 mmol) was dissolved in 9:1 THF/CH 3 CN (30 mL) and cooled to 4 C. with an ice/water bath. DIAD (850 L, 4.32 mmol) was added slowly. After stirring 15 min, a solution of Example 273B (1.0 g, 2.88 mmol) in THF (4 mL) was added slowly. The solution was allowed to warm to rt and stirred for over night. The solution was concentrated and the residual oil was purified by flash chromatography (20-40% EtOAc in hexane) to give the desired product (1.0 g, 75%). MS (DCI) m/z 329, 331 (M 1) .

Method 1. A 100 mL RBF was charged with Example 273C (950 mg, 2.88 mmol), Example 203B (1.14 g, 2.88 mmol), Pd 2 (dba) 3 (263 mg, 0.288 mmol), and tri-o-tolylphosphine (263 mg), and was purged with N 2 . Anhydrous DMF (35 mL) and Et 3 N (1.2 mL) were added via syringe. The solution was purged with N 2 again and was heated at 72 C. for 4 h. After cooled, ethyl acetate (150 mL) was added. The mixture was washed with brine (200 mL) and water (200 mL). The ethyl acetate solution was concentrated and the residual oil was separated by flash chromatography (50-80% EtOAc in hexane) to give the desired product (634 mg, 65%). MS (APCI) m/z 481 (M 1) .

Method 2. To a stirred solution of PPh 3 (2.16 g, 8.24 mmol) in THF (130 mL) and CH 3 CN (20 mL) at 0 C. was added DIAD (1.62 mL, 8.24 mmol) slowly via syringe. After 20 min the resulting light yellow solution was canulated onto Example 272 (2.74 g, 5.50 mmol) in THF (150 mL). The reaction mixture was stirred 6 h at 23 C. and then silica gel was added and the volatiles removed on a rotary evaporator. Flash chromatography (50-60-70-80% EtOAc/hexanes) gave 3.72 g of a white solid which was a 1.33:1 mixture of triphenylphosphine oxide: aziridine. R f 0.50 (EtOAc). This was used without further purification.

To a suspension of CuBr SMe 2 (25 mg, 0.12 mmol) and Example 273D (100 mg, 0.21 mmol) in THF (6 mL) was added 3-trifluoromethoxyphenylmagnesium bromide (0.5 solution in THF, 1.6 mL, 0.8 mmol) at approximately 35 C. The formed clear solution was allowed to warm up to 20 C. within 40 min and was partitioned between ether and water. The organic layer was concentrated and the residue was separated by flash chromatography (40-65% EtOAc in hexane) to give the desired product (88 mg, 66%). MS (APCI) m/z 643 (M 1) .

The following compounds were prepared by substituting the appropriate Grignard reagents for 3-trifluoromethoxyphenylmagnesium bromide in Example 274.

The following compounds were prepared by substituting appropriate Girgnard reagents for 3-trifluoromethoxyphenyl-mangnesium bromide in Example 348.

A 250 mL RBF was charged with Example 12B (1.58 g, 7.59 mmol), Example 203B (3.0 g, 7.59 mmol), Pd 2 (dba) 3 (696 mg, 0.76 mmol), and tri-o-tolylphosphine (696 mg), and was purged with N 2 . Anhydrous DMF (60 mL) and Et 3 N (3.17 mL) were added via syringe. The solution was purged with N 2 again and was heated at 70 C. for 15 h. After cooled, ethyl acetate (300 mL) was added. The mixture was washed with brine (500 mL) and water (500 mL). The ethyl acetate solution was concentrated and the residual oil was separated by flash chromatography (40-65% EtOAc in hexane) to give the desired produc. (1.86 g, 68%). MS (APCI) m/z 360 (M 1) .

A 25 mL RBF was charged with Example 351A (150 mg, 0.417 mmol), Boc-phenylalaminol (157 mg, 0.625 mmol), DBAD (144 mg, 0.625 mmol) and Ph 3 P (163 mg, 0.625 mmol), and was purged with nitrogen. THF (8 mL) was added at 0 C. After stirring at 0 C. for 30 min the ice-H 2 O bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (20-40% EtOAc in hexane) to provide the desired product (215.0 mg, 87%). MS (APCI) m/z 593 (M 1) .

The following compounds were prepared by substituting the appropriate Boc-aminoalcohol for Boc-phenylalaminol in Example 351.

The desired product was prepared by substituting Example 12B for 3-bromo-5-hydroxypyridine and Boc-3-methyl-phenylalaminol for Boc-tryptophanol in Example 102.

The title compound was prepared by substituting Example 13A for Example 2A and Example 38A for Example 27A in Example 27B.

The title compound was prepared by substituting Example 13A for Example 2A in Example 27B. MS (APCI) m/z 529 (M 1) .

A 10 mL RBF was charged with Example 363A (100 mg, 0.189 mmol), zinc cyanide (56 mg, 0.47 mmol) and Pd(PPh 3 ) 4 (44 mg, 0.0378 mmol), and was purged with nitrogen. Anhydrous DMF (3 mL) was added and the solution was purged with nitrogen again. The reaction mixture was stirred at 90 C. for 70 h. After cooled, the mixture was partitioned between ethyl acetate and brine, and the organic phase was washed with water. The Organic layer was concentrated and the residue was separated by flash chromatography (40-100% EtOAc in hexane) to give the desired product (87.4 mg, 89%). MS (APCI) m/z 520 (M 1) .

The following compounds were prepared by substituting the appropriate tributylsannyl reagents for (1,1,1-tributylstannyl)benzene in Example 364.

The desired product was obtained by substituting Example 80E for example 363A in Example 363B.

The desired product was prepared by substituting Example 386A for Example 2A in Example 27B. MS (APCI) m/z 365 (M 1) .

To a solution of Example 386B (70 mg, 0.192 mmol) in pyridine (3 mL) was added 2-naphthalenesulfonyl chloride (87 mg, 0.384 mmol) at rt. The formed yellow solution was stirred at rt for 15 h. Pyridine was removed under reduced pressure and the residual oil was purified by flash chromatography (0-15% CH 3 OH in 2:1 EtOAc/hexane) to provide the desire product (69 mg, 65%). MS (APCI) m/z 555 (M 1) .

A 100 mL RBF was charged with 3-bromo-5-hydroxypyridine (949 mg, 5.45 mmol), Example 393A (2.0 g, 6.45 mmol) and Ph 3 P (1.72 g, 6.54 mmol), and was purged with nitrogen. THF (22 mL) was added at 0 C. After stirring at 0 C. for 10 min, DEAD (1.03 mL, 6.54 mmol) was added via syringe. The reaction mixture was stirred at 0 C. for 1 h and at rt overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (5-30% EtOAc in hexane) to provide the desired product (1.76 g, 70%). MS (DCI) m/z 461, 463 (M 1) .

A 100 mL RBF was charged with Example 393B (1.60 g, 3.47 mmol), Example 203B (1.37 g, 3.47 mmol), Pd 2 (dba) 3 (318 mg, 0.347 mmol), and tri-o-tolylphosphine (318 mg), and was purged with N 2 . Anhydrous DMF (50 mL) and Et 3 N (1.45 mL) were added via syringe. The solution was purged with N 2 again and was heated at 75 C. for 5 h. After cooled, ethyl acetate (200 mL) was added. The mixture was washed with brine (250 mL) and water (250 mL). The ethyl acetate solution was concentrated and the residual oil was separated by flash chromatography (20-60% EtOAc in hexane) to give the desired product (1.51 g, 71%). MS (DCI) m/z 613 (M 1) .

To a solution of Example 393C (1.122 g, 1.83 mmol) in THF (20 mL) was added TBAF (1.92 mL) at rt. The solution was stirred at rt for 1 h and was concentrated. The residual oil was separated by flash chromatography (0-15% CH 3 OH in 2:1 EtOAc/hexane) to give the title compound (0.82 g, 90%). MS (DCI) m/z 499 (M 1) .

A 25 mL RBF was charged with phenol (42 mg, 0.45 mmol), Example 393D (150 mg, 0.3 mmol) and Ph 3 P (142 mg, 0.54 mmol), and was purged with nitrogen. THF (4 mL) was added at 0 C. After stirring at 0 C. for 10 min, DEAD (85 L, 0.54 mmol) was added via syringe. The reaction mixture was stirred at 0 C. for 1 h and at rt overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (20-60% EtOAc in hexane) to provide the desire product (163 mg, 95%). MS (DCI) m/z 575 (M 1) .

To a solution of BOC-5-hydroxy-tryptophan (5.9 g, 18.4 mmol) and iodomethane (3.43 mL) in DMF (80 mL) was added powered KHCO 3 (3.68 g). The reaction mixture was stirred at rt for 4 hours. EtOAc (500 mL) was added and the mixture was washed with brine (500 mL) and water (500 mL). The organic phase was concentrated and the residual oil was triturated with CH 2 Cl 2 (20 mL). The formed white solid was collected by filtration, washed with CH 2 Cl 2 (20 mL) and dried to give the desired product (4.48 g, 73%). MS (DCI) m/z 335 (M 1) .

To a solution of Example 400A (1.20 g, 3.59 mmol) in DMF (20 mL) was added t-butyldimethylsilyl chloride (649 mg, 4.3 mmol), imidazole (293 mg, 4.3 mmol) and DMAP (50 mg) at rt. The reaction mixture was stirred at rt for 16 hours. EtOAc (100 mL) was added and the mixture was washed with brine (100 mL) and water (100 mL). The organic phase was concentrated and the residual oil was purified by flash chromatography (10-40% EtOAc in hexane) to give the desire product (1.6 g, 100%). MS (DCI) m/z 466 (M 18) .

To a solution of Example 400B (1.50 g, 3.3 mmol) in THF (15 mL) was slowly added LiAlH 4 powder (127 mg, 3.3 mmol) in several portion at rt. After the addition, the reaction mixture was becoming sticky and the stirring stopped. The temperature of the mixture arises to 50 C. Ether (30 mL) was added and the mixture was stirred for 20 min. Methanol (2 mL) and diluted HCl was added slowly and the mixture was extracted with ether. The organic phase was washed with water and concentrated. The residue was separated by flash chromatography (20-60% EtOAc in hexane) to give the desired product (982 mg, 70%). MS (DCI) m/z 421 (M 1) .

A 100 mL RBF was charged with 3-bromo-5-hydroxypyridine (432 mg, 2.48 mmol), Example 400C (950 mg, 2.26 mmol) and Ph 3 P (711 mg, 2.71 mmol), and was purged with nitrogen. THF (15 mL) was added at 0 C. After stirring at 0 C. for 10 min, DEAD (427 L, 2.71 mmol) was added via syringe. The reaction mixture was stirred at 0 C. for 1 h and at rt overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (10-50% EtOAc in hexane) to provide the desired product (1.05 g, 80%). MS (APCI) m/z 576, 578 (M 1) .

The desire product was prepared by substituting Example 400D for Example 202A in Example 203C. MS (DCI) m/z 728 (M 1) .

To a solution of Example 400E (850 mg, 1.17 mmol) in THF (10 mL) was added TBAF (1.28 mL, 1.28 mmol) at rt. The solution was stirred at rt for 2 h and was concentrated. The residual oil was purified by flash chromatography (0-15% CH 3 OH in 2:1 EtOAc/hexane) to give the desired product (530 mg, 74%). MS (DCI) m/z 614 (M 1) .

A 25 mL RBF was charged with Example 400F (100 mg, 0.163 mmol) and Ph 3 P (85 mg, 0.325 mmol), and was purged with nitrogen. THF (4 mL) and methanol (14 L) were added at 0 C. After stirring at 0 C. for 10 min, DEAD (51 L, 0.325 mmol) was added via syringe. The reaction mixture was stirred at 0 C. for 1 h and at rt over weekend. The reaction mixture was concentrated and the residue was separated by flash chromatography (50-80% EtOAc in hexane) to provide the desired product (33 mg, 32%). MS (APCI) m/z 628 (M 1) .

A 100 mL RBF was charged with 3-bromo-5-hydroxypyridine (1.67 g, 9.58 mmol), 2-hydroxy-3-(1H-indol-3-yl)-propionic acid methyl ester (2.1 g, 9.58 mmol) which was synthesized according to literature method (M. E. Jung et al J. Org. Chem . 1999, 64, 2976) and Ph 3 P (3.01 g, 11.5 mmol), and was purged with nitrogen. THF (40 mL) was added at 0 C. After stirring at 0 C. for 10 min, DEAD (1.81 mL, 11.5 mmol) was added via syringe. The reaction mixture was stirred at 0 C. for 1 h and at rt overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (20-60% EtOAc in hexane) to provide the desired product (3.4 g, 94%). MS (DCI) m/z 375, 377 (M 1) .

To a solution of Example 405A (3.2 g, 8.5 mmol) in THF (20 mL) and ether (30 mL) was slowly added LiAlH 4 powder (323 mg, 8.5 mmol) in several portion at rt. While LAH was added a lot of solid material precipitated from the solution and the temperature arises to about 40 C. Water (2 mL) and diluted HCl was added slowly and the mixture was neutralized with NaHCO 3 and extracted with ethyl acetate. The organic phase was washed with water and concentrated. The residue was separated by flash chromatography (20-80% EtOAc in hexane) to give the desired product (1.24 g, 42%). MS (DCI) m/z 347, 349 (M 1) .

A 50 mL RBF was charged with Example 405B (580 mg, 1.67 mmol), Example 203B (660 mg, 1.67 mmol), Pd 2 (dba) 3 (153 mg, 0.167 mmol), and tri-o-tolylphosphine (153 mg), and was purged with N 2 . Anhydrous DMF (22 mL) and Et 3 N (0.698 mL) were added via syringe. The solution was purged with N 2 again and was heated at 70 C. for 15 h. After cooled, ethyl acetate (100 mL) was added. The mixture was washed with brine (100 mL) and water (100 mL). The ethyl acetate solution was concentrated and the residual oil was separated by flash chromatography (0-15% CH 3 OH in 2:1 EtOAc/hexane) to give the desired product (656 mg, 79%). MS (APCI) m/z 499 (M 1) .

A 50 mL RBF was charged with Example 405C (580 mg, 1.16 mmol) and Ph 3 P (456 mg, 1.74 mmol), and was purged with nitrogen. THF (14 mL) was added at 0 C., followed by addition of DPPA (375 L, 1.74 mmol). After stirring at 0 C. for 1 min, DEAD (274 L, 1.74 mmol) was added via syringe. The reaction mixture was stirred at 0 C. for 0.5 h and at rt overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (20-80% EtOAc in hexane) to provide the desired product (534 mg, 87%). MS (APCI) m/z 524 (M 1) .

To a solution of Example 406A (480 mg) in ethanol was added 10% Pd/C (160 mg) under nitrogen. This suspension was purged with hydrogen (3 circles) and was stirred under hydrogen (balloon) for 4 h. The solid material was filtered off and the filtrate was concentrated to give the desired product (443 mg, 97%). MS (APCI) m/z 498 (M 1) .

To a solution of Example 386A (50 mg, 0.158 mmol) in pyridine (2 mL) was added 2-naphthalenesulfonyl chloride (72 mg, 0.316 mmol) at rt. The formed yellow solution was stirred at rt for 15 h. Pyridine was removed by blowing with nitrogen and the residual yellow solid was purified by flash chromatography (30-60% EtOAc in hexane) to the desired product (81 mg, 100%). MS (DCI) m/z 506, 508 (M 1) .

A 25 mL RBF was charged with Example 407A (78 mg, 0.154 mmol), Example 203B (45 mg, 0.154 mmol), Pd 2 (dba) 3 (14 mg, 0.0154 mmol), and tri-o-tolylphosphine (14 mg), and was purged with N 2 . Anhydrous DMF (4 mL) and Et 3 N (64 L) were added via syringe. The solution was purged with N 2 again and was heated at 70 C. for 15 h. After cooled, ethyl acetate (50 mL) was added. The mixture was washed with brine (50 mL) and water (50 mL). The ethyl acetate solution was concentrated and the residual oil was separated by flash chromatography (A: 2:1 EtOAc/hexane, 0-15% CH 3 OH/A) to give the desired product (54 mg, 63%). MS (APCI) m/z 558 (M 1) .

The following compounds were prepared by substituting the appropriate tributylsannyl reagents for (1,1,1-tributylstannyl)benzene and Example 362A for 80E in Example 364.

To a solution of 5-Bromo-pyridin-3-ol (0.50 g, 2.87 mmol), oxiranyl-methanol (0.38 mL, 5.74 mmol) and triphenylphosphine (1.50 g, 5.74 mmol) in anhydrous THF (20 mL) was added di-tert-butyl azodicarboxylate (DBAD) (1.32 g, 5.74 mmol) and the reaction mixture stirred at room temperature for 18 hrs and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10%-35% ethyl acetate/hexanes to provide the desire product (0.48 g, 73%).

A solution of Example 436A (500 mg, 2.17 mmol) and 1H-Benzoimidazole (28 mg, 2.39 mmol) in 2-propanol (10 mL) was refluxed under N 2 for 2 hrs. The reaction mixture was cooled, diluted with ethyl acetate(50 mL) and washed with brine (2 25 mL). The residue was concentrated and purified by flash column chromatography on silica gel eluting with 100% ethyl acetate to 5% methanol/ethyl acetate to provide the desire product (1.08 mmol, 50%).

The product was prepared by substituting Example 436B for Example 202A in Example 203B.

The desired compound was prepared by substituting morpholine for 1H-Benzoimidazole in Example 437B

To a solution of the Example 437A (250 mg, 0.79 mmol), isoindole-1,3-dione (121 mg, 0.82 mmol) and triphenylphosphine (240 mg, 0.92 mmol) in anhydrous THF (10 mL) was added DIAD (0.16 mL, 0.83 mmol) and stirred at room temperature for 45 mins. The concentrated residue was then purified by flash column chromatography eluting with 60% ethyl acetate/hexanes to give the desired intermediate which was dissolved in absolute ethanol (10 mL). Hydrazine monohydrate (40 L) was added and the reaction mixture refluxed for 3 hrs. The cloudy solution was cooled, concentrated and dissolved in DMF (10 mL). Di-tert-butyl-dicarbonate (271 mg, 1.25 mmol) and triethyl amine (0.18 mL, 1.25 mmol) were added and the clear solution stirred at room temperature for 15 hrs. The clear solution was diluted with ethyl acetate (25 mL) and washed with brine (25 mL) and water (25 mL). The concentrated residue was further purified by flash column chromatography eluting with 15% ethyl acetate/hexanes to give the desired product.

The product was prepared by substituting Example 437B for Example 202A in Example 203B.

A solution of 2-(3-phenyl-propyl)-oxirane (3.0 g, 18.27 mmol) and benzimidazole (2.37 g, 20.1 mmol) in anhydrous 2-propanol (50 mL) was purged with nitrogen and refluxed for 2.5 hrs. The reaction mixture was cooled, concentrated and purified by flash column chromatography on silica gel 0 (1 min)-15% (16 min) methanol in 2:1 ethyl acetate/hexanes to provide the desired product (4.72 g, 91%).

To a solution of Example 441A (1.0 g, 3.54 mmol) and triphenylphosphine (1.39 g, 5.31 mmol) in anhydrous THF (30 mL) was added diphenylphosphoryl azide (1.14 mL, 5,31 mmol) at 0 C. followed by the addition of DEAD (836 L). The reaction mixture was stirred at 0 C. for 30 mins and at room temperature for 15 hrs. The concentrated residue was then purified by flash column chromatography on silica gel eluting with 60%-80% ethyl acetate/hexanes to provide the desired product.

To a solution of the Example 441B ( 1 g, 3.54 mmol) in ethanol (25mL) was added 10% Pd/C (230 mg) under nitrogen. This suspension was purged with hydrogen and was stirred under hydrogen (balloon) for 1 h. The solid material was filtered off and the filtrate was concentrated. The residual foam was dissolved in anhydrous DMF (20 mL). Triethylamine (1.08 mL, 7.78 mmol) and di-tert-butyl dicarbonate (0.85 g, 3.89 mmol) were then added at room temperature and the solution stirred under nitrogen for 2 h. EtOAc (200 mL) was added and the mixture was washed with brine (200 mL), and water (100 mL). The organic phase was concentrated and the residue was purified by flash chromatography 60-80%(5 min) EtOAc in hexane to give desired product.

To a solution of the Example (0.78 g) in methanol (20 mL) was added 10% Pd C (450 mg) under nitrogen. This reaction mixture was purged with hydrogen and was stirred under hydrogen at 86 C. for 3.5 days (balloon). The filtrate was concentrated and the residual oil was separated by flash chromatography (0-15% CH 3 OH in 2:1 EtOAc/hexane) to give the desired product (199.7 mg, 33%).

To a solution of 5-bromo-pyridin-3-ol (102 mg, 0.58 mmol), Example 441D (154 mg, 0.53 mmol) and triphenylphosphine (208 mg, 0.793 mmol) in anhydrous THF (20 mL) was added DEAD (125 L, 0.79 mmol) and the reaction mixture stirred at room temperature for 2 hrs and concentrated. The residue was purified by flash column chromatography on silica gel (0-15% CH 3 OH in 2:1 EtOAc/hexane) to give the desired product (100 mg, 43%).

The product was prepared by substituting Example 447E for Example 202A in Example 203B.

A solution of DIPA (1.73 g, 17.16 mmol) in THF (100 ml) was treated dropwise with n-BuLi (6.86 ml, 17.16 mmol) at 0 C., stirred for 30 min. at 0 C. To the reaction Example 442A (3.56 g, 14.3 mmol) in THF (10 ml) was added dropwise at 78 C. The resulting solution was stirred 1 hours at 78 C. The mixture was quenched with methyl formate (2.0 ml). The reaction solution was partitioned between ethylacetate and water. The organic layer was washed (brine), dried (Na 2 SO 4 ), filtered and concentrated under vacumm. Purification on silica gel with 20% ethyl acetate/hexane to provide the title compound (2.2 g, 56%). MS (DCI/NH 3 ) m/e 278 (M 1) .

To a solution of Example 442C (1.02 g, 3.4 mmol) in dichloromethane (10 ml) THA (1 ml) was added. The resulting solution was stirred for two hours. The reaction solution was partitioned between ethylacetate and water. The organic layer was washed (brine), dried (Na 2 SO 4 ), filtered and concentrated under vacumm. Purification on silica gel with 40% ethyl acetate/hexane to provide the title compound (600 mg, 98%). MS (DCI/NH 3 ) m/e 181 (M 1) .

A solution of oxindole (665 mg, 5.0 mmol) in THF (10 ml) was treated dropwise with n-BuLi (4.4 ml, 11.0 mmol) at 78 C., stirred for 30 min. at 78 C. To the reaction methyliodine (2 ml) was added dropwise at 78 C. The resulting solution was warmed up to room temperature. The mixture was quenched with water. The reaction solution was partitioned between ethylacetate and water. The organic layer was washed (brine), dried (Na 2 SO 4 ), filtered and concentrated under vacumm. Purification on silica gel with 30% ethyl acetate/hexane to provide the title compound (630 mg, 86%). MS (DCI/NH 3 ) m/e 148 (M 1) .

To a solution of Example 444B (625 mg, 4.25 mmol) in acetonitrile (10 ml) NBS (757 mg, 4.25 mmol) was added at 10 C. The mixture was stirred at 10 C. for 1 hours and 0 C. for 2 hours. The reaction solution was partitioned between ethylacetate and water. The organic layer was washed (brine), dried (Na 2 SO 4 ), filtered and concentrated under vacumm. Purification on silica gel with 30% ethyl acetate/hexane to provide the title compound (640 mg, 66%). MS (DCI/NH 3 ) m/e 227 (M 1) .

A solution of Example 444A (500 mg, 3.4 mmol) in THF (10 ml) was treated dropwise with n-BuLi (2.7 ml, 6.8 mmol) at 78 C., stirred for 30 min. at 78 C. To the reaction methyliodine (2 ml) was added dropwise at 78 C. The resulting solution was warmed up to room temperature. The mixture was quenched with water. The reaction solution was partitioned between ethylacetate and water. The organic layer was washed (brine), dried (Na 2 SO 4 ), filtered and concentrated under vacumm. Purification on silica gel with 30% ethyl acetate/hexane to provide the title compound (410 mg, 75%). MS (DCI/NH 3 ) m/e 162 (M ) .

The title compound was prepared by substituting Example 445A for Example 102A in Example 112. MS (DCI/NH 3 ) m/e 176 (M 1) .