JP2005516927A - 3- (Phenyl-alkoxy) -5- (phenyl) -pyridine derivatives and related compounds as kinase inhibitors for cancer treatment - Google Patents

Abstract

The compounds of formula (I) are useful for inhibiting protein kinases and treating cancer. Also disclosed are compositions that inhibit protein kinases and methods of inhibiting protein kinases in a patient.
[Chemical 1]

Description

  The present invention relates to compounds useful for the inhibition of protein kinases, methods for producing said compounds, compositions containing said compounds, and therapeutic methods using said compounds.

  It has been clearly demonstrated that protein kinases are important in the progression of many disease states induced by inappropriate growth of cells. It is common to see that these kinases are upregulated in many hyperproliferative conditions such as cancer. These kinases can be important in cellular signaling, where their inappropriate activation induces cellular proliferation (eg, EGFR, ERBB2, VEGFR, FGFR, PDGFR, c-Met, IGF -1R, RET, TIE2). Alternatively, they may be involved in intracellular signal transduction (eg c-Src, PKC, Akt, PKA, C-Abl, PDK-1). In many cases, these signal transduction genes are recognized proto-oncogenes. Many of these kinases are located near the G1-S transition (eg, Cdk2, Cdk4), at the G2-M transition (eg, Wee1, Myt1, Chk1, Cdc2) or at the spindle checkpoint (Plk, Aurora1 or 2, Bub1 or 3), controlling cell cycle progression. Furthermore, kinases are intimately associated with DNA damage responses (eg, ATM, ATR, Chk1, CHk2). Dysregulation of these cellular functions (cell signaling, signal transduction, cell cycle control, and DNA repair) are all hallmarks of hyperproliferative diseases, particularly cancer. Thus, pharmacological modulation of one or more kinases is likely to be useful for slowing or stopping disease progression in these diseases.

  In an embodiment of that principle, the present invention provides a compound of formula (I):

（式中、
Ｘは、Ｃ（Ｒ^８）およびＮから成る群より選択され、この場合、Ｒ^８は、水素、アルキル、アミノ、カルボキシ、シアノ、ハロ、ヒドロキシおよびアミドから成る群より選択され；
Ｘ’は、ＣおよびＮから成る群より選択され；
Ｙは、ＣおよびＮから成る群より選択され；
Ｙ’は、Ｃ（Ｒ^９）およびＮから成る群より選択され、この場合、Ｒ^９は、水素および−Ｌ^２−Ｌ^３（Ｒ^３）（Ｒ^６）から成る群より選択され；
Ｚは、ＣおよびＮから成る群より選択されるが；
但し、Ｘ、Ｘ’、Ｙ、Ｙ’およびＺ’のうちの０、１または２個がＮであることを条件とし；
Ｌ^１は、結合、−Ｏ−、−ＮＲ^５−、アルケニル、アルキニル、−Ｃ（Ｏ）−、−Ｓ−、−Ｓ（Ｏ）−、−Ｓ（Ｏ）_２−、−Ｓ（Ｏ）_２Ｎ（Ｒ^５）−、−Ｎ（Ｒ^５）Ｓ（Ｏ）_２−、−Ｃ（Ｒ^１２）_２−、−Ｃ（Ｒ^１２）_２Ｎ（Ｒ^５）−、−Ｎ（Ｒ^５）Ｃ（Ｏ）−、および−Ｃ（Ｏ）Ｎ（Ｒ^５）−から成る群より選択され、この場合、各基は、その左端がＲ^１に結合し、その右端が芳香族環に結合しているように描かれており；
Ｌ^２は、結合、−Ｏ−、−Ｃ（Ｒ^１２）_２−、−Ｓ−、−Ｎ（Ｒ^５）−、−Ｎ（Ｒ^５）Ｃ（Ｏ）−、および−Ｃ（Ｏ）Ｎ（Ｒ^５）−から成る群より選択され；
Ｌ^３は、結合、アルキリデンおよびアルキレンから成る群より選択され、この場合、アルキリデンおよびアルキレンは、アルコキシ、アミノ、シアノおよびヒドロキシから成る群より独自に選択された１個または２個の置換基で場合によっては置換されており；
Ｒ^１は、アリール、ヘテロアリールおよび複素環から成る群より選択され；
Ｒ^２およびＲ^４は、独自に、不在であるか、水素、アルケニル、アルキル、アルキニル、アミノ、アリール、アリールアルキニル、シアノ、シアノアルケニル、ハロ、ヘテロアリール、複素環、ヒドロキシアルキルおよびニトロから成る群より選択され；または
Ｒ^２とＬ^１は、それらが結合している炭素原子と一緒に、アリール、ヘテロアリールおよび複素環から成る群より選択された環を形成しており；または
Ｒ^４とＬ^２は、それらが結合している炭素原子と一緒に、アリール、ヘテロアリールおよび複素環から成る群より選択された環を形成しているが；
但し、Ｌ^３がアルキリデンである時には、Ｒ^４とＬ^２は、それらが結合している炭素原子と一緒に、アリール、ヘテロアリールおよび複素環から成る群より選択された環を形成していることを条件とし；
Ｒ^３は、不在であるか、水素、アリール、アリールアルコキシ、アリールアルキルアミノ、アリールアルキルチオ、アリールオキシ、アリールチオ、シクロアルキル、ヘテロアリール、ヘテロアリールアルコキシ、ヘテロアリールオキシおよび複素環から成る群より選択され；
Ｒ^６は、水素、アリール、アリールアルコキシ、アリールアルキルアミノ、アリールアルキルチオ、アリールオキシ、アリールチオ、シクロアルキル、ヘテロアリール、ヘテロアリールアルコキシ、ヘテロアリールオキシおよび複素環から成る群より選択されるが；
但し、Ｌ^１およびＬ^２が結合である時には、Ｒ^３およびＲ^６のうちの少なくとも一方は、水素以外であることを条件とし；
Ｒ^５は、水素、アルキル、アルキルカルボニル、アルキルスルホニル、アリールカルボニル、アリールスルホニルおよびヘテロアリールスルホニルから成る群より選択され；
Ｒ^７は、不在であるか、水素、アルキル、シアノアルケニルおよび−Ｌ^２−Ｌ^３（Ｒ^３）（Ｒ^６）から成る群より選択され；または
Ｒ^７とＬ^１は、それらが結合している炭素原子と一緒に、アリール、ヘテロアリールおよび複素環から成る群より選択された環を形成しており；ならびに
各Ｒ^１２は、水素、アルケニル、アルキル、アルキニル、アミノ、アリール、シアノ、ハロ、ヘテロアリール、複素環およびニトロから成る群より選択される）
の化合物またはその治療上許容される塩を提供する。

(Where
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 amide;
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, where 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 ¹ is a bond, —O—, —NR ⁵ —, alkenyl, alkynyl, —C (O) —, —S—, —S (O) —, —S (O) ₂ —, —S (O). _{^{2 N (R 5) -,}} - N (R 5) S (O) 2 -, - C (R 12) 2 -, - C (R 12) 2 N (R 5) -, - N (R 5) Selected from the group consisting of C (O)-, and -C (O) N (R ⁵ )-, wherein each group has its left end bound to R ¹ and its right end bound to an aromatic ring. Is drawn as;
L ² represents a bond, —O—, —C (R ¹² ) ₂ —, —S—, —N (R ⁵ ) —, —N (R ⁵ ) C (O) —, and —C (O) N. Selected from the group consisting of (R ⁵ ) —;
L ³ is selected from the group consisting of a bond, alkylidene and alkylene, in which case the alkylidene and alkylene are one or two substituents independently selected from the group consisting of alkoxy, amino, cyano and hydroxy Has been replaced by;
R ¹ is selected from the group consisting of aryl, heteroaryl and heterocycle;
R ² and R ⁴ are independently absent or comprise the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, arylalkynyl, cyano, cyanoalkenyl, halo, heteroaryl, heterocycle, hydroxyalkyl and nitro Or R ² and L ¹ together with the carbon atom to which they are attached form a ring selected from the group consisting of aryl, heteroaryl and heterocycle; or R ⁴ and L 1 ² together with the carbon atom 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 atom to which they are attached form a ring selected from the group consisting of aryl, heteroaryl and heterocycle Subject to
R ³ is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle ;
R ⁶ is selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle;
Provided that when L ¹ and L ² are a bond, at least one of R ³ and R ⁶ is other than hydrogen;
R ⁵ is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl and heteroarylsulfonyl;
R ⁷ is absent or selected from the group consisting of hydrogen, alkyl, cyanoalkenyl and -L ² -L ³ (R ³ ) (R ⁶ ); or R ⁷ and L ¹ are Together with the carbon atoms forming a ring selected from the group consisting of aryl, heteroaryl and heterocycle; and each R ¹² is hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, Selected from the group consisting of heteroaryl, heterocycle and nitro)
Or a therapeutically acceptable salt thereof.

  In another embodiment, the present invention provides compounds of formula (II):

（式中、
Ｌ^１は、結合、−Ｏ−、−Ｎ（Ｒ）^５−、アルケニル、アルキニル、−Ｎ（Ｒ^５）Ｃ（Ｏ）−、および−Ｃ（Ｏ）Ｎ（Ｒ^５）−から成る群より選択され；
Ｌ^２は、結合、−Ｏ−、−Ｎ（Ｒ）^５−、−Ｎ（Ｒ^５）Ｃ（Ｏ）−、および−Ｃ（Ｏ）Ｎ（Ｒ^５）−から成る群より選択され；
Ｌ^３は、結合、アルキリデンおよびアルキレンから成る群より選択され、この場合、アルキリデンおよびアルキレンは、アミノ、シアノおよびヒドロキシから成る群より独自に選択された１個または２個の置換基で場合によっては置換されており；
Ｒ^１は、アリール、ヘテロアリールおよび複素環から成る群より選択され；
Ｒ^２およびＲ^４は、水素、アルケニル、アルキニル、アリールアルキニル、アミノ、シアノ、シアノアルケニル、ハロ、ヒドロキシアルキルおよびヘテロアリールから成る群より独自に選択され、この場合、ヘテロアリールは、フリル、ピラジニル、チアゾリルおよびチエニルから成る群より選択され選択され；または
Ｒ^２とＬ^１は、それらが結合している炭素原子と一緒に、ジヒドロピロリル、ピラゾールおよびフェニルから成る群より選択された環を形成しており；または
Ｒ^４とＬ^２は、それらが結合している炭素原子と一緒に、ジヒドロピロリル、フェニル、ピリジニルおよびピロリルから成る群より選択された環を形成しており、この場合、前記環は、オキソで場合によっては置換されているが；
但し、Ｌ^３がアルキリデンである時には、Ｒ^４とＬ^２は、それらが結合している炭素原子と一緒に、ジヒドロピロリル、フェニル、ピリジニルおよびピロリルから成る群より選択された環（この場合の環は、オキソで場合によっては置換されていることもある）を形成していることを条件とし、；
Ｒ^３は、不在であるか、水素、アリール、アリールアルコキシ、アリールアルキルチオ、アリールオキシ、アリールチオ、シクロアルキル、ヘテロアリール、ヘテロアリールアルコキシ、ヘテロアリールオキシおよび複素環から成る群より選択され；
Ｒ^６は、水素、アリール、アリールアルコキシ、アリールアルキルチオ、アリールオキシ、アリールチオ、シクロアルキル、ヘテロアリール、およびヘテロアリールアルコキシ、ヘテロアリールオキシおよび複素環から成る群より選択されるが；
但し、Ｌ^１およびＬ^２が結合である時には、Ｒ^３およびＲ^６のうちの少なくとも一方は、水素以外であることを条件とし；
Ｒ^５は、水素、アルキル、アルキルカルボニル、アルキルスルホニル、アリールカルボニル、アリールスルホニルおよびヘテロアリールスルホニルから成る群より選択され；ならびに
Ｘは、Ｃ（Ｒ^８）およびＮから成る群より選択され、この場合、Ｒ^８は、水素、アミノ、カルボキシ、シアノおよびハロから成る群より選択される）
の化合物またはその治療上許容される塩を提供する。

(Where
L ¹ is from the group consisting of a bond, —O—, —N (R) ⁵ —, alkenyl, alkynyl, —N (R ⁵ ) C (O) —, and —C (O) N (R ⁵ ) —. Selected;
L ² is selected from the group consisting of a bond, —O—, —N (R) ⁵ —, —N (R ⁵ ) C (O) —, and —C (O) N (R ⁵ ) —;
L ³ is selected from the group consisting of a bond, alkylidene and alkylene, where alkylidene and alkylene are optionally one or two substituents independently selected from the group consisting of amino, cyano and hydroxy Has been replaced;
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, where heteroaryl is furyl, pyrazinyl, Or selected from the group consisting of thiazolyl and thienyl; or R ² and L ¹ together with the carbon atom to which they are attached form a ring selected from the group consisting of dihydropyrrolyl, pyrazole and phenyl. Or R ⁴ and L ² together with the carbon atom to which they are attached form a ring selected from the group consisting of dihydropyrrolyl, phenyl, pyridinyl and pyrrolyl, The ring is optionally substituted with oxo;
Provided that when L ³ is alkylidene, R ⁴ and L ² together with the carbon atom to which they are attached are rings selected from the group consisting of dihydropyrrolyl, phenyl, pyridinyl and pyrrolyl (in this case The ring is formed to be optionally substituted with oxo);
R ³ is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle;
R ⁶ is selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, and heteroarylalkoxy, heteroaryloxy and heterocycle;
Provided that when L ¹ and L ² are a bond, 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, where , R ⁸ is selected from the group consisting of hydrogen, amino, carboxy, cyano and halo)
Or a therapeutically acceptable salt thereof.

  In another embodiment, the present invention provides compounds of formula (III)

（式中、
Ｌ^１は、結合、−Ｏ−、−Ｎ（Ｒ）^５−、アルケニル、アルキニルおよび−Ｎ（Ｒ^５）Ｃ（Ｏ）−から成る群より選択され；
Ｌ^２は、結合、−Ｏ−、−Ｎ（Ｒ）^５−、−Ｎ（Ｒ^５）Ｃ（Ｏ）−、および−Ｃ（Ｏ）Ｎ（Ｒ^５）−から成る群より選択され；
Ｌ^３は、アルキレンであり、この場合、アルキレンは、アミノおよびヒドロキシから成る群より独自に選択された１個または２個の置換基で場合によっては置換されており；
Ｒ^１は、アリール、ヘテロアリールおよび複素環から成る群より選択され；
Ｒ^２およびＲ^４は、水素およびハロから成る群より独自に選択され；
Ｒ^３およびＲ^６は、水素、アリール、アリールアルコキシおよびヘテロアリールから成る群より独自に選択されるが；
但し、Ｌ^１およびＬ^２が結合である時には、Ｒ^３およびＲ^６のうちの少なくとも一方は、水素以外であることを条件とし；ならびに
Ｒ^５は、水素およびアルキルから成る群より選択される）
の化合物またはその治療上許容される塩を提供する。

(Where
L ¹ is selected from the group consisting of a bond, —O—, —N (R) ⁵ —, alkenyl, alkynyl and —N (R ⁵ ) C (O) —;
L ² is selected from the group consisting of a bond, —O—, —N (R) ⁵ —, —N (R ⁵ ) C (O) —, and —C (O) N (R ⁵ ) —;
L ³ is alkylene, in which case the alkylene is optionally 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 a bond, 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)
Or a therapeutically acceptable salt thereof.

In another embodiment, the invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is alkenyl; ^{L 2} is a ^{bond, -O -, - C (R} 12) 2 -, - S ^{-, - N (R 5)} -, - N (R 5) C (O) -, and ^{-C (O) N (R 5} ) - is selected from the group consisting of; or ^{L 3} is a bond, Selected from the group consisting of alkylidene and alkylene, where alkylidene and alkylene are alkoxy, Mino, optionally with one or two substituents independently selected from the group consisting of cyano and hydroxy is substituted; R ¹ is aryl, is selected from the group consisting of heteroaryl and heterocycle; R ² and R ⁴ are independently absent or from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, arylalkynyl, cyano, cyanoalkenyl, halo, heteroaryl, heterocycle, hydroxyalkyl and nitro it is selected; is R ^3, or is absent, hydrogen, aryl, arylalkoxy, arylalkyl amino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle more selected; ^{R 6} is Hydrogen, aryl, arylalkoxy, arylalkyl amino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, is selected from the group consisting heteroaryloxy and heterocyclic; R ⁵ is hydrogen, alkyl, Selected from the group consisting of 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 Provided is a compound of formula (I) selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle and nitro.

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is alkenyl; ^{L 2} is a -O-; ^{L 3} is alkylene, in this case, 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; ² and R ⁴ are hydrogen, a Independently selected from the group consisting of lukenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, wherein heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl and thienyl R ³ is hydrogen; R ⁶ consists of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle; it is selected from the group; and; R ⁷ is either absent hydrogen, is selected from the group consisting of alkyl and cyanoalkenyl, provides compounds of formula (I).

In another embodiment, the invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is alkenyl; ^{L 2} is a -O-; ^{L 1} is alkenyl; ^{L 2} is, -O-; L ³ is alkylene, in which case the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy; R ¹ There, heteroaryl; ^{R 2} and ^{R 4} Independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, where heteroaryl is from the group consisting of furyl, pyrazinyl, thiazolyl and thienyl R ³ is hydrogen; R ⁶ is hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle And R ⁷ is absent or is selected from the group consisting of hydrogen, alkyl and cyanoalkenyl.

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is alkenyl; ^{L 2} is a -O-; ^{L 3} is alkylene Yes, in which case 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 Is independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, where heteroaryl is furyl, pyrazinyl, thiazolyl and It is selected from the group consisting of and thienyl; R ³ is hydrogen; R ⁶ is heteroaryl; and R ⁷ is hydrogen, to provide a compound of formula (I).

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is alkenyl; ^{L 2} is a -O-; ^{L 3} is alkylene Yes, in which case 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 Is independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, where heteroaryl is furyl, pyrazinyl, thiazolyl and It is selected from the group consisting of and thienyl; R ³ is hydrogen; R ⁶ is aryl; and R ⁷ is hydrogen, to provide a compound of formula (I).

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is alkenyl; ^{L 2} is a -O-; ^{L 3} is a bond; ^{R 1} is R ² and R ⁴ are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, where heteroaryl Is Selected from the group consisting of furyl, pyrazinyl, thiazolyl and thienyl; R ³ is absent; R ⁶ is a heterocycle; and R ⁷ is absent or consists of hydrogen, alkyl and cyanoalkenyl There is provided a compound of formula (I), wherein:

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is alkenyl; ^{L 2} is a -O-; ^{L 3} is a bond R ¹ is heteroaryl; R ² and R ⁴ are hydrogen; R ³ is absent; R ⁶ is a heterocycle; and R ⁷ is hydrogen. A compound of I) is provided.

In another embodiment, the invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is alkenyl; ^{L 2 is, -N (R 5) C (} O) - and is, is ^{L 3} Alkylene, in which case the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy; R ¹ is aryl, heterocycle and heteroaryl is selected from the group consisting of; R ² Oyo R ⁴ is hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, independently selected from the group consisting of hydroxyalkyl and heteroaryl, where the heteroaryl is furyl, pyrazinyl, thiazolyl and thienyl R ³ is hydrogen; R ⁶ is hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryl Provided is a compound of formula (I) selected from the group consisting of oxy and heterocycle; and R ⁷ absent or selected from the group consisting of hydrogen, alkyl and cyanoalkenyl.

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is alkenyl; ^{L 2 is, -N (R 5) C (} O) - in Yes; L ³ is alkylene, where 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, where heteroaryl is furyl , Pilaj Le, is selected from the group consisting of thiazolyl and thienyl; R ³ is hydrogen; R ⁶ is heteroaryl; and R ⁷ is hydrogen, to provide a compound of formula (I).

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is alkenyl; ^{L 2 is, -N (R 5) C (} O) - in Yes; L ³ is alkylene, where 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, where heteroaryl is furyl , Pilaj Le, is selected from the group consisting of thiazolyl and thienyl; R ³ is hydrogen; R ⁶ is aryl; and R ⁷ is hydrogen, to provide a compound of formula (I).

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is alkynyl; ^{L 2} is a ^{bond, -O -, - C (R} 12) 2 -, - S ^{-, - N (R 5)} -, - N (R 5) C (O) -, and ^{-C (O) N (R 5} ) - is selected from the group consisting of; or ^{L 3} is a bond, Selected from the group consisting of alkylidene and alkylene, where alkylidene and alkylene are alkoxy, Mino, optionally with one or two substituents independently selected from the group consisting of cyano and hydroxy is substituted; R ¹ is aryl, is selected from the group consisting of heteroaryl and heterocycle; R ² and R ⁴ are hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, arylalkynyl, cyano, cyanoalkenyl, halo, heteroaryl, heterocyclic, independently selected from the group consisting of 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 But hydrogen, aryl Arylalkoxy, arylalkyl amino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, is selected from the group consisting heteroaryloxy and heterocyclic; R ⁵ is hydrogen, alkyl, alkylcarbonyl, alkyl Selected from the group consisting of sulfonyl, arylcarbonyl, arylsulfonyl and heteroarylsulfonyl; R ⁷ is absent or selected from the group consisting of hydrogen, alkyl and cyanoalkenyl; and each R ¹² is hydrogen, alkenyl, Provided is a compound of formula (I) selected from the group consisting of alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle and nitro.

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is alkynyl; ^{L 2} is a -O-; ^{L 3} is alkylene, in this case, 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 hydrogen, a Independently selected from the group consisting of lukenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, wherein heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl and thienyl R ³ is hydrogen; R ⁶ consists of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle; Provided are compounds of formula (I), selected from the group; and R ⁷ absent or selected from the group consisting of hydrogen, alkyl and cyanoalkenyl.

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is a bond; ^{L 2} is a ^{bond, -O -, - C (R} 12) 2 -, - S ^{-, - N (R 5)} -, - N (R 5) C (O) -, and ^{-C (O) N (R 5} ) - is selected from the group consisting of; or ^{L 3} is a bond, Selected from the group consisting of alkylidene and alkylene, where alkylidene and alkylene are alkoxy, amino Are optionally substituted with one or two substituents independently selected from the group consisting of cyano and hydroxy; R ¹ is aryl, it is selected from the group consisting of heteroaryl and heterocycle; R ² and R ⁴ is 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 Hydrogen, aryl, ant Ruarukokishi, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, is selected from the group consisting heteroaryloxy and heterocyclic; R ⁵ is hydrogen, alkyl, alkylcarbonyl, alkyl Selected from the group consisting of sulfonyl, arylcarbonyl, arylsulfonyl and heteroarylsulfonyl; R ⁷ is absent or selected from the group consisting of hydrogen, alkyl and cyanoalkenyl; and each R ¹² is hydrogen, alkenyl, Provided is a compound of formula (I) selected from the group consisting of alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle and nitro.

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is a bond; ^{L 2} is a -O-; ^{L 3} is alkylene, in this case, 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 hydrogen, alkeni Independently selected from the group consisting of ru, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, wherein heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl and thienyl R ³ is hydrogen; R ⁶ consists of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle; Provided are compounds of formula (I), selected from the group; and R ⁷ absent or selected from the group consisting of hydrogen, alkyl and cyanoalkenyl.

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is a bond; ^{L 2} is a -O-; ^{L 3} is alkylene Yes, in which case 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 Is independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, where heteroaryl is furyl, pyrazinyl, thiazolyl and thiol. Provided are compounds of formula (I), selected from the group consisting of enyl; R ³ is hydrogen; R ⁶ is aryl; and R ⁷ is hydrogen.

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is a bond; ^{L 2} is a -O-; ^{L 3} is alkylene Yes, in which case 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 Is independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, where heteroaryl is furyl, pyrazinyl, thiazolyl and thiol. Provided are compounds of formula (I), selected from the group consisting of enyl; R ³ is hydrogen; R ⁶ is heteroaryl; and R ⁷ is hydrogen.

In another embodiment, the invention the X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen; X ′ is N; Y is Y is C (R ⁹ ), in which case R ⁹ is —L ² -L ³ (R ³ ) (R ⁶ ); Z is C; L ¹ is L ² is —O—; L ³ is alkylene, in which case the alkylene is a substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy R ¹ is heteroaryl; R ² and R ⁴ are from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl Selected independently 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 invention provides that X is N; X ′ is C; Y is N; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is a bond; ^{L 2} is a -O-; ^{L 3} is alkylene Yes, in which case 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, where heteroaryl is furyl, pyrazinyl, thiazolyl and Yo It is selected from the group consisting of finely thienyl; R ³ is hydrogen; R ⁶ is aryl; and R ⁷ is hydrogen, to provide a compound of formula (I).

In another embodiment, the invention provides that X is N; X ′ is C; Y is N; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is a bond; ^{L 2} is a -O-; ^{L 3} is alkylene Yes, in which case 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, where heteroaryl is furyl, pyrazinyl, thiazolyl and Yo It is selected from the group consisting of finely thienyl; R ³ is hydrogen; R ⁶ is heteroaryl; and R ⁷ is hydrogen, to provide a compound of formula (I).

In another embodiment, the invention provides that 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; ² is —O—; L ³ is alkylene, in which case 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 In this case, heteroary Wherein R ³ 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 to provide a compound of formula (I) To do.

In another embodiment, the invention provides that 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; ² is —O—; L ³ is alkylene, in which case 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 In this case, heteroary R is selected from the group consisting of furyl, pyrazinyl, thiazolyl and thienyl; a compound of formula (I) wherein R ³ is hydrogen; R ⁶ is heteroaryl; and R ⁷ is hydrogen provide.

In another embodiment, the invention provides that 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; ² is —O—; L ³ is alkylene, in which case 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 In this case, heteroary Wherein R ³ 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 to provide a compound of formula (I) To do.

In another embodiment, the invention provides that 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; ² is —O—; L ³ is alkylene, in which case 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 In this case, heteroary R is selected from the group consisting of furyl, pyrazinyl, thiazolyl and thienyl; a compound of formula (I) wherein R ³ is hydrogen; R ⁶ is heteroaryl; and R ⁷ is hydrogen provide.

In another embodiment, the invention provides that 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 Yes, in which case 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, where heteroaryl is furyl, pyrazinyl, thiazolyl and Yo It is selected from the group consisting of finely thienyl; R ³ is hydrogen; R ⁶ is aryl; and R ⁷ is hydrogen, to provide a compound of formula (I).

In another embodiment, the invention provides that 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 Yes, in which case 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, where heteroaryl is furyl, pyrazinyl, thiazolyl and Yo It is selected from the group consisting of finely thienyl; R ³ is hydrogen; R ⁶ is heteroaryl; and R ⁷ is hydrogen, to provide a compound of formula (I).

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is a bond; ^{L 2} is, -N ^{(R 5)} - a and; ^{L 3} is an alkylene In this case, the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy; R ¹ is from the group consisting of aryl, heterocycle and heteroaryl It is selected; ^{R 2} and ^{R 4} are hydrogen Independently selected from the group consisting of alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, wherein 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 hydrogen, aryl, arylalkoxy, Selected from the group consisting of arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle; The R ⁷ are either absent hydrogen, is selected from the group consisting of alkyl and cyanoalkenyl, provides compounds of formula (I).

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is a bond; ^{L 2} is, -N ^{(R 5)} - a and; ^{L 3} Is alkylene, in which case the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy; R ¹ is heteroaryl; ² and R ⁴ are hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, independently selected from the group consisting of hydroxyalkyl and heteroaryl, where the heteroaryl is furyl, pyrazinyl, thiazol And it is selected from the group consisting of thienyl; R ³ is hydrogen; R ⁵ is hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, is selected from the group consisting of arylsulfonyl and heteroarylsulfonyl; R ⁶ is And heteroaryl; and R ⁷ is hydrogen, provides a compound of formula (I).

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is a bond; ^{L 2} is, -N ^{(R 5)} - a and; ^{L 3} Is alkylene, in which case the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy; R ¹ is heteroaryl; ² and R ⁴ are hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, independently selected from the group consisting of hydroxyalkyl and heteroaryl, where the heteroaryl is furyl, pyrazinyl, thiazol And it is selected from the group consisting of thienyl; R ³ is hydrogen; R ⁵ is hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, is selected from the group consisting of arylsulfonyl and heteroarylsulfonyl; R ⁶ is Provides a compound of formula (I) wherein R ⁷ is hydrogen.

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is a bond; ^{L 2 is, -N (R 5) C (} O) - and is, is ^{L 3} Alkylene, in which case the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy; R ¹ is aryl, heterocycle and heteroaryl It is selected from the group consisting of; ^{R 2} and ^{R 4} , Hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, wherein heteroaryl is the group consisting of furyl, pyrazinyl, thiazolyl and thienyl R ³ is hydrogen; R ⁶ is hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and hetero Provided are compounds of formula (I) selected from the group consisting of rings; and R ⁷ is absent or selected from the group consisting of hydrogen, alkyl and cyanoalkenyl.

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is a bond; ^{L 2 is, -N (R 5) C (} O) - in Yes; L ³ is alkylene, where 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, where heteroaryl is furyl , Pyrazinyl, It is selected from the group consisting of azolyl and thienyl; R ³ is hydrogen; R ⁶ is heteroaryl; and R ⁷ is hydrogen, to provide a compound of formula (I).

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is a bond; ^{L 2 is, -N (R 5) C (} O) - in Yes; L ³ is alkylene, where 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, where heteroaryl is furyl , Pyrazinyl, It is selected from the group consisting of azolyl and thienyl; R ³ is hydrogen; R ⁶ is aryl; and R ⁷ is hydrogen, to provide a compound of formula (I).

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is, -N ^{(R 5)} - a and; ^{L 2} is a ^{bond, -O -, - C (R} 12 ^{_{) 2 -, - S -,}} - N (R 5) -, - N (R 5) C (O) -, and ^{-C (O) N (R 5} ) - is selected from the group consisting of; ^{L 3} is Are selected from the group consisting of alkylidene and alkylene, wherein alkylidene and alkylene are Optionally substituted with one or two substituents independently selected from the group consisting of cis, 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; 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, a Lumpur, arylalkoxy, arylalkyl amino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, it is selected from the group consisting heteroaryloxy and heterocyclic; R ⁵ is hydrogen, alkyl, alkyl Selected from the group consisting of carbonyl, 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 hydrogen Provided is a compound of formula (I) selected from the group consisting of alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle and nitro.

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is, -N ^{(R 5)} - a and; ^{L 2} is a -O-; ^{L 3} is alkylene In which case the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy; R ¹ consists of aryl, heterocycle and heteroaryl It is selected from the group; ^{R 2} and ^{R 4,} water , Alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, wherein 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 hydrogen, aryl, arylalkoxy Selected from the group consisting of: arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle; R ⁷ to beauty, or is absent, hydrogen, is selected from the group consisting of alkyl and cyanoalkenyl, provides compounds of formula (I).

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is, -N ^{(R 5)} - a and; ^{L 2} is a -O-; L ³ is alkylene, in which case the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy; R ¹ is aryl, 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, If hetero Reel, furyl, pyrazinyl, thiazolyl and is selected from the group consisting of thienyl; is R ^3, is hydrogen; R ⁵ is comprised of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, aryl sulfonyl and heteroarylsulfonyl Provided are compounds of formula (I), selected from the group; R ⁶ is heteroaryl; and R ⁷ is hydrogen.

In another embodiment, the invention provides that X is N; X ′ is C; Y is C; Y ′ is C (R ⁹ ), wherein R ^{9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is, -N ^{(R 5)} - a and; ^{L 2} is a -O-; L ³ is alkylene, in which case the alkylene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy; R ¹ is aryl, 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, If hetero Reel, furyl, pyrazinyl, thiazolyl and is selected from the group consisting of thienyl; is R ^3, is hydrogen; R ⁵ is comprised of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, aryl sulfonyl and heteroarylsulfonyl Provided are compounds of formula (I), selected from the group; R ⁶ is aryl; and R ⁷ is hydrogen.

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where 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 Is independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl and heteroaryl, where heteroaryl is furyl, pyrazinyl, thiazolyl and thiol. Is selected from the group consisting of nil; R ³ is located at absent; R ⁶ is a heterocyclic; and R ⁷ is either absent hydrogen, is selected from the group consisting of alkyl and cyanoalkenyl, wherein A compound of (I) is provided.

In another embodiment, the invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{L 1} is 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 ) —. In this case, each group is depicted as having its left end attached to R ¹ and its right end attached to an aromatic ring; L ³ is alkylidene, where 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 atom to which they are attached form a ring selected from the group consisting of aryl, heteroaryl and heterocycle; R ³ is absent, Hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy Shi, is selected from the group consisting heteroaryloxy and heterocyclic; R ⁶ is hydrogen, aryl, arylalkoxy, arylalkyl amino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryl Is selected from the group consisting of oxy and heterocycle; R ⁵ is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl and heteroarylsulfonyl; R ⁷ is absent, hydrogen, is selected from the group consisting of alkyl and cyanoalkenyl; and each R ¹² is hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocyclic, and nitro That is selected from the group provides a compound of formula (I).

In another embodiment, the invention relates to X being selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen; X ′ is C; Y is be C; Y 'is a C ^{(R 9),} in this case, ^{R 9 is} an ^{-L 2 -L 3 (R 3)} (R 6); Z is located at C; ^{L 1} is L ³ is alkylidene, wherein alkylidene is optionally substituted with one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy; R ¹ is , Heteroaryl, in this case is heteroquinolinyl; R ⁴ and L ² together with the carbon atom to which they are attached form a heterocycle, in which case the heterocycle is Pyrrolidinyl substituted with oxo; R ³ is water R ⁶ is heteroaryl, where heteroaryl is indolyl; and R ⁷ is hydrogen, providing compounds of formula (I).

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide And X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ^2- L ³ (R ³ ) (R ⁶ ); Z is C; R ² and L ¹ together with the carbon atom to which they are attached form a ring that is aryl The aryl ring in this case is phenyl; L ² is —O—; L ³ is alkylene, in which the alkylene is selected from the group consisting of alkoxy, amino, cyano and hydroxy Optionally substituted with one substituent It is; R ¹ is heteroaryl; R ³ is located at absent; R ⁶ is heteroaryl; and R ⁷ is either absent hydrogen, from the group consisting of alkyl and cyanoalkenyl A selected compound of formula (I) is provided.

In another embodiment, the invention provides that 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 atom to which they are attached, a ring that is aryl. And the aryl ring in this case is phenyl; L ² is —O—; L ³ is alkylene, where alkylene is a group consisting of alkoxy, amino, cyano and hydroxy Optionally substituted with one more selected substituent; R ¹ is heteroaryl; R ³ is absent; R ⁶ is heteroaryl; and R ⁷ is hydrogen A compound of formula (I) is provided.

In another embodiment, the invention provides that 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 atom to which they are attached, a ring that is aryl. And the aryl ring in this case is phenyl; L ² is —O—; L ³ is alkylene, where alkylene is a group consisting of alkoxy, amino, cyano and hydroxy Optionally substituted with one more selected substituent; R ¹ is heteroaryl; R ³ is absent; R ⁶ is aryl; and R ⁷ is hydrogen There is provided a compound of formula (I).

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X ′ is selected from the group consisting of C and N; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L be ^{3 (R 3) (R 6} ); Z is located at C; ^{R 2} and ^{L 1} is, together with the carbon atom to which they are attached to form a ring is heteroaryl In which case heteroaryl is pyrazolyl; L ² is a bond; L ³ is alkylene, in which case alkylene is one selected from the group consisting of alkoxy, amino, cyano and hydroxy In some cases It is; R ¹ is aryl, selected from the group consisting of heterocycle and heteroaryl; R ³ is hydrogen; R ⁶ is aryl, selected from the group consisting of heterocycle and heteroaryl; and R Provide a compound of formula (I), wherein ⁷ is absent or selected from the group consisting of hydrogen, alkyl and cyanoalkenyl.

In another embodiment, the invention provides that X is C (R ⁸ ), wherein R ⁸ is hydrogen; X ′ is N; Y is C; Y ′ Is C (R ⁹ ), where R ⁹ is -L ² -L ³ (R ³ ) (R ⁶ ); Z is C; R ² and L ¹ are Together with the carbon atoms to which it is attached forms a ring that is heteroaryl, where heteroaryl is pyrazolyl; L ² is a bond; L ³ is alkylene, in this case , 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; ^6, aryl; and ^{R 7} is absent, compound of formula (I) To provide.

In another embodiment, the invention provides that X is C (R ⁸ ), wherein R ⁸ is hydrogen; X ′ is N; Y is C; Y ′ Is C (R ⁹ ), where R ⁹ is -L ² -L ³ (R ³ ) (R ⁶ ); Z is C; R ² and L ¹ are Together with the carbon atoms to which it is attached forms a ring that is heteroaryl, where heteroaryl is pyrazolyl; L ² is a bond; L ³ is alkylene, in this case , 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 Hisage and R ⁷ is absent, the compound of formula (I); but, aryl To.

In another embodiment, the present invention, X is selected from the group consisting of C (R ⁸ ) and N, wherein R ⁸ is hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy and amide X is C; Y is C; Y ′ is C (R ⁹ ), where R ⁹ is —L ² -L ³ (R ³ ). (R ⁶ ); Z is C; R ⁷ and L ¹ together with the carbon atom to which they are attached form a ring selected from the group consisting of aryl, heteroaryl and heterocycle L ² is —O—; L ³ is alkylene, in which case the alkylene is optionally one substituent selected from the group consisting of alkoxy, amino, cyano and hydroxy It is substituted; R ¹ is, Ally Is selected from the group consisting of heterocycle and heteroaryl; R ³ is hydrogen; and R ⁶ is aryl, selected from the group consisting of heterocycle and heteroaryl, provides compounds of formula (I) .

In another embodiment, the invention provides that 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 are heteroaryl together with the carbon atom to which they are attached. Forming a ring, where heteroaryl is pyridinyl; L ² is —O—; L ³ is alkylene, in which alkylene is from alkoxy, amino, cyano and hydroxy R ¹ is heteroaryl; R ³ is hydrogen; and R ⁶ is heteroaryl, optionally substituted with one substituent selected from the group consisting of ).

In another embodiment, the invention relates to X being 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 are heteroaryl together with the carbon atom to which they are attached. Forming a ring, wherein heteroaryl is pyridinyl; L ² is —O—; L ³ is alkylene, in which alkylene is from alkoxy, amino, cyano and hydroxy Formula (I), optionally substituted with one substituent selected from the group consisting of; R ¹ is heteroaryl; R ³ is hydrogen; and R ⁶ is aryl. Of the compound.

  In another embodiment, the present 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 present invention relates to a patient in need of such treatment comprising administering to a patient a therapeutically acceptable amount of a compound of formula (I) or a therapeutically acceptable salt thereof. Methods of inhibiting protein kinases are provided.

(Detailed description of the invention)
As used herein, the following terms have the following meanings:
As used herein, the term “alkenyl” refers to a group derived from a straight or branched chain hydrocarbon of up to 6 atoms containing at least one double bond.

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

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

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

  As used herein, the term “alkyl” refers to a group derived from a straight or branched chain saturated hydrocarbon having 1 to 6 atoms.

As used herein, the term “alkylene” refers to a divalent group derived from a straight or branched chain saturated hydrocarbon having 1 to 6 atoms.
As used herein, the term “alkylcarbonyl” refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.

  As used herein, the term “alkylidene” refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond is a member of the moiety to which the alkenyl group is attached.

  As used herein, the term “alkylsulfonyl” refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.

  As used herein, the term “alkynyl” is a group derived from a straight or branched chain hydrocarbon of 2 to 6 carbon atoms containing at least one triple bond.

  As used herein, the term “amido” refers to an amino group that is attached to the parent molecular moiety through a carbonyl group.

As used herein, the term “amino” refers to —NR ^a R ^b , where R ^a and R ^b are hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, Composed of aryl, arylalkenyl, arylalkyl, cycloalkyl, haloalkylcarbonyl, (NR ^c R ^d ) alkylcarbonyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, (heterocycle) alkenyl and (heterocycle) alkyl Independently selected from the group wherein the aryl, the aryl moiety of the arylalkenyl, the arylalkyl, the heteroaryl, the heteroarylalkenyl and the heteroaryl moiety of the heteroarylalkyl, And the heterocyclic moiety of said (heterocyclic) alkenyl and said (heterocyclic) alkyl is a group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro and oxo It may be optionally substituted with 1, 2, 3, 4 or 5 more independently selected substituents.

  As used herein, the term “aminoalkyl” refers to an amino group that is attached to the parent molecular moiety through an alkyl group.

As used herein, the term “aryl” refers to a phenyl group or a bicyclic or tricyclic fused ring structure, wherein one or more of the fused rings is a phenyl group. An example of a bicyclic fused ring structure is a phenyl group fused to a cycloalkyl group or another phenyl group as defined herein. An example of a tricyclic fused ring structure is a bicyclic fused ring structure fused to a cycloalkyl group or other phenyl group as defined herein. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl group of the present invention includes alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylthio, amino, aminoalkyl, secondary 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 , optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of A group, said arylalkoxy The aryl portion of the arylalkyl and the arylcarbonyl, the heteroaryl of the heteroaryl, the heteroarylalkoxy and the heteroarylalkyl, the heterocycle, the (heterocycle) alkoxy and the heterocycle of the (heterocycle) alkyl The moiety is optionally further substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl and nitro. It is sometimes done.

As used herein, the term “arylalkenyl” refers to an aryl group that is attached to the parent molecular moiety through an alkenyl group.
As used herein, the term “arylalkoxy” refers to an aryl group that is attached to the parent molecular moiety through an alkoxy group.

  As used herein, the term “arylalkyl” refers to an aryl group that is attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “arylalkylamino” refers to an arylalkyl group attached to the parent molecular moiety through a nitrogen atom, wherein the nitrogen atom is replaced with hydrogen.

  As used herein, the term “arylalkylidene” refers to an aryl group that is attached to the parent molecular moiety through an alkylidene group.

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

  As used herein, the term “arylalkynyl” refers to an aryl group that is attached to the parent molecular moiety through an alkynyl group.

  As used herein, the term “arylcarbonyl” refers to an aryl group that is attached to the parent molecular moiety through a carbonyl group.

  As used herein, the term “aryloxy” refers to an aryl group that is attached to the parent molecular moiety through an oxygen atom.

  As used herein, the term “arylsulfonyl” refers to an aryl group that is attached to the parent molecular moiety through a sulfonyl group.

  As used herein, the term “arylthio” refers to an aryl group that is attached to the parent molecular moiety through a sulfur atom.

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

  As used herein, the term “carboxy” refers to —C (O) OH.

  As used herein, the term “cyano” refers to —CN.

  As used herein, the term “cyanoalkenyl” refers to a cyano group attached to the parent molecular moiety through an alkenyl group.

  As used herein, the term “cyanoalkyl” refers to a saturated monocyclic, bicyclic or tricyclic hydrocarbon ring structure of 3 to 12 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, bicyclo [3.1.1] heptyl, adamantyl and the like.

  As used herein, the term “(cycloalkyl) alkylidene” refers to a cycloalkyl group attached to the parent molecular moiety by an alkylidene group.

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

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

  As used herein, the term “haloalkyl” refers to an alkyl group substituted by 1, 2, 3 or 4 halogen atoms.

  As used herein, the term “haloalkylcarbonyl” refers to a haloalkyl group attached to the parent molecular moiety through a carbonyl group.

  As used herein, the term “heteroaryl” refers to an aromatic 5 or 6 membered ring in which at least one atom is selected from the group consisting of N, O and S, and the remaining atoms are carbon. Point to. The 5-membered ring has two double bonds, and the 6-membered ring has three double bonds. A heteroaryl group is attached to the parent molecular group through a substitutable carbon or nitrogen atom in the ring. The term “heteroaryl” refers to a ring in which a heteroaryl ring is fused to an aryl group as defined herein, a heterocycle as defined herein, or a further heteroaryl group. Also includes structure. Examples of heteroaryl are benzothienyl, benzooxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinolinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxadiazolyl, oxazolyl, purinyl, Thiazolyl, thienopyridinyl, thianyl, 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 are alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkynyl, alkylcarbonyl, amino, aminoalkyl, aryl, arylalkoxy, arylalkyl, arylalkylthio, arylalkynyl, aryloxy, carboxy, cyano , Cycloalkyl, halo, haloalkoxy, haloalkyl, second heteroaryl group, heteroarylalkoxy, heteroarylalkyl, heterocycle, (heterocycle) alkoxy, (heterocycle) alkyl, hydroxy, hydroxyalkyl, nitro and oxo Optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of said aryl, said arylalkoxy, Reelalkyl, arylarylthio, arylaryl of arylalkynyl and aryloxy, second heteroaryl group, heteroarylalkoxy and heteroaryl moiety of heteroarylalkyl, heterocycle, and (heterocycle) alkoxy And the heterocycle portion of the (heterocycle) alkyl is 1, independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro and oxo, It may optionally be further substituted with 2, 3, 4 or 5 substituents.

  As used herein, the term “heteroarylalkenyl” refers to a heteroaryl group that is attached to the parent molecular moiety through an alkenyl group.

  As used herein, the term “heteroarylalkoxy” refers to a heteroaryl group that is attached to the parent molecular moiety through an alkoxy group.

  As used herein, the term “heteroarylalkyl” refers to a heteroaryl group that is attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “heteroarylalkylidene” refers to a heteroaryl group attached to the parent molecular moiety through an alkylidene group.

  As used herein, the term “heteroaryloxy” refers to a heteroaryl group that is attached to the parent molecular moiety through an oxygen atom.

  As used herein, the term “heteroarylsulfonyl” refers to a heteroaryl group that is attached to the parent molecular moiety through a sulfonyl group.

  As used herein, the term “heterocycle” is a cyclic, non-aromatic 3, 4, 5, 6 or 7 member selected from the group consisting of oxygen, nitrogen and sulfur and containing at least one atom. Refers to the ring. The 5-membered ring has zero or one double bond, and the 6- and 7-membered rings have zero, one or two double bonds. The heterocyclic groups of the present invention are attached to the parent molecular group through substitutable carbon or nitrogen atoms in the ring. The term “heterocycle” also encompasses structures in which the heterocycle is fused with an aryl group, as defined herein, or with additional heterocycle groups. Examples of the heterocyclic group of the present invention are aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinolinyl, dihydrobenzodioxinyl, dihydro [1,3] Oxazolo [4,5-b] pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morolinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl , Piperidinyl, thiomorpholinyl and the like. The heterocyclic group of the present invention includes alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylidene, amino, aminoalkyl, aryl, arylalkoxy, arylalkyl, arylalkylidene, cyano, (cycloalkyl) alkylidene, halo. , Haloalkoxy, haloalkyl, heteroalkyl, heteroarylalkoxy, heteroarylalkyl, heteroarylalkylidene, iminohydroxy, second heterocycle, (heterocycle) alkoxy, (heterocycle) alkyl, (heterocycle) alkylidene, hydroxy, hydroxy Optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, nitro and oxo, in which case the aryl The arylalkoxy and the aryl moiety of the arylalkyl, the heteroaryl, the heteroarylalkoxy, the heteroarylalkyl and the heteroarylalkylidene heteroaryl moiety, the second heterocycle, and the (heterocycle) alkoxy, Heterocycle) alkyl and the heterocycle portion of said (heterocycle) alkylidene are independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro and oxo Optionally further substituted with 1, 2, 3, 4 or 5 substituents.

  As used herein, the term “(heterocyclic) alkenyl” refers to a heterocyclic group that is attached to the parent molecular moiety through an alkenyl group.

  As used herein, the term “(heterocyclic) alkoxy” refers to a heterocyclic group that is attached to the parent molecular moiety through an oxygen atom.

  As used herein, the term “(heterocyclic) alkyl” refers to a heterocyclic group attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “(heterocyclic) alkylidene” refers to a heterocyclic group attached to the parent molecular moiety by an alkylidene group.

  As used herein, the term “hydroxy” refers to —OH.

  As used herein, the term “hydroxyalkyl” refers to a hydroxy group that is attached to the parent molecular moiety through an alkyl group.

  As used herein, the term “iminohydroxy” refers to ═N (OH).

As used herein, the term “—NR ^c R ^d ” refers to two groups, R ^c and R ^d , which are attached to the parent molecular moiety by a nitrogen atom. R ^c and R ^d are each independently selected from hydrogen and alkyl.

As used herein, the term “(NR ^c R ^d ) alkyl” refers to a —NR ^c R ^d group attached to the parent molecular moiety by an alkyl group.

As used herein, the term “(NR ^c R ^d ) alkylcarbonyl” refers to an (NR ^c R ^d ) alkyl group attached to the parent molecular moiety by a carbonyl group.

As used herein, the term “nitro” refers to —NO ₂ .

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

As used herein, the term “sulfonyl” refers to —S (O) ₂ —.

  The compounds herein can exist as therapeutically acceptable salts.

  As used herein, the term “therapeutically acceptable salt” is water-soluble, oil-soluble, water-dispersible or oil-dispersible, without undue toxicity, irritation and allergic reaction, Represents a salt or zwitterionic form of a compound of the present invention that is suitable for therapy and is commensurate with a reasonable profit / loss ratio and effective for their intended use. Said salts can be prepared during the final isolation and purification of the compound or separately by reacting the amino group with a suitable acid. Typical acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate Salt, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane Sulfonate (Isethionate), lactate, maleate, mesitylene sulfonate, methane sulfonate, naphthylene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, pamoate , Pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphoric acid , Glutamate, bicarbonate, p- toluenesulfonate, and undecanoate salts. In addition, the amino group in the compound of the present invention includes methyl chloride, ethyl chloride, propyl chloride, butyl chloride, methyl bromide, ethyl bromide, propyl bromide, butyl bromide, methyl iodide, ethyl iodide, and iodide. Propyl, butyl iodide, dimethyl sulfate, diethyl sulfate, dibutyl sulfate, diamyl sulfate, decyl chloride, lauryl chloride, myristyl chloride, stearyl chloride, decyl bromide, lauryl bromide, myristyl bromide, stearyl bromide, decyl iodide, It may be quaternized with lauryl iodide, myristyl iodide, stearyl iodide, benzyl bromide and phenethyl bromide. Examples of acids that can be utilized to produce therapeutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and oxalic acid, maleic acid, succinic acid and citric acid And organic acids.

  Basic addition salts are prepared by reacting a carboxylic acid with a suitable base such as a metal cation hydroxide, carbonate or bicarbonate, or with ammonia or an organic primary, secondary or tertiary amine. Can be prepared during general isolation and purification. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum, as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, Such as pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N, N-dibenzylphenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine Non-toxic quaternary amine cations. Other representative organic amines suitable for the formation of basic addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

  The compounds of the present invention can also exist as therapeutically acceptable prodrugs. The term “therapeutically acceptable prodrug” refers to a reasonable profit / loss ratio suitable for use in contact with a patient's tissue without undue toxicity, irritation and allergic reaction, and their intended use Refers to prodrugs or zwitterions that are effective. The term “prodrug” refers to a compound that is converted in vivo to the parent compound of formula (I), for example, by hydrolysis in blood.

When any variable, substituent, or term (eg, aryl, heterocycle, R ^12, etc.) occurs more than once in a formula or general structure, its definition at each occurrence is as at all other occurrences It has nothing to do with its definition. Also, combinations of substituents and / or variables are allowed only if such a combination results in a stable combination.

  Since the present compound has carbon-carbon double bonds, the present 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 present invention encompasses both isomers or mixtures thereof having the ability to inhibit protein kinases. These substituents are shown as being in configuration E or Z. In this case, the term “E” represents a higher order substituent on the opposite side of the carbon-carbon double bond, and the term “Z” represents a higher order substituent on the same side of the carbon-carbon double bond. .

  There are asymmetric centers in the compounds of the present invention. These centers are indicated by the symbol “R” or “S” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the present invention encompasses all stereoisomeric forms or mixtures thereof having the ability to inhibit protein kinases. Individual stereoisomers of the compounds can be prepared from commercially available starting materials containing chiral centers, or prepared as a mixture of enantiomeric products, then converted to a mixture of diastereomers, separated or recrystallized, It can be prepared by chromatographic methods or by separation such as direct separation of enantiomers on a column for chiral chromatography. The specific stereochemical starting compounds are either commercially available or can be prepared and resolved by techniques known in the art.

  In accordance with the therapeutic methods and pharmaceutical compositions of the present invention, the compound can be administered alone or in combination with other anticancer agents. When using the present compounds, the effective dose for the specific treatment of any particular patient is the disease to be treated and the severity of the disease; the activity of the specific compound used; the specific composition utilized. The patient's age, weight, general health, sex and diet; number of doses; mode of administration; excretion rate of the compound utilized; duration of treatment; and in conjunction with or simultaneously with the compound used Depends on factors such as the drug used. The compound is a unit dosage formulation containing a carrier, adjuvant, diluent, vehicle or combinations thereof, orally, parenterally, utilizing osmotic pressure (nasal spray), rectally, vaginally It can be administered internally or locally. The term “parenteral” includes infusion, as well as subcutaneous, intravenous, intramuscular and intrasternal injection.

  Aqueous or oily suspensions for parenteral administration of the compounds can be formulated with dispersing, wetting or suspending agents. Injectable formulations may also be injectable solutions or suspensions in diluents or solvents. Among the acceptable diluents or solvents that may be employed are water, saline, Ringer's solution, buffer, monoglycerides, diglycerides, fatty acids (such as oleic acid), and fixed oils (such as monoglycerides or diglycerides).

  The anticancer effects of compounds for parenteral administration can be prolonged by delaying their absorption. One method of delaying absorption of a particular compound is administration of an injectable depot containing a suspension of the compound in a crystalline, amorphous or otherwise water-insoluble form. The absorption rate of a compound depends on its physical state and consequently on its dissolution rate. Another method of delaying absorption of a particular compound is administration of an injectable depot containing the compound as an oily solution or suspension. Yet another method of delaying the absorption of a particular compound is to use a microcapsule matrix of the compound entrapped in a liposome, microemulsion or biodegradable polymer (such as polylactide-polyglycolide, polyorthoester or polyanhydride). Injectable depot form of administration. 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 compound. The absorption rate can be delayed by using a rate controlling membrane or by trapping the compound in 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. The active compounds in these solid dosage forms are sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, tableting lubricants and tableting aids (magnesium stearate or fine Diluents such as crystalline cellulose may optionally be included. Capsules, tablets and pills can also contain buffering agents, and tablets and pills can be provided with enteric or other controlled release coatings. Powders and propellants can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder or mixtures thereof. The propellant may additionally contain customary propellants such as chlorofluorohydrocarbons or their substitutes.

  Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water. These compositions can also contain adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring and flavoring 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 include excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth gum, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof. Can also be included. Suppositories for rectal or vaginal administration use this compound as a suitable non-irritating agent such as cacao butter or polyethylene glycol, each of which is solid at room temperature but fluid in the rectum or vagina. It can be prepared by mixing with the form. Ophthalmic formulations including eye drops, ophthalmic ointments, powders and solutions are also contemplated as being within the scope of the present invention.

  The total daily dose of a compound administered to a host in single or divided doses is about 0.1 to about 200 mg, preferably about 0.25 to about 100 mg / kg body weight. Dosage compositions may contain these amounts, or may contain those divisors that make up the daily dose.

Determination of biological activity Enzymatic assay:
The Akt1 assay uses His-Akt1-S36 (truncated Akt1 with a His tag at the N-terminus), Akt1 at amino acids 139-460 and the following point mutants: S378A, S381A, T450D and S473D. The His-Akt1-S36 assay was performed in 1 μM His-Akt1 in 50 μL reaction buffer (20 mM HEPES pH 7.5, 10 mM MgCl ₂ , 0.009% Triton X-100) for 30 minutes at room temperature. Perform in 96 well plates by incubating S36, 5 μM biotin-BAD-peptide (biotin) and 5 μM ³³ P-ATP. The reaction is stopped by the addition of 25 μL stop buffer (4M NaCl and 0.1M EDTA). Transfer the sample to a flash plate coated with streptavidin. The BAD-peptide phosphorylation in the reaction is measured by counting the plates with TopCount. Other kinase assays (Akt2, Akt3, PKA, PKC, Erk2, Chk1, Cdc2, Src, CK2, MAPK AP kinase 2, and SGK) are similar using their specific biotinylated peptide substrates and buffer conditions. Do. The compounds of the invention inhibited Akt from 0 to 100% at a concentration of 1 μM. Preferred compounds had a percent inhibition between 77 and 100 at 1 μM, and more preferred compounds had a percent inhibition between 92 and 100 at 1 μM. Accordingly, the compounds of the present invention are useful for the treatment of diseases caused or exacerbated by increased protein kinase levels.

Synthetic Methods Abbreviations used in the following schemes and example descriptions are: diethyl azodicarboxylate is DEAD; tetrahydrofuran is THF; methyl t-butyl ether is MTBE; triphenylphosphine is PPh ₃ ; acetic acid The salt is OAc; tri-o-tolylphosphine is P (o-tol) ₃ ; dibenzylideneacetone is dba; 1,2-dimethoxyethane is DME; 2,2′-bis (diphenylphosphino)- 1,1′-binaphthyl is BINAP; 4-dimethylaminopyridine is DMAP; diphenylphosphinoferrocene is dppf; diphenylphosphinoethane is dppe; 1-ethyl-3- [3- (dimethylamino) propyl hydrochloride Carbodiimide is EDC; 1-hydroxybenzotriazole is HOBt 1,3-dicyclohexylcarbodiimide is DCC; dimethylformamide is DMF; N-methylpyrrolidinone is NMP; dimethyl sulfoxide is DMSO; t-butoxycarbonyl is Boc; trifluoroacetic acid is TFA; diisobutylaluminum hydride; Is DIBAL; n-butyllithium is n-BuLi; 9-borabicyclo [3.3.1] nonane is 9-BBN; isopropoxide is OiPr; dimethylacetamide is DMA; 2,2′-azo Bisisobutyronitrile is AIBN; triethylamine is TEA; and N-borosuccinimide is NBS.

The compounds and methods of this invention are better understood in connection with the following synthetic schemes, which illustrate the ways in which the compounds of this invention can 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 stated below.

  The present invention is meant to encompass compounds having the formula (I) when prepared by synthetic methods or by metabolic processes. Preparation of the compounds of the present invention by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

図式１に示されているように、式（２）（Ｚは、Ｃｌ、Ｂｒ、ＩまたはＯＴｆである）の化合物は、トリフェニルホスフィンおよび活性化剤（ＤＥＡＤなど）の存在下、式（３）の化合物で処理することにより、式（４）の化合物に転化させることができる。この反応は、ニートで行うことができ、またはＴＨＦ、ジエチルエーテルおよびＭＴＢＥなどの溶媒の存在下で行うことができる。反応温度は、典型的には約−１０℃から約３５℃であり、反応時間は、典型的には約８から約２４時間である。

As shown in Scheme 1, the compound of formula (2) (Z is Cl, Br, I or OTf) can be synthesized in the presence of triphenylphosphine and an activator (such as DEAD) in the formula (3 ) Can be converted to a compound of formula (4). This reaction can be carried out neat or in the presence of solvents such as THF, diethyl ether and MTBE. The reaction temperature is typically about −10 ° C. to about 35 ° C., and the reaction time is typically about 8 to about 24 hours.

In the presence of a palladium catalyst and optional additives (such as triethylamine), the compound of the formula (4) has the formula (5) [M is B (OH) ₂ , SN (R ^a ) ₃ (where R ^a is Can be converted to a compound of formula (Ia) by treatment with a compound of the formula: Examples of palladium catalysts include Pd (PPh ₃ ) ₄ , and Pd (OAc) ₂ , and P (o-tol) ₃ . Exemplary solvents include toluene, acetonitrile and DME. The reaction is typically conducted at a temperature between about 60 ° C. and about 110 ° C., and the reaction temperature is typically about 4 to about 12 hours.

図式２は、式（６）（Ｚ^１およびＺ^２は、独自に、Ｃｌ、Ｂｒ、ＩまたはＯＴｆである）の化合物を、図式１に記載した手順に従って式（７）の化合物で処理することにより、式（８）の化合物に転化させることができることを示している。これらの化合物は、ベンゾフェノンイミン、パラジウム触媒および塩基で処理することにより、式（９）の化合物に転化させることができる。パラジウム触媒の例には、Ｐｄ_２ｄｂａ、ならびにＢＩＮＡＰ、ｄｐｐｆまたはｄｐｐｅなどの配位子が挙げられる。代表的な塩基には、ナトリウムｔ−ブトキシドおよびカリウムｔ−ブトキシドが挙げられる。典型的に、反応は、トルエン、アセトニトリルまたはＤＭＥなどの溶媒中、約６０℃から約９０℃の温度、約８から約２４時間の時間で行われる。

Scheme 2 treats a compound of formula (6) (Z ¹ and Z ² are independently Cl, Br, I or OTf) with a compound of formula (7) according to the procedure described in Scheme 1. Shows that it can be converted to a compound of formula (8). These compounds can be converted to compounds of formula (9) by treatment with benzophenone imine, palladium catalyst and base. Examples of palladium catalysts include Pd ₂ dba and ligands such as BINAP, dppf or dppe. Exemplary bases include sodium t-butoxide and potassium t-butoxide. Typically, the reaction is conducted in a solvent such as toluene, acetonitrile or DME at a temperature of about 60 ° C. to about 90 ° C. for a time of about 8 to about 24 hours.

  A compound of formula (9) can be treated with a compound of formula (10) in the presence of an acid such as acetic acid, followed by treatment with sodium cyanoborohydride to yield a compound of formula (Ib). Representative solvents include methanol and ethanol. This reaction is typically conducted at about 20 ° C. to about 70 ° C., and the reaction time is typically about 1 to about 4 hours.

図式３は、式（Ｉｃ）の化合物の調製を示している。式（１ｌ）（Ｚは、Ｂｒである）の化合物を、ＣＯ雰囲気下、パラジウム触媒で処理して、式（１２）の化合物を生じることができる。パラジウム触媒の例には、ＰｄＣｌ_２・ｄｐｐｆ、ＰｄＣｌ_２とＢＩＮＡＰ、ならびにＰｄＣｌ_２・ｄｐｐｅが挙げられる。代表的な溶媒には、ＴＨＦ、水、ＤＭＥおよびそれらの混合物が挙げられる。この反応は、典型的には約８０℃から約１００℃で行われ、反応時間は、典型的には約１２から約２４時間である。

Scheme 3 shows the preparation of a compound of formula (Ic). A compound of formula (1l) (Z is Br) can be treated with a palladium catalyst in a CO atmosphere to give a compound of formula (12). Examples of palladium catalysts include PdCl ₂ · dppf, PdCl ₂ and BINAP, and PdCl ₂ · dppe. Exemplary solvents include THF, water, DME, and mixtures thereof. This reaction is typically conducted at about 80 ° C. to about 100 ° C., and the reaction time is typically about 12 to about 24 hours.

  A compound of formula (12) can be converted to a compound of formula (Ic) by treatment with a substituted amine in the presence of a coupling agent. Exemplary 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 the reaction time is typically about 12 to about 24 hours.

図式４に示されているように、当業者には公知の方法を使用して、式（１３）の化合物を加水分解して、式（１４）の化合物を生じることができる。式（１４）の化合物は、図式３に記載した条件を使用して、式（Ｉｄ）の化合物に転化させることができる。

As shown in Scheme 4, compounds of formula (13) can be hydrolyzed to yield compounds of formula (14) using methods known to those skilled in the art. A compound of formula (14) can be converted to a compound of formula (Id) using the conditions described in Scheme 3.

図式５は、式（Ｉｅ）の化合物の合成を示している。式（１５）の化合物は、還元剤で処理することにより、式（１６）の化合物に転化させることができる。還元剤の例には、Ｐｄ／Ｃとギ酸アンモニウム、Ｐｄ／Ｃと水素、およびＰｔＯ_２と水素が挙げられる。代表的な溶媒には、メタノールおよびエタノールが挙げられる。この反応は、典型的には約５０℃から約７０℃で行われ、反応時間は、典型的には約１５分から約２時間である。

Scheme 5 shows the synthesis of compounds of formula (Ie). A compound of formula (15) can be converted to a compound 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. This reaction is typically conducted at about 50 ° C. to about 70 ° C., and the reaction time is typically about 15 minutes to about 2 hours.

  A compound of formula (16) can be converted to a compound of formula (Ie) by treatment with an electrophile such as a halo-substituted heteroaryl group. Examples of solvents used for these reactions include ethanol and methanol. This reaction is typically conducted at about 50 ° C. to about 70 ° C., and the reaction time is typically about 6 to about 18 hours.

図式６に示されているように、化合物（８）は、パラジウム触媒および塩基（炭酸セシウムまたは炭酸ナトリウムなど）の存在下、式（１７）［Ｍは、Ｂ（ＯＲ^Ｚ）_２であり、この場合、Ｒ^Ｚは、水素またはアルキルである］の化合物で処理することにより、式（Ｉｆ）（この場合、Ｌ^２は、結合である）の化合物に転化させることができる。代表的なパラジウム触媒には、ＰｄＣｌ_２・ｄｐｐｆ、Ｐｄ（ＰＰｈ_３）_４、およびＰｄＣｌ_２（ＰＰｈ_３）_２が挙げられる。これらの反応に使用される溶媒の例には、ＤＭＦ、ＤＭＥおよびＮＭＰが挙げられる。この反応は、典型的には約３０℃から約１００℃で行われ、反応時間は、典型的には約４から約１２時間である。

As shown in Scheme 6, compound (8) has formula (17) [M is B (OR ^Z ) ₂ in the presence of a palladium catalyst and a base (such as cesium carbonate or sodium carbonate) In which case R ^Z is hydrogen or alkyl] can be converted to a compound of formula (If), where L ² is a bond. Exemplary palladium catalysts include PdCl ₂ · dppf, Pd (PPh ₃ ) ₄ , and PdCl ₂ (PPh ₃ ) ₂ . Examples of solvents used for these reactions include DMF, DME and NMP. This reaction is typically conducted at about 30 ° C. to about 100 ° C., and the reaction time is typically about 4 to about 12 hours.

図式７に示されているように、図式３に記載した条件を使用し、式（９）の化合物を式（１８）の化合物と反応させて、式（Ｉｇ）の化合物を生じることができる。

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

  The present invention will now be described in connection with certain preferred embodiments, which are not intended to limit the scope of the invention. On the contrary, the present invention encompasses all alternatives, modifications and equivalents included in the scope of the claims. Accordingly, the following examples, including preferred embodiments, will illustrate the preferred practice of the present invention. The examples are intended to illustrate certain preferred embodiments, and to provide what appears to be the most useful and easily understood description of the procedures and conceptual aspects of the present invention. It is understood that

Example 1
N, N-dimethyl-N- [2-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) ethyl] amine

Example 1A
N- {2-[(5-Bromopyridin-3-yl) oxy] ethyl} -N, N-dimethylamine At room temperature, N, N-dimethylethanolamine (0.5 mL) in DMF (10 mL). The solution 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 / hexanes gave the desired product (0.8 g, 78%). _{MS (DCI / NH 3) m} / e246 (M + H) +.

(Example 1B)
N, N-dimethyl-N- [2-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) ethyl] amine Example 1A in acetonitrile (15 mL) (0 0.8 g, 3.27 mmol), 4-vinylpyridine (0.69 g, 5.53 mmol), tri-o-tolylphosphine (0.6 g, 1.96 mmol), palladium acetate (0.16 g, 0.65 mmol) and A mixture of triethylamine (0.66 g, 6.53 mmol) was stirred at 80 ° C. for 8 hours. The reaction mixture was 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 10% methanol / dichloromethane gave the desired product (0.64 g, 73%).

(Example 2)
(1S) -2- (1H-Indol-3-yl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine

(Example 2A)
tert-Butyl (1S) -2-[(5-hydroxypyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylcarbamate At 0 ° C., 3-bromo-5-hydroxypyridine ( 2.0 g, 11.5 mmol), L-Boc-tryptophanol (3.67 g, 12.6 mmol) and triphenylphosphine (4.53 g, 17.3 mmol) and DEAD (3.01 g, 17.3 mmol). Treated dropwise, warmed to room temperature, stirred overnight and concentrated. The concentrate was purified by flash column chromatography on silica gel with hexane / ethyl acetate (4: 1) to give the desired product (4.55 g, 88.7%). _{MS (DCI / NH 3) m} / e446,448 (M + H) +.

(Example 2B)
tert-Butyl (1S) -2- (1H-indol-3-yl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxo) methyl] ethyl Carbamate The desired product was prepared in Example 1B by using Example 2A instead of Example 1A. _{MS (DCI / NH 3) m} / e471 (M + H) +.

(Example 2C)
(1S) -2- (1H-Indol-3-yl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine at room temperature A solution of Example 2B (603 mg, 1.28 mmol) in dichloromethane (20 mL) was treated with 4N HCl in dioxane (5 mL), stirred for 2 h, and concentrated. The residue was dissolved in water (1.5 mL) and lyophilized to give the desired product as the hydrochloride salt (610 mg, 99%).

(Example 2D)
(1S) -2- (1H-Indol-3-yl) -1 [({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine at room temperature, A solution of Example 2B (500 mg, 1.06 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL), stirred for 2 hours and concentrated. The residue was dissolved in water (1.5 mL) and lyophilized to give the desired product as the trifluoroacetate salt (643 mg, 85%).

(Example 3)
(1R) -2- (1H-Indol-3-yl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine Desired formation Prepared as the hydrochloride salt in Example 2A by using D-Boc-tryptophanol instead of L-Boc-tryptophanol and then treating as described for Examples 2B and 2C. did.

(Example 4)
1- (1H-Indol-3-yl) -3-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) propan-2-ol Acetic acid ( A solution of Example 2C (150 mg, 0.400 mmol) in 2.4 mL) was treated with NaNO ₂ (117 mg, 1.70 mmol) in several portions, stirred for 18 hours, and with water (40 μL). Quench, stir for an additional hour, pour into 2N NaOH and extract with isopropanol / dichloromethane. The combined extracts were concentrated. The residue was treated with LiOH.H ₂ O (25 mg) in THF / water (1 mL / 0.5 mL), heated to 55 ° C. overnight, diluted with dichloromethane, washed with water and dried (MgSO ₄ ). , Filtered and concentrated. The residue was purified by HPLC on a C18 column with 0% to 100% CH ₃ CN / H ₂ O / 0.1% TFA to give the desired product as the trifluoroacetate salt (9.7 mg 5%).

(Example 5)
(1S) -2- (1-Benzothien-3-yl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine desired formation Product in Example 2A using 2-tert-butoxycarbonylamino-3-benzo [b] thiophen-3-yl-propan-1-ol instead of L-Boc-tryptophanol; Prepared as the trifluoroacetate salt by processing as described for Examples 2B and 2D.

(Example 6)
(1S) -2,2-diphenyl-1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine The desired product was obtained as Example 2A. Prepared as the hydrochloride salt by using L-Boc-diphenylalaninol in place of L-Boc-tryptophanol and then treating as described for Examples 2B and 2C.

(Example 7)
(1S) -1- {4-[(2,6-dichlorobenzyl) oxy] benzyl} -2-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) Ethylamine The desired product is obtained in Example 2A using L-Boc- (4- (2,6-dichlorobenzyloxy) phenyl) alaninol instead of L-Boc-tryptophanol, followed by Example 2B. And prepared as the hydrochloride salt by treatment as described for 2C.

(Example 8)
(1S) -2- (Benzyloxy) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine The desired product was Prepared as the hydrochloride salt at 2A by using L-Boc-3-benzyloxyalaninol in place of L-Boc-tryptophanol and then treating as described for Examples 2B and 2C.

Example 9
N, N-dimethyl-N-[(1S, 2S) -1-methyl-2-phenyl-2-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) Ethyl] amine

(Example 9A)
5-Bromopyridin-3-yl acetate A mixture of 3-bromo-5-hydroxypyridine (9.00 g, 51.7 mmol), acetic anhydride (6.0 mL) and triethylamine (12.0 mL) in THF (50 mL). Heat to reflux overnight, cool to room temperature, dilute with diethyl ether, wash with water, 5% NaHCO ₃ , water and brine, dry (MgSO ₄ ), filter and concentrate to give the desired product Product (9.37 g, 84%) was obtained.

(Example 9B)
5-[(E) -2-Pyridin-4-ylvinyl] pyridin-3-ol Example 9A (9.37 g, 43.3 mmol), 4-vinylpyridine (14.0 mL, 130 mmol) in acetonitrile (40 mL). ), Tri-o-tolylphosphine (13.5 g, 44.4 mmol), palladium acetate (2.65 g, 11.8 mmol) and triethylamine (120 mL, 0.861 mmol) were heated to reflux overnight, Partition between water 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 5% methanol / dichloromethane with 0.5% ammonia gave acetic acid (8.53 g). This was stirred with LiOH / H ₂ O (6.00 g, 143 mmol) in THF / water (40 mL / 20 mL) at room temperature for 4 hours, concentrated, adjusted to pH 7 with 1N HCl (aq) and filtered. . The filtrate was washed with water and dried under vacuum at 60 ° C. to give the desired product (7.23 g, 84%).

(Example 9C)
N, N-dimethyl-N-[(1S, 2S) -1-methyl-2-phenyl-2-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) Ethyl] amine The desired product is obtained in Example 2A, respectively, as in Example 9B and (1S, 2S) -2- (dimethylamino) -1-phenylpropan-1-ol. Prepared as trifluoroacetic acid by using in place of hydroxypyridine and L-Boc-tryptophanol and then treating as described for Examples 2B and 3D.

(Example 10)
(1S) -2- (2-Naphtyl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine The desired product was run In Example 2A, L-Boc- (2-naphthyl) alaninol was used in place of L-Boc-tryptophanol and then processed as described for Examples 2B and 2D.

(Example 11)
N-[(2S) -2-amino-3- (1H-indol-3-yl) propyl] -N- {5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} amine

(Example 11A)
3-Bromo-5-[(E) -2-pyridin-4-ylvinyl] pyridine 3,5-Dibromopyridine (5.56 g, 23.4 mmol), 4-vinylpyridine (5. 5) in acetonitrile (100 mL). 1 mL), palladium acetate (1.05 g), tri-o-tolylphosphine (5.00 g) and triethylamine (33 mL) were heated at 80 ° C. overnight and concentrated. The residue was partitioned between 5% NaHCO ₃ and dichloromethane and filtered. The filtrate was separated and the organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4% methanol / dichloromethane to give the desired product (2.18 g, 36%). (DCI / NH ₃ ) m / e 261, 263 (M + H) ⁺

(Example 11B)
5-[(E) -2-Pyridin-4-ylvinyl] pyridin-3-amine Example 11A (1.88 g, 7.2 mmol), benzophenone imine (1.22 mL), Pd ₂ (dba) ₃ (66 mg) , BINAP (125 mg), sodium tert-butoxide (0.97 g), and toluene (19 mL) were heated to 80 ° C. overnight and concentrated. The residue was purified by flash column chromatography on silica with ethyl acetate to give a solid (2.44 g). This was stirred with 2N HCl (aq) (5.0 mL) in THF (50 mL) at room temperature for 2 h and concentrated. The residue was dissolved in 0.5N HCl (aq) (100 mL) and washed three times with ethyl acetate. The aqueous layer was adjusted to pH 11 with 1N NaOH and extracted with dichloromethane. The combined extracts were washed with water, dried (MgSO ₄ ), filtered and concentrated to give the desired product (1.23 g, 87%).

(Example 11C)
tert-butyl (1S) -2- (1H-indol-3-yl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} amino) methyl] ethyl Carbamate Example 11B (52 mg, 0.264 mmol), L-Boc-tryptophanal (J. Med. Chem., 1985, 28 (12), 1874) (80 mg, 0.277 mmol) in methanol (4 mL). And a mixture of acetic acid (80 μL) was stirred at room temperature for 3 hours, refluxed for 2 hours, cooled to room temperature, treated with sodium cyanoborohydride (35 mg), stirred for 1 hour and filtered. The filtrate was concentrated and the residue was purified by HPLC on C18 with 0% to 100% CH ₃ CN / H ₂ O / 0.1% TFA to give the desired product (43 mg, 35%). _{MS (DCI / NH 3) m} / e470 (M + H) +.

(Example 11D)
N-[(2S) -2-amino-3- (1H-indol-3-yl) propyl] -N- {5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} amine At room temperature, a solution of Example 11C (40 mg, 0.085 mmol) in dichloromethane (3.0 mmol) is treated with dioxane (0.5 mL), stirred for 1 hour and concentrated to give the desired product. , Obtained as the hydrochloride salt (30 mg, 74%).

(Example 12)
(1S) -2-({2-Chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) -1- (1H-indol-3-ylmethyl) ethylamine

(Example 12A)
A solution of 3- (benzyloxy) -5-bromo-2-chloropyridine POCl ₃ (3- (benzyloxy) -5-bromopyridine N-oxide (2.0 g, 7.1 mmol) in (20 mL) was added. Stir at 100 ° C. for 7 hours, cool to room temperature, concentrate, treat with ethyl acetate (50 mL), wash with brine, dry (MgSO ₄ ), filter and concentrate. Purification by flash column chromatography on silica gel with ethyl acetate / hexanes afforded the desired product (1.0 g, 40%) MS (DCI / NH ₃ ) m / e 299 (M + H) ⁺ .

(Example 12B)
A mixture of Example 12A in 5-bromo-2-chloro-3-hydroxypyridine 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 SO 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 / hexanes gave the desired product (0.51 g, 72%). _{MS (DCI / NH 3) m} / e209 (M + H) +.

(Example 12C)
tert-Butyl (1S) -2-[(5-Bromo-2-chloropyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylcarbamate The desired product is obtained in Example 2A. Example 12B was prepared by substituting for 3-bromo-5-hydroxypyridine (0.78 g, 66%). _{MS (DCI / NH 3) m} / e481 (M + H) +.

(Example 12D)
(1S) -2-({2-chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) -1- (1H-indol-3-ylmethyl) ethylamine desired The product was prepared as the trifluoroacetate salt in Examples 2B and 2D by using Example 12 instead of Example 2A.

(Example 13)
(1S) -2-({6-Chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) -1- (1H-indol-3-ylmethyl) ethylamine

(Example 13A)
tert-Butyl (1S) -2-[(5-Bromo-6-chloropyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylcarbamate 5-Bromo- in THF (100 mL) 6-chloro-3-hydroxypyridine (2.50 g, 12 mmol), N-α- (tert-butoxycarbonyl) -L-tryptophanol (3.77 g, 18 mmol) and triphenylphosphine (4.72 g, 18 mmol) Was stirred at 0 ° C. for 20 minutes, treated with DEAD (2.83 mL, 18 mmol), stirred for 1 hour, allowed to warm to room temperature, stirred for 15 hours, treated with ethyl acetate (300 mL) and brine. Washed, dried (MgSO ₄ ), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate / hexanes to give the desired product (4.58 g, 80%). MS (APCI) m / e 480, 482 (M + H) ^<+> .

(Example 13B)
tert-Butyl (1S) -2-({6-chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) -1- (1H-indol-3-ylmethyl) Ethylcarbamate A solution of Example 13A (1.50 g, 3.125 mmol), Pd ₂ (dba) ₃ (71 mg, 0.078 mmol) and tri-o-tolylphosphine (71 mg, 0.23 mmol) in DMF (30 mL). Was treated with 4-vinylpyridine (492 mg, 4.68 mmol) and triethylamine (1.30 mL, 9.4 mmol), purged with nitrogen and heated to 100 ° C. for 4 hours. was treated with ethyl acetate (200 mL), washed with brine, dried (MgSO _4), filtered, and concentrated. concentrates, Purification by flash column chromatography on silica gel with 5% ethyl acetate / hexanes afforded the desired product (1.37 g, 87%) MS (APCI) m / E 505, 507 (M + H ) ⁺ .

(Example 13C)
(1S) -2-({6-chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) -1- (1H-indol-3-ylmethyl) ethylamine desired The product was prepared as the trifluoroacetate salt in Example 2D by using Example 13B instead of Example 2B.

(Example 14)
(1S) -2- (1H-Indol-3-yl) -1-({[5- (pyridin-4-ylethynyl) pyridin-3-yl] oxy} methyl) ethylamine

(Example 14A)
tert-Butyl (1S) -2- (1H-indol-3-yl) -1-[({5-[[trimethylsilyl) ethynyl] pyridin-3-yl} oxy) methyl] ethylcarbamate Example 2A (500 mg, 1.12 mmol), Pd ₂ Cl ₂ (PPh ₃ ) ₂ (77 mg, 0.112 mmol) and CuI (52 mg, 0.27 mmol), purged with nitrogen, DMF (7 mL), trimethylsilylacetylene (475 μL, 3 .36 mmol) and triethylamine (468 μL, 3.36 mmol), stirred at 50 ° C. for 15 h, cooled to room temperature, 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 with 1: 2 ethyl acetate / hexanes to give the desired product (417 mg, 80%). MS (APCI) m / e 464 (M + H) ^<+> .

(Example 14B)
tert-Butyl (1S) -2-[(5-ethynylpyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylcarbamate Example 14A (400 mg) in THF (6 mL) at room temperature. , 0.86 mmol) 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) and brine. Washed, dried (MgSO ₄ ), filtered and concentrated. The residual oil was purified by flash column chromatography on silica gel with 40% ethyl acetate / hexanes to give the desired product (290 mg, 86%). MS (APCI) m / e 392 (M + H) ^<+> .

(Example 14C)
tert-Butyl (1S) -2- (1H-indol-3-yl) -1-({[5- (pyridin-4-ylethynyl) pyridin-3-yl] oxy} methyl) ethylcarbamate Example 14B (150 mg , 0.384 mmol), 4-bromopyridine hydrochloride (75 mg, 0.34 mmol), Pd ₂ Cl ₂ (PPh ₃ ) ₂ (27 mg, 0.0384 mmol) and CuI (18 mg, 0.093 mmol) with nitrogen Purge, treat with DMF (4 mL) and triethylamine (214 μL, 1.54 mmol), stir at 50 ° C. for 20 hours, cool to room temperature, treat with ethyl acetate (50 mL), wash with brine, Dry (MgSO ₄ ), filter and concentrate. The residue was purified by flash column chromatography on silica gel with 2: 1 ethyl acetate / hexanes to give the desired product (122 mg, 68%). MS (APCI) m / e 469 (M + H) ^<+> .

(Example 14D)
(1S) -2- (1H-Indol-3-yl) -1-({[5- (pyridin-4-ylethynyl) pyridin-3-yl] oxy} methyl) ethylamine The desired product is obtained in Example 2D. Example 14C was prepared as the trifluoroacetate salt by substituting Example 14B for Example 2B.

(Example 15)
(1S) -2- (1H-Indol-3-yl) -1-[({5-[(Z) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine methanol (3 mL The mixture of Example 14D (40 mg, 0.11 mmol), 5% Pd / BaSO ₄ (8.1 mmol) and quinoline (8.1 μL) in) was stirred at room temperature for 12 hours under hydrogen (20 psi). And filtered. The filtrate was concentrated and the residual oil was purified by HPLC on C18 with 0% to 100% CH ₃ CN / H ₂ O / 0.1% TFA to give the desired product (30 mg 75%).

(Example 16)
(2S) -2-Amino-4-phenyl-N- {5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} butanamide

(Example 16A)
tert-Butyl (1S) -3-Phenyl-1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} amino) carbonyl] propylcarbamate Example 11B (200 mg, 1. 0 mmol), HOBt (210 mg), EDC (290 mg), DMAP (25 mg) and Boc-homophenylalanine were stirred at room temperature overnight and concentrated. The residue was dissolved in ethyl acetate and washed successively with water, 5% NaHCO ₃ and water, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol / dichloromethane to give the desired product (192 mg, 41%). _{MS (DCI / NH 3) m} / e459 (M + H) +.

(Example 16B)
(2S) -2-Amino-4-phenyl-N- {5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} butanamide The desired product is carried out in Example 2C. Prepared as the trifluoroacetate salt by using Example 16A instead of Example 2B. (173 mg, 89%).

(Example 17)
5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} -N-pyridin-4-ylnicotinamide

(Example 17A)
5-{[(2S) -2-[(tert-butoxycarbonyl) amino] -3- (1H-indol-3-yl) propyl] oxy} nicotinic acid in THF / water (6.3 mL / 6.3 mL) A solution of Example 2A (1.30 g, 3.02 mmol) and PdCl ₂ · ddpf (123 mg) was heated to 100 ° C. under CO (800 psi) for 19 hours, cooled to room temperature, and diluted with water. The mixture was extracted with dichloromethane and the combined extracts were washed with water, dried (MgSO ₄ ), filtered and concentrated to give the desired product (912 mg, 76%). _{MS (DCI / NH 3) m} / e396 (M + H) +.

(Example 17B)
tert-butyl (1S) -2- (1H-indol-3-yl) -1-[({5-[(pyridin-4-ylamino) carbonyl] pyridin-3-yl} oxy) methyl] ethylcarbamate DMF ( A solution of Example 17A (410 mg, 1.0 mmol), 4-aminopyridine (100 mg, 1.0 mmol), EDC (960 mg), and HOBt (680 mg) in 10 mL) was stirred overnight at room temperature and dichloromethane. Diluted with, washed with water, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with ethyl acetate / methanol (8: 1) to give the desired product (87 mg, 18%). _{MS (DCI / NH 3) m} / e488 (M + H) +.

(Example 17C)
5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy> -N-pyridin-4-ylnicotinamide The desired product is carried out in Example 2C. Prepared as the hydrochloride salt by using Example 17B instead of Example 2B (27 mg, 31%).

(Example 18)
N- (aminoethyl) -5-[(E) -2-pyridin-4-ylvinyl] nicotinamide

(Example 18A)
Ethyl 5-[(E) -2-pyridin-4-ylvinyl] nicotinic acid The desired product is obtained in Example 1B by using 3-bromo-5-ethoxycarbonylpyridine instead of Example 1A. Prepared. _{MS (DCI / NH 3) m} / e355 (M + H) +.

(Example 18B)
5-[(E) -2-Pyridin-4-ylvinyl] nicotinic acid 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 give the desired product. _{MS (DCI / NH 3) m} / e227 (M + H) +.

(Example 18C)
N- (Aminoethyl) -5-[(E) -2-pyridin-4-ylvinyl] nicotinamide The desired product is obtained in Examples 17B and 17C, respectively, in Example 18B and N-tert-butoxycarbonylamino. Ethylamine was prepared as the hydrochloride salt by substituting Example 17A and 4-aminopyridine.

(Example 19)
N-[(2E) -3- (4-bromophenyl) prop-2-enyl] -N- [2-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} Oxy) ethyl] amine

(Example 19A)
(2E) -3- (4-Bromophenyl) prop-2-en-1-ol-A solution of ethyl 4-bromocinamide (5.430 g, 22.07 mmol) in toluene (20 mL) at -78 ° C. Treat with DIBAL (1.5 M in toluene, 37.0 mL, 55.5 mmol) for 10 min, stir at −78 ° C. for 30 min, warm to room temperature, stir for 1 h, 10% HCl (aq. ) And extracted twice with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO ₄ ), filtered and concentrated to give the desired product (4.463 g, 95%). ^{_{MS (DCI / NH 3) m}} / e212,214 (M + H) +, 228,230 (M + 18) +.

(Example 19B)
1-bromo-4-[(1E) -3-chloroprop-1-enyl] benzene Example 19A (2.0 g, 9.387 mmol) and SOCl ₂ (3.5 mL, 47.9 mmol) in benzene (10 mL) Was stirred at room temperature for 24 hours and concentrated to give the desired product (2.167 g, 99%). _{(DCI / NH 3) m /} e231,233,235 (M + H) +.

(Example 19C)
1-({5-[(E) -2-Pyridin-4-ylvinyl] pyridin-3-yl} oxy) ethanamine The desired product is obtained in Examples 2A and 2C, respectively, Examples 9B and N- Prepared as the hydrochloride salt by using tert-butoxycarbonylaminoethanol (200 mg, 1.00 mmol) instead of 3-bromo-5-hydroxypyridine and L-Boc-tryptophanol.

(Example 19D)
N-[(2E) -3- (4-bromophenyl) prop-2-enyl] -N- [2-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} Oxy) ethyl] amine A solution of Example 19C (100 mg, 0.285 mmol), Example 19B (66.0 mg, 0.285 mol) and triethylamine (250 μL, 1.79 mmol) in DMF (5 mL) at room temperature. Stir for 3 days and pour into water. The aqueous layer was washed 3 times with dichloroethane and the combined extracts were washed with water, dried (MgSO ₄ ), filtered and concentrated. The residue was chromatographed on silica gel with dichloromethane / methanol / NH ₄ OH (100: 5: 0.5) to give the free base. This material was treated with 2M HCl / Et ₂ O to give the hydrochloride salt (34.0 mg, 22%).

(Example 20)
^{N 4 - (3 - {[} (2S) -2- amino-3- (1H-indol-3-yl) propyl] oxy} phenyl) pyrimidine-2,4-diamine

(Example 20A)
tert-Butyl (1S) -2- (1H-Indol-3-yl) -1-[(3-nitrophenoxy) methyl] ethylcarbamate The desired product is obtained in Example 2A with 3-nitrophenol 3 Prepared by using instead of bromo-5-hydroxypyridine (257 mg, 61%). _{MS (DCI / NH 3) m} / e412 (M + H) +, 319 (M + 18) +.

(Example 20B)
tert-Butyl (1S) -2- (3-aminophenoxy) -1- (1H-indol-3-ylmethyl) ethylcarbamate Example 20A (247 mg, 0.600 mmol), ammonium formate (400 mg) in methanol (10 mL). , 6.34 mmol) and 10% Pd / C (25 mg) were warmed to reflux for 30 min, cooled to room temperature, filtered through diatomaceous earth (Celite®) and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate / hexane (1: 1) to give the desired product (200 mg, 87%). _{MS (DCI / NH 3) m} / e382 (M + H) +.

(Example 20C)
tert-Butyl (1S) -2- {3-[(2-aminopyrimidin-4-yl) amino] phenoxy} -1- (1H-indol-3-ylmethyl) ethylcarbamate Implementation in ethanol (0.5 mL) A solution of Example 20B (41.2 mg, 0.108 mmol) and 2-amino-4-chloropyrimidine (14.0 mg, 0.108 mmol) was heated to 80 ° C. for 13 hours and dichloromethane / methanol / NH ₄ OH (100: 5: 0.5) and purified by flash column chromatography on silica gel to give the desired product (50 mg, 98%). _{MS (DCI / NH 3) m} / e475 (M + H) +.

(Example 20D)
N ⁴ - a - (3 {[(2S) -2- amino-3- (1H-indol-3-yl) propyl] oxy} phenyl) pyrimidine-2,4-diamine The desired product, Example 2C Example 20C was prepared as the hydrochloride salt by using instead of Example 2B (33 mg, 81%).

(Example 21)
(1R) -3- {6-Chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} -1- (1H-indol-3-ylmethyl) propylamine

(Example 21A)
6-Chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-amine 3-amino-5-bromo-6-chloropyridine (2.0 g, 9. 9) in DMF (30 mL). 64 mmol), Pd ₂ (dba) ₃ (440 mg, 0.48 mmol), tri-o-tolylphosphine (438 mg, 1.44 mmol), 4-vinylpyridine (2.08 mL, 19.28 mmol), and triethylamine (4. (03 mL, 29 mmol) was stirred at 100 ° C. for 15 h, treated with ethyl acetate (200 mL), washed twice with brine, dried (MgSO ₄ ), filtered and concentrated. The residual solid was recrystallized from hexane / dichloromethane to give the desired product (1.86 g, 84%). MS (APCI) m / e 232 (M + H) ^<+> .

(Example 21B)
2-Chloro-5-iodo-3-[(E) -2-pyridin-4-ylvinyl] pyridine Example 21A (1.0 g, 4.3 mmol) in 30% H ₂ SO ₄ (10 mL) at 0 ° C. ) With NaNO ₂ (386 mg, 5.6 mmol), stirred for 5 h, treated with a solution of NaI (2.1 g, 14 mmol) in H ₂ O (2 mL), stirred for 2 h, Further treated with NaI (2.1 g, 14 mmol), stirred for 2 h, poured into 30% NaOH (aq (200 mL) at 0 ° C., extracted 3 times with 10% methanol / ethyl acetate. Combined organic phase. Was dried (MgSO ₄ ), filtered and concentrated The residual solid was purified by flash column chromatography on silica gel with 70% ethyl acetate / hexanes to give the desired product. (1.03 g, 70%) MS (DCI) m / e 343 (M + H) ⁺ .

(Example 21C)
tert-Butyl (1S) -1- (1H-indol-3-ylmethyl) prop-2-enylcarbamate of methyltriphenylphosphonium bromide (5.65 g, 15.81 mmol) in THF (50 mL) at 0 ° C. The suspension was treated with n-BuLi (2.5 M solution in hexane, 6.33 mL, 15.81 mmol), stirred for 10 minutes, warmed to room temperature, stirred for 30 minutes, cooled to 0 ° C., Treat with a solution of L-Boc-tryptophanal (3.80 g, 13.2 mmol) in THF (10 mL), stir for 2 h, treat with diethyl ether (200 mL), wash with brine, dry (MgSO ₄ ), filtered and concentrated. The residual oil was purified by flash column chromatography on silica gel with 20% ethyl acetate / hexanes to give the desired product (700 mg, 18%). MS (DCI) m / e 287 (M + H) ^<+> .

(Example 21D)
tert-Butyl (1R) -3- {6-Chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} -1- (1H-indol-3-ylmethyl) propylcarbamate 0 Treat a solution of Example 21C (100 mg, 0.35 mmol) in THF (3 mL) at 9 ° C. with 9-BBN (0.5 M solution in THF, 0.70 mL, 0.35 mmol) and slowly to room temperature. Stir overnight while warming 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. Cannulated, purged with nitrogen, and stirred for 8 hours at 50 ° C. 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 give the desired product (69 mg, 40%).

(Example 21E)
(1R) -3- {6-Chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} -1- (1H-indol-3-ylmethyl) propylamine Desired product Was prepared as the trifluoroacetate salt in Example 2D by using Example 21D instead of Example 2B.

(Example 22)
4- (5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) benzonitrile

(Example 22A)
tert-Butyl (1S) -2-{[5- (4-cyanophenyl) pyridin-3-yl] oxy} -1- (1H-indol-3-ylmethyl) ethylcarbamate in ethylene glycol dimethyl ether (20 mL) at room temperature Of Example 2A (250 mg, 0.56 mmol) was treated with tetrakis (triphenylphosphine) palladium (0) (32 mg, 0.03 mmol), stirred for 10 min and (in ethanol (5.0 mL)) Treat with 4-cyanophenyl) boronic acid (123 mg, 0.84 mmol), stir for 15 minutes, treat with 2M Na ₂ CO ₃ (aq) (1.4 mL), heat to reflux for 4 hours and cool to room temperature. And concentrated. The concentrate was purified by flash column chromatography on silica gel with hexane / ethyl acetate (1: 1) to give the desired product (230 mg, 88%). _{MS (DCI / NH 3) m} / e469 (M + H) +.

(Example 22B)
4- (5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) benzonitrile in dichloromethane (2.0 mL) at 0 ° C. A solution of Example 22A (20 mg, 0.043 mmol) was treated dropwise with trifluoroacetic acid (0.5 mL) and stirred for 2 hours while warming to room temperature. The reaction mixture was concentrated to give the desired product as the trifluoroacetate salt (27 mg, 88%).

(Example 23)
N-[(2S) -2-amino-3- (1H-indol-3-yl) propyl] -N′-isoquinolin-5-ylpyridin-3,5-diamine

(Example 23A)
Isoquinolin-5-yl trifluoromethanesulfonate At 0 ° C., a mixture of 5-hydroxyisoquinoline (1.6 g, 11.0 mmol) and triethylamine (1.38 g, 13.6 mmol) in dichloromethane (25 mL) was added to triflic anhydride. Treat slowly with (3.35 gm, 12.1 mmol), stir overnight while warming to room temperature, dilute with dichloromethane, wash 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 give the desired product (1.54 g, 50%).

(Example 23B)
3-Amino-5-bromopyridine A solution of 3M NaOH (250 mL) at room temperature was treated with bromine (25.9 g, 162 mmol), stirred for 15 min, and treated with 5-bromonicotinamide (25 g, 124 mmol). For 45 minutes, heated from 85 ° C. to 100 ° C. for 3 hours, cooled to room temperature, adjusted to pH 1 with 10% HCl (aq) and washed twice with dimethyl 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 give the desired product (13.3 g, 62%).

(Example 23C)
N- (5-Bromopyridin-3-yl) isoquinolin-5-amine Example 23A (500 mg, 1.8 mmol), Example 23B (600 mg, 3.5 mmol), Pd ₂ (dba) _{3 in} 10 mL toluene. (42 mg, 0.045 mmol), a mixture of BINAP (56 mg, 0.09 mmol) and sodium tert-butoxide (350 mg, 3.6 mmol) was heated to reflux for 2 hours, diluted with water and extracted three times with ethyl acetate. . The combined extracts were washed successively with saturated NaHCO ₃ , water and brine, dried (Na ₂ SO ₄ ) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3% methanol / dichloromethane to give the desired compound (97 mg, 18%).

(Example 23D)
N- (diphenylmethylene) -N′-isoquinolin-5-ylpyridin-3,5-diamine Example 23C (175 mg, 0.58 mmol), benzophenone imine (150 mg, 0.83 mmol), Pd ₂ (3 mL in 3 mL toluene. A mixture of dba) ₃ (54 mg, 0.06 mmol), BINAP (55 mg, 0.09 mmol) and sodium tert-butoxide (80 mg, 0.82 mmol) was heated from 75 ° C. to 60 ° C. for 4 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3% methanol / dichloromethane to give the desired product (150 mg, 64%).

(Example 23E)
N-isoquinolin-5-ylpyridin-3,5-diamine A mixture of Example 23D (145 mg, 0.36 mmol) in 3 mL THF at room temperature was treated with 10 drops of water and 3 drops of concentrated HCl for 2 hours. Stir and concentrate. The residue was partitioned between ethyl acetate and concentrated NaHCO ₃ (aq). The aqueous layer was extracted 3 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 give the desired product (59 g, 68%).

(Example 23F)
tert-Butyl (1S) -2- (1H-indol-3-yl) -1-({[5- (isoquinolin-5-ylamino) pyridin-3-yl] amino} methyl) ethylcarbamate 2 mL dichloromethane at room temperature A mixture of Example 23E (55 mg, 0.23 mmol) and L-Boc-tryptophanal (84 mg, 0.29 mmol) in Ti (iPrO) ₄ (1 mL), stirred for 2 h and concentrated. did. The residue was dissolved in 2 mL ethanol and treated with NaBH ₃ CN (30 mg, 0.46 mmol), stirred for 2 hours, diluted with water and filtered. The filtrate 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 give the desired product (28 mg, 24%).

(Example 23G)
N-[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] -N′-isoquinolin-5-ylpyridin-3,5-diamine Example 23F in dichloromethane in 2 mL at room temperature The solution was treated with 0.5 mL TFA, stirred for 3 hours and concentrated. The concentrate is purified by reverse layer HPLC on a C18 column with 0% to 100% CH ₃ CN / H ₂ O / 0.1% TFA and the residue is dissolved in water and lyophilized to give the desired product The product was obtained as the trifluoroacetate salt (27 mg, 70%).

(Example 24)
N-[(2S) -2-amino-3- (1H-indol-3-yl) propyl] -N- [5- (isoquinolin-5-yloxy) pyridin-3-yl] amine

(Example 24A)
5-[(5-Bromopyridin-3-yl) oxy] isoquinoline In a sealed tube, 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) were purged. The reaction was heated to 240 ° C. for 10 minutes in a personal chemical microwave. The reaction mixture 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 give the desired product (0.071 g, 23%). .

(Example 24B)
N-[(2S) -2-amino-3- (1H-indol-3-yl) propyl] -N- [5- (isoquinolin-5-yloxy) pyridin-3-yl] amine The desired product is Prepared in Example 23D by using Example 24A instead of Example 23C and then treating as described in Examples 23E, 23F and 23G.

(Example 25)
(2S) -2-Amino-3- (1H-indol-3-yl) -N- [5- (1,6-naphthalidin-2-yl) pyridin-3-ol] propanamide

(Example 25A)
2,2-Dimethyl-N-pyridin-4-ylpropanamide 200 mL A mixture of 4-aminopyridine (10 g, 106 mmol) and pivaloyl chloride (12.9 g, 107 mmol) in dichloromethane was cooled to 0 ° C. and triethylamine ( 10.9 g, 108 mmol), warmed to room temperature, stirred overnight and diluted with water. The aqueous layer was extracted 3 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 give the desired product (14 g, 74%).

(Example 25B)
N- (3-Formylpyridin-4-yl) -2,2-dimethylpropanamide A mixture of Example 25A (11.4 g, 64 mmol) in 200 mL THF was cooled to −78 ° C. and 1. Treat with 6M nBuLi (100 mL, 160 mmol), warm to 0 ° C., stir for 1 hour, treat with DMF (22 g, 215 mmol) in 100 mL THF, warm to room temperature, stir for 1 hour, dilute with brine, Extracted 3 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 give the desired product (9.1 g, 69%).

(Example 25C)
A solution of Example 25B (870 mg, 4.2 mmol) in 4-aminonicotinaldehyde 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 6 times with 20% isopropanol / chloroform. The combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired product (450 mg, 87%).

(Example 25D)
5-acetylnicotinamide 5-bromonicotinamide (2.5 g, 12.4 mmol), tributyl (1-ethoxyvinyl) lead (5.0 g, 13.8 mmol) and dichlorobis (triphenylphosphine) palladium in 25 mL toluene A mixture of (II) (800 mg, 1.1 mmol) was heated to reflux for 3 hours. The mixture was cooled to room temperature, treated with 25 mL 2N HCl (aq), stirred for 1 h, the aqueous layer was washed with ethyl acetate, adjusted to pH> 7 with solid K ₂ CO ₃ , 20% isopropanol / Extracted 6 times into chloroform. The combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired product (1.6 g, 78%).

(Example 25E)
5- (1,6-naphthyridin-2-yl) nicotinamide Example 25C (450 mg, 3.68 mmol) and Example 25D (605 mg, 3.68 mmol) in 20 mL ethanol and 1.2 mL 10% NaOH (aq) ) Was heated to reflux for 3 hours and concentrated. The solid was collected and rinsed with ethyl acetate to give the desired product (740 mg, 80%).

(Example 25F)
5- (1,6-Naphthyridin-2-yl) pyridin-3-amine The desired product was prepared in Example 23B by using Example 25E instead of 5-bromonicotinamide.

(Example 25G)
tert-Butyl (1S) -1- (1H-Indol-3-ylmethyl) -2-{[5- (1,6-naphthyridin-2-yl) pyridin-3-yl] amino} -2-oxoethylcarbamate The desired product was used in Example 16A, Example 25F (100 mg, 0.45 mmol) and L-Boc-tryptophan (150 mg, 0.49 mmol), respectively, instead of Example 11B and Boc-homophenylalanine. It was prepared by.

(Example 25H)
(2S) -2-Amino-3- (1H-indol-3-yl) -N- [5- (1,6-naphthyridin-2-yl) pyridin-3-yl] propanamide The desired product is Prepared as the trifluoroacetate salt in Example 2D by using Example 25G instead of Example 2B.

(Example 26)
N-[(2S) -2-amino-3- (1H-indol-3-yl) propyl] -N- [5- (1,6-naphthyridin-2-yl) pyridin-3-yl] amine desired The product was prepared as the trifluoroacetate salt in Examples 23F and 23G by using Example 25F instead of Example 23E.

(Example 27)
(1S) -2- (1H-Indol-3-yl) -1-{[(5-Isoquinolin-6-ylpyridin-3-yl) oxy] methyl} ethylamine

(Example 27A)
6- (Trimethylstannanyl) isoquinoline A solution of 6-bromoisoquinoline (0.35 g, 1.7 mmol) in DMA (6 mL) was added to hexamethyldilead (0.55 mL, 1.9 mmol) and Pd (PPh ₃ ) _4. (0.23 g, 0.2 mmol), stirred at 100 ° C. for 1 h, 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 hexane / ethyl acetate to give the desired product (0.247 g, 50%).

(Example 27B)
tert-Butyl (1S) -2- (1H-indol-3-yl) -1-{[(5-Isoquinolin-6-ylpyridin-3-yl) oxy] methyl} ethylcarbamate Example in 6 mL DMF A solution of 27A (0.25 g, 0.86 mmol) and Example 2A (0.444 g, 1.00 mmol) was added to Pd ₂ (dba) ₃ (0.08 g, 0.086 mmol), tri-o-tolylphosphine ( 0.02 g, 0.04 mmol) and triethylamine (0.15 mL, 1.0 mmol), heated in a sealed tube to 75 ° C. for 8 hours and concentrated. The residue was purified by flash column chromatography on silica gel with 2.5% methanol / dichloromethane to give the desired product (0.125 g, 30%).

(Example 27C)
(1S) -2- (1H-Indol-3-yl) -1-{[(5-Isoquinolin-6-ylpyridin-3-yl) oxy] methyl} ethylamine Example 27B in dichloromethane (3 mL) at room temperature A solution of (0.125 g, 0.25 mmol) was treated with TFA (400 μL), stirred for 1 h and concentrated. The concentrate was diluted azeotropically twice with diethyl ether and the residue was purified by reverse phase HPLC on a C18 column with 0% to 100% CH ₃ CN / H ₂ O / 0.1% TFA. Purification gave the desired product as the di-trifluoroacetate salt (0.110 g, 70%).

(Example 28)
(1R) -2- (1H-Indol-3-yl) -1-{[(5-quinolin-6-ylpyridin-3-yl) oxy] methyl} ethylamine

(Example 28A)
tert-Butyl (1R) -2-[(5-hydroxypyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylcarbamate The desired product is obtained in Example 2A as L- Prepared by using D-Boc-tryptophanol instead of Boc-tryptophanol.

(Example 28B)
(1R) -2- (1H-Indol-3-yl) -1-{[(5-quinolin-6-ylpyridin-3-yl) oxy] methyl} ethylamine The desired product is obtained in Example 27B. 28A was used in place of 2A and then prepared as the trifluoroacetate salt by removing the Boc group as in Example 27C.

(Example 29)
(1S) -2-[(6-Chloro-5-isoquinolin-6-ylpyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylamine The desired product is obtained in Example 27. Prepared as the trifluoroacetate salt by using Example 13A instead of Example 2A.

(Example 30)
(1S) -2-[(2-Chloro-5-isoquinolin-6-ylpyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylamine The desired product is obtained in Example 27. Example 12C was prepared as the trifluoroacetate salt by using in place of Example 2A (0.02 g, 80%).

(Example 31)
(1R) -1- (1H-Indol-3-ylmethyl) -3- (5-isoquinolin-6-ylpyridin-3-yl) propylamine

(Example 31A)
A solution of 3,5-dibromopyridine (284 mg, 1.2 mmol), Pd ₂ (dba) ₃ (110 mg, 0.12 mmol) and tri-o-tolylphosphine (110 mg, 0.36 mmol) in DMF (15 mL). , Treated with Example 27A (500 mg, 1.2 mmol) and triethylamine (500 μL, 3.6 mmol), purged with nitrogen, heated to 70 ° C. for 6 hours, heated to room temperature, treated with ethyl acetate (100 mL), brine Washed with, dried (MgSO ₄ ), filtered and concentrated. The residual oil was purified by flash column chromatography on silica gel with ethyl acetate to give the desired product (110 mg, 32%). MS (APCI) m / e 285, 287 (M + H) ^<+> .

(Example 31B)
(1R) -1- (1H-Indol-3-ylmethyl) -3- (5-isoquinolin-6-ylpyridin-3-ol) propylamine The desired compound is obtained in Example 21D instead of Example 21B. Prepared as the trifluoroacetate salt using Example 31A and removing the Boc protecting group as described for Example 21B.

(Example 32)
5- (5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) -1H-isoindole-1,3 (2H) -dione

(Example 32A)
tert-Butyl (1S) -2- (1H-indol-3-yl) -1-({[5-trimethylstannanyl] pyridin-3-yl} oxy) methyl) ethylcarbamate Example in DMA (15 mL) A solution of 2A (1 g, 2.23 mmol) was treated with hexamethylditine (1.8 mL, 5.6 mmol) and Pd (PPh ₃ ) ₄ (0.4 g, 0.2 mmol) for 75 days. The mixture was heated to 0 ° C., 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 hexane / ethyl acetate to give the desired product (0.4 g, 34%). .

(Example 32B)
tert-Butyl (1S) -2-{[5- (1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl) pyridin-3-yl] oxy} -1- (1H-indole -3-ylmethyl) ethylcarbamate 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 added to Pd ₂ dba ₃ (0. 04g, 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. in a sealed tube for 6 hours and concentrated. The residue was purified by flash column chromatography on silica gel with 1: 1 hexane / ethyl acetate to give the desired product (0.116 g, 55%).

(Example 32C)
5- (5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) -1H-isoindole-1,3- (2H)- Dione The desired product was prepared as the trifluoroacetate salt in Example 27C by using Example 32B instead of Example 27B.

(Example 33)
5- (5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) isoindoline-1-one (Example 33A)
Methyl 4-bromo-2-methylbenzoate A solution of 4-bromo-2-methylbenzoic acid (1.0 g, 4.7 mmol) in methanol (24 mL) was treated with 20 drops of HCl and refluxed for 6 hours. Heat and concentrate to give the desired product (1.07 g, 100%).

(Example 33B)
Methyl 4-bromo-2- (bromomethyl) benzoate A solution of Example 33A (1.02 g, 4.47 mmol) in CCl ₄ (22 mL) was added to AIBN (0.065 g, 0.4 mmol) and NBS (0.955 g). 5.4 mmol), heated to reflux for 4 hours, washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired product (1.1 g, 79%). It was.

(Example 33C)
5-Bromoisoindoline-1-one At room temperature, a solution of Example 33B (1.1 g, 3.57 mmol) in THF (20 mL) was added to 1N NH _{3 in} methanol (7.14 mL, 7.14 mmol). And stirred for 24 hours and filtered. The filtrate was washed with diethyl ether (100 mL) to give the desired product (0.4 g, 52%).

(Example 33D)
5- (5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) isoindolin-1-one Prepared as the trifluoroacetate salt at 32 by using Example 33C instead of 6-bromophthalimide.

(Example 34)
(1S) -2-[(5-Cinolin-6-ylpyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylamine

(Example 34A)
N- (2-acetylphenyl) acetamide At room temperature, a solution of 2′-aminoacetophenone (5.0 g, 37 mmol) in dichloromethane (150 mL) was added to triethylamine (5.3 mL, 40 mmol) and acetyl chloride (3.2 mL). 45 mmol), stirred for 3 hours and then washed with water. The aqueous layer was extracted with ethyl acetate (2 × 20 mL) and the combined extracts were concentrated to give the desired product (6.5 g, 100%).

(Example 34B)
N- (2-acetyl-4-bromophenyl) acetamide A solution of Example 34A (6.5 g, 37 mmol) in acetic acid (100 mL) at room temperature was treated with Br ₂ (4 mL, 84 mmol) and 1 Stir for 15 minutes, pour into water (200 mL) and filter. The solid is washed with water (2 × 100 mL) and hexane (2 × 100 mL), dissolved in diethyl ether, washed with brine (50 mL), concentrated and the desired product (8.5 g, 89 %).

(Example 34C)
6-Bromosinolin-4 (1H) -one A solution of Example 34B (6.28 g, 24.4 mmol) in THF (75 mL) was treated with concentrated HCl (aq) (15 mL) and water (15 mL). Heat to reflux for hours and concentrate to remove THF. This aqueous solution was treated with additional water (5 mL) and concentrated HCl (5 mL), cooled to 0 ° C., and divided into 5 portions with a solution of NaNO ₂ (1.85 g, 26.84 mmol) in water (10 mL). Treat and slowly warm to room temperature over 2 hours and stir 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 give the desired product (3.0 g, 54%).

(Example 34D)
A solution of Example 34C (0.4 g, 1.8 mmol) in 6-bromo-4-chlorocinoline POCl ₃ ((2.5 mL) was heated to 100 ° C. for 2 hours and slowly poured onto ice. Was cooled to 0 ° C. and adjusted with 50% NaOH to pH 5 to 7. The aqueous layer was extracted with ethyl acetate (2 × 50 mL) and the combined organic layers were concentrated. Purification by flash column chromatography on silica gel with ethyl acetate gave the desired product (0.190 g, 43%).

(Example 34E)
6-Bromo-4-hydrazine Cinoline A solution of Example 34D (2.6 g, 10.6 mmol) in ethanol (70 mL) was treated with hydrazine monohydrate (3 mL, 90% solution) at room temperature. Stir for 3 days and filter. The solid was washed with water (50 mL) and diethyl ether (50 mL) and dried under vacuum to give the desired product (2.5 g, 100%).

(Example 34F)
6-Bromocinoline A solution of Example 34E (3.5 g, 14 mmol) in water (50 mL) was heated to reflux and a solution of CuSO ₄ (2.8 g, 17.5 mmol) in water (20 mL) was added dropwise. Treated, 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 hexane / ethyl acetate to give the desired product (0.7 g, 24%).

(Example 34G)
(1S) -2-[(5-Cinolin-6-ylpyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylamine The desired product is obtained in Example 32, Example 34F. Was prepared as the trifluoroacetate salt by using in place of 6-bromophthalimide.

(Example 35)
(1S) -2-{[5- (1H-indazol-5-yl) pyridin-3-yl] oxy} -1- (1H-indol-3-ylmethyl) ethylamine

(Example 35A)
5-Bromo-1H-indazole A mixture of 5-bromo-2-fluorobenzaldehyde (10 g, 49.2 mmol) and 98% hydrazine (20 mL) was heated to reflux for 5 hours, poured onto ice and filtered. The solid was recrystallized from H ₂ O / methanol to give the desired product (3.7 g, 38%).

(Example 35B)
(1S) -2-{[5- (1H-indazol-5-yl) pyridin-3-yl] oxy}-(1H-indol-3-ylmethyl) ethylamine The desired product is obtained in Example 32. Prepared as the trifluoroacetate salt by using Example 35A instead of 6-bromophthalimide.

(Example 36)
5- (5-{[(2S) -2-amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) -1,3-dihydro-2H-indol-2-one desired The product of was prepared as the trifluoroacetate salt in Example 32 by using 5-bromooxindole instead of 6-bromophthalimide.

(Example 37)
(1S) -2-{[5- (2,1,3-Benzoxadiazol-5-yl) pyridin-3-yl] oxy} -1- (1H-indol-3-ylmethyl) ethylamine desired formation The product was prepared as the trifluoroacetate salt in Example 32 by using 5-chloro-2,1,3-benzoxazole instead.

(Example 38)
(1S) -2- (1H-Indol-3-yl) -1-{[(5-thieno [2,3-c] pyridin-2-ylpyridin-3-yl) oxy] methyl} ethylamine

(Example 38A)
2- (Trimethylstannanyl) thieno [2,3-c] pyridine thieno [2,3-c] pyridine (J. Wikel et al., J. Heterocycl. Chem., 1993) in THF (50 mL) at 78 ° C. 30,289) (2.0 g, 14.8 mmol) was treated with n-butyllithium (2.5 M solution in hexane, 7.1 mL, 17.8 mmol), warmed to 0 ° C., stirred for 15 min, − Cool to 78 ° C. and slowly treat with trimethyltin chloride (3.54 g, 17.8 mmol) in THF (10 mL), warm to room temperature for 2 hours, and partition between ethyl acetate and brine. The ethyl acetate solution was washed with water and concentrated. The residue was purified by flash chromatography (10% to 35% ethyl acetate in hexanes) to give the desired product (3.15 g, 71%). NS (APCI) m / e 298 (M + H) ⁺ .

(Example 38B)
(1S) -2- (1H-Indol-3-yl) -1-{[(5-thieno [2,3-c] pyridin-2-ylpyridin-3-yl) oxy] methyl} ethylamine desired product Was prepared as the trifluoroacetic acid in Examples 27B and 27C by using Example 38A instead of Example 27A.

(Example 39)
(3Z) -5- (5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) -3- (1H-pyrrole-2- Ilmethylene) -1,3-dihydro-2H-indole-2-one The desired product is obtained in Example 32 as 5-bromo-3- (1H-pyrrol-2-ylmethylene) -1,3-dihydro-indole. Prepared as the trifluoroacetate salt by using 2-one in place of 6-bromophthalimide (L. Sun et al., J. Med. Chem., 1998, 41, 2588).

(Example 40)
6- (5-{[(2R) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) -1,3-benzothiazol-2 (3H) -one The desired product was prepared in Example 32 by using 6-bromo-2-benzothiazolinone instead of 6-bromophthalimide.

(Example 41)
2- (1H-Indol-3-yl) -2- (5-isoquinolin-6-ylpyridin-3-yl) ethanamine

(Example 41A)
tert-Butyl 3- (Cyanomethyl) -1H-indole-1-carboxylate 3-Cyanomethylindole (7.50 g, 48 mmol), di-tert-butyl dicarbonate (11.5 g, 52) in dichloromethane (200 mL). .8 mmol), and a solution of DMAP (300 mg) was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel with dichloromethane to give the desired product (11.44 g, 93%). _{MS (DCI / NH 3) m} / e257 (M + H) +.

(Example 41B)
tert-Butyl 3-[(5-bromopyridin-3-yl) (cyano) methyl] -1H-indole-1-carboxylate Example 41A (5.46 g, 21) in DMF (25 mL) at room temperature. .3 mmol) and 3,5-dibromopyridine (5.03 g, 21.3 mmol) were treated in several portions with NaH (60% in mineral oil, 1.08 g, 25.6 mmol). 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, 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 / hexane (1: 7) to give the desired product (336 mg, 4%). _{MS (DCI / NH 3) m} / e413 (M + H) +.

(Example 41C)
tert-Butyl 3- [cyano (5-isoquinolin-6-ylpyridin-3-yl) methyl] -1H-indole-1-carboxylate The desired product is obtained in Example 27B and Example 41B in Example 2A. It was prepared by using instead of

(Example 41D)
2- (1H-Indol-3-yl) -2- (5-isoquinolin-6-ylpyridin-3-yl) ethanamine Example 41C (159 mg, 0.345 mmol), RaNi 2800 (525 mg) in methanol (20 mL). ), Ammonia (2 mL) and triethylamine (2 mL) were stirred under hydrogen (60 psi) for 73 h at room temperature and concentrated. The residue was triturated with ethyl acetate and methanol. The resulting solid was dissolved in trifluoroacetic acid (1 mL), stirred at room temperature for 5 minutes and concentrated. The residue was purified by HPLC on a C18 column with 0-100% CH ₃ CN / H ₂ O / 0.1% TFA to give the desired product as the trifluoroacetate salt (64 mg, 26% ).

(Example 42)
2- (1H-Indol-3-yl) -3- (5-isoquinolin-6-ylpyridin-3-yl) propan-1-amine

(Example 42A)
(2Z) -3- (5-Bromopyridin-3-yl) -2- (1H-indol-3-yl) acrylonitrile 3-Cyanomethylindole (156 mg, in absolute ethanol (1.5 mL) at room temperature 1.0 mmol) was treated with 21% sodium ethoxide in ethanol (450 μL), stirred for 1 hour, and 3-bromopyridine-5-carboxaldehyde (J. Heterocycl. Chem., 1995, 32, 1801). ) (187 g, 1.0 mmol), stirred overnight and concentrated. The residue was purified by flash column chromatography on silica gel with 2% methanol / dichloromethane to give the desired product (52 mg, 16%). _{MS (DCI / NH 3) m} / e325 (M + H) +.

(Example 42B)
2- (1H-Indol-3-yl) -3- (5-isoquinolin-6-ylpyridin-3-yl) propan-1-amine The desired product is obtained in Examples 41C and 41D and Example 42A Prepared as the trifluoroacetate salt by using in place of Example 41B.

(Example 43)
(1S) -2- (1H-Indol-3-yl) -1-{[(6-Pyridin-4-ylquinolin-3-yl) methyl} ethylamine

(Example 43A)
6-Bromo-3-hydroxyquinoline-4-carboxylic acid A solution of 5-bromoisatin (2.26 g, 10 mmol) and potassium hydroxide (4.48 g, 80 mmol) in water (10 mL) was warmed until the material dissolved. 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 give the desired product (1.5 g, 58%). _{MS (DCI / NH 3) m} / e269 (M + H) +.

(Example 43B)
6-Bromo-3-hydroxyquinoline A solution of Example 43A (1.5 g, 5.6 mmol) in nitrobenzene (10 mL) was refluxed for 5 minutes, cooled to room temperature and filtered again. The solid was washed with hexane and dried to give the desired product (0.68 g, 55%). _{MS (DCI / NH 3) m} / e225 (M + H) +.

(Example 43C)
tert-Butyl (1S) -2-[(6-bromoquinolin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylcarbamate The desired product is obtained in Example 2A as Example Prepared by using 43B instead of 3-bromo-5-hydroxypyridine. Purification by flash column chromatography on silica gel with 100% ethyl acetate gave the desired product (0.89 g, 72%). _{MS (DCI / NH 3) m} / e497 (M + H) +.

(Example 43D)
tert-Butyl (1S) -2- (1H-indol-3-yl) -1-{[(6-Pyridin-4-ylquinolin-3-yl) oxy] methyl} ethylcarbamate Performed in DMF (10 mL) Example 43C (0.33 g, 0.67 mmol), pyridine-4-boronic acid (0.13 g, 0.99 mmol), cesium fluoride (0.2 g, 1.34 mmol) and tetrakistriphenylphosphine palladium (0.038 g) , 0.034 mmol) was stirred for 8 h at 100 ° C., treated with ethyl acetate (10 mL), 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 give the desired product (0.25 g, 76%). _{MS (DCI / NH 3) m} / e495 (M + H) +.

(Example 43E)
(1S) -2- (1H-Indol-3-yl) -1-{[(6-Pyridin-4-ylquinolin-3-yl) oxy] methyl} ethylamine The desired product is obtained in Example 27C. Prepared as the trifluoroacetate salt by using Example 43D instead of Example 27B.

(Example 44)
(3Z) -3-[(2S) -2-Amino-3- (1H-indol-3-yl) propylidene] -5-isoquinolin-6-yl-1,3-dihydro-2H-pyrrolo [2,3 -B] pyridin-2-one

(Example 44A)
tert-Butyl (1S, 2Z) -2- (5-bromo-2-oxo-1,2-dihydro-3H-pyrrolo [2,3-b] pyridin-3-ylidene) -1- (1H-indole- 3-ylmethyl) ethylcarbamate 5-Bromo-7-aza-oxindole (D. Mazeas et al., Heterocycles 1999, 50, 1065) (213 mg, 1.0 mmol), L-BOC-tryptophanal (290 mg) in ethanol. , 1.0 mmol) and piperidine (40 μL) were refluxed for 2.5 h and concentrated. The residue was triturated with dichloromethane (1 mL) and hexane (6 mL) and dried to give the desired product (512 mg). _{MS (DCI / NH 3) m} / e483,485 (M + H) +.

(Example 44B)
(3Z) -3-[(2S) -2-Amino-3- (1H-indol-3-yl) propylidene] -5-isoquinolin-6-yl-1,3-dihydro-2H-pyrrolo [2,3 -B] Pyridin-2-one The desired product was prepared in Example 27 by using Example 44A (260 mg) instead of Example 2A.

  The new examples were prepared according to the procedure described in Example 1 using the appropriate alcohols.

(Example 45)
3-Butoxy-5- [2- (4-pyridinyl) vinyl] pyridine

(Example 46)
3-methoxy-5- [2- (4-pyridinyl) vinyl] pyridine

(Example 47)
Hydrochloric acid S-3- [2-amino-3-phenyl-propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine

(Example 48)
Hydrochloric acid 3- [2- (1H-3-indolyl) -ethoxyl] -5- [2- (4-pyridinyl) vinyl] pyridine

(Example 49)
3- [2- (1H-3-Indolyl) -propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine

(Example 50)
Hydrochloric acid S-3- [2-amino-3- (4-benzyloxy] phenyl-propyloxy] -5- [2- (4-pyridinyl) vinyl] pyridine

(Example 51)
3- (Piperidin-4-yl) -5- [2- (4-pyridinyl) vinyl] pyridine

(Example 52)
Hydrochloric acid R-3-2-amino-3-benzyloxypropyloxyl} -5- [2- (4-pyridinyl) vinyl] pyridine

(Example 53)
3- (1-Methyl-imidazole-4-methoxy) -5- [2- (4-pyridinyl) vinyl] pyridine

(Example 54)
S-3- {2-amino-3- [3-hydroxyphenyl] -propyloxyl} -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate

(Example 55)
S-3- {2-amino-3- [3-cyanophenyl] -propyloxyl} -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride

(Example 56)
3- [1- (4-Cyanobenzyl) -imidazole-4-methoxyl] -5- [2- (4-pyridinyl) vinyl] pyridine

(Example 57)
S-3- [2-Amino-3- (1-methyl-1H-3-indolyl) -propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride

(Example 58)
S-3- [2-Dimethylamino-3- (1H-3-indolyl) -propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride

(Example 59)
S-3- [2-Amino-3- (1-naphthyl) -propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride

(Example 60)
3- (2-Aminoethoxyl) -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride

(Example 61)
3- (3-Aminoethoxyl) -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride

(Example 62)
S-3- (2-Amino-3-methylbutyloxyl) -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride

(Example 63)
3- (1-Methyl-3-piperidinyloxyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate

(Example 64)
3- (2-Chlorobenzyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate

(Example 65)
3- (N-benzyl-N-methylaminoethoxyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate

Example 66
3- (6- (N, N-dimethylamino) hexyloxyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate

(Example 67)
3- (2-thiophenoxy-ethoxyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate

(Example 68)
3- (1-Methyl-3-pyrrolidinyloxy) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate

(Example 69)
3-[(1-Methyl-2-piperidinyl) methoxyl] -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate

(Example 70)
3- (1-Pyridinyl-ethoxyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate

(Example 71)
4- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -N-hydroxyl-benzamidine trifluoroacetate

(Example 71A)
4- {5-[(2S) -2-BOC amine-3- (1H-indol-3-yl) -propoxy] -piperidin-3-yl} -N-hydroxyl-benzamidine Toluene (7.0 mL) and methanol To a solution of Example 22 (200 mg, 0.43 mmol) in (0.5 mL) was added hydroxylamine hydrochloride (33 mg, 0.48 mmol) and tert-butoxypotassium (54 mg, 0.48 mmol) and the mixture was added to Stir for 8 hours at room temperature under nitrogen. Further hydroxylamine hydrochloride (33 mg, 0.48 mmol) and potassium tert-butoxy (54 mg, 0.48 mmol) were added and the mixture was heated to 80 ° C. for 16 hours. The mixture was concentrated and purified by column chromatography on silica gel using dichloromethane / methanol (15: 1) as the solvent system. 130 mg (61%) of product was obtained as a white powder.

_{MS (DCI / NH 3) m} / z487 (M-OH + 2H).

(Example 71B)
4- {5- (2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -N-hydroxyl-benzamidine trifluoroacetate salt The desired product is Prepared in Example 22B by using Example 71A instead of Example 22A.

(Example 72)
4- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -benzamidine trifluoroacetic acid

(Example 72A)
4- {5-[(2S) -2-BOC-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -benzamidine Example in glacial acetic acid (5.0 mL) To a solution of 71 product (110 mg, 0.22 mmol) was added acetic anhydride (0.15 ml, 1.6 mmol) and the mixture was stirred at room temperature for 2 hours. Acetic anhydride was hydrolyzed by adding 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 hours. The mixture was filtered through a pad of diatomaceous earth (Celite®) and the filtrate was washed with acetic acid. The combined filtrates were evaporated under high vacuum and the residue was triturated with ethyl acetate. 80 mg (39%) of product was obtained as a beige powder.

(Example 72B)
4- {5-[(2S) -2-Amino-3- (1H-indol-3-yl) -proxy] -pyridin-3-yl} -benzamidine trifluoroacetate salt The desired product is obtained according to Example 22B. Example 72A was prepared by substituting Example 72A for Example 22A.

(Example 73)
3-[(2S) -2-Amino-3- (1H-3-indolyl) -propyloxyl] -6- (3-pyridinyl) -quinoline The desired product is obtained in Example 43 as pyridine-3- Boronic acid was prepared by using in place of pyridine-4-boronic acid.

(Example 74)
3-[(2S) -2-Amino-3- (1H-3-indolyl) -propyloxyl] -6- (3-quinolinyl) -quinoline The desired product is obtained in Example 43 as quinoline-3- Boronic acid was prepared by using in place of pyridine-4-boronic acid.

(Example 75)
3-[(2S) -2-amino-3- (1H-3-indolyl) -propyloxyl] -5- [2- (2-amino-4-pyridinyl) vinyl] pyridine trifluoroacetate

(Example 75A)
2-Amino-4-iodopyridine 2-Fluoro-4-iodopyridine (3.0 g, 13.5 mmol), acetylamide (15.8 g, 269 mmol) and potassium carbonate (9.2 g, 67 mmol) were added to 180 ° C. For 7 hours, poured into ice (100 g), extracted with ethyl acetate, washed with brine, dried (MgSO ₄ ), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate / hexanes to give the title compound (1.1 g, 37%). _{MS (DCI / NH 3) m} / e221 (M + H).

(Example 75B)
N, N-Bis (tert-butyloxylcarbonyl) amino-4-iodopyridine A solution of the product from Example 75A above (1.0 g, 4.5 mmol) in THF (25 mL) was added to 1.0 M LiHMDS ( (9.0 mL, 9.0 mmol), treated dropwise, 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 hexane / ethyl acetate to give the desired product (1.0 g, 53%). _{MS (DCI / NH 3) m} / z421 (M + H).

(Example 75C)
N, N-bis (tert-butyloxylcarbonyl) amino-4-vinyl lysine The product from Example 75B above (0.7 g, 1.67 mmol), vinyl tributyltin (0.83 g, 2.6 mmol) and tetrakis- (Triphenylphosphine) -palladium (0) (0.12 g, 0.11 mmol) is heated at 100 ° C. for 6 hours, cooled to room temperature, treated with ethyl acetate (10 mL), washed with brine and dried. (MgSO ₄ ), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% ethyl acetate / hexanes to give the title compound) (0.4 g, 75%). _{MS (DCI / NH 3) m} / e321 (M + H).

(Example 75D)
3-[(2S) -2- (N-tert-butoxycarbonyl) amino-3- (1H-3-indolyl) -propyloxy] -5- {2- [2- (N, N-bis (tert- Butoxycarbonyl) amino] -4-pyridinyl) vinyl} pyridine The desired product was prepared in Example 2B by using Example 75 instead of 4-vinylpyridine. Purification on silica gel eluting with 100% ethyl acetate gave the title compound (0.15 g 49%). _{MS (DCI / NH 3) m} / e685 (M + H).

(Example 75E)
4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -vinyl) -pyridin-2-ylamine desired formation The product was prepared in Example 2C by using Example 75D instead of Example 2B. Purification on HPLC gave the title compound (0.06 g, 70%).

(Example 76)
5-[(2S) -2- (amino-3- (1H-3-indolyl) -propyloxyl] -3- [2- (2-amino-4-pyridinyl) vinyl] -2-chloro-pyridine trifluoro Acetate The desired product was prepared in Example 75 by using 3-bromo-2-chloro-5-hydroxypyridine instead of 3-bromo-2-chloro-5-hydroxypyridine.

(Example 77)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-naphthalen-2-yl-pyridin-3-yloxy) -ethylamine The desired product is obtained in Example 27 as 2-bromo Naphthalene was prepared by using instead of 6-bromoisoquinoline.

(Example 78)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-5-yl-pyridin-3-yloxy) -ethylamine

(Example 78A)
5-Bromoisoquinoline 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., sodium nitrate (0.95 g, 13.8 mmol) in 6 mL water. ) And was stirred at 0 ° C. for 20 minutes. While keeping at 0 ° C., this solution 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 hour. The reaction was neutralized with NaOH (50%) and extracted with ethyl acetate (3x). The combined organic layers were concentrated in vacuo and chromatographed using 1: 1 hexane / ethyl acetate to give 1.4 g of product (50%).

(Example 78B)
(1S) -1- (1H-Indol-3-ylmethyl] -2- (5-isoquinolin-5-yl-pyridin-3-yloxy) -ethylamine The desired product is obtained in Example 27, Example 78A Was prepared in place of 6-bromoisoquinoline.

(Example 79)
6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -2H-isoquinolin-1-one The desired product is run In Example 27, 2-hydroxyisoquinoline was prepared by substituting 6-bromoisoquinoline.

(Example 80)
(1S) -2- [5- (3-Chloro-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 80A)
6-Bromo-indan-1,2-dione 1-oxime A solution of 5-bromo-1-indanone (1.8 g, 8.5 mmol) in ethanol (150 mL) was cooled to 0 ° C. and t-butylnitrite ( 2.1 ml), stirred at room temperature for 2 hours, filtered and the desired product washed with ether. Yield 76%. _{MS (DCI / NH 3) m} / e242 (M + 1) +.

(Example 80B)
A suspension of Example 80A (1.5 g, 6.2 mmol) in 6-bromo-1,3-dichloro-isoquinoline POCL ₃ (40 mL) was treated with PCl ₅ (1.55 g, 7.4 mmol). HCl gas was introduced until the solution was saturated. The reaction was stirred at 60 ° C. for 6 hours and concentrated under vacuum. The residue was slowly hydrolyzed with 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 / hexanes to give the title compound (1.7 g, 100%). _{MS (DCI / NH 3) m} / e278 (M + H) +.

(Example 80C)
6-Bromo-3-chloro-isoquinoline 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) Reflux for hours, reflux under hot conditions and concentrate under vacuum. The residue was made basic 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 / hexanes to give the title compound (0.81 g, 50%). _{MS (DCI / NH 3) m} / e244 (M + H) +.

(Example 80D)
3-Chloro-6-trimethylstannalyl-isoquinoline The desired product was prepared in Example 27A by using Example 80C instead of 6-bromoisoquinoline. _{MS (DCI / NH 3) m} / e327 (M + H) +.

Example 80E
(1S)-[2- [5- (3-Chloro-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester The desired product was prepared in Example 27B by using Example 80D instead of Example 27A. _{MS (DCI / NH 3) m} / e530 (M + H) +.

(Example 80F)
(1S) -2- [5- (3-Chloro-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine The desired product is obtained from Example 27C. Example 80E was prepared in place of Example 27B.

(Example 81)
(1S) -2-([3,4 ′] bipyridinyl-5-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine trifluoroacetate The desired product is obtained in Example 27 as 4 Prepared by using tributylstannylpyridine instead of Example 27A.

(Example 82)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (2-pyridin-2-yl-vinyl) -pyridin-3-yloxy] -ethylamine The desired product is obtained in Example 2. In 2-vinylpyridine in place of 4-vinylpyridine.

(Example 83)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-pyridin-3-ylethynyl-pyridin-3-yloxy) -ethylamine trifluoroacetic acid The desired product is obtained in Example 14. Prepared by using 3-bromopyridine instead of 4-bromopyridine.

(Example 84)
(1S) -2- [5- (2-Fluoro-pyridin-4-ylethynyl) -pyridin-3-yloxy] -1- (1H-indol-4-ylmethyl) -ethylamine trifluoroacetate salt The desired product In Example 14, 4-iodo-2-fluoropyridine was prepared by substituting 4-bromopyridine for 4-bromopyridine.

(Example 85)
(1S) -4- [5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-ylethynyl] -pyridin-2-ol trifluoroacetate in acetic acid (5 mL) Of N-BOC protected Example 84 (45 mg, 0.093 mmol) was heated at 80 ° C. for 15 hours and at 100 ° C. for 5 hours. The solution was concentrated and the residual oil was dissolved in CH ₂ Cl ₂ (5 mL). Trifluoroacetic acid (1.25 mL) was added at 0 ° C. The residue was purified by HPCL (Zorbax, C-18) to give the title compound (15 mg, 33%).

(Example 86)
(1S) -2- [6-Chloro-5- (1-chloro-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine trifluoroacetate The compound was prepared in Example 27 by using Example 13A instead of Example 2A and Example 80D instead of Example 27A.

(Example 87)
Bis- [3- (4-Bromo-phenyl) -allyl]-{2- [5- (2-pyridin-4-yl-vinyl) -pyridin-3-yloxy] -ethyl} -amine hydrochloride Obtained from the less polar product in Example 19D (5.3 mg, 3%).

(Example 88)
Hydrochloride ^N 4 - [3- (2- Amino - ethoxy) - phenyl] - pyrimidine-2,4-diamine The title compound, in Example 20, in place of N-Boc-aminoethanol with BOC- tryptophanase Nord Prepared by use.

Example 89
trans- [4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propylamino] -pyridin-3-yl} -vinyl) -pyrimidine-2- Yl] -carbamic acid ethyl ester trifluoroacetate

(Example 89A)
trans-4-[(5-Bromo-pyridin-3-yl) -vinyl] -2-amino-pyrimidine 5-bromo-pyridine-3-carbaldehyde (436 mg, 2.34 mmol) in formic acid (96%, 3 mL) ) And 2-amino-4-methylpyrimidine (246 mg, 2.35 mmol) were heated for 18 hours. After cooling to room temperature, it was diluted with water and basified to pH˜13 with 1N NaOH. This mixture was then extracted with methylene chloride. The combined extracts were 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} / z277,279 (M + 1) +.

(Example 89B)
trans-4-[(5-Bromo-pyridin-3-yl) -vinyl] -2- [bis (tert-butoxycarbonyl) amino] -pyrimidine Example 89A (429 mg, 1.58 mmol) in THF (10 mL). , (BOC) ₂ O (1.040 g, 4.77 mmol), DMAP (50 mg, 0.41 mmol) and triethylamine (670 μL, 4.81 mmol) were stirred at room temperature overnight. The reaction was concentrated, chromatographed on silica gel and eluted with AcOEt: hexane (1: 1) to give the title compound (511 mg, 68%). _{MS (DCI / NH 3) m} / z477,479 (M + 1).

(Example 89C)
trans-4-[(5-Amino-pyridin-3-yl) -vinyl] -2- (tert-butoxycarbonyl) amino-pyrimidine Example 89B was prepared according to the procedure described for Example 51, steps 4 and 5. Converted to the title compound. _{MS (DCI / NH 3) m} / z314 (M + 1) +.

(Example 89D)
trans- [4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propylamino] -pyridin-3-yl} -vinyl) -pyrimidine-2- Yl] -carbamic acid ethyl ester trifluoroacetate salt The title compound was prepared in Example 11 by using Example 89C instead of Example 11B.

(Example 90)
1-amino-6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -isoquinoline trifluoroacetate

(Example 90A)
A solution of 6-bromo-1-chloroisoquinoline POCl ₃ (6-bromo-1-hydroxyisoquinoline (9.205 g, 41.0 mmol) in (100 mL) was heated to 100 ° C. for 4 hours. 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 chromatographed on silica gel. And eluted 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) ⁺ .

(Example 90B)
1-amino-6-bromoisoquinoline A mixture of the salt product of Example 90A (264 mg, 1.09 mmol), acetamide (1.3 g) and K ₂ CO ₃ (0.45 g) was heated at 180 ° C. for 5 hours. did. After cooling to room temperature, the mixture was dissolved in ethyl acetate, 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} / z223,225 (M + 1) +.

(Example 90C)
1-[(Bis (tert-butoxycarbonyl)] amino-6-bromoisoquinoline Example 90B (616 mg, 2.76 mmol), BOC ₂ O (1.81 g), DMAP (67 mg) and triethylamine in acetonitrile (15 mL) (1.15 mL) was stirred at room temperature for 2 h The reaction was concentrated and the residue was chromatographed on silica gel eluting with AcOEt: hexane (3: 7) to give the title Compound (1.18 g, 71%) was obtained, MS (DCI / NH ₃ ) m / z 423 (M + 1) ⁺ .

(Example 90D)
1-amino-6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -isoquinoline trifluoroacetate salt Prepared in Example 32 by using Example 90C instead of 6-bromophthalimide.

(Example 91)
6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1-chloro-isoquinoline trifluoroacetate salt Prepared in Example 32 by using Example 90A instead of 6-bromophthalimide.

(Example 92)
(2S) -2-Amino-3- (1H-indol-3-yl) -N- [5- (2-pyridin-4-yl-vinyl) -pyridin-3-yl] -propionamide In Example 16, it was prepared by using Boc-tryptophan instead of Boc-homnophenylalanine.

(Example 93)
Hydrochloric acid (2S) -2-amino-3- (naphth-1-yl) -N- [5- (2-pyridin-4-yl-vinyl) -pyridin-3-yl] -propionamide In Example 16, it was prepared by using Boc-3- (1-naphthyl) alanine instead of Boc-homnophenylalanine.

(Example 94)
Hydrochloric acid (2S) -2-amino-3-naphthyl-N- [5- (2-pyridin-4-yl-vinyl) -pyridin-3-yl] -propionamide The title compound was prepared as the -Prepared by using phenylalanine instead of Boc-homnophenylalanine.

(Example 95)
Hydrochloric acid (2S) -2-amino-3- (imidazol-4-yl) -N- [5- (2-pyridin-4-yl-vinyl) -pyridin-3-yl] -propionamide In Example 16, it was prepared by using bis (Boc) -histidine instead of Boc-homnophenylalanine.

(Example 96)
(1R) -2- (1H-Indol-3-yl) -1-{[(5-Isoquinolin-6-ylpyridin-3-yl) oxy] methyl} ethylamine The title compound was prepared in Example 27 using the R— Boc-tryptophanol was prepared by using in place of L-Boc-tryptophanol.

(Example 97)
(1S) -5- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazol-3-ylamine

(Example 97A)
2-Fluoro-5- (trimethylstannyl) benzonitrile The desired product was prepared in Example 27A by using 5-bromo-2-fluorobenzonitrile instead of 6-bromoisoquinoline.

(Example 97B)
(1S)-[2- [5- (3-Cyano-4-fluoro-phenyl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester The desired product was prepared in Example 27B by using Example 97A instead of Example 27A.

(Example 97C)
(1S)-[2- [5- (3-Amino-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert- Butyl ester A mixture of Example 97B (120 mg, 0.25 mmol) and 98% hydrazine (5 mL) was heated to reflux for 5 hours, poured into ice, diluted with brine, extracted with ethyl acetate and dried over MgSO _4. And concentrated. Purification by flash chromatography (7% MeOH / CH ₂ Cl ₂ ) gave the desired product (103 mg, 84%).

(Example 97D)
(1S) -5- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazol-3-ylamine The desired product was run In Example 27C, Example 97C was prepared as the trifluoroacetate salt by substituting Example 27B for Example 27B.

(Example 98)
(1S) -6- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazol-3-ylamine The desired product was run In Example 97, 4-bromo-2-fluorobenzonitrile was prepared as trifluoroacetic acid by substituting for 5-bromo-2-fluorobenzonitrile.

Example 99
2-Amino-N-[(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -acetamide

(Example 99A)
{[(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylcarbamoyl] -methyl> -carbamic acid tert-butyl ester CH Example 27C (175 mg, 0.35 mmol), N-Boc-glycine (91 mg, 0.52 mmol), EDC (100 mg), iPt ₂ EtN (0.30 mL) and DMAP (10 mg) in ₂ Cl ₂ (7 mL). Was stirred overnight at room temperature, diluted with EtOAc, washed with water and brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol / CH ₂ Cl ₂ to give the desired product (112 mg, 58%).

(Example 99B)
2-Amino-N-[(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -acetamide The desired product In Example 27C, Example 99A was prepared as the trifluoroacetate salt by substituting Example 27B.

(Example 100)
(2S) -2-Amino-N-[(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -propionamide The desired product was prepared in Example 99 by using L-Boc-alanine instead of N-Boc-glycine.

(Example 101)
2-Dimethylamino-N-[(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -acetamide Desired product Was prepared in Example 99A by using N, N-dimethylglycine instead of N-Boc-glycine.

(Example 102)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 102A)
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), 30 Stir for min, carefully dilute with water and acidify with 10% HCl (aq). This aqueous solution was extracted with Et ₂ O, rinsed successively with 10% HCl (aq), water and brine, dried (MgSO ₄ ) and evaporated sufficient to proceed to the next step. The desired product of purity (26.6 g, 99%) was obtained.

(Example 102B)
1- (5-Bromo-2-fluoro-phenyl) -ethanone A solution of Example 102A (26.6 g, 121 mmol) and manganese (IV) oxide (53 g, 610 mmol) in p-dioxane (500 mL) was brought to reflux. For 4 hours, cooled, filtered through Celite®, evaporated and purified by flash chromatography (5% to 10% Et ₂ O / hexanes) to give the desired product almost colorless. Obtained as an oil and solidified on standing (20.5 g, 78%).

(Example 102C)
A mixture of 5-bromo-3-methyl-1H-indazole 102B (10 g, 46 mmol) and 98% hydrazine (25 mL) was heated to reflux for 9 hours and poured onto ice. The precipitate was collected and purified by flash chromatography (1: 1 Et ₂ O: hexanes) to give the desired product as a white solid (5.8 g, 60%).

(Example 102D)
3-methyl-5-trimethylstannanyl-1H-indazole Example 102C (10.08 g, 47.8 mmol), hexamethyl-di-lead 2 (18 g, 55 mmol) and tetrakis (triphenylphosphine) in toluene (100 ml) ) A mixture of palladium (5.5 g, 4.8 mmol) was stirred at 95 ° C. for 6 hours. The mixture was then evaporated and the residue was dissolved in ethyl acetate (300 ml) and washed with saturated sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml). Ethyl acetate was removed by evaporation and the residue was purified by flash column chromatography on silica gel, eluting with 1: 4 ethyl acetate / hexanes to give the desired product (80%). MS: (ESI) m / z 409 (M + H) ^<+> .

(Example 102E)
(1S)-{1- (1H-Indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethyl} -carbamic acid tert- Butyl ester The desired product was prepared in Example 27B by using Example 102D instead of Example 27A.

(Example 102F)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine The desired product was run In Example 27C, Example 102E was prepared as the trifluoroacetate salt by substituting Example 27B.

(Example 103)
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- (1H-pyrrol-2-yl) -1H-indazol-5-yl] -pyridin-3-yloxy} -ethylamine

(Example 103A)
5-Bromo-2-fluoro - benzoic acid 5-bromo-2-fluorobenzaldehyde (810mg, 4.0mmol), 15% NaOH ( aq) (3mL), MeOH (5mL ) and _{30% H 2 O 2 (5mL} ) And the 30% mixture was stirred for 2 hours at room temperature and then acidified with 10% HCl (aq). The resulting white solid was collected, rinsed with water and dried to give the desired product (670 mg, 77%).

(Example 103B)
5-Bromo-2-fluoro-benzoyl chloride Example 103A (665 mg, 3.0 mmol) in thionyl chloride (7 mL) was heated at reflux for 2 hours, concentrated and azeotroped with toluene to give a colorless oil, Continued without further purification.

(Example 103C)
(5-Bromo-2-fluoro-phenyl)-(1H-pyrrol-2-yl) -methanone 103B (720 mg, 3.0 mmol) and pyrrole in 1,2-dichloroethane (10 mL) at 0 ° C. 203 mg, 3.0 mmol) was treated with AlCl ₃ in several portions, stirred overnight while gently warming to room temperature, treated with ice and 1N HCl, and stirred for 1.5 hours. , Extracted with CH ₂ Cl ₂ . The extract is rinsed with water and saturated NaHCO ₃ (aq), dried over Na ₂ SO ₄ , concentrated, isolated by flash chromatography (10% EtOAc / hexanes) and the desired product as a purple solid (252 mg, 31%) was obtained.

(Example 103D)
5-Bromo-3- (1H-pyrrol-2-yl) -1H-indazole The desired product was prepared in Example 102C by using Example 103C instead of Example 102B.

(Example 103E)
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- (1H-pyrrol-2-yl) -1H-indazol-5-yl] -pyridin-3-yloxy} -ethylamine desired The product was prepared in Example 27 by using Example 103D instead of 6-bromoisoquinoline.

(Example 104)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-phenyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine The desired product was run In Example 102, prepared by using phenylmagnesium bromide instead of methylmagnesium bromide.

(Example 105)
(1S) -2- [5- (3-Cyclopropyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine The desired product is In Example 102, prepared by using cyclopropyl magnesium bromide instead of methyl magnesium bromide.

(Example 106)
(1S) -2- [5- (3-Ethyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine The desired product was run In Example 102, prepared by using cyclopropyl magnesium bromide instead of methyl magnesium bromide.

(Example 107)
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [3- (1-methyl-1H-imidazol-2-yl) -1H-indazol-5-yl] -pyridine-3 -Iyloxy} -ethylamine The desired product was prepared in Example 102 by using N-methyl-2-imidazolyllithium chloride instead of methylmagnesium bromide.

(Example 108)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-thiazol-2-yl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine Desired formation The product was prepared in Example 102 by using 2-thiazolyl chloride chloride instead of methylmagnesium bromide.

(Example 109)
(1S) -2- {5- [3- (1H-imidazol-2-yl) -1H-indazol-5-yl] -pyridin-3-yloxy} -1- (1H-indol-3-ylmethyl)- Ethylamine

(Example 109A)
(1S)-[1- (1H-Indol-3-ylmethyl) -2- (5- {3- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-2-yl] -1H-indazole-5 -Yl} -pyridin-3-yloxy) -ethyl] -carbamic acid tert-butyl ester The desired product is obtained in Example 102 without the final step, N- [2-trimethylsilanyl) ethoxy chloride]. Methyl) -2-imidazolyllithium was prepared by using instead of methylmagnesium bromide.

(Example 109B)
(1S) -2- {5- [3- (1H-imidazol-2-yl) -1H-indazol-5-yl] -pyridin-3-yloxy} -1- (1H-indol-3-ylmethyl)- A solution of Example 109A (40 mg, 0.06 mmol) in ethylamine MeOH (4 mL) was treated with conc. HCl (1 mL), heated at reflux for 6 h, concentrated and 0% to 100% CH ₃ CN / H. Purification by reverse phase HPLC on a C18 column with ₂ O / 0.1% TFA gave the desired product as the trifluoroacetate salt.

(Example 110)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-thiophen-2-yl-1H-indazol-5-yl) -pyridin-4-yloxy] -ethylamine Desired formation The product was prepared in Example 102 by using 2-thiophenyllithium chloride instead of methylmagnesium bromide.

(Example 111)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-morpholin-4-yl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 111A)
5-Bromo-3-morpholin-4-yl-1H-indazole The reaction between Example 35A and morpholine is described in US Pat. Wizeciono, K.M. Majewska, J .; Dudzinska-Usareviez, M .; Performed according to the procedure described by Bernas, Pharmzie, 1986, 41, 472-474.

(Example 111B)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-morpholin-4-yl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine desired formation The product was prepared in Example 27 by using Example 111A instead of 6-bromoisoquinoline.

(Example 112)
(1S) -2- [5- (1,3-Dimethyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 112A)
5-Bromo-1,3-dimethyl-1H-indazole 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 minutes at room temperature, iodomethane (456 mg, 3.21 mmol) was added and the reaction was stirred for 2 hours, then diluted with water and extracted with EtOAc. The extract is rinsed with water and brine, dried (MgSO ₄ ), evaporated and isolated by flash chromatography (1: 1 Et ₂ O: hexanes) to give the desired product (360 mg, 67%). Obtained.

  (Example 112B)

  The desired product was prepared as the trifluoroacetate salt in Example 27 by using Example 112A instead of 6-bromoisoquinoline.

(Example 113)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [3- (3-methyl-1H-indazol-5-yl) -phenoxy] -ethylamine The desired product is obtained in Example 102. Prepared as the trifluoroacetate salt by using 3-bromophenol in place of 3-bromo-5-hydroxypyridine.

(Example 114)
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [3- (4-methyl-piperazin-1-yl) -1H-indazol-5-yl] -pyridin-3-yloxy } -Ethylamine

(Example 114A)
5-Bromo-3- (4-methyl-piperazin-1-yl) -1H-indazole The reaction between Example 35A and N-methylpiperazine was performed as described in US Pat. Wizeciono, K.M. Majewska, J .; Dudzinska-Usarewicz, M .; Performed according to the procedure described by Bermas, Pharmzie, 1986, 41, 472-474.

(Example 114B)
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [3- (4-methyl-piperazin-1-yl) -1H-indazol-5-yl] -pyridin-3-yloxy } -Ethylamine The desired product was prepared in Example 27 by using Example 114A instead of 6-bromoisoquinoline.

(Example 115)
(1S)-(5- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazol-3-yl) -dimethyl-amine

(Example 115A)
(5-Bromo-1H-indazol-3-yl) -dimethylamine The reaction between Example 35A and dimethylamine is described in U.S. Pat. Wizeciono, K.M. Majewska, J .; Dudzinska-Usarewiez, M .; Performed according to the procedure described by Bermas, Pharmzie, 1986, 41, 472-474.

(Example 115B)
(1S)-(5- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazol-3-yl) -dimethyl-amine desired The product of was prepared in Example 27 by using Example 115A instead of 6-bromoisoquinoline.

(Example 116)
(1S)-(4- (5- (2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -benzyl) -phenyl-amine

(Example 116A)
(1S)-[2- [5- (4-Formyl-phenyl) -pyridin-3-yloxy]-(1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester In Example 22, 4-formylphenylboronic acid was prepared by using instead of 4-cyanophenylboronic acid. MS: (ESI) m / z 472 (M + H) ^<+> .

(Example 116B)
(1S)-{1- (1H-Indol-3-ylmethyl) -2- [5- (4-phenylaminomethyl-phenyl) -pyridin-3-yloxy] -ethyl} -carbamic acid tert-butyl ester 2 mL A solution of Example 116A (0.03 g, 0.06 mmol) in MeOH was cooled to 0 ° C., then aniline (0.018 g, 0.2 mmol), NaBH ₃ CN (0.004 g, 0.06 mmol) and Treated with AcOH (1 ml). The mixture was warmed to room temperature overnight. The mixture was diluted with ethyl acetate (20 ml) and washed with water (10 ml) and brine (10 ml). Ethyl acetate was evaporated and the residue was used without further purification.

(Example 116C)
(1S)-(4- (5- (2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -benzyl) -phenyl-amine The desired product was run Prepared in Example 27C by using Example 116B instead of Example 27B.

(Example 117)
(1S)-(4- (5- (2-Amino-3- (1H-indol-3-yl) propoxy-pyridin-3-yl) -phenyl) -methanol

(Example 117A)
(1S)-{2- [5- (4-Hydroxymethyl-phenyl) -pyridin-3-yloxy] -1-phenyl-ethyl} -carbamic acid tert-butyl ester Example 116A (0.03 g, 0.06 mmol) ) Was dissolved in 2 mL of MeOH, cooled to 0 ° C. and then treated with NaBH ₄ (0.003 g, 0.08 mmol). The mixture was warmed to room temperature over 2 hours. The mixture was diluted with ethyl acetate (20 ml) and washed with water (10 ml) and brine (10 ml). The ethyl acetate was evaporated and the residue was used without further purification.

(Example 117B)
(1S)-(4- (5- (2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -methanol The desired product is obtained from Example 27C. Example 117A was prepared by substituting Example 117A for Example 27B.

(Example 118)
(1S) -2- (5- (4-Fluoro-phenyl) -pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine The desired product is obtained in Example 22, 4 Prepared by using fluorophenylboronic acid instead of 4-cyanophenylboronic acid.

(Example 119)
(1S) -4- (5- (2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -benzoic acid The desired product is obtained in Example 22. Prepared by using 4-hydroxycarbonylphenylboronic acid instead of 4-cyanophenylboronic acid.

(Example 120)
(1S) -2- (3-Bromo-5-isoquinolin-6-yl-phenoxyoxy) -1- (1H-indol-3-ylmethyl) -ethylamine

Stage 1
(Example 120A)
(2S)-[1- (3,5-Dibromo-phenoxymethyl) -2- (1H-indol-3-yl) -ethyl] -carbamic acid tert-butyl ester 3,5-dibromo in THF (30 mL) -Of 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) The solution was stirred at 0 ° C. for 30 minutes. To this mixture was added a solution of di-tert-butyl azidodicarboxylate (1.45 g, 9.2 mmol) in 5 ml of THF. The mixture was warmed to room temperature and then stirred at room temperature for 20 hours. Evaporated in THF and the residue was dissolved in ethyl acetate (75 ml) and washed with saturated sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml). The ethyl acetate was evaporated 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. 1.33 g of product was recovered (64%).

(Example 120B)
(2S)-[1- (3-Bromo-5-isoquinolin-6-yl-phenoxymethyl) -2- (1H-indol-3-yl) -ethyl] -carbamic acid tert-butyl ester in 5 mL of DMF A solution of Example 120A (0.6 g, 01.1 mmol) and 6-trimethylstannanyl-isoquinoline (0.26 g, 1 mmol) was added to 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 hours, then cooled, diluted with ethyl acetate (75 ml) and washed with saturated sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml). The ethyl acetate was evaporated 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.

0.2 g of product was recovered (30%). MS (ESI) m / z 572 (M + H) ⁺

(Example 120C)
(1S) -2- (3-Bromo-5-isoquinolin-6-yl-phenoxyoxy) -1- (1H-indol-3-ylmethyl) -ethylamine The desired product is obtained in Example 27C Prepared by using 120B instead of Example 27B.

(Example 121)
N4- (3- (5- (2-Amino-3- (1H-indol-3-yl) -propoxy-3-yl) -phenyl) -pyrimidine-2,4-diamine

(Example 121A)
(1S)-[2- [5- (3-Amino-phenyl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester desired product Was prepared in Example 22 by using 3-aminophenylboronic acid instead of 4-cyanophenylboronic acid.

(Example 121B)
(1S)-[2- {5- [3- (2-Amino-pyrimidin-4-ylamino) -phenyl] -pyridin-3-yloxy} -1- (1H-indol-3-ylmethyl) -ethyl]- Carbamic acid tert-butyl ester 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.

(Example 121C)
(1S)-[2- [5- (3-Amino-phenyl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester desired product Was prepared in Example 27C by using Example 121B instead of Example 27B.

(Example 122)
(1S) -3- (2-Amino-3- (1H-indol-3-yl) -propoxy) -5-isoquinolin-6-yl-phenylamine

(Example 122A)
(1S)-[2- [3- (Benzhydridene-amino) -5-isoquinolin-6-yl-phenoxy] -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester 5 mL A solution of Example 120B (0.165 g, 0.29 mmol) and benzophenone imine (0.1 mL, 0.6 mmol) in toluene was added to Pd ₂ dba ₃ (0.026 g, 0.028 mmol), BINAP (0.036 g). , 0.058 mmol) and sodium t-butoxide (0.042 g, 0.44 mmol). The reaction was heated to 80 ° C. overnight and then to 95 ° C. for 24 hours. The mixture was cooled and filtered through celite. The residue was purified by flash column chromatography on silica gel and eluted with 1: 1 ethyl acetate / hexane. 0.175 g of product was recovered (90%). MS (ESI) m / z 673 (M + H) ⁺

(Example 122B)
(1S) -3- (2-Amino-3- (1H-indol-3-yl) -propoxy) -5-isoquinolin-6-yl-phenylamine Example 122A (0.175 g, 0 in 2 mL THF) .26 mmol) was cooled to 0 ° C. and then treated with 1 mL of 3N HCl. The mixture was stirred at 0 ° C. for 15 minutes and then at room temperature for 4 hours. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel, eluting with 10% methanol in methylene chloride. 0.029 g of product was recovered (23%).

(Example 123)
4- (5-Isoquinolin-6-yl-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester

(Example 123A)
4- (5-Bromo-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester 3,5-dibromo-pyridine (12.8 g, 68.8 mmol) and piperazine-1 in 200 mL dioxane A solution of carboxylic acid tert butyl ester (10 g, 42.4 mmol) was added to Pd ₂ (dba) ₃ (5 g, 5.5 mmol), 2- (di-tbutyl-phosphino) biphenyl (4 g, 13.4 mmol) and Treated with sodium t-butoxide (7.2 g, 75 mmol). The reaction was heated to 95 ° C. for 8 hours, 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. 2.9 g of product was recovered (20%). MS (ESI) m / z 344 (M + H) ^<+> .

(Example 123B)
4- (5-Isoquinolin-6-yl-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester The desired product is obtained in Example 123B and Example 123A is replaced by Example 27A. Prepared by use.

(Example 124)
6- (5-Piperazin-1-yl-pyridin-3-yl) -isoquinoline The desired product was prepared in Example 27C by using Example 123 instead of Example 27B.

(Example 125)
((2S) -2-amino-5- (5- (2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl- (3-chloro-phenyl- Methanone The title compound was prepared in Example 32 by using 2-amino-5-iodo-3′-chlorobenzophenone instead of Example 32A.

(Example 126)
(1S) -N6- (3- (5- (2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -9H-purine-2,6- Diamine The title compound was prepared in Example 121 by using 6-chloro-9H-purin-2-ylamine instead of 4-chloro-2-pyrimidinylamine.

(Example 127)
(3- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -pyrimidin-2-yl-amine In Example 121, 2-chloropyrimidine was prepared by substituting 4-chloro-2-pyrimidinylamine.

(Example 128)
(3- (5-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -thiazol-2-yl-amine In Example 121, 2-chlorothiazole was prepared by substituting 4-chloro-2-pyrimidinylamine.

(Example 129)
N- (3- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -acetamide

(Example 129A)
(1S)-[2- [5- (3-Acetylamino-phenyl) -pyrimidin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester Example 121A (0.05 g, 0.11 mmol) was dissolved 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 at room temperature overnight 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.

(Example 129B)
N- (3- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -acetamide The desired product was run Prepared in Example 27C by using Example 129A instead of Example 27B.

(Example 130)
6- (5- (4- (1H-Indol-3-ylmethyl) -piperazin-1-yl) -pyridin-3-yl) -isoquinoline The title compound is obtained in Example 116B, Example 124 in aniline, 3 -Prepared by using formylindole instead of Example 116A.

(Example 131)
3-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -5-isoquinolin-6-yl-benzoic acid

(Example 131A)
3-[(2S) -2-tert-butoxycarbonylamino-3- (1H-indol-3-yl) -propoxy] -5-isoquinolin-6-yl-benzoic acid Example 120 (0) in 6 mL DMF 0.2 g, 0.3 mmol) was added to a solution of 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. and then bubbled with CO for 30 minutes. The mixture was heated to 80 ° C. overnight, then cooled, neutralized with HCl and washed with ethyl acetate. Water was evaporated to give the product. MS (ESI) m / z 538 (M + H) ^<+> .

(Example 131B)
3-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -5-isoquinolin-6-yl-benzoic acid The desired product is obtained in Example 27C Prepared by using 131A instead of Example 27B.

(Example 132)
4- (5-((2S) -2-Amino-3 (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenylamine The desired product is obtained in Example 22, 4 -Prepared by using aminophenylboronic acid instead of 4-cyanophenylboronic acid.

(Example 133)
N- (4- (5-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl-acetamide The desired product is At 129, Example 132 was prepared by using instead of Example 121A.

(Example 134)
N6- (4- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -9H-purine-2,6- Diamine The title compound was prepared in Example 126 by using Example 132 instead of Example 121A.

(Example 135)
^{N 4 - (4- (5 -} ((2S) -2- amino-3- (1H-indol-3-yl) - propoxy) - pyridin-3-yl) - phenyl) - pyrimidine-2,4-diamine The title compound was prepared in Example 121 by using Example 132 instead of Example 121A.

(Example 136)
(4- (5-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -pyrimidin-3-yl) -phenyl) -pyrimidin-2-yl-amine In Example 127, Example 132 was prepared by using instead of Example 121A.

(Example 137)
3-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -5-isoquinolin-6-yl-benzonitrile

(Example 137A)
(1S)-[2- (3-Cyano-5-isoquinolin-6-yl-phenoxy) -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester 3 mL dioxane and 1 mL Treat a solution of Example 120 (0.15 g, 0.3 mmol) in DMF with Pd (PPh ₃ ) ₄ (0.030 g, 0.026 mmol) and zinc cyanide (0.037 g, 0.3 mmol). did. 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 with 1: 1 ethyl acetate / hexane. 0.108 g of product was recovered (79%). MS (ESI) m / z 519 (M + H) ^<+> .

(Example 137B)
3-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -5-isoquinolin-6-yl-benzonitrile The desired product is obtained in Example 27C 137A was prepared by using instead of Example 27B.

(Example 138)
5′-Benzyloxy-5-isoquinolin-6-yl- (3,3 ′)-bipyridinyl

(Example 138A)
6- (5-Bromo-pyridin-3-yl) -isoquinoline The title compound was prepared in Example 27B by using 3,5-dibromopyridine instead of Example 2A.

(Example 138B)
3-Benzyloxy-5-trimethylstannanyl-pyridine The title compound was prepared in Example 27A by using 3-benzyloxy-5-bromopyridine instead of 6-bromoisoquinoline.

(Example 138C)
5′-Benzyloxy-5-isoquinolin-6-yl- (3,3 ′)-bipyridinyl The title compound was obtained in Example 27B, Example 138A in Example 2A and Example 138B in place of Example 27A. Prepared by use.

(Example 140)
(7-5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -pyrido (2,3-d) pyrimidin-4-yl) -Phenyl-amine

(Example 140A)
2-Amino-6-chloro-nicotinic acid A mixture of 2,6-dichloro-nicotinic acid (17.77 g, 92.6 mmol) in concentrated aqueous ammonia (173 mL) at 200 psi was heated to 130 ° C. for 24 hours. . The mixture was evaporated and the residue was dissolved in water (200 mL), neutralized with conc. HCl and then extracted into ether (200 ml). The ether was evaporated to give 12 g of product (75%). _{MS (DCI / NH 3) m} / z173 (M + 1) +.

(Example 140B)
2-Amino-6-chloro-nicotinamide To a mixture of Example 140A (11.9 g, 69.2 mmol) in 1,2-dichloroethane (100 mL) was added thionyl chloride (30 mL, 411 mmol) and DMF (catalyst). It was. The mixture was refluxed for 4 hours and then evaporated. The residue was dissolved in ether (200 mL) and ammonia was bubbled for 15 minutes. The mixture was stirred at room temperature overnight and washed with water (110 mL) and brine (100 ml). The ether was evaporated to give 9.2 g of product (78%). _{MS (DCI / NH 3) m} / z172 (M + 1) +.

(Example 140C)
A mixture of Example 140B in 7-chloro-pyrido [2,3-d] pyrimidin-4-ol triethylorthoformate (30 mL) was refluxed for 6 hours and then cooled. Hexane (150 mL) was added and the solid formed was purified and washed with water and hexanes to give 0.27 g of product (26%). _{MS (DCI / NH 3) m} / z = 182 (M + 1).

(Example 140D)
A mixture of Example 140C (1 g, 5.5 mmol) in 4,7-dichloro-pyrido [2,3-d] pyrimidine phosphorus oxychloride (40 mL) was refluxed for 2 hours, then cooled and evaporated. The residue was dissolved in ethyl acetate (75 ml) and washed with saturated sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL). Ethyl acetate was evaporated to give 0.8 g of product (73%).

(Example 140E)
(7-Chloro-pyrido [2,3-d] pyrimidin-4-yl) -phenyl-amine Example 140D (0.5 g, 2.5 mmol) in THF (25 mL) and 2-propanol (2.5 ml). ) And aniline (0.23 mL, 2.5 mmol) at 0 ° C. for 1 hour. Stir at room temperature for 2 days. The THF was evaporated and the residue was dissolved in ethyl acetate (75 ml) and washed with water (50 ml) and brine (50 ml). Ethyl acetate was evaporated and the residue was purified by flash column chromatography on silica gel, eluting with 1: 1 ethyl acetate / hexane. 0.15 g of product was recovered (23%). MS (ESI) m / z 390 (M + H) ^<+> .

(Example 140F)
(7-5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -pyrido (2,3-d) pyrimidin-4-yl) -Phenyl-amine The title compound was prepared in Example 27 by using Example 140E instead of 6-bromoisoquinoline.

(Example 141)
(7- (5-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -pyrido (2,3-d) pyrimidin-4-yl ) -Ethyl-amine The title compound was prepared in Example 140 by using ethylamine instead of aniline.

(Example 142)
(7- (5-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -pyrido (2,3-d) pyrimidin-4-yl ) -Benzyl-amine The title compound was prepared in Example 140 by using benzylamine instead of aniline.

(Example 143)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (6-isoquinolin-6-yl-pyrazin-2-yloxy) -ethylamine The title compound was obtained in Example 27 as 6-chloro-pyrazine. Prepared by using 2-ol in place of 3-bromo-5-hydroxypyridine.

  (1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1-phenyl-ethylamine

(Example 144A)
(1S)-[2- (5-Bromo-pyridin-3-yloxy) -1-phenyl-ethyl] -carbamic acid tert-butyl ester 5-bromo-pyridin-3-ol in THF (15 mL) (0. 3 g, 1.7 mmol), a solution of (2-hydroxy-1-phenyl-ethyl) -carbamic acid tert-butyl ester (0.41 g, 1.7 mmol), and triphenylphosline (0.52 g, 2 mmol). Stir at 0 ° C. for 30 minutes. To this mixture was added a solution of di-t-butyl azidodicarboxylate (0.46 g, 2 mmol) in 5 ml of THF. The mixture was warmed to room temperature and then stirred at room temperature for 20 hours. The THF was evaporated and the residue was dissolved in ethyl acetate (75 ml) and washed with saturated sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml). The ethyl acetate was evaporated 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. A mixture of 0.82 g of product and di-tert-butyl azidodicarboxylate was recovered. MS (ESI) m / z 395 (M + H) ^<+> .

(Example 144B)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1-phenyl-ethylamine The title compound is used in Example 27 and Example 144A is used instead of Example 2A. It was prepared by.

(Example 145)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (6- (3-methyl-1H-indazol-5-yl) -pyrazin-2-yloxy) -ethylamine The title compound was obtained in Example 143. Example 102C was prepared by substituting Example 102C for 6-bromoisoquinoline.

  The following compounds were made according to the procedure used in Example 27 or 102 using the appropriate Boc protected N-Boc-aminoethanol.

(Example 146)
(1S) -1-cyclohexylmethyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine

(Example 147)
(1S) -1-Benzyl-2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 148)
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-phenyl-ethylamine

(Example 149)
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-phenyl-ethylamine

(Example 150)
4-((2S) -2-amino-3- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) propyl) -benzonitrile

(Example 151)
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-naphthalen-2-ylmethyl-ethylamine

(Example 152)
4-((2S) -2-amino-3- (5-isoquinolin-6-yl-pyridin-3-yloxy-propyl) -benzonitrile

(Example 153)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1-naphthalen-2-ylmethyl) -ethylamine

(Example 154)
(1S) -1-Benzyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine

(Example 155)
(1S) -1- (4-Fluoro-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 156)
(1S) -1 (4-Fluoro-benzyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine

(Example 157)
2-((2S) -2-Amino-3- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -propyl) -benzonitrile

  2-((2S) -2-amino-3- (5-isoquinolin-6-yl) -pyridin-3-yloxy) -propyl) -benzonitrile

(Example 159)
(1S) -2-5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-pyridin-4-ylmethyl-ethylamine

(Example 160)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1-pyridin-4-ylmethyl-ethylamine

(Example 161)
(1S) -1- (4-Methyl-benzyl) -2- (5 (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 162)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1- (4-methyl-benzyl) -ethylamine

(Example 163)
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-quinolin-3-ylmethyl-ethylamine

(Example 164)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1-quinolin-3-ylmethyl-ethylamine

(Example 165)
(1R) -1-Benzyl-2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 166)
(1R) -1-Benzyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine

(Example 167)
4-((2S) -2-amino-3- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -propyl) -phenol

(Example 168)
(1S) -1- (4-Benzyloxy-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 169)
(1S) -1- (3-Methyl-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 170)
(1S) -1- (2-Methyl-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 171)
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1- (4-nitro-benzyl) -ethylamine

(Example 172)
(1S) -1- (4-Methoxy-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 173)
(1S) -1-Biphenyl-4-ylmethyl-2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 174)
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-naphthalen-1-ylmethyl-ethylamine

  (1S) -1- (3-Chloro-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 176)
3 ((2S) -2-amino-3- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -propyl] -benzonitrile

(Example 177)
(1S) -1- (3,4-Difluoro-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 178)
(1S) -1- (3,4-Dimethoxy-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 179)
(1S) -1- (3-Fluoro-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 180)
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1- (3-trifluoromethyl-1-benzyl) -ethylamine

(Example 181)
(1S) -1- (4-Ethoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 182)
(1S) -1- (4-tert-butyl-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 183)
(1S) -1- (4-Methoxy-3-methyl-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine

(Example 184)
2-((2S) -2-Amino-3- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -propyl) -4-methyl-phenol

(Example 185)
(1S) -1-Methyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 186)
(±) -1- (1H-Benzimidazol-2-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine

(Example 187)
(±) -1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine

(Example 188)
(1S) -1- (2-Fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] ethylamine

(Example 189)
(1S) -1- (2-Chloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 190)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-thiophen-2-ylmethyl-ethylamine

(Example 191)
(1R) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 192)
1- (4-Chloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 193)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-pyrrol-1-yl-benzyl) -ethylamine

(Example 194)
(1S) -1- (4-Methyl-benzylsulfonylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 195)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2-trifluoromethyl-benzyl) -ethylamine

(Example 196)
(1R) -1-Benzyl-3- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propylamine

(Example 197)
(1R) -1-Benzyl-4- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -butylamine

(Example 198)
(1S) -1- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -3-phenyl-propylamine

(Example 199)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1- (1-methyl-1H-indol-3-ylmethyl) -ethylamine trifluoroacetate

(Example 199)
(1S)-[1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -dimethyl-amine

(Example 200)
(1S) -1-Benzo [b] thiophen-3-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 201)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-thiophen-3-ylmethyl-ethylamine

(Example 202)
(1S) -1-Benzyloxymethyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine

(Example 202A)
(1S)-[1-Benzyloxymethyl-2- (5-bromo-pyridin-3-yloxy) -ethyl] -carbamic acid tert-butyl ester Was prepared instead of Boc-tryptophanol.

(Example 202B)
(1S)-[1-Benzyloxymethyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -carbamic acid tert-butyl ester The desired product is obtained in Example 27B. Prepared by substituting Example 202A for Example 2A.

(Example 202C)
(1S) -1-Benzyloxymethyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine Example 202B was performed with the desired product in Example 202, Example 27C. Prepared by using instead of Example 27A.

(Example 203)
(1S) -1-Benzyloxymethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 203A)
5-Bromo-3-methyl-indole-1-carboxylic acid tert-butyl ester Example 102C (1.0 g, 4.7 mmol), TEA (526 mg, 5.2 mmol), DMAP in CH ₃ CN (15 mL) A solution of (200 mg, 1.6 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.0 mmol) was stirred at room temperature for 3 h and simply by flash chromatography (30% Et ₂ O / hexane). On release, the desired product was obtained as a white solid (1.4 g, 95%).

(Example 203B)
3-Methyl-5-trimethylstannylindazole-1-carboxylic acid tert-butyl ester Example 203A (1.35 g, 4.3 mmol), hexamethylditine (1.56 g, 4. 5 ml) in toluene (15 mL). 8 mmol) and Pd (PPh ₃ ) ₄ (250 mg, 0.22 mmol) were stirred at 85 ° C. overnight, evaporated and purified by flash chromatography (20% Et ₂ O / hexanes) to give the desired The product was obtained (1.32 g, 77%).

(Example 203C)
(2S) -5- [5- (3-Benzyloxy-2-tert-butoxycarbonylamido-propoxy) -pyridin-3-yl] -3-methyl-indazole-carboxylic acid tert-butyl ester Example 202B was prepared by substituting Example 203B for Example 27A.

(Example 203D)
(1S) -1-Benzyloxymethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine The desired product is carried out in Example 27C. Prepared by substituting Example 203C for Example 27B.

(Example 204)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1- (naphthalen-2-yloxymethyl) -ethylamine

(Example 204A)
(1S)-[1-Hydroxymethyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -carbamic acid tert-butyl ester Example 202B (290 mg, 0.60 mmol) was added to formic acid. Ammonium (377 mg, 5.97 mmol), MeOH (wet) (15 mL), and 10% Pd / C (320 mg) were added sequentially. The resulting black reaction mixture was warmed to 70 ° C. for 6 days, then cooled to room temperature and filtered through celite. K ₂ CO ₃ (50 mg) and silica gel were added and the dilution was removed on a rotary evaporator. Flash chromatography _{(2-3-5-7% MeOH / CH 2 Cl} 2), was recovered 89 mg (38%) as a starting material and a colorless wax solid 40mg (14%).

(Example 204B)
(1S)-[2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1- (naphthalen-2-yloxymethyl) -ethyl] -carboxylic acid tert-butyl ester 2-naphthol (15 mg, 101 μmol), Example 204A (20 mg, 51 μmol), DBAD (17 mg, 76 μmol) and PPh ₃ -polymer (3 mmol / g) (34 mg, 101 μmol) were combined in a 10 mL round bottom flask. THF (2 mL) was added and the reaction mixture was stirred at 23 ° C. for 2 days, then rotary evaporated with silica gel. Flash chromatography (2-3-5% to 10% MeOH / CH ₂ Cl ₂ ) gave 19 mg (73%) as a colorless wax solid.

(Example 204C)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1- (naphthalen-2-yloxymethyl) -ethylamine The desired product is obtained in Example 27C and in Example 204B. Was prepared in place of Example 27B.

(Example 205)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1- (pyridin-3-yloxymethyl) -ethylamine The desired product is obtained in Example 204 as 3-hydroxy Prepared as the tri-TFA salt by using pyridine in place of 2-naphthol.

(Example 206)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1- (quinolin-7-yloxymethyl) -ethylamine The desired product is obtained in Example 204 as 7-hydroxy Prepared as the trifluoroacetate salt by using quinoline instead of 2-naphthol.

(Example 207)
(2S) -4- [2-Amino-3- (5-isoquinolin-6-yl-pyridin-3-yloxy) -propoxy] -benzonitrile The desired product is obtained in Example 204 as 4-cyanophenol. Was used instead of 2-naphthol.

(Example 208)
(2S) -N ′-(5- (3-Methyl-1H-indazol-5-yl) -pyridine-3-phenyl-propane-1,2-diamine

(Example 208A)
(2S)-{1-[(5-Bromo-pyridin-3-ylamino) -methyl] -2-phenyl-ethyl} -carbamic acid tert-butyl ester Example 23B in CH ₂ Cl ₂ (15 ml) (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) at room temperature. For 2 hours. The solvent was evaporated and the residue was dissolved in 15 ml EtOH. This solution was treated with NaBH ₃ CN (0.5 g, 4.9 mmol) and then stirred at room temperature overnight. The mixture was diluted with ethyl acetate (50 ml) and washed with water (25 ml) and brine (25 ml). Ethyl acetate was evaporated 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 2.8 g of product (30%). Obtained. MS: (ESI) m / z 408 (M + H) ^<+> .

(Example 208B)
(2S) -5- [5- (2-tert-Butoxycarbonylamino-3-phenyl-propylamino) -pyridin-3-yl] -3-methyl-indazole-1-carboxylic acid tert-butyl ester desired formation The product was prepared in Example 203C by using Example 208A instead of Example 202A.

(Example 208C)
(2S) -N ′-(5- (3-Methyl-1H-indazol-5-yl) -pyridine-3-phenyl-propane-1,2-diamine The desired product is carried out in Example 27C. Example 208B was prepared by using instead of Example 27B.

(Example 209)
(2S) -N- (2-Amino-3-phenyl-propyl) -N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -methylsulfonamide Pyridine (8 ml ) Was added dropwise to Example 208B (500 mg, 0.90 mmol) in an ice bath. The reaction mixture was warmed to room temperature and stirred for 12 hours. The solvent was removed by bubbling nitrogen through the reaction flask. The residue was chromatographed on silica gel and eluted with EtOAc to give the Boc protected product, which was deprotected according to the procedure described in Example 27C to give the title compound as the trifluoroacetate salt (21.2 mg, 4%).

(Example 210)
(2S) -N- (2-amino-3-phenyl-propyl) -N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -benzenesulfonamide desired formation The product was prepared as the trifluoroacetate salt in Example 209 by using benzenesulfonyl chloride instead of methanesulfonyl chloride.

(Example 211)
(2S) -N- (2-amino-3-phenyl-propyl) -N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -benzamide The desired product Prepared as the trifluoroacetate salt in Example 209 by using benzoyl chloride instead of methanesulfonyl chloride.

(Example 212)
(2S) -N- (2-Amino-3-phenyl-propyl) -N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -acetamide The desired product Prepared as the trifluoroacetate salt in Example 209 by using acetyl chloride in place of methanesulfonyl chloride.

(Example 213)
(2S) -3- [2-Amino-3- (1H-indol-3-yl) -propylidene] -5-isoquinolin-6-yl-1,3-dihydro-indol-2-one The desired product Prepared as the trifluoroacetate salt in Example 44, using 5-bromooxindole instead of 5-bromo-7-aza-oxindole.

(Example 214)
(1S) -2- (5-Isoquinolin-6-yl-pyridin-3-yloxy) -1- (1-methyl-1H-indol-3-ylmethyl) -ethylamine Prepared as the trifluoroacetate salt by using bromo-7-azaindole (D. Mazeas et al., Heterocycles 1990, 50, 1065) instead of 6-bromophthalimide.

(Example 215)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (1H-pyrrolo [2,3-b] pyridin-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 215A)
(1S) -N- [1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -2-nitro-benzenesulfonamide cooled ice To a solution of Example 27 (400 mg, 1.01 mmol) and DIEA (1.06 mL, 6.06 mmol) in THF (30 mL) in a bath was added 2-nitrobenzenesulfonyl chloride (896 mg, 4.04 mmol). . The reaction was warmed to room temperature for 12 hours. The reaction mixture is concentrated and the resulting crude oil is 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} / z580 (M + 1) +.

(Example 215B)
(1S) -N- [1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -N-methyl-2-nitro-benzenesulfone Amide To a solution of Example 215A (260 mg, 0.45 mmol), MeOH (16 μL, 4.5 mmol) and Ph ₃ P (591 mg, 2.25 mmol) in THF (10 mL) in an ice bath, DEAD (329 mg, 2 .25 mmol) was added dropwise. The reaction was warmed to room temperature for 12 hours. The reaction mixture was concentrated and the resulting crude oil was purified by flash column chromatography and extracted with EtOAc and EtOAc / MeOH (40: 3) to give the title compound (47 mg, 18%). _{MS (DCI / NH 3) m} / z594 (M + 1) +.

(Example 215C)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (1H-pyrrolo [2,3-b] pyridin-5-yl) -pyridin-3-yloxy] -ethylamine DMF (5 ml ), A mixture of Example 215B (47 mg, 0.08 mmol), PhSH (9.7 μL, 0.095 mmol) and K ₂ CO ₃ (33 mg, 0.237 mmol) was stirred at room temperature for 2 hours. The reaction was concentrated to dryness. The resulting residue was purified by C18 HPLC to give the title compound (34.2 mg, 58%).

(Example 216)
(1S) -2- {5- [2- (2-Fluoro-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 216A)
2-Fluoro-4-vinylpyridine in dioxane (20 mL), 2-fluoro-4-iodopyridine (2.23 g, 10.0 mmol), tributylvinyllead (3.8 g, 12 mmol) and Pd ₂ Cl ₂ (PPh A mixture of ₃ ) ₂ (703 mg, 1.0 mmol) was heated at 80 ° C. overnight under nitrogen. After cooling, ethyl acetate (40 ml) and saturated aqueous KF were added to the reaction mixture. The mixture was stirred for 30 minutes. The organic layer was separated, washed with water, dried (MgSO ₄ ) and concentrated. The resulting residue was purified by flash column chromatography, eluting with hexane / ethyl acetate (20: 1) to give the title compound (463 mg, 38%).

(Example 216B)
(1S)-[2- {5- [2- (2-Fluoro-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -1- (1H-indol-3-ylmethyl) -ethyl]- Carbamic acid tert-butyl ester The desired product was prepared as the trifluoroacetate salt in Example 2 by using Example 216A instead of 4-vinylpyridine (1.067 g, 84%).

(Example 217)
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [2- (2-methoxy-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -ethylamine

(Example 217A)
(1S)-(1- (1H-Indol-3-ylmethyl) -2- {5- [2- (2-methoxy-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -ethyl)- Carbamic acid tert-butyl ester A mixture of Example 216B (100 mg, 0.2 mmol), NaOMe (25% in MeOH) in MeOH (10 mL) was refluxed for 8 hours. The mixture was concentrated to give the crude product.

(Example 217B)
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [2- (2-methoxy-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -ethylamine Example 217A Was treated with TFA (1 mL) at room temperature for 10 minutes. TFA was removed and the crude material was purified on C18 HPLC to give the title compound (101.8 mg, 69%).

(Example 218)
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [2- (2-phenoxy-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -ethylamine Example 216B A mixture of (50 mg, 0.1 mmol), phenol (94 mmol, 1.0 mmol) and KOH (11.2 mg, 0.2 mmol) was heated in a sealed vessel at 140 ° C. for 2 hours. The mixture was concentrated to dryness. The residue was then treated with TFA (1 mL) for 10 minutes at room temperature. TFA was removed and the crude product was purified on C18 HPLC to give the title compound (4.3 mg, 5.3%).

(Example 219)
(1S) -2- {5- [2- (2-Benzylsulfanyl-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -1- (1H-indol-3-ylmethyl) -ethylamine Title compound Was obtained as the trifluoroacetate salt in Example 218 by using benzylthiol instead of phenol.

(Example 220)
[4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -vinyl) -pyridin-2-yl]- Cyclopropyl-amine A mixture of Example 216 (100 mg, 0.2 mmol) and cyclopropylamine (1.5 mL) was heated at 125 ° C. for 36 hours. The mixture was concentrated to dryness. The residue was then treated with TFA (1 mL) for 10 minutes at room temperature. After removing TFA, the crude product was purified on C18 HPLC to give the title compound (4.1 mg, 3%).

(Example 221)
[4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -vinyl) -pyridin-3-yl}- (Vinyl) -pyridin-2-yl] -benzyl-amine The title compound was prepared as the trifluoroacetate salt in Example 220 by using benzylamine instead of cyclopropylamine (38.2 mg, 23 %).

(Example 222)
[4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -vinyl) -pyridin-3-yl}- (Vinyl) -pyridin-2-yl] -ethyl-amine The title compound was prepared as the trifluoroacetate salt in Example 220 by using ethylamine instead of cyclopropylamine (16 mg, 15%).

(Example 223)
[4- (1- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -vinyl) -pyridin-2-yl]- Methyl-amine The title compound was prepared as the trifluoroacetate salt in Example 220 by using methylamine instead of cyclopropylamine (11.9 mg, 8%).

(Example 224)
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [2- (2-Indol-1-yl-pyridin-4-yl) -vinyl] -pyridin-3-yloxy}- Ethylamine A mixture of Example 216 (100 mg, 0.2 mmol), indole (48 mg, 0.4 mmol) and NaH (60%) (29 mg, 0.72 mmol) in DMF (5 mL) at 125 ° C. 1. Heated for 5 hours. The mixture was concentrated to dryness. The residue was then treated with TFA (1 mL) at room temperature for 10 minutes. After removing TFA, the crude product was purified on C18 HPLC to give the title compound (8.1 mg, 5%).

(Example 225)
(±) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2-methyl-1H-indol-3-ylmethyl) -ethylamine

(Example 225A)
3-Bromo-2-hydroxyimino-propionic acid ethyl ester Ethyl bromopyruvic acid (5.0 mL, 39.8 mmol) was added to hydroxyamine hydrochloride (2.52 g, in H ₂ O (10 mL) and CHCl ₃ (10 mL). 36.2 mmol). The reaction mixture is capped and when CH ₂ Cl ₂ and H ₂ O are added, it is stirred overnight at 23 ° C., the layers are separated, the organics are dried over Na ₂ SO ₄ and the evaporates are Removal on a rotary evaporator gave 7.58 g (100%) as a white solid. ¹ H NMR (300 MHz, DMSO-D6) δ ppm 1.26 (t, J = 7.12 Hz, 3H) 4.20 (s, 2H), 4.24 (m, 2H), 13.19 (s, 1H) .

(Example 225B)
2-Hydroxyimino-3- (2-methyl-1H-indol-3-yl) -propionic acid ethyl ester The desired product is obtained according to the method of the reference (J. Chem. Soc. Chem. Comm 1979, 1089). Prepared. To 2-methylindole (1.28 g, 9.76 mmol) and Na ₂ CO ₃ (1.24 g, 11.7 mmol) in CH ₂ Cl ₂ was added Example 225A (2.05 g, 9.76 mmol). . The resulting reaction mixture was stirred at 23 ° C. overnight when H ₂ O was added, the layers were separated, and the organic layer was dried over Na ₂ SO ₃ . Flash chromatography (20-30-50-70% EtOAc / hexanes) gave 1.41 g (56%) as a green solid.

(Example 225C)
(±) -2-tert-Butoxycarbonylamino-3- (2-methyl-1H-indol-3-yl) -propionic acid ethyl ester The desired compound was prepared according to the method of references (Angew. Chem. Int. Ed. Engl. 1979, 78, and Tet. Lett. 1988, p447). Aluminum wheels (1.18 g, 43.8 mmol) were cut into long thin (1 cm) strips and then placed in a 2% aqueous HgCl ₂ solution (each strip for 30 seconds). Each strip was immediately washed sequentially with H ₂ O, MeOH, and Et ₂ O. Each strip was then immediately cut into small pieces (˜1 × 0.5 cm) in Example 225B (1.14 g, 4.38 mmol) in THF (60 mL) and H ₂ O (6 mL) and placed in a water bath. And kept at room temperature. The mixture was stirred vigorously at 23 ° C. After a short time, a pure black solid began to form and bubbling was observed. The reaction mixture was stirred for 3 hours, then filtered through celite and the filtrate was washed with Et ₂ O. All evaporates were removed on a rotary evaporator. In MeOH (50 mL) was added followed _{Na 2 CO 3 (0.51g, 4.82mmol} ) and _Boc 2 O (1.00g, _4.60mmol) and. The resulting reaction mixture was stirred at 23 ° C. for 30 minutes, then silica gel was added and the evaporate was removed on a rotary evaporator. Flash chromatography (10-30-40-50% EtOAc / hexanes) gave 1.33 g (88%) as an off-white solid.

(Example 225D)
(±)-[2-Hydroxy-1- (2-methyl-1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester Example 225C in a 500 mL round bottom flask equipped with a stir bar (1.30 g, 3.75 mmol) and CaCl ₂ (anhydride) (0.83 g, 7.51 mmol) to EtOH (wet) (30 mL), THF (20 mL) and NaBH ₄ (0.57 g, 15.0 mmol). ) Was added continuously. The resulting cloudy reaction mixture was stirred at 23 ° C. for 1 hour, then poured onto 1M citric acid and extracted with EtOAc. The organic extract was washed with brine and dried over MgSO ₄ . Silica gel and NaHCO ₃ (100 mg) were added and volatiles were removed on a rotary evaporator. Flash chromatography (35-50-60% EtOAc / hexanes) gave 1.08 g (95%) as a white solid.

(Example 225E)
(±)-[2- (5-Bromo-pyridin-3-yloxy) -1- (2-methyl-1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester In Example 2A, Example 225D was prepared by substituting Boc-tryptophanol.

(Example 225F)
(±)-[1- (2-Methyl-1H-indol-3-ylmethyl) -2- (5-trimethylstannanyl-pyridin-3-yloxy) -ethyl] -carbamic acid tert-butyl ester Example 225D ( 350 mg, 0.76 mmol), Pd (PPh ₃ ) ₄ (88 mg, 0.08 mmol) and hexamethylditine (300 mg, 0.92 mmol) were combined in a 25 mL round bottom flask equipped with a stir bar. The flask was evacuated and replaced with argon. Toluene (4 mL) was added and the resulting reaction mixture was warmed to 100 ° C. for 2 hours and then cooled to room temperature. Flash chromatography (30-40-50-60% EtOAc / hexanes) gave 294 mg (71%) as a yellow solid.

(Example 225G)
(±)-[2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2-methyl-1H-indol-3-ylmethyl) -ethyl]- Carbamic acid tert-butyl ester Bromo-methylindazole (71 mg, 0.33 mmol), Example 225F (200 mg, 367 mmol), Pd ₂ dba ₃ (61 mg, 0.7 mmol) and P (o-tol) ₃ (41 mg, 0 .14 mmol) were combined in a 10 mL round bottom flask equipped with a stir bar. DMF (2 mL) was added and the atmosphere in the flask was evacuated and replaced with argon twice. Et ₃ N (0.09 mL, 0.67 mmol) was added and the reaction mixture was warmed to 80 ° C. for 5 hours and then cooled to room temperature. EtOAc was added and the resulting mixture was filtered through celite. The filtrate was washed twice with H ₂ O and once with brine. Silica gel was added and the evaporate was removed on a rotary evaporator. Flash chromatography (70-85-100% EtOAc / hexanes) gave 48 mg (28%) as a yellow solid.

(Example 225H)
(±) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2-methyl-1H-indol-3-ylmethyl) -ethylamine In Example 27C, Example 225G was prepared as the trifluoroacetate salt by using in place of Example 27B (31.9 mg, 84%).

(Example 226)
7- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -quinazolin-2-ylamine

(Example 226A)
7-Bromo-quinazolin-2-ylamine 4-Bromo-2-fluoro-benzaldehyde (0.61 g, 3 mmol), guanidine (1.05 g, 5.83 mmol) and DMF were heated at 140 ° C. for 2.5 hours. . 50 ml of water was added to this mixture. The orange precipitate was filtered and washed with water. The solid was dissolved in 2N HCl and filtered. The HCl solution was neutralized with ammonium hydroxide. The off-white solid was filtered and dried under vacuum to give the desired product (91 mg, 14%).

(Example 226B)
7- {5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -quinazolin-2-ylamine The desired product is obtained in Example 32. Example 226A was prepared as a tri-TFA salt by substituting Example 226A for 6-bromophthalimide.

(Example 227)
2-Phenyl-2- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -ethylamine

(Example 227A)
(2,6-Difluoro-pyridin-3-yl) -pyridin-4-yl-methanol-To diisopropylamine (9.3 mL, 66.1 mmol) in THF (100 mL) at -78 ° C was added n-BuLi (hexane. 23.1 mL of a 2.5 M solution, 57.8 mmol) was added dropwise via a syringe. 2,6-Difluoropyridine (5.0 mL, 55.1 mmol) in THF (100 mL) at −78 ° C. was added dropwise via cannula to the LDA solution prepared above to give a clear yellow-green solution. Got. Isonicotinaldehyde (6.3 mL, 66.1 mmol) was added and a white precipitate was formed. The reaction mixture was warmed to room temperature and then glacial acetic acid (3.3 mL, 57.8 mmol) was added. Silica gel was added and volatiles were removed on a rotary evaporator. Flash chromatography (80-100% EtOAc / hexanes-3-5-7% MeOH / EtOAc) gave 8.48 g (69%) as an off-white solid.

(Example 227B)
(2,6-Difluoro-pyridin-3-yl) -pyridin-4-yl-methanone Example 227A (7.36 g, 33.1 mmol) and MnO ₂ (8.46 g, 99.4 mmol) were added to a stirring bar. Mix in a 500 mL round bottom flask equipped. 1,4-Dioxane (120 mL) was added and the resulting black mixture was warmed to 110 ° C. MnO ₂ (˜22 g) was added in an amount of 2 g every few hours over 2 days. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was washed with EtOAc and then all volatiles were removed on a rotary evaporator. Flash chromatography (50-70-80% EtOAc / hexanes) gave 4.61 g (63%) as a green solid.

(Example 227C)
6-Fluoro-3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridine Into 227B (4.20 g, 19.1 mmol) in 1,4-dioxane (100 mL) was added hydrazine hydrate. (0.93 mL, 19.1 mmol) was added. The resulting yellow reaction mixture was stirred at 23 ° C. for 20 minutes, then silica gel was added and volatiles were removed on a rotary evaporator. Flash chromatography (60-80-100% EtOAc / Hexane-1% to 5% MeOH / EtOAc) gave 2.49 g (61%) as a white solid.

(Example 227D)
Phenyl- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -acetonitrile Example 227C in DMF (20 mL) at −35 ° C. (0.96 g, 4 To a stirred mixture of .48 mmol) was added benzyl cyanide (1.55 mL, 13.4 mmol) followed by NaH (0.57 g of 95% NaH, 22.4 mmol). The resulting dark red mixture was stirred for 15 minutes while slowly warming to -20C. At this point, most of the foam had ceased and then the reaction was quickly warmed to room temperature and overnight to 100 ° C. 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 extract was washed twice with H ₂ O and once with brine. Silica gel was added and volatiles were removed on a rotary evaporator. Flash chromatography (60-80-100% EtOAc-3% MeOH / EtOAc) gave 1.14 g (82%) as an orange solid.

(Example 227E)
2-Phenyl-2- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -ethylamine Example 227D was carried out on the desired product in Example 41D. Prepared by using instead of Example 41C (84 mg, 27%).

(Example 228)
Naphthalen-2-yl- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -acetonitrile The desired product is obtained in Example 227D using 2-naphthylacetonitrile. Prepared by using in place of benzyl nitrile (244 mg, 42%).

(Example 229)
2-Naphthalen-2-yl-2- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -ethylamine The desired product is carried out in Example 41D. Example 228 was prepared by using instead of Example 41C.

(Example 230)
(3-Isoquinolin-6-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -phenyl-acetonitrile

(Example 230A)
Isoquinoline-6-carbaldehyde A solution of 6-bromoisoquinoline (19.9 g, 95.6 mmol), PdCl ₂ (dppf) · CH ₂ Cl ₂ (1.8 g) and triethylamine (30 mL) in toluene (50 mL) was added. Heated at 130 ° C. under 850 psi H ₂ / CO (1: 1) for 4 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated and the residue was purified by flash chromatography, eluting with 70-80-90-100% EtOAc / hexanes to give 6.11 g (41%) of the aldehyde as a yellow solid.

(Example 230B)
(3-Isoquinolin-6-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -phenyl-acetonitrile The desired product (244 mg, 42%) was obtained in Example 227. Prepared by using 230A instead of isonicotinaldehyde.

(Example 231)
2- (3-Isoquinolin-6-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -2-phenyl-ethylamine Example 230 was carried out with the desired product in Example 41D. Prepared by using instead of Example 41C.

(Example 232)
(1S) -1-Benzyl-2- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-5-yloxy) -ethylamine

(Example 232B)
5- (tert-butyl-dimethyl-silanyloxy) -2-fluoro-pyridine 2-fluoro-4-hydroxypyridine (1.00 g, 8.84 mmol) and BDCS reagent (0.5 M TBSCl, 1.0 M imidazole in DMF) ) (35.4 mL, 17.7 mmol) was stirred at room temperature for 1 hour. The reaction was poured into 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 / hexane to give the title compound (1.96 g, 98%).

(Example 232B)
5- (tert-Butyl-dimethyl-silanyloxy) -3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridine The desired product is obtained in Example 227A and Example 232A in 2,6 Prepared according to the procedure used for Example 227C by using in place of difluoropyridine.

(Example 232C)
5- (tert-Butyl-dimethyl-silanyloxy) -3-pyridin-4-yl-pyrazolo [3,4-b] pyridine-1-carboxylic acid tert-butyl ester The desired product is obtained in Example 203A. Example 232B was prepared by using instead of Example 102C (75%).

(Example 232D)
5-Hydroxy-3-pyridin-4-yl-pyrazolo [3,4-b] pyridine-1-carboxylic acid tert-butyl ester Example 232C (91 mg, 0.213 mmol) and TBAF (THF in THF (10 mL) 1M, 213 μL, 0.213 mmol) was stirred at room temperature for 5 minutes. The reaction was concentrated. The residue was purified by flash chromatography eluting with 5% methanol / CH ₂ Cl ₂ to give the desired product (75%).

(Example 232E)
5-((2S) -2-tert-butoxycarbonylamino-3-phenyl-propoxy) -3-pyridin-4-yl-pyrazolo [3,4-b] pyridine-1-carboxylic acid tert-butyl ester Title compound Was prepared in Example 238B by using Example 232D in place of Example 238A and Boc-4′-bromophenylalaninol.

(Example 232F)
(1S) -1-Benzyl-2- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-5-yloxy) -ethylamine Example 232E in CH ₂ Cl ₂ (4 mL) 39 mg, 71 μmol) was added 4-methoxybenzyl mercaptan (30 μL, 214 μmol) followed by TFA (1 mL). The resulting yellow reaction mixture was stirred for 50 minutes at 23 ° C., where all volatiles were removed on a rotary evaporator. K ₂ CO ₃ (excess) and MeOH (5 mL) were added and the resulting mixture was stirred for 1 hour at 23 ° C. where silica gel was added and volatiles were removed on a rotary evaporator. Flash column chromatography (EtOAc-5-10-12% MeOH / CH ₂ Cl ₂ ) yielded a light yellow wax acid product, which was dissolved in 20% MeOH / CH ₂ Cl ₂ and dissolved in 1N HCl (Et 1 mL 1N solution in ₂ O, 1 mmol) and stirred for 1 hour. Volatiles were removed to give 11 mg (17%, 2 steps) of a yellow solid that was the bis-HCl salt.

(Example 233)
2-Benzyl-3- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propylamine The desired product is obtained in Example 102 as (2-benzyl-3 -Hydroxy-propyl) -carbamic acid tert-butyl ester (Khumveeporn, K .; Ullmann, A .; Matsumoto, K .; Davis, BG; Jones, J. B. Tetrahedron: Asymmetry 2001, 12, 249) .

(Example 234)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (2-pyridin-4-yl- [1,7] naphthyridin-5-yloxy] -ethylamine

(Example 234A)
3-Bromo-5- (4-methoxy-benzyloxy) -pyridine 3-bromo-5-hydroxypyridine (14.7 g, 84.3 mmol), tetrabutylammonium iodide (0.3 g, 0.8 mmol) and K ₂ CO ₃ (14.0 g, 101 mmol) was combined in a dry 500 mL round bottom flask equipped with a stir bar. DMF (170 mL) was added followed by PMBCl (12.0 mL, 88.5 mmol). The resulting brown mixture was stirred at 23 ° C. for 3.5 days, then silica gel was added and volatiles were removed on a rotary evaporator. Flash chromatography (10-20-40% EtOAc / hexanes) gave 14.1 g (57%) of an orange solid.

(Example 234B)
3-Amino-5- (4-methoxy-benzyloxy) -pyridine 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 equipped with a stir bar. 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, then cooled to room temperature, diluted with Et ₂ O and filtered through celite. Volatiles were removed on a rotary evaporator. Flash chromatography (30-40-50% EtOAc / hexanes) gave a crude orange oil that was dissolved in THF (180 mL) and 1N HCl (60 mL). The resulting orange mixture was stirred for 15 minutes and then partitioned between 30% EtOAc / hexanes and 0.5M HCl. The layers were separated and the organic layer was washed once with 0.5M HCl. The combined HCl layers were washed once with 30% EtOAc / hexane and then cooled to 0 ° C. 50% aqueous NaOH was added until the mixture was basic on litmus paper, and the mixture was then extracted twice with CH ₂ Cl ₂ . The combined organic extracts were dried over Na ₂ SO ₄ and the volatiles were removed on a rotary evaporator to give 8.92 g (71%, 2 steps) as a yellow solid.

(Example 234C)
[5- (4-Methoxy-benzyloxy) -pyridin-3-yl] -carbamic acid tert-butyl ester Stirring of Example 234B (8.92 g, 38.7 mmol) in THF (240 mL) at 23 ° C. To the solution, NaHMDS (0.6 M solution in toluene, 129 mL) was added dropwise via a syringe. The resulting opaque tan mixture was stirred for 5 minutes and then Boc ₂ O (8.45 g, 38.7 mmol) was added all at once. The opacity of the mixture disappeared, leaving a clear tan solution. The pH of the aqueous layer was ˜8. The organic layer was washed with brine and combined with silica gel before the volatiles were removed on a rotary evaporator. Flash chromatography (30-40-50-70% EtOAc / 10% hexane _{-5% MeOH / CH 2 Cl 2} ), bis -Boc protection of 1.69 (10%), as an orange solid, 7.04 g (55%) of the desired mono-Boc protect was obtained as a yellow solid and 1.51 g (17%) of the starting amine as an orange solid. Data on Bis-Boc.

(Example 234D)
[4-Formyl-5- (4-methoxy-benzyloxy) -pyridin-3-yl] -carbamic acid tert-butyl ester Example 78C (2.50 g, 7) in THF (125 mL) at -78 ° C. .4 mmol) was added dropwise via a syringe, n-BuLi (2.5 M solution in hexane, 6.64 mL, 16.6 mmol). The resulting dark orange reaction mixture was slowly warmed to -10 ° C over 45 minutes and then cooled again to -78 ° C. Methyl formate (1.40 mL, 22.6 mmol) was added dropwise via syringe and the reaction was stirred for an additional 10 minutes at -78 ° C. Saturated aqueous NH ₄ Cl was added to quench the reaction mixture warmed to room temperature. H ₂ O and Et ₂ O were added and the layers were separated. The organics were washed with brine and dried over MgSO ₄ . Flash chromatography (20-40-60-80% EtOAc / hexanes) recovered 0.3 g (12%) of starting material to give 1.7 g (63%) as a yellow solid.

(Example 234E)
5- (4-Methoxy-benzyloxy)-[1,7] naphthyridin-2-ol Bis (2,2,2-trifluoroethyl) (methoxycarbonylmethyl) phosphate in THF (45 mL) at -78 ° C To (1.27 mL, 5.99 mmol), KHMDS (0.5 M solution in toluene, 11.1 mL, 5.53 mmol) was added dropwise via a syringe. The resulting clear, light yellow solution was added dropwise via cannula to Example 234D (1.65 g, 4.60 mmol) in THF (60 mL) at −78 ° C. The resulting opaque yellow reaction mixture was stirred at −78 ° C. for 20 minutes when saturated aqueous NH ₄ Cl was added, and the quenched reaction mixture was allowed to warm to room temperature. H ₂ O and Et ₂ O were added and the layers were separated. The organics were washed with brine and dried over MgSO ₄ . Flash chromatography (40-50-60-70% EtOAc / hexanes) gave 1.98 g of crude product, a 5: 1 mixture of Z; E olefin isomers. The crude product in THF (150 mL) was stirred for 30 minutes at 23 ° C. with the addition of silica gel and the volatiles were removed on a rotary evaporator. By flash chromatography (60% to 100% EtOAc / hexanes-5% to 10% MeOH / CH ₂ Cl ₂ ), 0.23 g (12%) of the E-olefin as a yellow solid, 0.98 g (75%, The desired product of 2 steps) was obtained as a white solid.

(Example 234F)
2-Chloro-5- (4-methoxy-benzyloxy)-[1,7] naphthyridine To a suspension of Example 234D (2.21 g, 7.83 mmol) in DMF (50 mL) at 23 ° C. was added POCl. ₃ ((2.2 mL, 23.5 mmol) was added. All solid starting materials were dissolved and the resulting yellow reaction mixture was warmed for 6 hours at 45 ° C. The color of the reaction was yellow to dark reddish brown. The reaction was poured onto NaHCO ₃ (13.2 g, 157 mmol) in water (250 mL) in a 1 L Erlenmeyer flask with vigorous stirring.The product was poured into EtOAc and Et _2. and extracted with O, 2 times and the organic extracts with H _{2 O,} washed once with brine. silica gel was added, the volatiles were removed on a rotary evaporator. flash chromatograph The over (20-30-40-50% EtOAc / hexanes) to give 1.86g (79%) as an off-white solid.

(Example 234G)
5- (4-Methoxy-benzyloxy) -2-pyridin-4-yl- [1,7] naphthyridine Example 234F (164 mg, 0.55 mmol), 4-tributylstannylpyridine (401 mg, 1.09 mmol), Pd ₂ dba ₃ (50 mg, 0.06 mmol) and 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl (43 mg, 0.11 mmol) were added in a 10 mL round bottom flask equipped with a stir bar. Mixed. The flask was evacuated and replaced twice with argon. DMF (2 mL) and Et ₃ N (0.5 mL, 3.27 mmol) were added and the reaction mixture was warmed to 100 ° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and Et ₂ O, and filtered through celite. The filtrate was washed twice with H ₂ O and once with brine. Silica gel was added and volatiles were removed on a rotary evaporator. The 5% MeOH / _CH 2 Cl ₂ from the flash chromatography (70% from 100% EtOAc / hexanes to 2%, to give 92mg (49%) as a yellow solid.

(Example 234I)
2-Pyridin-4-yl- [1,7] naphthyridin-5-ol Example 234H (108 mg, 0.32 mmol) in a 50 mL round bottom flask equipped with a stir bar was added to 1N in EtOH (8 mL). A mixture of HCl (1.6 mL, 1.57 mmol) was added. The resulting reaction mixture was warmed to 90 ° C. for 2 hours, cooled to room temperature, and then poured onto K ₂ CO ₃ (120 mg, 0.87 mmol) in a 100 mL round bottom flask. MeOH (10 mL) was added, the mixture was stirred vigorously for 1 hour, silica gel was added at this point and the volatiles were removed by rotary evaporator. Flash chromatography (3-5-7-12% MeOH / CH ₂ Cl ₂ ) provided 52 mg (74%) as an off-white solid.

(Example 234J)
(1S)-[1- (1H-Indol-3-ylmethyl) -2- (2-pyridin-4-yl- [1,7] naphthyridin-5-yloxy) -ethyl] -carbamic acid tert-butyl ester desired The product of was prepared in Example 27A by using Example 232I instead of 3-bromo-5-hydroxypyridine.

(Example 234K)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (2-pyridin-4-yl- [1,7] naphthyridin-5-yloxy] -ethylamine The desired product is obtained in Example 232E. Example 234K was prepared as the trifluoroacetate salt by substituting Example 232D for Example 232D.

(Example 235)
(1R) -1- (1H-Indol-3-ylmethyl) -2- (2-pyridin-4-yl)-[1,7] naphthyridin-5-yloxy) -ethylamine The desired product is obtained in Example 234. In Boc-R-tryptophanol in place of Boc-L-tryptophanol.

(Example 236)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-ylsulfanyl) -ethylamine

(Example 236A)
3-Bromo-5- (4-methoxy-benzylsulfanyl) -pyridine To a suspension of sodium hydride (370 mg, 60% in mineral oil, 9.25 mmol) in DMF (30 ml), (4-methoxy-phenyl) -Methaneethiol (1.25 ml, 9 mmol) was added. The resulting solution was stirred at room temperature for 1 hour and added to 3,5-dibromopyridine (2.13 g, 8.99 mmol) in DMF (30 ml). The mixture was stirred at room temperature for 48 hours. The reaction solution was partitioned between ether and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. Purified on silica gel and eluted with 5% ethyl acetate / hexanes to give the title compound (1.75 g, 63%).

(Example 236B)
5-Bromo-pyridine-3-thiol 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 cooling to room temperature, the solution was dried in vacuo. Purified on silica gel and eluted with 5% ethyl acetate in hexanes to give the crude title compound (mixed with disulfide).

(Example 236C)
(1S)-[2- (5-Bromo-pyridin-3-ylsulfanyl) -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester To 100 ml RBF, 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 hour and at room temperature for 22 hours. The reaction mixture was concentrated and the residue was separated by flash chromatography (30% EtOAc in hexanes) to give 0.614 g of product with DBAD.

(Example 236D)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-ylsulfanyl) -ethylamine The desired product is obtained in Example 27 Prepared by using 236C instead of Example 2A.

(Example 237)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-methyl-1H-indol-5-yl) -pyridin-3-ylsulfanyl] -ethylamine Prepared at 236 by using Example 102C instead of 6-bromoisoquinoline.

(Example 238)
(1S) -1- (4-Bromo-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 238A)
5- (5-Hydroxy-pyridin-3-yl) -3-methyl-indazole-1-carboxylic acid tert-butyl ester The desired product was subjected to 3-bromo-5-hydroxypyridine in Example 203C. Prepared by using instead of Example 203B.

(Example 238B)
(1S)-{1- (4-Bromo-benzyl) -2- [5- (3-methyl-1H-indol-5-yl) -pyridin-3-yloxy] -ethyl} -carbamic acid tert-butyl ester The desired product is obtained in Example 2A using Example 238A in place of 3-bromo-5-hydroxypyridine and 3′-bromo-Boc-phenylalaninol in place of Boc-tryptophanol. Was prepared according to the procedure described for Example 2A.

(Example 238C)
(1S) -1- (4-Bromo-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine The desired product is obtained in Example 27. Example 238B was prepared as the trifluoroacetate salt by substituting Example 238B for Example 27B.

(Example 239)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (2-methyl-quinazolin-7-yl) -pyridin-3-yloxy] -ethylamine

(Example 239A)
7-Bromo-2-methyl-quinazoline 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 to give 47 mg of product in 4% yield. MS (ESI) m / e 223 (M + 1) ^<+> .

(Example 239B)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (2-methyl-quinazolin-7-yl) -pyridin-3-yloxy] -ethylamine The desired product is obtained in Example 32. Example 239A was prepared in place of 6-bromophthalimide.

(Example 240)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (1H-indol-5-yl) -pyridin-3-yloxy] -ethylamine The desired product is obtained in Example 32. , 5-bromoindole was used in place of 6-bromophthalimide.

(Example 241)
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5-4- (1H-tetrazol-5-yl) -phenyl] -pyridin-3-yloxy} -ethylamine The desired product is Prepared in Example 32 by using 5- (4-bromo-phenyl) -1H-tetrazole instead of 6-bromophthalimide.

(Example 242)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyrimidin-4-yloxy) -ethylamine

(Example 242A)
5-Bromo-pyrimidin-4-ol Pyrimidin-4-ol (366 mg, 3.8 mmol) and AcOH were cooled to 0 ° C. Br ₂ (0.27 ml) was added slowly via syringe. The mixture was stirred at room temperature for 3 hours. AcOH was removed under pressure. The residue was dissolved in CH ₂ Cl ₂ and washed with saturated NaHCO ₃ , brine and dried over MgSO ₄ . The solvent was removed and the product was purified by flash column chromatography to give the desired product (605 mg, 91%).

(Example 242B)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyrimidin-4-yloxy) -ethylamine The title compound was obtained in Example 27 and Example 242A in 3 -Prepared by using instead of bromo-5-hydroxypyridine.

(Example 243)
(1S) -1-Benzyl-2- [3- (3-methyl-1H-indazol-5-yl) -phenoxy] -ethylamine

(Example 243A)
[1-Benzyl-2- (3-bromo-phenoxy) -ethyl] -carbamic acid tert-butyl ester The desired product is obtained in Example 2A by replacing 3-bromophenol with 3-bromo-5-hydroxypyridine. Instead, and prepared by using L-Boc-phenylalaninol instead of L-Boc-tryptophanol.

(Example 243B)
5- [3-((2S) -2-tert-butoxycarbonylamino-3-phenyl-propoxy) -phenyl] -3-methyl-indazole-1-carboxylic acid tert-butyl ester Prepared at 102E by substituting Example 243A for Example 2A.

(Example 243C)
(1S) -1-Benzyl-2- [3- (3-methyl-1H-indazol-5-yl) -phenoxy] -ethylamine The desired product is obtained in Example 27C and Example 243B in Example 27B. Prepared as the trifluoroacetate salt by using instead of

(Example 244)
(1S) -1-Benzyl-2- [6- (3-methyl-1H-indazol-5-yl) -pyridin-2-yloxy] -ethylamine The desired product is obtained in Example 243 as Example 3. Prepared as the trifluoroacetate salt by using -bromo-6-hydropyridine instead of 3-bromophenol.

(Example 245)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-thiophen-3-yl-benzyl) -ethylamine

(Example 245A)
(1S)-[2-Hydroxy-1- (4-iodo-benzyl) -ethyl] -carbamic acid tert-butyl ester Rodriguez, M .; Llinares, S.M. Doulut, A.D. Heiz, J .; Prepared from L-Boc- (4-indophenyl) alanine according to the procedure described by Martinez Tetrahedron Letters 1991, 32 (7), 923-926.

(Example 245B)
(1S)-[2- (5-Bromo-pyridin-3-yloxy) -1- (4-iodo-benzyl) -ethyl] -carbamic acid tert-butyl ester The desired product is obtained in Example 2A. Example 245A was prepared by substituting L-Boc-tryptophanol.

(Example 245C)
(1S)-[2- (5-Bromo-pyridin-3-yloxy) -1- (4-thiophen-3-yl-benzyl) -ethyl] -carbamic acid tert-butyl ester 1: 2 MeOH: DME (5 mL ), Example 245B (200 mg, 0.37 mmol), 3-thiopheneboronic acid (50 mg, 0.39 mmol), Pd (PPh ₃ ) ₄ (25 mg, 0.02 mmol) and CsF (115 mg, 0.76 mmol). The solution of was heated at reflux for 4 hours, cooled, diluted with water and extracted with EtOAc. The extract was rinsed with brine, dried (MgSO ₄ ), evaporated and purified by flash chromatography (30% Et ₂ O / hexanes) to give the desired product (145 mg, 79%).

(Example 245D)
(1S)-[2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-thiophen-3-yl-benzyl] -ethyl] -carbamic acid tert-Butyl ester The desired product was prepared in Example 102E by using Example 245 instead of Example 2A.

(Example 245E)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-thiophen-3-yl-benzyl) -ethylamine The desired product In Example 27C, Example 245D was prepared as the trifluoroacetate salt by substituting Example 27B.

(Example 246)
(1S) -1- (4-Iodo-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine The desired product is obtained in Example 238. Prepared as the trifluoroacetate salt by using Boc-3′-bromophenylalaninol in place of Example 245A.

(Example 247)
[4-((2S) -2-Amino-3-phenyl-propoxy) -2- (3-methyl-1H-indazol-5-yl) -phenyl] -methanol

(Example 247A)
(1S)-[1-Benzyl-2- (3-chloro-4-formyl-phenoxy) -ethyl] -carbamic acid tert-butyl ester The desired product is obtained in Example 2A as 2-chloro-4- Prepared by using hydroxybenzaldehyde in place of 3-bromo-5-hydroxypyridine and L-Boc-phenylalaninol in place of L-Boc-triphanol.

(Example 247B)
(1S)-{1-Benzyl-2- [4-formyl-3- (3-methyl-1H-indazol-5-yl) -phenoxy] -ethyl} -carbamic acid tert-butyl ester in DMF (4 mL) A solution of Example 102D (230 mg, 0.78 mmol) and Example 247A (300 mg, 0.77 mmol) was added to Pd ₂ (dba) ₃ (73 mg, 0.008 mmol), 2-dicyclohexylphosphino-2′-. Treat with (N, N-dimethylamino) biphenyl (61 mg, 0.15 mmol) and triethylamine (97 mg, 0.96 mmol), treat at 110 ° C. for 4 hours, partition between brine and ETOAc, Filter through Celite) and extract with EtOAc. The extract was rinsed with brine, dried (MgSO ₄ ), concentrated and purified by flash chromatography (40% EtOAc / hexanes) to give the desired product (235 mg, 63%).

(Example 247C)
(1S)-{1-Benzyl-2- [4-hydroxymethyl-3- (3-methyl-1H-indazol-5-yl] -phenoxy] -ethyl} -carbamic acid tert-butyl ester in EtOH (4 mL) A solution of Example 247B (225 mg, 0.46 mmol) was treated with NaBH ₄ (26 mg, 0.70 mmol), stirred for 30 minutes, diluted with water and extracted into EtOAc. Was rinsed with brine, dried (MgSO ₄ ), concentrated and purified by flash chromatography (60% EtOAc / hexanes) to give the desired product (150 mg, 66%).

(Example 247D)
[4-((2S) -2-Amino-3-phenyl-propoxy) -2- (3-methyl-1H-indazol-5-yl) -phenyl] -methanol Example 247C (115 mg, 0.23 mmol) was prepared. It was heated at 190 ° C. for 45 min, then purified by flash column chromatography on silica gel eluting with 10% MeOH / CH ₂ Cl ₂ to give the desired product (17 mg, 19%).

(Example 248)
(1S) -2- [5- (1H-benzotriazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 248A)
4-Bromo-benzene-1,2-diamine 4-bromo-2-nitroaniline (1 g, 4.6 mmol) and SnCl ₂ .2H ₂ O in MeOH (30 mL) containing 5 to 6 drops of concentrated HCl ( (6.2 g, 27.6 mmol) was heated at reflux for 5 h, concentrated, suspended in saturated NaHCO ₃ (aq) and extracted with EtOAc. The extract was rinsed with brine, dried (MgSO ₄ ) and concentrated to give a product of sufficient purity to continue.

(Example 248B)
Treat a mixture of Example 248A (262 mg, 1.4 mmol) in 5-bromo-1H-benzotriazole 10% H ₂ SO ₄ (4 mL) with NaNO ₂ (120 mg, 1.7 mmol) in water (1 mL). And stirred for 30 minutes, diluted with water and extracted with EtOAc. The extract was rinsed with brine, dried (MgSO ₄ ), concentrated and purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ) to give the desired product.

(Example 248C)
5-Bromo-benzotriazole-1-carboxylic acid tert-butyl ester 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. And stirred for 1 hour at −20 ° C., then 2 hours at room temperature, evaporated and dissolved in THF (4 mL). This solution was added to a solution of pyridine (426 mg, 5.4 mmol) in THF (3 mL) at −20 ° C. with ofBuOH (1 mL) and then stirred at room temperature overnight. The solid was removed by filtration and rinsed with EtOAc. The filtrate was rinsed with water and brine, dried (MgSO ₄ ), concentrated and purified by flash chromatography (1: 1 Et ₂ O: hexanes) to give the desired product (970 mg, 76%). .

(Example 248D)
(1S) -2- [5- (1H-benzotriazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine The desired product is obtained in Example 32. Example 248C was prepared as the trifluoroacetate salt by using in place of 6-bromophthalimide.

(Example 249)
(1S) -2- [5- (1H-benzotriazol-5-yl) -pyridin-3-yloxy] -1-benzyl-ethylamine

(Example 249A)
(1S)-[1-Benzyl-2- (5-bromo-pyridin-3-yloxy) -ethyl] -carbamic acid tert-butyl ester The desired product is obtained in Example 2A using L-Boc-phenylalani Prepared by substituting anol for L-Boc-tryptophanol.

(Example 249B)
(1S)-[1-Benzyl-2- (5-trimethylstannanyl-pyridin-3-yloxy) -ethyl] -carbamic acid tert-butyl ester The desired product is obtained in Example 32A with Example 249A. Prepared by using instead of Example 2A.

(Example 249C)
5- [5-((2S) -2-tert-butoxycarbonylamino-3-phenyl-propoxy) -pyridin-3-yl] -benzothiazole-1-carboxylic acid tert-butyl ester Performed in DMF (6 mL) A solution of Example 249B (400 mg, 0.81 mmol) and Example 73C (255 mg, 0.85 mmol) was added to Pd ₂ (dba) ₃ (111 mg, 0.12 mmol), tri-o-tolylphosphine (74 mg, 0.24 mmol). ) And triethylamine (102 mg, 1.0 mmol), heated at 110 ° C. for 4 hours, partitioned between brine and EtOAC, filtered through Celite® and extracted with EtOAc. The extract was rinsed with brine, dried (MgSO ₄ ), concentrated and purified by flash chromatography (80% EtOAc / CH ₂ Cl ₂ ) to give the desired product (110 g, 25%).

(Example 249D)
(1S) -2- [5- (1H-benzotriazol-5-yl) -pyridin-3-yloxy] -1-benzyl-ethylamine The desired product is obtained in Example 27C and Example 249C in Example. Prepared as the trifluoroacetate salt by using in place of 27B.

(Example 250)
(1S) -1-Benzyl-2- [5- (3-morpholin-4-yl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine The desired product is obtained in Example 249. Example 111A was prepared as the trifluoroacetate salt by substituting Example 249A for Example 249A.

(Example 251)
(1S) -1-Benzyl-2- {5- [3- (4-methyl-piperazin-1-yl) -1H-indazol-5-yl] -pyridin-3-yloxy} -ethylamine The desired product In Example 249, Example 114A was prepared as the trifluoroacetate salt by substituting Example 249A.

(Example 252)
(1S)-{5- [5- (2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl} -dimethyl-amine The desired product is obtained in Example 249. Example 115A was prepared as the trifluoroacetate salt by substituting Example 115A for Example 249A.

(Example 253)
(1S)-{5- [5- (2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl}-(2-methoxy-ethyl) -amine

(Example 253A)
(5-Bromo-1H-indazol-3-yl)-(2-methoxy-ethyl) -amine The reaction between Example 35A and O-methylethanolamine is described in U.S. Pat. Wrzeiono, K.M. Majewska, J .; Dudzinska-Usarewicz, M .; The procedure was as described by Bernas, Pharmzi, 1986, 41, 472-474.

(Example 253A)
(1S)-{5- [5- (2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl}-(2-methoxy-ethyl) -amine desired formation The product was prepared as the trifluoroacetate salt in Example 249 by using Example 253A instead of Example 249A.

(Example 254)
{5- [5-((2S) -2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl}-(2-morpholin-4-yl-ethyl)- Amine

(Example 254A)
(5-Bromo-1H-indazol-3-yl)-(2-morpholin-4-yl-ethyl) -amine The reaction between Example 35A and 4- (2-aminoethyl) morpholine is described in US Pat. Wrzeciono, K.M. Majewska, J .; Dudzinska-Usarewicz, M .; The procedure was as described by Bernas, Pharmzi, 1986, 41, 472-474.

(Example 254B)
{5- [5-((2S) -2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl}-(2-morpholin-4-yl-ethyl)- Amine The desired product was prepared as the trifluoroacetate salt in Example 249 by using Example 254A instead of Example 249A.

(Example 255)
5- [5-((2S) -2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-ylamine The desired product is obtained in Example 97 as Example 249A. Was prepared as the trifluoroacetate salt by using in place of Example 2A.

(Example 256)
N- {5- [5-((2S) -2-amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl} -2,2,2-trifluoro-acetamide

(Example 256A)
5-Bromo-1H-indazol-3-ylamine The desired product was prepared in Example 35A by using 5-bromo-2-fluorobenzonitrile instead of 5-benzo-2-fluorobenzaldehyde. .

(Example 256B)
N- (5-Bromo-1H-indazol-3-yl) -2,2,2-trifluoro-acetamide 256A (2.5 g, 12 mmol) and trifluoroacetic anhydride (3.4 mL, in pyridine (50 mL)) The 24 mmol solution was stirred at room temperature for 2 h, acidified with 10% HCl (aq) and extracted with EtOAc The extract was rinsed with water and brine, dried (MgSO ₄ ) and concentrated. And purified by flash chromatography (1: 1 EtOAc: hexanes) to give the desired product (3.0 g, 84%).

(Example 256C)
N- {5- [5-((2S) -2-amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl} -2,2,2-trifluoro-acetamide The desired product was prepared as the trifluoroacetate salt in Example 249 by using Example 256B instead of Example 249A.

(Example 257)
(2S) -2-Amino-N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -3-phenyl-propionamide

(Example 257A)
5- (5-Amino-pyridin-3-yl) -3-methyl-indazole-carboxylic acid tert-butyl ester The desired product is obtained in Example 27B, Example 203B in place of Example 27A, and Example 23B was prepared by using instead of Example 2A.

(Example 257B)
5- [5-((2S) -2-tert-butoxycarbonylamino-3-phenyl-propionylamino) -pyridin-3-yl] -3-methyl-indazole-1-carboxylic acid tert-butyl ester desired formation The product was prepared in Example 25G by using Example 257A instead of Example 25E and L-Boc-phenylalanine instead of Boc-tryptophan.

(Example 257C)
(2S) -2-Amino-N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -3-phenyl-propionamide The desired product is obtained in Example 27C. Prepared as the trifluoroacetate salt by using Example 257B instead of Example 27B.

(Example 258)
(1S) -2- [5- (3-Benzyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine The desired product was run Prepared as the trifluoroacetate salt in Example 102 by using benzylmagnesium chloride instead of methylmagnesium bromide.

(Example 259)
(1S) -1-Benzyl-2- [5- (3-benzyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine The desired product is obtained in Example 258 as Example 249B. Was prepared as the trifluoroacetate salt by using in place of Example 2A.

(Example 260)
(1S) -2- [5- (3-Benzyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-methyl-ethylamine

(Example 260A)
(1S)-[2- (5-Bromo-pyridin-3-yloxy) -1-methyl-ethyl] -carbamic acid tert-butyl ester The desired product is obtained in Example 2A using Boc-alaninol as Boc- Prepared by using instead of tripropanol.

(Example 260B)
(1S)-[1-Methyl-2- (5-trimethylstannanyl-pyridin-3-yloxy) -ethyl] -carbamic acid tert-butyl ester The desired product is obtained in Example 249B with Example 260A. Prepared by using instead of Example 249A.

(Example 260C)
(1S) -2- [5- (3-Benzyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-methyl-ethylamine The desired product is obtained in Example 258 as Example 260B. Was prepared in place of Example 32A.

(Example 261)
(6- {5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -cinolin-4-yl) -phenyl-amine

(Example 261A)
(6-Bromo-cinolin-4-yl) -phenyl-amine A solution of Example 34D (500 mg, 2.5 mmol) and aniline (1.5 mL) in MeOH (11 mL) was stirred at room temperature for 2.5 hours. The resulting precipitate was collected, rinsed with water and dried under vacuum to give the desired product (400 mg, 62%).

(Example 261B)
(6- {5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -cinolin-4-yl) -phenyl-amine Desired formation The product was prepared as the trifluoroacetate salt in Example 27 by using Example 261A instead of Example 27A.

(Example 262)
(1S) -2- [5- (1H-Indazol-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine The desired product is obtained in Example 35. Prepared as the trifluoroacetate salt by using 4-bromo-2-fluorobenzaldehyde instead of 5-bromo-2-fluorobenzaldehyde

(Example 263)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -2,3-dihydro-isoindol-1-one

(Example 263A)
4-Bromo-2-methyl-benzoic acid methyl ester A solution of 4-bromo-2-methylbenzoic acid (1.0 g, 4.7 mmol) in MeOH (24 mL) containing 20 drops of concentrated HCl was refluxed for 6 hours. And concentrated to give the desired product (1.1 g, 100%).

(Example 263B)
4-Bromo-2-bromomethyl-benzoic acid methyl ester A solution of the example (1.02 g, 4.5 mmol) in CCl ₄ (22 mL) was treated with AIBN (65 mg, 0.4 mmol) and refluxed for 4 hours. , Washed with water, dried (Na ₂ SO ₄ ) and concentrated to give the desired product (1.1 g, 79%).

(Example 263C)
5-Bromo-2,3-dihydro-isoindol-1-one

(Example 263D)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -2,3-dihydro-isoindol-1-one desired The product was prepared as the trifluoroacetate salt in Example 36 by using Example 263C instead of 5-bromooxindole.

(Example 264)
6- {5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-cinolin-4-one Prepared as the trifluoroacetate salt in Example 32 by using Example 34A instead of 6-bromophthalimide.

(Example 265)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (4-phenyl-cinolin-6-yl) -pyridin-3-yloxy] -ethylamine

(Example 265A)
1- (1H-Indol-3-ylmethyl) -2- [5- (4-phenyl-cinolin-6-yl) -pyridin-3-yloxy] -ethylamine Example 34C in THF (10 mL) (200 mg, 0 .8 mmol) was treated with 3.0 M phenylmagnesium bromide (1.6 mL, 4.8 mmol) in Et ₂ O, stirred at room temperature for 4 h, saturated NH ₃ Cl (aq) was added, Extracted with EtOAc. The extract was rinsed with brine, dried (MgSO ₄ ), concentrated and purified by flash chromatography (30% EtOAc / hexanes) to give the desired product (67 mg, 29%).

(Example 265B)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (4-phenyl-cinolin-6-yl) -pyridin-3-yloxy] -ethylamine The desired product is obtained in Example 32. Prepared as the trifluoroacetate salt by using Example 265A instead of 6-bromophthalimide.

(Example 266)
(6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -cinolin-4-yl) -benzyl-amine

(Example 266A)
Benzyl- (6-bromo-cinolin-4-yl) -amine A solution of 34D (100 mg, 0.41 mmol) and benzylamine (0.5 mL) in MeOH (3 mL) was stirred for 24 hours at room temperature and concentrated. And suspended in Et ₂ O and the precipitate was collected to give the desired product (100 mg, 78%).

(Example 266B)
(6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -cinolin-4-yl) -benzyl-amine desired formation The product was prepared as the trifluoroacetate salt in Example 32 by using Example 266A instead of 6-bromophthalimide.

(Example 267)
(6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -cinolin-4-yl) -methyl-amine desired formation The product was prepared as the trifluoroacetate salt in Example 266 by using methylamine instead of benzylamine.

(Example 268)
(6- {5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -cinolin-4-ylamine The desired product was Prepared as the trifluoroacetate salt at 266 by using ammonia instead of benzylamine.

(Example 269)
[(3S) -3- (5-isoquinolin-6-yl-pyridin-3-yloxymethyl) -1,2,3,4-tetrahydro-b-carbolin-9-yl] -methanol 2 drops concentrated H _A solution of Example 27 (100 mg, 0.19 mmol) and 37% formaldehyde (aq) (18 μL) in water (10 mL) containing ₂ CO ₄ was heated at reflux for 3 hours, evaporated and 0% to 100% Purification by reverse phase HPLC on a C18 column with CH ₃ CN / H ₂ O / 0.1% TFA afforded the desired product as the trifluoroacetate salt.

(Example 270)
3- (5-Isoquinolin-6-yl-pyridin-3-yloxymethyl) -2,3,4,9-tetrahydro-1H-β-carboline in water (1 mL) containing concentrated H ₂ SO ₄ (6 μL) Of Example 27 (100 mg, 0.19 mmol) and 37% formaldehyde (aq) (17 μL) were stirred overnight at room temperature, neutralized with NH ₃ / MeOH, concentrated and flash chromatographed ( Purification by 10% MeOH / CH ₂ Cl ₂ ) gave the desired product.

(Example 271)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazole-3-carboxylic acid

(Example 271A)
1H-indazole-3-carboxylic acid methyl ester A solution of 3-carboxyindazole (2.0 g, 12.3 mmol) and concentrated HCl (2 mL) in MeOH (50 mL) was heated at reflux overnight, concentrated, and 2N Dilute with NaOH (aq) and extract with EtOAc. The extract was rinsed with brine, dried (MgSO ₄ ) and concentrated to give the desired product.

(Example 271B)
5-Iodo-1H-indazole-3-carboxylic acid methyl ester Example 271A (300 mg, 1.7 mmol), bis (trifluoroacetoxy) iodobenzene (800 mg, 1.9 mmol) in CH ₂ Cl ₂ (10 mL) , And iodine (253 mg, 1.0 mmol) were stirred overnight at room temperature and treated with sodium bisulfite (aq). The precipitate was collected, rinsed with water and hexane, and dried under vacuum to give the desired product (180 mg, 36%).

(Example 271C)
5- {5-[(2S) -2-tert-butoxycarbonylamino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazole-3-carboxylic acid methyl ester The desired product was prepared in Example 32B by using Example 271B instead of 6-bromophthalimide.

(Example 271D)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazole-3-carboxylic acid methyl ester desired product Was prepared in Example 27C by using Example 271C instead of Example 27B.

(Example 271E)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazole-3-carboxylic acid in MeOH (1 mL). A solution of Example 271D (150 mg, 0.34 mmol) and 1N NaOH (5 mL) was heated at reflux for 6 h, concentrated and 0% to 100% CH ₃ CN / H ₂ O / 0.01% with TFA. The desired product was prepared as the trifluoroacetate salt by purification by reverse phase HPLC on C18.

(Example 272)
5- [5-((2S) -2-tert-butoxycarbonylamino-3-hydroxy-propoxy) -pyridin-3-yl] -3-methyl-indazole-1-carboxylic acid tert-butyl ester Example 203 ( 719 mg, 1.22 mmol) was dissolved in 30 mL EtOAc in a 100 mL round bottom flask equipped with a stir bar. Attaching a combination vacuum / Ar / _{H 2} connection pipe, vent gas from the flask, it was filled twice Ar. Pd / C (800mg, 10wt. % ( Based on the dry)) was added, evacuated and the flask was filled with _{H 2} 2 times. The resulting black mixture was stirred vigorously and warmed to 50 ° C. for 20 h, where TLC showed ˜70% consumption of starting material. Another 480 mg of Pd / C was added and a fresh H ₂ balloon was attached. The reaction was stirred for an additional 26 hours at 50 ° C., at which point it was cooled to room temperature, evacuated from the flask, and filled with Ar. The cooled reaction mixture was filtered through celite and the filter residue was washed with EtOAc. The filtrate was rotoevaporated and then dried in house vacuum to give the desired product (540 mg, 89%) as a colorless foam / solid.

(Example 273)
5- [5-((2S) -aziridin-2-ylmethoxy) -pyridin-3-yl] -3-methyl-1H-indazole

(Example 273A)
(1R)-[2- (5-Bromo-pyridin-3-yloxy) -1- (tert-butyl-dimethyl-silanyloxymethyl) -ethyl] -carbamic acid tert-butyl ester 100 mL RBF -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 purged with nitrogen. THF (30 mL) was added at 0 ° C. After stirring at 0 ° C. for 10 minutes, DEAD (1.41 mL, 8.93 mmol) was added via syringe. The reaction mixture was stirred at 0 ° C. for 0.5 hour and at room temperature for 2 hours. The reaction mixture was concentrated and the residue was separated by flash chromatography (5% to 25% EtOAc in hexanes) to give the desired product (3.14 g, 99%). MS (DCI) m / z 461, 463 (M + 1) ^<+> .

(Example 273B)
(1S)-[2- (5-Bromo-pyridin-3-yloxy) -hydroxymethyl-ethyl] -carbamic acid tert-butyl ester of Example 273A (3.14 g, 6.8 mmol) in THF (40 mL) To the solution was added TBAF (7.14 mL, 7.14 mmol) at room temperature. The solution was stirred at room temperature for 1 hour and concentrated. The residual oil was purified by flash chromatography (40% to 80% EtOAc in hexanes) to give the desired product (2.19 g, 93%). MS (DCI) m / z 347, 349 (M + 1) ^<+> .

(Example 273C)
(2S) -2- (5-Bromo-pyridin-3-yloxymethyl) -aziridine-1-carboxylic acid tert-butyl ester Ph ₃ P (1.13 g, 4.32 mmol) was added to 9: 1 THF / CH. ₃ Dissolved in CN (30 mL) and cooled in an ice / water bath to 4 ° C. DIAD (850 μL, 4.32 mmol) was added slowly, stirred for 15 min, then Example 273B in THF (4 mL). (1.0 g, 2.88 mmol) of solution was added slowly and the solution was allowed to warm to room temperature and stirred overnight The solution was concentrated and the residual oil was flash chromatographed (20% to 40% in hexanes). EtOAc) to give the desired product (1.0 g, 75%) MS (DCI) m / z 329, 331 (M + 1) ⁺ .

(Example 273D)
5- [5-((2S) -1-tert-butoxycarbonyl-aziridin-2-ylmethoxy) -pyridin-3-yl] -3-methyl-indazole-carboxylic acid tert-butyl ester Method 1. Add 100 mL of RBF , filled with example 273C (950 mg, 2.88 mmol), example _{203B (1.14g, 2.88mmol), Pd} 2 (dba) 3 (263mg, 0.288mmol) and tri -o- tolyl phosphine (263 mg) And purged with N ₂ . Anhydrous DMF (35 mL) and Et ₃ N (1.2 mL) were added via syringe. The solution was purged again with N ₂ and heated at 72 ° C. for 4 hours. After cooling, 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% to 80% EtOAc in hexanes) 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) via syringe. Slowly added. After 20 minutes, the resulting light yellow solution was cannulated onto Example 272 (2.74 g, 5.50 mmol) in THF (150 mL). The reaction mixture was stirred at 23 ° C. for 6 hours, then silica gel was added and the volatiles were 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: aziridine oxide. _Rf = 0.50 (EtOAc). This was used without further purification.

(Example 273E)
5- [5-((2S) -aziridin-2-ylmethoxy) -pyridin-3-yl] -3-methyl-1H-indazole The desired product is obtained in Example 27C and Example 273D in Example 27B. It was prepared by using instead of

(Example 274)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (3-trifluoromethoxy-benzyl) -ethylamine

(Example 274A)
5- {5-[(2S) -2-tert-butoxycarbonylamino-3- (3-trifluoromethoxy-phenyl) -propoxy] -pyridin-3-yl} -3-methyl-indazole-1-carboxylic acid tert-Butyl ester To a suspension of CuBr-SMe ₂ (25 mg, 0.12 mmol) and Example 273D (100 mg, 0.21 mmol) in THF (6 mL) at approximately -35 ° C. Fluoromethoxyphenylmagnesium (0.5M solution in THF, 1.6 mL, 0.8 mmol) was added. The clear solution formed was warmed to −20 ° C. within 40 minutes and partitioned between ether and water. The organic layer was concentrated and the residue was separated by flash chromatography (40% to 65%, EtOAc in hexanes) to give the desired product (88 mg, 66%). MS (APCI) m / z 643 (M + 1) ^<+> .

(Example 274B)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (3-trifluoromethoxy-benzyl) -ethylamine The desired product was run In Example 27C, Example 274A was prepared as trifluoroacetic acid by using in place of Example 27B.

  The following compounds were prepared in Example 274 by using the appropriate glial reagent in place of 3-trifluoromethoxyphenylmagnesium bromide.

(Example 275)
(1S) -1- (3,5-Dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 276)
(1S) -1- (2,3-Dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 277)
(1S) -1-Biphenyl-3-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 278)
(1S) -1- (3-Chloro-4-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

（実施例２７９）
（１Ｓ）−１−（４−クロロ−３−フルオロ−ベンジル）−２−［５−（３−メチル−１Ｈ−インダゾール−５−イル）−ピリジン−３−イルオキシ］−エチルアミン

(Example 279)
(1S) -1- (4-Chloro-3-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 280)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-trifluoromethoxy-benzyl) -ethylamine

(Example 281)
(1S) -1- (2-Fluoro-4-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 282)
(1S) -1- (3-Fluoro-5-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 283)
(1S) -1- (2-Methoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 284)
(3-{(2S) -2-amino-3- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propyl} -phenyl) -dimethyl-amine

(Example 285)
(1S) -1- (4-Chloro-2-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 286)
(1S) -1- (3-Iodo-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 287)
(1S)-(1S) -1- (3-Fluoro-4-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 288)
(1S) -1- (3-Fluoro-4-methoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

Example 289
(1S) -2- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (3,4-dichloro-benzyl) -ethylamine

(Example 290)
(1S) -1- (2-Fluoro-6-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 291)
(1S) -1- (4-Fluoro-3-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 292)
(1S) -1-furan-2-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 293)
(1S) -1-Benzofuran-2-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 294)
(1S) -1- (3-Fluoro-4-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 295)
(1S) -1- (4-Chloro-3-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 296)
(1S) -1-furan-3-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 297)
(1S) -1- (2-Fluoro-5-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 298)
(1S) -1- (3-Chloro-5-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 299)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (3,4,5-trifluoro-benzyl) -ethylamine

(Example 300)
(1S) -1- (4-Fluoro-3-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 301)
(1S) -1- (2,4-Dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 302)
(1S) -1- (4-Chloro-3-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

Example 303
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2-trifluoromethoxy-benzyl) -ethylamine

(Example 304)
(1S) -1- (2,5-dimethoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 305)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-methoxysulfanyl-benzyl) -ethylamine

(Example 306)
(1S) -1- (2-cyclohexyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 307)
(1S) -1- (2,5-Dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 308)
(1S) -1- (2,5-Dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 309)
(1S) -1- (2,3-Dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 310)
(1S) -1- (3,4-Dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 311)
(1S) -1- (2,4-Dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 312)
(1S) -1- (3-Fluoro-4-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 313)
(1S) -1- (3,5-Dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 314)
(1S) -1-Biphenyl-2-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 315)
(1S) -1- (3,4-Dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 316)
(1S) -1- (2,3-Difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 317)
(1S) -1- (2,5-Difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 318)
(1S) -1- (2,6-Dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 319)
(1S) -1- (2,4-Difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 320)
(1S) -1- (2,6-Dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 321)
(1S) -1- (2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy ] -Ethylamine

(Example 322)
(1S) -1- (3,5-Difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 323)
(1S) -1- (2,6-Difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 324)
(1S) -1-Benzo [1,3] dioxol-5-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 325)
(1S) -1- (4-Fluoro-3-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 326)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2,4,6-trimethylbenzyl) -ethylamine

(Example 327)
(1S) -1- (2,4-Dimethoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 328)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-trifluoromethyl-benzyl) -ethylamine

(Example 329)
(1S) -1- (5-Fluoro-2-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 330)
(1S) -1- (3,5-Bis-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 331)
(1S) -1- (4-Fluoro-2-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 332)
(1S) -1- (5-Fluoro-2-methoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 333)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2-methyl-naphthalen-1-ylmethyl) -ethylamine

(Example 334)
(1S) -1- (2,2-Difluoro-benzo [1,3] dioxol-4-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy ] -Ethylamine

(Example 335)
(1S) -1- (4-Fluoro-naphthalen-1-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 336)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2,2,3,3-tetrafluoro-2,3-dihydro- Benzo [1,4] dioxin-6-ylmethyl) -ethylamine

(Example 337)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-methyl-naphthalen-1-ylmethyl) -ethylamine

(Example 338)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2,4,6-trifluoro-benzyl) -ethylamine

(Example 339)
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2,3,4-trifluoro-benzyl) -ethylamine

(Example 340)
(1S) -1- (4-Bromo-2-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 341)
(1S) -1- (4-Bromo-3-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 342)
(1S) -1- (2-Bromo-4,6-difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 343)
(1S) -1- (4-Bromo-3-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 344)
(1S) -Bromo-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 345)
(1S) -1- (3-Methoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 346)
(1S) -1- (3-Bromo-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 347)
(1S) -1- (2-Methoxy-naphthalen-1-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 348)
(1R) -1- (4-Chloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 348A)
5- [5-((2R) -1-tert-butoxycarbonyl-aziridin-2-ylmethoxy) -pyridin-3-yl] -3-methyl-indazole-1-carboxylic acid tert-butyl ester In Example 273D, (S)-[1- (tert-butyl-dimethyl-silanyloxymethyl) -2-hydroxy-ethyl] -carbamic acid tert-butyl ester was converted to (R)-[1- ( Prepared by using in place of tert-butyl-dimethyl-silanyloxymethyl) -2-hydroxy-ethyl] -carbamic acid tert-butyl ester. MS (APCI) m / z 481 (M + 1) ^<+> .

(Example 348B)
(1R) -1- (4-Chloro-benzyl) -2- [5- (3-methyl-1H-indazol-yl) -pyridin-3-yloxy] -ethyl The desired product is obtained in Example 274. Example 348A was prepared as the trifluoroacetate salt by substituting Example 273A for Example 273D and 4-chlorophenylmagnesium bromide for 3-trifluoromethoxyphenylmagnesium bromide.

  The following compounds were prepared in Example 348 by using the appropriate glial reagent in place of 3-trifluoromethoxyphenylmagnesium bromide.

(Example 349)
(1R) -1-Benzo [1,3] dioxol-5-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 350)
(1R) -1- (3-Fluoro-4-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 351)
(1S) -1-Benzyl-2- [6-chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 351A)
5- (2-Chloro-5-hydroxy-pyridin-3-yl) -3-methyl-indazole-1-carboxylic acid tert-butyl ester 250 mL of RBF was added to Example 12B (1.58 g, 7.59 mmol), Charged with Example 203B (3.0 g, 7.59 mmol), Pd ₂ (dba) ₃ (696 mg, 0.76 mmol) and tri-o-tolylphosphine (696 mg) and purged with N ₂ . Anhydrous DMF (60 mL) and Et ₃ N (3.17 mmol) were added via syringe. The solution was purged again with N ₂ and heated at 70 ° C. for 15 hours. After cooling, 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% to 65% EtOAc in hexanes) to give the desired product (1.86 g, 68%). MS (APCI) m / z 360 (M + 1) ^<+> .

(Example 351B)
5- [5-((2S) -2-tert-butoxycarbonylamino-3-phenyl-propoxy) -2-chloro-pyridin-3-yl] -3-methyl-indazole-carboxylic acid tert-butyl ester 25 mL RBF was charged with Example 351A (150 mg, 0.417 mmol), Boc-phenylalaninol (157 mg, 0.625 mmol), DBAD (144 mg, 0.625 mmol) and Ph ₃ P (163 mg, 0.625 mmol); Purge with nitrogen. THF (8 mL) was added at 0 ° C. After stirring at 0 ° C. for 30 minutes, the ice H ₂ O bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (20% to 40% EtOAc in hexanes) to give the desired product (215.0 mg, 87%). MS (APIC) m / z 593 (M + 1) ^<+> .

(Example 351C)
(1S) -1-Benzyl-2- [6-chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine The desired product is obtained in Example 27C. Prepared as the trifluoroacetate salt by using Example 351B instead of Example 27B.

  The following compounds were prepared in Example 351 by using the appropriate Boc-amino alcohol in place of Boc-phenylalaninol.

(Example 352)
(1S) -1- (4-Bromo-benzyl) -2- [6-chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 353)
(1S) -1- (4-Chloro-benzyl) -2- [6-chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 354)
(1S) -2- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-cyclohexylmethyl-ethylamine

(Example 355)
(1S) -2- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2,6-dimethyl-benzyl) -ethylamine

(Example 356)
(1S) -1- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -2-phenyl-propylamine The desired product is At 102, Example 12B was prepared by substituting 3-bromo-5-hydroxypyridine and Boc-3-methyl-phenylalaninol instead of Boc-tryptophanol.

(Example 357)
(1S) -1- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -2,2-diphenyl-ethylamine The desired product is run In Example 102, Example 12B was prepared by substituting 3-bromo-5-hydroxypyridine and Boc-3,3-diphenylalaninol instead of Boc-tryptophanol.

(Example 358)
(1S) -1- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -2-phenyl-propylamine The desired product is obtained in Example 102. Prepared by using Boc-3-methyl-phenylalaninol instead of Boc-tryptophanol.

(Example 359)
(1S) -1- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -2,2-diphenyl-ethylamine The desired product is obtained in Example 102. , Boc-3,3-diphenylalaninol was used in place of Boc-tryptophanol.

(Example 360)
(1S) -3-Methyl-1- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -butylamine The desired product was made in Example 102. Example 12B was prepared by substituting 3-bromo-5-hydroxypyridine for Boc-lucinol and Boc- for tryptophanol.

(Example 361)
(1S) -2- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine Desired formation The product was prepared in Example 102 by using Example 12B instead of 3-bromo-5-hydroxypyridine.

(Example 362)
(1S) -2- (6-Chloro-5-thieno [2,3-c] pyridin-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 362A)
(1S)-[2- (6-Chloro-5-thieno [2,3-c] pyridin-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethyl]- Carbamic acid tert-butyl ester The title compound was prepared in Example 27B by using Example 13A in place of Example 2A and Example 38A in place of Example 27A.

(Example 362B)
(1S) -2- (6-Chloro-5-thieno [2,3-c] pyridin-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine Example 27C was prepared by substituting Example 362A for Example 27B.

(Example 363)
5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -3-isoquinolin-6-yl-pyridin-2-carbonitrile

(Example 363A)
(1S)-[2- (6-Chloro-5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester Title Compound Was prepared in Example 27B by using Example 13A instead of Example 2A. MS (APCI) m / z 529 (M + 1) ^<+> .

(Example 363B)
(1S)-[2- (6-Cyano-5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester 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 purged with nitrogen. Anhydrous DMF (3 mL) was added and purged again with nitrogen. The reaction mixture was stirred at 90 ° C. for 70 hours. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic layer was washed with water. The organic layer was concentrated and the residue was separated by flash chromatography (40% to 100% EtOAc in hexanes) to give the desired product (87.4 mg, 89%). MS (APCI) m / z 520 (M + 1) ^<+> .

(Example 363C)
5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -3-isoquinolin-6-yl-pyridin-2-carbonitrile The desired product is obtained in Example 27C. Example 363B was prepared as the trifluoroacetate salt by using in place of Example 27B.

(Example 364)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-phenyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine

(Example 364A)
(1S)-{1- (1H-Indol-3-ylmethyl) -2- [5- (3-phenyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethyl} -carbamic acid tertbutyl ester dried Example 80E (150 mg, 0.28 mmol), (1,1,1-tributylstannanyl) benzene (137 mg, 0.57 mmol), tris (dibenzylideneacetone) -dipalladium (27 mg, 0 in DMF (10 ml) .028 mmol) and 2-dicyclohexylphosphino-2′-dimethylamino-1,1′-biphenyl (22 mg, 0.057 mmol) were added triethylamine under N ₂ . The resulting solution was stirred at 100 ° C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. Purification on silica gel with 60% ethyl acetate / hexanes afforded the title compound (70 mg, 47%). _{MS (DCI / NH 3) m} / e571 (M + 1) +.

(Example 364B)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-phenyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine The title compound is obtained in Example 27C. Prepared as the trifluoroacetate salt by using Example 354A instead of Example 27B.

  The following compounds were prepared in Example 364 by using the appropriate tributylsanyl reagent in place of (1,1,1-tributylstannyl) benzene.

(Example 365)
(1S) -2- [5- (3-Ethyl-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 366)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-pyridin-4-yl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine

（実施例３６７）
（１Ｓ）−２−［５−（３−フラン−２−イル−イソキノリン−６−イル）−ピリジン−３−イルオキシ］−１−（１Ｈ−インドール−３−イルメチル）−エチルアミン

(Example 367)
(1S) -2- [5- (3-Furan-2-yl-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 368)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-phenylethynyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine

(Example 369)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-prop-1-ynyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine

(Example 370)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-vinyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine

(Example 371)
(1S) -6- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -isoquinoline-3-carbonitrile

(Example 371A)
(1S)-[2- [5- (3-Cyano-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester The desired product was prepared in Example 363B by using Example 80E instead of Example 363A.

(Example 371B)
(1S) -6- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -isoquinoline-3-carbonitrile The desired product is obtained as an example. Prepared as the trifluoroacetate salt at 27C by using Example 371A instead of Example 27B.

(Example 372)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-6-vinyl-pyridin-3-yloxy) -ethylamine The desired product is obtained in Example 364. Prepared as the trifluoroacetate salt by using tributyl vinyl lead in place of tributyl phenyl lead and Example 363A in place of Example 80E.

(Example 373)
(1S) -2- (6-Ethyl-5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine The desired product is obtained in Example 364. Prepared as the trifluoroacetate salt by using tributylethynyllead in place of tributylphenyllead and Example 363A in place of Example 80E.

(Example 374)
(1S) -2- (6-furan-2-yl-5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) ethylamine The desired product is At 364, it was prepared as the trifluoroacetate salt by using tributylethynyllead in place of tributylstannylfuran and Example 363A in place of Example 80E.

(Example 375)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-6-phenylethynyl-pyridin-3-yloxy) -ethylamine The desired product is obtained in Example 364. Was prepared as the trifluoroacetate salt by using tributyl (phenylethynyl) zinc in place of tributylphenylzinc and Example 363A in place of Example 80E.

(Example 376)
6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -isoquinolin-5-ylamine The desired product is obtained in Example 32. Was prepared as a trifluoroacetate by using 5-amino-6-bromoisoquinoline instead of 6-bromophthalimide.

(Example 377)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (8-methyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine The desired product is obtained in Example 32. Was prepared as a trifluoroacetate salt by using 6-bromo-8-methyl-isoquinoline instead of 6-bromophthalimide.

(Example 378)
(1S) -2- [5- (4-Chloro-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine The compound was obtained in Example 38 as 4-chlorothieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine In Example 38, prepared by using 4-chlorothieno [2,3-c] pyridine in place of thieno [2,3-c] pyridine.

(Example 379)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (4-phenyl-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -ethylamine The compound was prepared in Example 38 by using 4-phenylthieno [2,3-c] pyridine in place of thieno [2,3-c] pyridine.

(Example 380)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (4-phenoxy-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -ethylamine The compound was prepared in Example 38 by using 4-phenoxythieno [2,3-c] pyridine instead of thieno [2,3-c] pyridine.

(Example 381)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (4-vinyl-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -ethylamine

(Example 381A)
(1S)-[2- [5- (4-Chloro-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethyl ] -Carbamic acid tert-butyl ester The title compound was prepared in Example 38 by using 4-chlorothieno [2,3-c] pyridine in place of thieno [2,3-c] pyridine. MS (APCI) m / z 535 (M + 1) ^<+> .

(Example 381B)
(1S)-{1- (1H-Indol-3-ylmethyl) -2- [5- (4-vinyl-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] ethyl} - the RBF carbamic acid tert- butyl ester 25 mL, example _{381A (102mg, 0.19mmol), Pd} 2 (dba) 3 (18mg, 0.019mmol), and 2-dicyclohexyl phosphino -2 '- (N, Charged with N-dimethylamino) biphenyl (15 mg, 0.038 mmol) and purged with nitrogen. Anhydrous DMF (5 mL), tributyl vinyl lead (111 μL, 0.38 mmol) and Et ₃ N (80 μL) were added via syringe. The solution was purged again with nitrogen and heated at 70 ° C. for 20 hours. After cooling, 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 / hexanes, 0% to 15% CH ₃ OH in A) to give the desired product (72 mg, 72 %). MS (APCI) m / z 527 (M + 1) ^<+> .

(Example 381C)
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (4-vinyl-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -ethylamine desired The product was prepared as the trifluoroacetate salt in Example 27C by using Example 381B instead of Example 27B.

(Example 382)
(1S) -2- [5- (4-Ethyl-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine methanol To a solution of Example 381A (50 mg, 0.063 mmol) in (4 mL) was added triethylamine (56 μL) and 10% Pd / C (20 mg) under nitrogen. The suspension was purged with H ₂ (balloon) and stirred at room temperature for 6 hours. Solid material was removed by filtration. The filtrate was concentrated and HPLC (Zorbax, C18, 250 × 2.54 column, mobile phase A: 0.1% TFA in H ₂ O, B: 0.1% TFA in CH ₃ CN, 0% to 100%. Gradient) to give the title compound (37.2 mg, 74%).

(Example 383)
(1S)-(2- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -thieno [2,3-c] pyridin-4-yl ) -Phenyl-amine

(Example 383A)
(1S)-{1- (1H-Indol-3-ylmethyl) -2- [5- (4-phenylamino-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy]- Ethyl} -carbamic acid tert-butyl ester 25 mL of RBF was added to Example 381A (100 mg, 0.186 mmol), Pd ₂ (bda) ₃ (17 mg, 0.0186 mmol) and 1,3-bis- (2,6 - filled with di -i- propylphenyl) imidazolinium (Nolan reagent) (16mg, 0.0372mmol), and purged with _{N 2.} Anhydrous dioxane (3 mL), aniline (21 mg, 0.224 mmol) and potassium tert-butoxide (1.0 M solution in THF, 0.279 mL) were added via syringe. The solution was purged again with N ₂ and heated at 100 ° C. for 20 hours. After cooling, ethyl acetate (50 mL) was added and the mixture was washed with brine (50 mL) and water. The EtOAc solution was concentrated and the residue was separated by flash chromatography (30% to 80% EtOAc in hexanes) to give the desired product (34 mg, 31%). MS (APIC) m / z 592 (M + 1) ^<+> .

(Example 383B)
(1S)-(2- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -thieno [2,3-c] pyridin-4-yl ) -Phenyl-amine The desired product was prepared as the trifluoroacetate salt in Example 27C by using Example 383A instead of Example 27B.

(Example 384)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3,3-difluoro-1,3-dihydro-indole- 2-one The desired product is obtained in Example 32 by using 5-bromo-3,3-difluoro-1,3-dihydro-indol-2-one instead of 6-bromophthalimide. Prepared as the trifluoroacetate salt.

(Example 385)
6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3H-oxazolo [4,5-b] pyridine-2- ON The desired product is obtained in Example 32 by using 6-bromo-3H-oxazolo [4,5-b] pyridin-2-one instead of 6-bromophthalimide to give the trifluoroacetate salt. As prepared.

(Example 386)
N1- (5-isoquinolin-6-yl-pyridin-3-yl) -ethane-1,2-diamine

(Example 386A)
[2- (5-Bromo-pyridin-3-ylamino) -ethyl] -carbamic acid tert-butyl ester 50 mL of RBF was added to 3,5-dibromopyridine (3.70 g, 15.6 mmol), t-butyl N- (2-Aminoethyl) carbamate (2.50 g, 15.6 mmol), Pd ₂ (dba) ₃ (714 mg, 0.78 mmol), (R) -BINAP (1.46 g, 2.34 mmol) and Cs ₂ CO ₃ (7.62 g, 23.4 mmol) and purged with N ₂ . Anhydrous toluene (120 mL) was added via syringe. The solution was purged again with N ₂ and heated at 100 ° C. overnight. After cooling, ethyl acetate (500 mL) was added and the mixture was washed with water. The EtOAc solution was concentrated and the residue was separated by flash chromatography (20% to 80% EtOAc in hexanes) to give the desired product (2.1 g, 43%). MS (DCI) m / z 316, 318 (M + 1) ^<+> .

(Example 386B)
[2- (5-Isoquinolin-6-yl-pyridin-3-ylamino) -ethyl] -carbamic acid tert-butyl ester The desired product is obtained in Example 27B and Example 386A in place of Example 2A. Prepared by use. MS (APCT) m / z 365 (M + 1) ^<+> .

(Example 386C)
N1- (5-Isoquinolin-6-yl-pyridin-3-yl) -ethane-1,2-diamine The desired product is used in Example 27C and Example 386B is used instead of Example 27B. Prepared as the trifluoroacetate.

(Example 387)
Naphthalene-2-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide

(Example 387A)
{2-[(5-Isoquinolin-6-yl-pyridin-3-yl)-(naphthalene-2-sulfonyl) -amino] -ethyl} -carbamic acid tert-butyl ester Example 386B in pyridine (3 mL) ( To a solution of 70 mg, 0.192 mmol) was added 2-naphthalenesulfonyl chloride (87 mg, 0.384 mmol) at room temperature. The formed yellow solution was stirred at room temperature for 15 hours. Pyridine was removed under reduced pressure and the residual oil was purified by flash chromatography (2: 1 EtOAc / hexanes from 0% to 15% CH ₃ OH) to give the desired product (69 mg, 65%). . MS (APCI) m / z 555 (M + 1) ^<+> .

(Example 387B)
Naphthalene-2-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide The desired product is obtained in Example 27C and Example 387B in Example 27B. Prepared as the trifluoroacetate salt by using instead of

(Example 388)
Naphthalene-1-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide The desired product is obtained in Example 387 using 1-naphthalenesulfonyl chloride. Prepared as the trifluoroacetate salt by using in place of 2-naphthalenesulfonyl chloride.

(Example 389)
5-Dimethylamino-naphthalene-1-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide The desired product is obtained in Example 387 as dansyl chloride Was prepared as the trifluoroacetate salt by using in place of 2-naphthalenesulfonyl chloride.

(Example 390)
Quinoline-5-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide The desired product is chlorinated in Example 387 with 8-quinolinesulfonyl chloride. Prepared as the trifluoroacetate salt by using in place of 2-naphthalenesulfonyl.

(Example 391)
Biphenyl-4-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide The desired product was obtained in Example 387 using biphenyl-4-sulfonyl chloride. Prepared as the trifluoroacetate salt by using in place of 2-naphthalenesulfonyl chloride.

(Example 392)
1-methyl-1H-imidazole-4-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide The desired product is Prepared as the trifluoroacetate salt by using 1-methylimidazol-4-sulfonyl instead of 2-naphthalenesulfonyl chloride.

(Example 393)
3-Amino-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propan-1-ol

(Example 393A)
[3- (tert-Butyl-dimethyl-silanyloxy) -2-hydroxy-propyl] -carbamic acid tert-butyl ester t-butyl N- (2,3-dihydroxypropyl) carbamate in CH ₂ Cl ₂ (75 mL) To a solution of (9.0 g, 47 mmol) was added t-butyldimethylsilyl chloride (7.80 g, 51.7 mmol), triethylamine (7.86 mL, 56.4 mmol) and DMAP (230 mg). The solution was stirred overnight at room temperature. After dilution with CH ₂ Cl ₂ (50 mL), the solution was washed with water (2 × 100 mL), dried over MgSO ₄ and concentrated. The residual oil was diluted under vacuum with Kugelroher to give the desired product (13.6 g, 95%). MS (DCI) m / z 306 (M + 1) ^<+> .

(Example 393B)
[2- (5-Bromo-pyridin-3-yloxy) -3- (tert-butyl-dimethyl-silanyloxy) -propyl] -carbamic acid tert-butyl ester To 100 mL of RBF, 3-bromo-5-hydroxypyridine ( 949 mg, 5.45 mmol), charged with Example 393A (2.0 g, 6.45 mmol) and Ph ₃ P (1.72 g, 6.54 mmol) and purged with nitrogen. THF (22 mL) was added at 0 ° C. After stirring for 10 minutes at 0 ° C., DEAD (1.03 mL, 6.54 mmol) was added via syringe. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (5-30% EtOAc in hexanes) to give the desired product (1.76 g, 70%). MS (DCI) m / z 461, 463 (M + 1) ^<+> .

(Example 393C)
5- {5- [2-tert-Butoxycarbonylamino-1- (tert-butyl-dimethyl-silanyloxymethyl) -ethoxy] -pyridin-3-yl} -3-methyl-indazole-1-carboxylic acid tert - the RBF butyl ester 100 m, example 393B (1.60g, 3.47mmol), example _{203B (1.37g, 3.47mmol), Pd} 2 (dba) 3 (318mg, 0.347mmol) and tri - Charged with o-tolylphosphine (318 mg) and purged with N ₂ . Anhydrous DMF (50 mL) and Et ₃ N (1.45 mL) were added via syringe. The solution was purged again with N ₂ and heated at 75 ° C. for 5 hours. After cooling, 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% to 60% EtOAc in hexanes) to give the desired product (1.51 g, 71%). MS (DCI) m / z 613 (M + 1) ^<+> .

(Example 393D)
5- [5- (2-tert-Butoxycarbonylamino-1-hydroxymethyl-ethoxy) -pyridin-3-yl] -3-methyl-indazole-1-carboxylic acid tert-butyl ester Performed in THF (20 mL) To a solution of Example 393C (1.122 g, 1.83 mmol) was added TBAF (1.92 mL) at room temperature. The solution was stirred at room temperature for 1 hour and concentrated. The residual oil was separated by flash chromatography (2: 1 EtOAc / hexane 1% to 25% CH ₃ OH) to give the title compound (0.82 g, 90%). MS (DCI) m / z 499 (M + 1) ^<+> .

(Example 393E)
3-Amino-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propan-1-ol The desired product is obtained in Example 27C, Example 393D. Was prepared as the HCl salt by using in place of Example 27B.

(Example 394)
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3-phenoxy-propylamine

(Example 394A)
5- [5- (2-tert-Butoxycarbonylamino-1-phenoxymethyl-ethoxy) -pyridin-3-yl] -3-methyl-indazole-1-carboxylic acid tert-butyl ester 25 mL of RBF was added to phenol ( 42 mg, 0.45 mmol), charged with Example 393D (150 mg, 0.3 mmol) and Ph ₃ P (142 mg, 0.54 mmol) and purged with nitrogen. THF (4 mL) was added at 0 ° C. After stirring for 10 minutes at 0 ° C., DEAD (85 μL, 0.54 mmol) was added via syringe. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (20-60% EtOAc in hexanes) to give the desired product (163 mg, 95%). MS (DCI) m / z 575 (M + 1) ^<+> .

(Example 394B)
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3-phenoxy-propylamine The desired product is Example 27C and Example 394A is Prepared as the trifluoroacetate salt by using in place of 27B.

(Example 395)
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3- (naphthalen-2-yloxy) -propylamine The desired product is obtained in Example 394. Prepared as the trifluoroacetate salt by using 2-naphthol instead of phenol.

(Example 396)
3- (Biphenyl-4-yloxy) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propylamine The desired product is obtained in Example 394. Prepared as the trifluoroacetate salt by using 4-phenylphenol instead of phenol.

2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3- (quinolin-7-yloxy) -propylamine The desired product is obtained in Example 394. Prepared as the trifluoroacetate salt by using 7-hydroxyquinoline instead of phenol.

(Example 398)
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3- (pyridin-4-yloxy) -propylamine The desired product is obtained in Example 394. Prepared as the HCl salt by using 4-hydroxypyridine instead of phenol.

(Example 399)
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3- (naphthalen-1-yloxy) -propylamine The desired product is obtained in Example 394. Prepared as the trifluoroacetate salt by using 1-naphthol instead of phenol.

(Example 400)
3-{(2S) -2-amino-3- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propyl} -1H-indole-5-ol

(Example 400A)
(2S) -2-tert-Butoxycarbonylamino-3- (5-hydroxy-1H-indol-3-yl) -propionic acid methyl ester BOC-5-hydroxy-tryptophan (5.9 g, 18.4 mmol) and iodomethane To a solution of (3.43 mL) in DMF (80 ml) was added double KHCO ₃ (3.68 g). The reaction mixture was stirred at room temperature for 4 hours. EtOAc (500 mL) was added and the mixture was washed with brine (500 mL) and water (500 mL). The organic layer 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) ^<+> .

(Example 400B)
(2S) -2-tert-Butoxycarbonylamino-3- [5- (tert-butyl-dimethyl-silanyloxy) -1H-indol-3-yl] -propionic acid methyl ester Example 400A (1.20 mg, 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 room temperature. The mixture was stirred at room temperature for 16 hours. EtOAc (100 mL) was added and the mixture was washed with brine (100 mL) and water (100 mL). The organic layer was concentrated and the residual oil was purified by flash column chromatography (10% to 40% EtOAc in hexanes) to give the desired product (1.6 g, 100%). MS (DCI) m / z 466 (M + 18) ^<+> .

(Example 400C)
(1S)-{2- [5- (tert-Butyl-dimethyl-silanyloxy) -1H-indol-3-yl] -1-hydroxymethyl-ethyl} -carbamic acid tert-butyl ester Example 400B (1.5 g (3.3 mmol) in THF (15 ml) was slowly added LiAlH ₄ powder (127 mg, 3.3 mmol) in several portions at room temperature. After the addition, when the reaction mixture became sticky, stirring was stopped. The temperature of the mixture was ~ 50 ° C. Ether (30 mL) was added and the mixture was stirred for 20 minutes. Methanol (2 mL) and diluted HCl were added slowly and the mixture was extracted with ether. The organic layer was washed with water and concentrated. The residue was separated by flash chromatography (20% to 60% EtOAc in hexanes) to give the desired product (982 mb, 72%). MS (DCI) m / z 421 (M + 1) ^<+> .

(Example 400D)
(1S)-{2- (5-Bromo-pyridin-3-yloxy) -1- [5- (tert-butyl-dimethyl-silanyloxy) -1H-indol-3-ylmethyl] -ethyl} -carbamic acid tert- Butyl ester 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 purged with nitrogen did. THF (15 mL) was added at 0 ° C. After stirring for 10 minutes at 0 ° C., DEAD (427 μL, 2.71 mmol) was added via syringe. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (10-50% EtOAc in hexanes) to give the desired product (1.05 g, 80%). MS (APCI) m / z 576, 578 (M + 1) ^<+> .

(Example 400E)
5- (5-{(2S) -2-tert-butoxycarbonylamino-3- [5- (tert-butyl-dimethyl-silanoyloxy) -1H-indol-3-yl] -propoxy} -pyridine-3 -Yl) -3-Methyl-indazole-1-carboxylic acid tert-butyl ester The desired product was prepared in Example 203A by using Example 400D instead of Example 202A. MS (DCI) m / z 728 (M + 1) ^<+> .

(Example 400F)
5- {5-[(2S) -2-tert-butoxycarbonylamino-3- (5-hydroxy-1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-methyl-indazole- 1-Carboxylic acid tert-butyl ester 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 room temperature. The solution was stirred at room temperature for 2 hours and concentrated. The residual oil was purified by flash chromatography (2: 1 EtOAc / hexanes from 0% to 15% CH ₃ OH) to give the desired product (530 mg, 74%). MS (DCI) m / z 614 (M + 1) ^<+> .

(Example 400G)
3-{(2S) -2-amino-3- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propyl} -1H-indole-5-ol desired formation The product was prepared as the trifluoroacetate salt in Example 27C by using Example 400F instead of Example 27B.

(Example 401)
(1S) -1- (5-Methoxy-1H-indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 401A)
5- {5-[(2S) -2-tert-butoxycarbonylamino-3- (5-methoxy-1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-methyl-indazole- 1-Carboxylic acid tert-butyl ester 25 mL of RBF was charged with Example 400F (100 mg, 0.163 mmol) and Ph ₃ P (85 mg, 0.325 mmol) and purged with nitrogen. THF (4 mL) and methanol (14 μL) were added at 0 ° C. After stirring for 10 minutes at 0 ° C., DEAD (51 μL, 0.325 mmol) was added via syringe. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature over the weekend. The reaction mixture was concentrated and the residue was separated by flash chromatography (50% to 80% EtOAc in hexanes) to give the desired product (33 mg, 32%). MS (APCI) m / z 628 (M + 1) ^<+> .

(Example 401B)
(1S) -1- (5-Methoxy-1H-indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine desired formation The product was prepared as the trifluoroacetate salt in Example 27C by using Example 401A instead of Example 27B.

(Example 402)
(1S) -1- (5-Ethoxy-1H-indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine desired formation The product was prepared as the trifluoroacetate salt in Example 401 by using ethanol instead of methanol.

(Example 403)
(1S) -1- (5-Butoxy-1H-indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine desired formation The product was prepared as the trifluoroacetate salt in Example 401 by using n-butanol instead of methanol.

(Example 404)
(1S) -1- (5-Isopropoxy-1H-indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) pyridin-3-yloxy] -ethylamine desired formation The product was prepared as the trifluoroacetate salt in Example 401 by using isopropanol instead of methanol.

(Example 405)
3- (1H-Indol-3-yl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] propan-1-ol

(Example 405A)
2- (5-Bromo-pyridin-3-yloxy) -3- (1H-indol-3-yl) -propanoic acid methyl ester To 100 mL of RBF, 3-bromo-5-hydroxypyridine (1.67 g, 9. 58 mmol), methyl 2-hydroxy-3- (1H-indol-3-yl) -propanoate synthesized according to the preparation procedure described in the literature (ME Jung et al. J. Org. Chem. 1999, 64, 2976) Charged with ester (2.1 g, 9.58 mmol), and Ph ₃ P (3.01 g, 11.5 mmol) and purged with nitrogen. THF (40 mL) was added at 0 ° C. After stirring at 0 ° C. for 10 minutes, DEAD (1.81 mL, 11.5 mmol) was added via syringe. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (20% to 60% EtOAc in hexanes) to give the desired product (3.4 g, 94%). MS (DCI) m / z 375, 377 (M + 1) ^<+> .

(Example 405B)
2- (5-Bromo-pyridin-3-yloxy) -3- (1H-indol-3-yl) -propan-1-ol Example 405A (3.2 g, 8.5 mmol) in THF (20 mL) and ether To the (30 mL) solution, LiAH ₄ powder (323 mg, 8.5 mmol) was slowly added in several portions at room temperature. During the addition of LAH, a lot of solid material precipitated from the solution and the temperature was about 40 ° C. Water (2 mL) and diluted HCl were added slowly and the mixture was neutralized with NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with water and concentrated. The residue was separated by flash chromatography (20% to 80% EtOAc in hexanes) to give the desired product (1.24 g, 42%). MS (DCI) m / z 347, 349 (M + 1) ^<+> .

(Example 405C)
5- {5- [1-hydroxymethyl-2- (1H-indol-3-yl) -ethoxy] -pyridin-3-yl} -3-methyl-indazole-1-carboxylic acid tert-butyl ester 50 mL RBF 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), It was purged with N _2. Anhydrous DMF (22 mL) and Et ₃ N (0.698 mL) were added via syringe. The solution was purged again with N ₂ and heated at 70 ° C. for 15 hours. After cooling, 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 (2: 1 EtOAc / hexanes from 0% to 15% CH ₃ OH) to give the desired product (656 mg, 79%). MS (APCI) m / z 499 (M + 1) ^<+> .

(Example 405D)
3- (1H-Indol-3-yl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propan-1-ol The desired product is run In Example 27C, Example 405C was prepared as trifluoroacetic acid by using in place of Example 27B.

(Example 406)
3- (1H-Indol-3-yl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propylamine

(Example 406A)
5- {5- [1-Azidomethyl-2- (1H-indol-3-yl) -ethoxy] -pyridin-3-yl} -3-methyl-indazole-1-carboxylic acid tert-butyl ester To 50 mL RBF And charged with Example 405C (580 mg, 1.16 mmol) and Ph ₃ P (456 mg, 1.74 mmol) and purged with nitrogen. THF (14 mL) was added at 0 ° C. followed by DPPA (375 μL, 1.74 mmol). After stirring at 0 ° C. for 1 minute, DEAD (274 μL, 1.74 mmol) was added via syringe. The reaction mixture was stirred at 0 ° C. for 0.5 h and at room temperature overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (20% to 80% EtOAc in hexanes) to give the desired product (534 mg, 87%). MS (APCI) m / z 524 (M + 1) ^<+> .

(Example 406B)
5- {5- [1-Aminomethyl-2- (1H-indol-3-yl) -ethoxy] -pyridin-3-yl} -3-methyl-indazole-1-carboxylic acid tert-butyl ester Example 406A To a solution of (480 mg) in ethanol was added 10% Pd / C (160 mg) under nitrogen. The suspension was purged with hydrogen (3 cycles) and stirred under hydrogen (barn) for 4 hours. 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) ^<+> .

(Example 406C)
3- (1H-Indol-3-yl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propylamine The desired product is obtained in Example 27C. Was prepared as trifluoroacetic acid by using Example 406B instead of Example 27B.

(Example 407)
Naphthalene-2-sulfonic acid (2-amino-ethyl)-[5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -amide

(Example 407A)
{2-[(5-Bromo-pyridin-3-yl)-(naphthalene-2-sulfonyl) -amino] -ethyl} -carbamic acid tert-butyl ester Example 386A (50 mg, 0.158 mmol) in pyridine (2 mL ) To the solution, 2-naphthalenesulfonyl chloride (72 mg, 0.316 mmol) was added at room temperature. The formed yellow solution was stirred at room temperature for 15 hours. Pyridine was removed by blowing nitrogen and the remaining yellow solid was purified by flash chromatography (30% to 60% EtOAc in hexanes) to give the desired product (81 mg, 100%). MS (DCI) m / z 506, 508 (M + 1) ^<+> .

(Example 407B)
{2-[[5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yl]-(naphthalene-2-sulfonyl) -amino] -ethyl} -carbamic acid tert-butyl ester 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 purged with N ₂ . Anhydrous DMF (4 mL) and Et ₃ N (64 μL) were added via syringe. The solution was purged again with N ₂ and heated at 70 ° C. for 15 hours. After cooling, 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 (0-15% CH ₃ OH / A, A: 2: 1 EtOAc / hexanes) to give the desired product (54 mg, 63 %) MS (APCI) m / z 558 (M + 1) ⁺ .

(Example 407C)
Naphthalene-2-sulfonic acid (2-amino-ethyl)-[5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -amide The desired product is obtained in Example 27C. Example 407B was prepared as trifluoroacetic acid by using in place of Example 27B.

(Example 408)
Biphenyl-4-sulfonic acid (2-amino-ethyl)-[5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -amide The desired product is obtained in Example 407. , 4-biphenylsulfonyl chloride was used as the trifluoroacetate salt by substituting 2-naphthalenesulfonyl chloride.

(Example 409)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-isopropylidene-1,3-dihydro-indole-2 -On The desired product is obtained in Example 32 as 5-bromo-3-isopropylidene-1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41 , 2588) in place of 6-bromophthalimide.

(Example 410)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (1H-imidazol-2-ylmethylene) -1, 3-Dihydro-indol-2-one The desired product is obtained in Example 32 as 5-bromo-3- (1H-imidazol-2-ylmethylene) -1,3-dihydro-indol-2-one (L Sun et al., J. Med. Chem., 1998, 41, 2588) was prepared as the trifluoroacetate salt by substituting for 6-bromophthalimide.

(Example 411)
5- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-pyridin-2-ylmethylene-1,3-dihydro-indole-2- On The desired product was obtained in Example 32 as 5-bromo-3-pyridin-2-ylmethylene-1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998). , 41, 2588) as a trifluoroacetate salt by using in place of 6-bromophthalimido.

(Example 412)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-furan-2-ylmethylene-1,3-dihydro- Indol-2-one The desired product was obtained in Example 32 as 5-bromo-3-furan-2-ylmethylene-1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41, 2588) was prepared as the trifluoroacetate salt by substituting for 6-bromophthalimide.

(Example 413)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (5-methyl-furan-2-ylmethylene)- 1,3-Dihydro-indole-2-one The desired product is obtained in Example 32 as 5-bromo-3- (5-methyl-furan-2-ylmethylene) -1,3-dihydro-indole-2. -Prepared as the trifluoroacetate salt by using ON (L. Sun et al., J. Med. Chem., 1998, 41, 2588) instead of 6-bromophthalimide.

(Example 414)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (4,5-dimethyl-furan-2-ylmethylene ) -1,3-dihydro-indol-2-one The desired product is obtained in Example 32 as 5-bromo-3- (4,5-dimethyl-furan-2-ylmethylene) -1,3-dihydro. Prepared as the trifluoroacetate salt by using indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41, 2588) instead of 6-bromophthalimide.

(Example 415)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-thiophen-2-ylmethylene-1,3-dihydro- Indol-2-one The desired product was obtained in Example 32 as 5-bromo-3-thiophen-2-ylmethylene-1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41, 2588) was prepared as the trifluoroacetate salt by substituting 6-bromophthalimide.

(Example 416)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (1-methyl-1H-pyrrol-2-ylmethylene ) -1,3-dihydro-indol-2-one The desired product is obtained in Example 32 as 5-bromo-3- (1-methyl-1H-pyrrol-2-ylmethylene) -1,3-dihydro Prepared as the trifluoroacetate salt by using indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41, 2588) instead of 6-bromophthalimide.

(Example 417)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) propoxy] -pyridin-3-yl} -3- (1H-indol-3-ylmethylene) -1,3 -Dihydro-indol-2-one The desired product is obtained in Example 32 as 5-bromo-3- (1H-indol-3-ylmethylene) -1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41, 2588) was prepared as the trifluoroacetate salt by substituting for 6-bromophthalimide.

(Example 418)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (1-phenyl-1H-pyrrol-3-ylmethylene ) -1,3-dihydro-indol-2-one The desired product is obtained in Example 32 as 5-bromo-3- (2,5-dimethyl-1-phenyl-1H-pyrrol-3-ylmethylene). Prepared as the trifluoroacetate salt by using -1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41, 2588) instead of 6-bromophthalimide. .

(Example 419)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-pyridin-3-ylmethylene-1,3-dihydro- Indol-2-one The desired product was obtained in Example 32 as 5-bromo-3-pyridin-3-ylmethylene-1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41, 2588) was prepared as the trifluoroacetate salt by using in place of 6-bromophthalimido.

(Example 420)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (1H-pyrrol-3-ylmethylene) -1, 3-Dihydro-indol-2-one The desired product is obtained in Example 32 as 5-bromo-3- (1H-pyrrol-3-ylmethylene) -1,3-dihydro-indol-2-one (L Sun et al., J. Med. Chem., 1998, 41, 2588) was prepared as the trifluoroacetate salt by substituting for 6-bromophthalimide.

(Example 421)
5- {5- (2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (tetrahydro-pyran-4-ylidene) -1,3 -Dihydro-2-one The desired product was obtained in Example 32 as 5-bromo-3- (tetrahydro-pyran-4-ylidene) -1,3-dihydro-indol-2-one (L. Sun et al. , J. Med. Chem., 1998, 41, 2588) was used as the trifluoroacetate salt by substituting for 6-bromophthalimide.

(Example 422)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (4-ethyl-3,5-dimethyl-1H -Pyrrole-2-ylmethylene) -1,3-dihydro-indol-2-one The desired product is obtained in Example 32 as 5-bromo-3- (4-ethyl-3,5-dimethyl-1H- By using pyrrol-2-ylmethylene) -1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41, 2588) instead of 6-bromophthalimide. Prepared as fluoroacetate.

(Example 423)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-cyclopropylmethylene-1,3-dihydro-indole- 2-one The desired product is obtained in Example 32 as 5-bromo-3-cyclopropylmethylene-1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998). , 41, 2588) in place of 6-bromophthalimide.

(Example 424)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-pyrrolidin-2-ylmethylene-1,3-dihydro- Indol-2-one The desired product was obtained in Example 32 as 5-bromo-3-pyrrolidin-2-ylmethylene-1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41, 2588) was prepared as the trifluoroacetate salt by using in place of 6-bromophthalimido.

(Example 425)
5- (5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -2-oxo-1,2-dihydro-indole -3-ylidenemethyl) -furan-2-carboxylic acid The desired product is obtained in Example 32 as 5- (5-bromo-2-oxo-1,2-dihydro-indole-3-ylidenemethyl) -furan- Prepared as the trifluoroacetate salt by using 2-carboxylic acid (L. Sun et al., J. Med. Chem., 1998, 41, 2588) instead of 6-bromophthalimide.

(Example 426)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-benzylidene-1,3-dihydro-indole-2- On The desired product was obtained in Example 32 as 3-benzylidene-5-bromo-1,3-dihydro-indol-2-one (L. Sun et al., J. Med. Chem., 1998, 41, 2588). ) As a trifluoroacetate salt by using instead of 6-bromophthalimide.

(Example 427)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indole-2,3-dione 3-oxime desired The product was prepared in Example 32 using 5-bromo-1H-indole-2,3-dione 3-oxime (L. Sun et al., J. Med. Chem., 1998, 41, 2588) of 6-bromophthalimido. Prepared as the trifluoroacetate salt by using instead.

(Example 428)
(1S) -2- (5-Benzo [b] thiophen-2-yl-6-furan-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine

  The following compounds were prepared in Example 364 by using the appropriate tributylsanyl reagent in place of (1,1,1-tributylstannyl) benzene and Example 362A in place of 80E.

(Example 429)
(1S) -2- (5-Benzo [b] thiophen-2-yl-6-vinyl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 430)
(1S) -2- (5-Benzo [b] thiophen-2-yl-6-thiophen-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 431)
(1S) -2- (5-Benzo [b] thiophen-2-yl-6-thiazol-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 432)
(1S) -2- (5-Benzo [b] thiophen-2-yl-6-pyrazin-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine

(Example 433)
{5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -3-benzo [b] thiophen-2-yl-pyridin-2-yl} -phenyl-amine The compound was prepared in Example 318 by using Example 362A instead of Example 381A.

(Example 434)
{5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -3-benzo [b] thiophen-2-yl-pyridin-2-yl} -pyridine-3- Ile-amine The title compound was prepared in Example 433 by using 3-aminopyridine instead of aniline.

(Example 435)
6- {5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3H-benzoxazol-2-one In Example 32, 6-bromo-3H-benzoxazol-2-one (C. Fluzat et al., J. Med. Chem., 1993, 36, 497) was prepared by substituting for 6-bromophthalimide.

(Example 436)
1-Benzimidazol-1-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 436A)
3-Bromo-5-oxiranylmethoxy-pyridine 5-Bromo-pyridin-3-ol (0.50 g, 2.87 mmol), oxiranyl-methanol (0.38 mL, 5.74 mmol) and triphenylphosphine (1. To a solution of 50 g, 5.74 mmol) in anhydrous THF (20 mL) was added di-tert-butylazodicarboxylate (DBAD) (1.32 g, 5.74 mmol) and the reaction mixture was stirred at room temperature for 18 hours. And concentrated. The residue was purified by flash chromatography on silica gel eluting with 10% to 35% ethyl acetate / hexanes to give the desired product (0.48 g, 73%).

(Example 436B)
1-Benzimidazol-1-yl-3- (5-bromo-pyridin-3-yloxy) -propan-2-ol Example 436A (500 mg, 2.17 mmol) and 1H-benzimidazole (28 mg, 2.39 mmol) Of 2-propanol (10 mL) was refluxed for 2 h under N ₂ . The reaction mixture was cooled, diluted with ethyl acetate (50 mL) and washed with brine (2 × 25 mL). The concentrated residue was purified by flash column chromatography on silica gel eluting with 100% ethyl acetate to 5% methanol / ethyl acetate to give the desired product (1.08 mmol, 50%).

(Example 436C)
5- [5- (3-Benzimidazol-1-yl-2-hydroxy-propoxy) -pyridin-3-yl] -3-methyl-indazole-1-carboxylic acid tert-butyl ester At 203B, Example 436B was prepared by substituting Example 202A.

(Example 436D)
1-Benzimidazol-1-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine The desired compound is obtained in Example 27C and in Example 436C. Was prepared as the trifluoroacetate salt in place of Example 27B.

(Example 437)
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-morpholin-4-ylmethyl-ethylamine

(Example 437A)
1- (5-Bromo-pyridin-3-yloxy) -3-morpholin-4-yl-propan-2-ol The desired compound is used in Example 437B using morpholine instead of 1H-benzimidazole. It was prepared by.

(Example 437B)
[2- (5-Bromo-pyridin-3-yloxy) -1-morpholin-4-ylmethyl-ethyl] -carbamic acid tert-butyl ester Example 437A (250 mg, 0.79 mmol), isoindole-1,3- To a solution of 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 minutes. The concentrated residue was purified by flash column chromatography, eluting with 60% ethyl acetate / hexanes to give the desired intermediate dissolved in absolute ethanol (10 mL). Hydrazine monohydrate (40 μL) was added and the reaction mixture was refluxed for 3 hours. The cloudy solution was cooled, concentrated and dissolved in DMF (10 mL). Di-tert-butyl-dicarbonate (271 mg, 1.25 mmol) and triethylamine (0.18 mL, 1.25 mmol) were added and the clear solution was stirred at room temperature for 15 hours. 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.

(Example 437C)
5- [5- (2-tert-Butoxycarbonylamino-3-morpholin-4-yl-propoxy) -pyridin-3-yl] -3-methyl-indazole-1-carboxylic acid tert-butyl ester Prepared in Example 203B by using Example 437B instead of Example 202A.

(Example 437D)
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-morpholin-4-ylmethyl-ethylamine The desired compound was obtained in Example 27C and Example 437C. Prepared as the trifluoroacetate salt by using in place of Example 27B.

(Example 438)
5- [5-((2S) -2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -1,3-dihydro-indol-2-one The desired product is obtained in Example 36. , Boc-phenylalaninol was used in place of Boc-tryptophanol.

(Example 439)
5- [5-((2S) -2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -3- (1H-pyrrol-2-ylmethylene) -1,3-dihydro-indole-2- On The desired product was prepared in Example 39 by using Boc-phenylalaninol instead of Boc-tryptophanol.

(Example 440)
5- [5-((2S) -2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -3-furan-2-ylmethylene-1,3-dihydro-indol-2-one Desired formation The product was prepared in Example 412 by using Boc-phenylalaninol instead of Boc-tryptophanol.

(Example 441)
(1S) -1-Benzimidazol-1-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine

(Example 441A)
(2R) -1-Benzimidazol-1-yl-3-benzyloxy-propan-2-ol 2- (3-phenyl-propyl) -oxirane (3.0 g, 18.27 mmol) and benzimidazole (2.37 g) A solution of 20.1 mmol) in anhydrous 2-propanol (50 mL) was purged with nitrogen and refluxed for 2.5 hours. The reaction mixture was cooled, concentrated and purified by flash column chromatography on silica gel (0: 1 (1 min) to 15% (16 min) methanol in 2: 1 ethyl acetate / hexanes) to give the desired product. (4.72 g, 91%) was obtained.

(Example 441B)
(2S) -1- (2-Azido-3-benzyloxy-propyl) 1H-benzimidazole anhydrous THF of Example 441A (1.0 g, 3.54 mmol) and triphenylphosphine (1.39 g, 5.31 mmol) To the (30 mL) solution was added diphenylphosphoryl azide (1.14 mL, 5.31 mmol) at 0 ° C. followed by DEAD (836 μL). The reaction mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 15 hours. The concentrated residue was purified by flash column chromatography on silica gel eluting with 60-80% ethyl acetate / hexanes to give the desired product.

(Example 441C)
(2-Benzimidazol-1-yl-1-benzyloxomethyl-ethyl) -carbamic acid tert-butyl ester To a solution of Example 441B (˜1 g, ˜3.54 mmol) in ethanol (25 mL), 10% under nitrogen. Of Pd / C (230 mg) was added. The suspension was purged with hydrogen and stirred under hydrogen (Barn) for 1 hour. Solid material was filtered off and the filtrate was concentrated. The remaining foam was dissolved in anhydrous DMF (20 mL). Trimethylamine (1.08 mL, 7.78 mmol) and di-tert-butyl dicarbonate (0.85 g, 3.89 mmol) were added at room temperature and the solution was stirred under nitrogen for 2 hours. 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 / hexanes) to give the desired product.

(Example 441D)
(1S)-(2-Benzimidazol-1-yl-1-hydroxymethyl-ethyl) -carbamic acid tert-butyl ester To a solution of the example (0.78 g) in methanol (20 mL) was added 10% Pd under nitrogen. -C (450 mg) was added. The reaction mixture was purged with hydrogen and stirred under hydrogen at 86 ° C. for 3.5 days (barn). The filtrate was concentrated and the residual oil was separated by flash chromatography (2: 1 EtOAc / hexanes from 0% to 15% CH ₃ OH) to give the desired product (199.7 mg, 33%).

(Example 441E)
(1S)-[1-Benzimidazol-1-ylmethyl-2- (5-bromo-pyridin-3-yloxy) -ethyl] -carbamic acid tert-butyl ester 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 μL, 0.79 mmol) and the reaction mixture was brought to room temperature. And stirred for 2 hours and concentrated. The residue was purified by flash column chromatography on silica gel (2: 1 EtOAc / CH ₃ OH in hexanes) to give the desired product (100 mg, 43%).

(Example 441F)
5- [5- (3-Benzoimidazol-1-yl-2-tert-butoxycarbonylamido-propoxy) -pyridin-3-yl] -3-methyl-imidazole-1-carboxylic acid tert-butyl ester Was prepared in Example 203B by using Example 447E instead of Example 202A.

(Example 441G)
(1S) -1-Benzimidazol-1-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine The desired compound is obtained in Example 27C. Prepared as the trifluoroacetate salt by using Example 441F instead of Example 27B.

(Example 442)
3- {3-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -5-isoquinolin-6-yl-pyridin-4-yl} -acrylonitrile

(Example 442A)
3-chloro-5- (4-methoxy-benzyloxy) -pyridine 3-chloro-5-hydroxypyridine (2.0 g, 17.0 mmol), 4-methoxybenzyl alcohol (2.85 g, 25.5 mmol) And DEAD (4.44 g, 25.5 mmol) was added dropwise to a solution of triphenylphosphine (6.68 g, 25.5 mmol) in anhydrous THF (100 ml). The resulting solution was stirred at room temperature for 3 hours. The reaction solution was separated into ethyl acetate and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification on silica gel using 20% ethyl acetate / hexanes afforded the title compound (1.9 g, 53%). _{MS (DCI / NH 3) m} / e250 (M + 1) +.

(Example 442B)
3-Chloro-5- (4-methoxy-benzyloxy) -pyridine-4-carbaldehyde To a solution of DIPA (1.73 g, 17.16 mmol) in THF (100 ml) was added n-BuLi (6.86 ml, 17.16 mmol). ) Was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. Example 442A (3.56 g, 14.3 mmol) reacted in THF (10 ml) was added dropwise at -78 ° C. The resulting solution was stirred at -78 ° C for 1 hour. The mixture was quenched with methyl formate (2.0 ml). The reaction solution was separated into ethyl acetate and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification on silica gel using 20% ethyl acetate / hexanes afforded the title compound (2.2 g, 56%). _{MS (DCI / NH 3) m} / e278 (M + 1) +.

(Example 442C)
3- [3-Chloro-5- (4-methoxy-benzyloxy) -pyridin-4-yl] -acrylonitrile LiHMDS (1 0.2 ml, 1.2 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. Treated with Example 442B (277 mg, 1 mmol) in THF (1 ml). The resulting solution was stirred for 1 hour. The mixture was quenched with water. The reaction solution was separated into ethyl acetate and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification on silica gel using 20% ethyl acetate / hexanes afforded the title compound (210 mg, 70%). _{MS (DCI / NH 3) m} / e301 (M + 1) +.

(Example 442D)
3- (3-Chloro-5-hydroxy-pyridin-4-yl) -acrylonitrile To a solution of Example 442C (1.02 g, 3.4 mmol) in dichloromethane (10 ml) was added THA (1 ml). The resulting solution was stirred for 2 hours. The reaction solution was separated into ethyl acetate and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification on silica gel using 40% ethyl acetate / hexanes afforded the title compound (600 mg, 98%). _{MS (DCI / NH 3) m} / e181 (M + 1) +.

(Example 442E)
(1S)-[2- [5-Chloro-4- (2-cyano-vinyl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-butyl ester Example 442D (430 mg, 2.39 mmol), N-α- (tert-butoxycarbonyl) -L-tryptophanol (762 mg, 2.6 mmol) and triphenylphosphine (1.38 g, 5.26 mmol) in anhydrous THF To the (40 ml) solution was added DBAD (880 mg, 3.82 mmol). The resulting solution was stirred at room temperature for 3 hours. The reaction solution was separated into ethyl acetate and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification on silica gel using 20% ethyl acetate / hexanes afforded the title compound (340 g, 32%). _{MS (DCI / NH 3) m} / e453 (M + 1) +.

(Example 442F)
(1S)-[2- [4- (2-Cyano-vinyl) -5-isoquinolin-6-yl-pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethyl] -carbamic acid tert-Butyl ester Example 442E (330 mg, 0.73 mmol), 6- (1,1,1-trimethylstannyl) -isoquinoline (276 mg, 0.95 mmol), tris (dibenzylideneacetone) -dipalladium (66. 8 mg, 0.073 mmol) and 2-dicyclohexylphosphino-2′-dimethylamino-1,1′-biphenyl (57.3 mg, 0.146 mmol) in anhydrous DMF (10 ml) were added triethylamine under N _2. It was. The resulting solution was stirred at 100 ° C. for 3 hours. The reaction solution was separated into ethyl acetate and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification on silica gel using 60% ethyl acetate / hexanes afforded the title compound (61 mg, 17%). _{MS (DCI / NH 3) m} / e546 (M + 1) +.

(Example 442G)
3- {3-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -5-isoquinolin-6-yl-pyridin-4-yl} -acrylonitrile

(Example 443)
(1S) -1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-4-methyl-pyridin-3-yloxy) -ethylamine The desired product is obtained in Example 442. Prepared by using methyl iodide in place of ethyl acetate and omitting the step of Example 442C.

(Example 444)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-methyl-1,3-dihydro-indole-2- on

(Example 444A)
To a solution of 3-methyl-1,3-dihydro-indol-2-one oxindole (665 mg, 5.0 mmol) in THF (10 ml) at −78 ° C. was added n-BuLi (4.4 ml, 11.0 mmol). The solution was added dropwise and stirred at −78 ° C. for 30 minutes. Methyl iodide (2 ml) was added dropwise to the reaction at −78 ° C. The resulting solution was warmed to room temperature. The reaction solution was separated into ethyl acetate and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification on silica gel using 30% ethyl acetate / hexanes afforded the title compound (630 mg, 86%). _{MS (DCI / NH 3) m} / e148 (M + 1) +.

(Example 444B)
5-Bromo-3-methyl-1,3-dihydro-indol-2-one Example 444B (625 mg, 4.25 mmol) in acetonitrile (10 ml) at −10 ° C. with NBS (757 mg, 4.25 mmol). Was added. The mixture was stirred at -10 ° C for 1 hour and at 0 ° C for 2 hours. The reaction solution was separated into ethyl acetate and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification on silica gel using 30% ethyl acetate / hexanes afforded the title compound (640 mg, 66%). _{MS (DCI / NH 3) m} / e227 (M + 1) +.

(Example 444C)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] pyridin-3-yl} -3-methyl-1,3-dihydro-indol-2-one The desired product was prepared in Example 32 by using Example 44B instead of 6-bromophthalimide.

(Example 445)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} 3,3-dimethyl-1,3-dihydro-indole-2 -ON

(Example 445A)
3,3-Dimethyl-1,3-dihydro-indol-2-one To a solution of Example 444A (500 mg, 3.4 mmol) in THF (10 ml) at −78 ° C., n-BuLi (2.7 ml, 6. 8 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 30 minutes. Methyl iodide (2 ml) was added dropwise to the reaction at −78 ° C. The resulting solution was warmed to room temperature. The mixture was quenched with water. The reaction solution was separated into ethyl acetate and water. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification on silica gel using 30% ethyl acetate / hexanes afforded the title compound (410 mg, 75%). _{MS (DCI / NH 3) m} / e162 (M +) +.

(Example 445B)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3,3-dimethyl-1,3-dihydro-indole- 2-one The title compound was prepared in Example 444 by using Example 445A instead of Example 444A.

(Example 446)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1,3,3-trimethyl-1,3-dihydro- Indol-2-one

(Example 446A)
1,3,3-Trimethyl-1,3-dihydro-indol-2-one The title compound was prepared in Example 112, using Example 445A instead of Example 102A. _{MS (DCI / NH 3) m} / e176 (M + 1) +.

(Example 446B)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1,3,3-trimethyl-1,3-dihydro- Indol-2-one The title compound was prepared in Example 444 by using Example 446A instead of Example 444A.

(Example 447)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-ethyl-1,3-dihydro-indole-2- On The title compound was prepared in Example 444 by using iodoethane instead of iodomethane.

(Example 448)
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-benzyl-1,3-dihydro-indole-2- On The title compound was prepared in Example 444 by using benzyl chloride instead of iodomethane.

  It will be apparent to those skilled in the art that the present invention is not limited to the above examples and may be practiced in other specific forms without departing from the essential characteristics of the invention. Accordingly, this embodiment is considered to be illustrative and not restrictive in all respects, with reference to the appended claims rather than the foregoing embodiments. All changes that come within the meaning and range equivalent to the range are preferably considered to be within the scope of the claims.

Claims (22)

Formula (I):

(Where
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 amide;
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, where 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 ¹ is a bond, —O—, —NR ⁵ —, alkenyl, alkynyl, —C (O) —, —S—, —S (O) —, —S (O) ₂ —, —S (O). _{^{2 N (R 5) -,}} - N (R 5) S (O) 2 -, - C (R 12) 2 -, - C (R 12) 2 N (R 5) -, - N (R 5) Selected from the group consisting of C (O)-, and -C (O) N (R ⁵ )-, wherein each group has its left end bound to R ¹ and its right end bound to an aromatic ring. Is drawn as;
L ² represents a bond, —O—, —C (R ¹² ) ₂ —, —S—, —N (R ⁵ ) —, —N (R ⁵ ) C (O) —, and —C (O) N. Selected from the group consisting of (R ⁵ ) —;
L ³ is selected from the group consisting of a bond, alkylidene and alkylene, in which case the alkylidene and alkylene are one or two substituents independently selected from the group consisting of alkoxy, amino, cyano and hydroxy Has been replaced by;
R ¹ is selected from the group consisting of aryl, heteroaryl and heterocycle;
R ² and R ⁴ are independently absent or comprise the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, arylalkynyl, cyano, cyanoalkenyl, halo, heteroaryl, heterocycle, hydroxyalkyl and nitro Or R ² and L ¹ together with the carbon atom to which they are attached form a ring selected from the group consisting of aryl, heteroaryl and heterocycle; or R ⁴ and L 1 ² together with the carbon atom 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 atom to which they are attached form a ring selected from the group consisting of aryl, heteroaryl and heterocycle Subject to
R ³ is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle ;
R ⁶ is selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle;
Provided that when L ¹ and L ² are a bond, at least one of R ³ and R ⁶ is other than hydrogen;
R ⁵ is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl and heteroarylsulfonyl;
R ⁷ is absent or selected from the group consisting of hydrogen, alkyl, cyanoalkenyl and -L ² -L ³ (R ³ ) (R ⁶ ); or R ⁷ and L ¹ are Together with the carbon atoms forming a ring selected from the group consisting of aryl, heteroaryl and heterocycle; and each R ¹² is hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, Selected from the group consisting of heteroaryl, heterocycle and nitro)
Or a therapeutically acceptable salt thereof. Formula (II):

(Where
L ¹ is from the group consisting of a bond, —O—, —N (R ⁵ ) —, alkenyl, alkynyl, —N (R ⁵ ) C (O) —, and —C (O) N (R ⁵ ) —. Selected;
L ² is selected from the group consisting of a bond, —O—, —N (R ⁵ ) —, —N (R ⁵ ) C (O) —, and —C (O) N (R ⁵ ) —;
L ³ is selected from the group consisting of a bond, alkylidene and alkylene, where alkylidene and alkylene are optionally one or two substituents independently selected from the group consisting of amino, cyano and hydroxy Has been replaced;
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, where heteroaryl is furyl, pyrazinyl, Or selected from the group consisting of thiazolyl and thienyl; or R ² and L ¹ together with the carbon atom to which they are attached form a ring selected from the group consisting of dihydropyrrolyl, pyrazole and phenyl. Or R ⁴ and L ² together with the carbon atom to which they are attached form a ring selected from the group consisting of dihydropyrrolyl, phenyl, pyridinyl and pyrrolyl, The ring is optionally substituted with oxo;
Provided that when L ³ is alkylidene, R ⁴ and L ² together with the carbon atom to which they are attached are rings selected from the group consisting of dihydropyrrolyl, phenyl, pyridinyl and pyrrolyl (in this case The ring is formed to be optionally substituted with oxo);
R ³ is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy and heterocycle;
R ⁶ is selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, and heteroarylalkoxy, heteroaryloxy and heterocycle;
Provided that when L ¹ and L ² are a bond, 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, where , R ⁸ is selected from the group consisting of hydrogen, amino, carboxy, cyano and halo)
Or a therapeutically acceptable salt thereof. Formula (III)

(Where
L ¹ is selected from the group consisting of a bond, —O—, —N (R ⁵ ) —, alkenyl, alkynyl and —N (R ⁵ ) C (O) —;
L ² is selected from the group consisting of a bond, —O—, —N (R ⁵ ) —, —N (R ⁵ ) C (O) —, and —C (O) N (R ⁵ ) —;
L ³ is alkylene, in which case the alkylene is optionally 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 a bond, 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)
Or a therapeutically acceptable salt thereof. The compound of claim 1, wherein L ¹ is alkenyl. Y ′ is C (R ⁹ ) (where R ⁹ is —L ² -L ³ (R ³ ) (R ⁶ ), where L ² is —O—); 5. A compound according to claim 4. N, N-dimethyl-N- [2-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) ethyl] amine;
(1S) -2- (1H-indol-3-yl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine;
(1R) -2- (1H-indol-3-yl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine;
1- (1H-indol-3-yl) -3-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) propan-2-ol;
(1S) -2- (1-benzothien-3-yl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine;
(1S) -2,2-diphenyl-1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine;
(1S) -2- {4-[(2,6-dichlorobenzyl) oxy] benzyl} -2-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy ) Ethylamine;
(1S) -2- (benzyloxy) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine;
N, N-dimethyl-N-[(1S, 2S) -1-methyl-2-phenyl-2-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) Ethyl] amine;
(1S) -2- (2-naphthyl) -1-[({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine;
(1S) -2-({2-chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) -1- (1H-indol-3-ylmethyl) ethylamine;
(1S) -2-({6-chloro-5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) -1- (1H-indol-3-ylmethyl) ethylamine;
(1S) -2- (1H-indol-3-yl) -1-[({5-[(Z) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy) methyl] ethylamine; and N -[(2E) -3- (4-Bromophenyl) prop-2-enyl] -N- [2-({5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} oxy 6. The compound of claim 5, selected from the group consisting of:) ethyl] amine. Y ′ is C (R ⁹ ) (in this case, R ⁹ is —L ² -L ³ (R ³ ) (R ⁶ )), where L ² is a bond, —N (R ⁵ ) — ^5. The compound of claim 4, wherein the compound is selected from the group consisting of: —N (R ⁵ ) C (O) —, and —C (O) N (R ⁵ ) —. N-[(2S) -2-amino-3- (1H-indol-3-yl) propyl] -N- {5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} amine ;
(2S) -2-amino-4-phenyl-N- {5-[(E) -2-pyridin-4-ylvinyl] pyridin-3-yl} butanamide;
N- (aminomethyl) -5-[(E) -2-pyridin-4-ylvinyl] nicotinamide; and (1R) -3- {6-chloro-5-[(E) -2-pyridine-4- Ylvinyl] pyridin-3-yl} -1- (1H-indol-3-ylmethyl) propylamine;
8. The compound of claim 7, wherein the compound is selected from the group consisting of: The compound of claim 1, wherein L ¹ is a bond. Y ′ is C (R ⁹ ) (where R ⁹ is —L ² -L ³ (R ³ ) (R ⁶ ), where L ² is —O—); 10. A compound according to claim 9. 4- (5-{[(2S) -2-amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) benzonitrile;
(1S) -2- (1H-indol-3-yl) -1-{[(5-isoquinolin-6-ylpyridin-3-yl) oxy] methyl} ethylamine;
(1R) -2- (1H-indol-3-yl) -1-{[(5-quinolin-6-ylpyridin-3-yl) oxy] methyl} ethylamine;
(1S) -2-[(6-Chloro-5-isoquinolin-6-ylpyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylamine;
(1S) -2-[(2-chloro-5-isoquinolin-6-ylpyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylamine;
5- (5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) -1H-isoindole-1,3 (2H) -dione ;
5- (5-{[(2S) -2-amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) isoindoline-1-one;
(1S) -2-[(5-Cinolin-6-ylpyridin-3-yl) oxy] -1- (1H-indol-3-ylmethyl) ethylamine;
(1S) -2-{[5- (1H-indazol-5-yl) pyridin-3-yl] oxy} -1- (1H-indol-3-ylmethyl) ethylamine;
5- (5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) -1,3-dihydro-2H-indol-2-one ;
(1S) -2-{[5- (2,1,3-benzooxadiazol-5-yl) pyridin-3-yl] oxy} -1- (1H-indol-3-ylmethyl) ethylamine;
(1S) -2- (1H-indol-3-yl) -1-{[(5-thieno [2,3-c] pyridin-2-ylpyridin-3-yl) oxy] methyl} ethylamine;
(3Z) -5- (5-{[(2S) -2-Amino-3- (1H-indol-3-yl) propyl] oxy} pyridin-3-yl) -3- (1H-pyrrole-2- Ylmethylene) -1,3-dihydro-2H-indol-2-one; and 6- (5-{[(2R) -2-amino-3- (1H-indol-3-yl) propyl] oxy} pyridine- 11. A compound according to claim 10 selected from the group consisting of 3-yl) -1,3-benzothiazol-2 (3H) -one. Y ′ is C (R ⁹ ) (where R ⁹ is —L ² -L ³ (R ³ ) (R ⁶ ), where L ² is a bond, —N (R ⁵ ) C (O) -, and -N ^{(R 5)} - it is selected from the group) consisting of a compound according to claim 9. (2S) -2-amino-3- (1H-indol-3-yl) -N- [5- (1,6-naphthyridin-2-yl) pyridin-3-yl] propanamide;
N-[(2S) -2-amino-3- (1H-indol-3-yl) propyl] -N- [5- (1,6-naphthyridin-2-yl) pyridin-3-yl] amine;
(1R) -1- (1H-indol-3-ylmethyl) -3- (5-isoquinolin-6-ylpyridin-3-yl) propylamine;
2- (1H-indol-3-yl) -2- (5-isoquinolin-6-ylpyridin-3-yl) ethanamine; and 2- (1H-indol-3-yl) -3- (5-isoquinoline-6) 13. A compound according to claim 12, selected from the group consisting of -ylpyridin-3-yl) propan-1-amine. Y ′ is C (R ⁹ ) (in this case, R ⁹ is —L ² -L ³ (R ³ ) (R ⁶ )), where L ² and R ⁴ are bonded to each other. The compound according to claim 9, which together with the atom forms a heterocycle.   (3Z) -3-[(2S) -2-Amino-3- (1H-indol-3-yl) propylidene] -5-isoquinolin-6-yl-1,3-dihydro-2H-pyrrolo [2,3 15. The compound of claim 14, which is -b] pyridin-2-one. The compound of claim 1, wherein L ¹ is selected from the group consisting of alkynyl, —N (R ⁵ ) C (O) —, —N (R ⁵ ) —, and —O—. (1S) -2- (1H-indol-3-yl) -1-({[5- (pyridin-4-ylethynyl) pyridin-3-yl] oxy} methyl) ethylamine;
5-{[(2S) -2-amino-3- (1H-indol-3-yl) propyl] oxy} -N-pyridin-4-ylnicotinamide;
^{N 4 - (3 - {[} (2S) -2- amino-3- (1H-indol-3-yl) propyl] oxy} phenyl) pyrimidine-2,4-diamine;
N-[(2S) -2-amino-3- (1H-indol-3-yl) propyl] -N′-isoquinolin-5-ylpyridin-3,5-diamine; and N-[(2S) -2- 17. A compound according to claim 16, selected from the group consisting of amino-3- (1H-indol-3-yl) propyl] -N- [5- (isoquinolin-5-yloxy) pyridin-3-yl] amine. . The compound of claim 1, wherein L ¹ and R ² together with the atoms to which they are attached form an aryl ring.   19. The compound of claim 18, which is (1S) -2- (1H-indol-3-yl) -1-{[(6-pyridin-4-ylquinolin-3-yl) oxy] methyl} ethylamine. 3-butoxyl-5- [2- (4-pyridinyl) vinyl] pyridine;
3-methoxyl-5- [2- (4-pyridinyl) vinyl] pyridine;
Hydrochloric acid S-3- [2-amino-3-phenyl-propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine;
Hydrochloric acid 3- [2- (1H-3-indolyl) -ethoxyl] -5- [2- (4-pyridinyl) vinyl] pyridine;
3- [2- (1H-3-indolyl) -propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine;
Hydrochloric acid S-3- [2-amino-3- (4-benzyloxyphenyl) -propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine;
3- (piperidin-4-yl) -5- [2- (4-pyridinyl) vinyl] pyridine;
Hydrochloric acid R-3- {2-amino-3-benzyloxypropyloxyl} -5- [2- (4-pyridinyl) vinyl] pyridine;
3- (1-methyl-imidazole-4-methoxyl) -5- [2- (4-pyridinyl) vinyl] pyridine;
S-3- {2-amino-3- [3-hydroxyphenyl] -propyloxyl} -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate;
S-3- {2-amino-3- [3-hydroxyphenyl] -propyloxyl} -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride;
3- [1- (4-cyanobenzyl) -imidazole-4-methoxyl] -5- [2- (4-pyridinyl) vinyl] pyridine;
S-3- [2-amino-3- (1-methyl-1H-3-indolyl) -propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride;
S-3- [2-Dimethylamino-3- (1H-3-indolyl) -propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride;
S-3- [2-Amino-3- (1-naphthyl) -propyloxyl] -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride;
3- (2-aminoethoxyl) -5- [2- (4-pyridinyl) vinyl] pyridine · hydrochloride;
3- (3-aminopropyloxyl) -5- [2- (4-pyridinyl) vinyl] pyridine · hydrochloride;
S-3- (2-Amino-3-methylbutyloxy) -5- [2- (4-pyridinyl) vinyl] pyridine hydrochloride;
3- (1-methyl-3-piperidinyloxyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate;
3- (2-chlorobenzyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate;
3- (N-benzyl-N-methylaminoethoxyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate;
3- (6- (N, N-dimethylamino) hexyloxy) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate;
3- (2-triphenoxyl-ethoxyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate;
3- (1-methyl-3-pyrrolidinyloxyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate;
3-[(1-methyl-2-piperidinyl) methoxyl] -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate;
3- (1-pyridinyl-ethoxyl) -5- [2- (4-pyridinyl) vinyl] pyridine trifluoroacetate;
4- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -N-hydroxyl-benzamidine trifluoroacetate;
4- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -benzamidine trifluoroacetate;
3-[(2S) -2-amino-3- (1H-3-indolyl) -propyloxyl] -6- (3-pyridinyl) -quinoline;
3-[(2S) -2-amino-3- (1H-3-indolyl) -propyloxyl] -6- (3-quinolinyl) -quinoline;
3-[(2S) -2-amino-3- (1H-3-indolyl) -propyloxyl] -5- [2- (2-amino-4-pyridinyl) vinyl] pyridine trifluoroacetate;
5-[(2S) -2- (amino-3- (1H-3-indolyl) -propyloxyl] -3- [2- (2-amino-4-pyridinyl) vinyl] -2-chloro-pyridine tri Fluoroacetates;
(1S) -1- (1H-indol-3-ylmethyl) -2- (5-naphthalen-2-yl-pyridin-3-yloxy) -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-5-yl-pyridin-3-yloxy) -ethylamine;
6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -2H-isoquinolin-1-one;
(1S) -2- [5- (3-Chloro-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -2-([3,4 '] bipyridinyl-5-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine trifluoroacetic acid;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (2-pyridin-2-yl-vinyl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- (5-pyridin-3-ylethynyl-pyridin-3-yloxy) -ethylamine trifluoroacetate;
(1S) -2- [5- (2-Fluoro-pyridin-4-ylethyl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine trifluoroacetate;
(1S) -4- {5- [2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-ylethynyl} -pyridin-2-ol trifluoroacetate;
(1S) -2- [6-Chloro-5- (1-chloro-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine trifluoroacetate ;
Bis- [3- (4-Bromo-phenyl) -allyl]-{2- [5- (2-pyridin-4-yl-vinyl) -3-yloxy] -ethyl} -amine hydrochloride;
Hydrochloric acid N ⁴ -[3- (2-Amino-ethoxy) -phenyl] -pyrimidine-2,4-diamine;
trans- [4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propylamino] -pyridin-3-yl} -vinyl) -pyrimidine-2- Yl] -carbamic acid ethyl ester / trifluoroacetate;
1-amino-6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -isoquinoline trifluoroacetate;
6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1-chloro-isoquinoline trifluoroacetate;
(2S) -2-amino-3- (1H-indol-3-yl) -N- [5- (2-pyridin-4-yl-vinyl) -pyridin-3-yl] -propionamide;
Hydrochloric acid (2S) -2-amino-3- (naphth-1-yl) -N- [5- (2-pyridin-4-yl-vinyl) -pyridin-3-yl] -propionamide;
Hydrochloric acid (2S) -2-amino-3-phenyl-N- [5- (2-pyridin-4-yl-vinyl) -pyridin-3-yl] -propionamide;
S-2-amino-3- (imidazol-4-yl) -N- [5- (2-pyridin-4-yl-vinyl) -pyridin-3-yl] -propionamide hydrochloride;
(1R) -2- (1H-indol-3-yl) -1-{[5-isoquinolin-6-ylpyridin-3-yl) oxy] methyl} ethylamine;
(1S) -5- {5- [2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazol-3-ylamine;
(1S) -6- {5- [2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazol-3-ylamine;
2-Amino-N-[(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -acetamide;
(2S) -2-Amino-N-[(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -propionamide ;
2-dimethylamino-N-[(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -acetamide;
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [3- (1H-pyrrol-2-yl) -1H-indazol-5-yl] -pyridin-3-yloxy}- Ethylamine;
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-phenyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Cyclopropyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -2- [5- (3-Ethyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [3- (1-methyl-1H-imidazol-2-yl) -1H-indazol-5-yl] -pyridine-3 -Yloxy} -ethylamine;
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-thiazol-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- {5- [3- (1H-imidazol-2-yl) -1H-indazol-5-yl] -pyridin-3-yloxy} -1- (1H-indol-3-ylmethyl)- Ethylamine;
(1S) -1- (1H-Indol-3-ylmethyl) -2- [5- (3-thiophen-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (3-morpholin-4-yl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (1,3-dimethyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -1- (1H-Indol-3-ylmethyl) -2- [3- (3-methyl-1H-indazol-5-yl) -phenoxy] -ethylamine;
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [3- (4-methyl-piperazin-1-yl) -1H-indazol-5-yl] -pyridin-3-yloxy } -Ethylamine;
(1S)-(5- {5- [2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazol-3-yl) -dimethyl-amine;
(1S)-(4- (5- (2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -benzyl) -phenyl-amine;
(1S)-(4- (5- (2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -methanol;
(1S) -2- (5- (4-Fluoro-phenyl) -pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S)-(4- (5- (2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -benzoic acid;
(1S) -2- (3-bromo-5-isoquinolin-6-yl-phenoxyoxy) -1- (1H-indol-3-ylmethyl) -ethylamine;
N4- (3- (5- (2- (2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -pyrimidine-2,4-diamine;
(1S) -3- (2-amino-3- (1H-indol-3-yl) -propoxy) -5-isoquinolin-6-yl-phenylamine;
4- (5-isoquinolin-6-yl-pyridin-3-yl) -piperazine-1-carboxylic acid t-butyl ester;
6- (5-Piperazin-1-yl-pyridin-3-yl) -isoquinoline;
((2S) -2-amino-5- (5- (2-amino-4- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl- (3-chloro-phenyl- Methanone;
(1S) -N6- (3- (5- (2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -9H-purine-2,6- Diamines;
(3- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -pyrimidin-2-yl-amine;
(3- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -thiazol-2-yl-amine;
N- (3- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -acetamide;
6- (5- (4- (1H-indol-3-ylmethyl) -piperazin-1-yl) -pyridin-3-yl) -isoquinoline;
3-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -5-isoquinolin-6-yl-benzoic acid;
4- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenylamine;
N- (4- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -acetamide;
N6- (4- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -9H-purine-2,6- Diamines;
N4- (4- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -pyrimidine-2,4-diamine;
(4- (5-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -phenyl) -pyrimidin-2-yl-amine;
3-((2S) -2-amino-3- (1H-indol-3-yl) -propoxy) -5-isoquinolin-6-yl-benzonitrile;
5′-benzyloxy-5-isoquinolin-6-yl- (3,3 ′) bipyridinyl;
(7- (5-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -pyrido (2,3-d) pyrimidin-4-yl ) -Phenyl-amine;
(7- (5-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -pyrido (2,3-d) pyrimidin-4-yl ) -Ethyl-amine;
(7- (5-((2S) -2-Amino-3- (1H-indol-3-yl) -propoxy) -pyridin-3-yl) -pyrido (2,3-d) pyrimidin-4-yl ) -Benzyl-amine;
(1S) -1- (1H-indol-3-ylmethyl) -2- (6-isoquinolin-6-yl-pyrazin-2-yloxy) -ethylamine;
(1S) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -1-phenyl-ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- (6- (3-methyl-1H-indazol-5-yl) -pyrazin-2-yloxy) -ethylamine;
(1S) -1-cyclohexylmethyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine;
(1S) -1-benzyl-2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-phenyl-ethylamine;
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-phenyl-ethylamine;
4-((2S) -2-amino-3- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) propyl) -benzonitrile;
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-naphthalen-2-ylmethyl-ethylamine;
4-((2S) -2-amino-3- (5-isoquinolin-6-yl-pyridin-3-yloxy-propyl) -benzonitrile;
(1S) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -1-naphthalen-2-ylmethyl) -ethylamine;
(1S) -1-benzyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine;
(1S) -1- (4-Fluoro-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -1- (4-fluoro-benzyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine;
2-((2S) -2-amino-3- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -propyl) -benzonitrile;
2-((2S) -2-amino-3- (5-isoquinolin-6-yl-pyridin-3-yloxy) -propyl) -benzonitrile;
(1S) -2-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-pyridin-4-ylmethyl-ethylamine;
(1S) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -1-pyridin-4-ylmethyl-ethylamine;
(1S) -1- (4-methyl-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (4-methyl-benzyl) -ethylamine;
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-quinolin-3-ylmethyl-ethylamine;
(1S) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -1-quinolin-3-ylmethyl-ethylamine;
(1R) -1-benzyl-2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1R) -1-benzyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine;
4-((2S) -2-amino-3- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -propyl) -phenol;
(1S) -1- (4-Benzyloxy-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -1- (3-methyl-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -1- (2-methyl-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1- (4-nitro-benzyl) -ethylamine;
(1S) -1- (4-methoxy-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -1-biphenyl-4-ylmethyl-2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -2- (5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1-naphthalen-1-ylmethyl-ethylamine;
(1S) -1- (3-Chloro-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
3-((2S) -2-amino-3- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -propyl) -benzonitrile;
(1S) -1- (3,4-difluoro-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -1- (3,4-dimethoxy-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -1- (3-Fluoro-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -1- (3-trifluoromethyl-benzyl) -ethylamine;
(1S) -1- (4-Ethoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-t-butyl-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
(1S) -1- (4-methoxy-3-methyl-benzyl) -2- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -ethylamine;
2-((2S) -2-amino-3- (5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy) -propyl) -4-methyl-phenol;
(1S) -1-methyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(±) -1- (1H-benzimidazol-2-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine;
(±) -1- (1H-indazol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine;
(1S) -1- (2-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2-chloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-thiophen-2-ylmethyl-ethylamine;
(1R) -1- (1H-indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
1- (4-chloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-pyrrol-1-yl-benzyl) -ethylamine;
(1S) -1- (4-methyl-benzenesulfanylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2-fluoromethyl-benzyl) -ethylamine;
(1R) -1-benzyl-3- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propylamine;
(1R) -1-benzyl-4- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -butylamine;
(1S) -1- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -3-phenyl-propylamine;
(1S) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (1-methyl-1H-indol-3-ylmethyl) -ethylamine trifluoroacetate;
(1S)-[1- (1H-Indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethyl] -dimethyl-amine;
(1S) -1-benzo [b] thiophen-3-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-thiophen-3-ylmethyl-ethylamine;
(1S) -1-benzyloxymethyl-2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -ethylamine;
(1S) -1-benzyloxymethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (naphthalen-2-yloxymethyl) -ethylamine;
(1S) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (pyridin-3-yloxymethyl) -ethylamine;
(1S) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (quinolin-7-yloxymethyl) -ethylamine;
(2S) -4- [2-amino-3- (5-isoquinolin-6-yl-pyridin-3-yloxy) -propoxy] -benzonitrile;
(2S) -N ′-(5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl) -3-phenyl-propane-1,2-diamine;
(2S) -N- (2-amino-3-phenyl-propyl) -N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -methanesulfonamide;
(2S) -N- (2-amino-3-phenyl-propyl) -N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -benzenesulfonamide;
(2S) -N- (2-amino-3-phenyl-propyl) -N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -benzamide;
(2S) -N- (2-amino-3-phenyl-propyl) -N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -acetamide;
(2S) -3- [2-amino-3- (1H-indol-3-yl) -propylidene] -5-isoquinolin-6-yl-1,3-dihydro-indol-2-one;
(1S) -2- (5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (1-methyl-1H-indol-3-ylmethyl) -ethylamine;
(1S)-(1H-Indol-3-ylmethyl) -2- [5- (1H-pyrrolo [2,3-b] pyridin-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- {5- [2- (2-Fluoro-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- {5- [2- (2-methoxy-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- {5- [2- (2-phenoxy-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -ethylamine;
(1S) -2- {5- [2- (2-Benzylsulfanyl-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -1- (1H-indol-3-ylmethyl) -ethylamine;
[4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -vinyl) -pyridin-2-yl]- Cyclopropyl-amine;
[4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -vinyl) -pyridin-2-yl]- Benzyl-amine;
[4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -vinyl) -pyridin-2-yl]- Ethyl-amine;
[4- (2- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -vinyl) -pyridin-2-yl]- Methyl-amine;
(1S)-(1H-indol-3-ylmethyl) -2- {5- [2- (2-indol-1-yl-pyridin-4-yl) -vinyl] -pyridin-3-yloxy} -ethylamine;
(±) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2-methyl-1H-indol-3-ylmethyl) -ethylamine;
7- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -quinazolin-2-ylamine;
2-phenyl-2- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -ethylamine;
Naphthalen-2-yl- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -acetonitrile;
2-naphthalen-2-yl-2- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -ethylamine;
(3-isoquinolin-6-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -phenyl-acetonitrile;
2- (3-isoquinolin-6-yl-1H-pyrazolo [3,4-b] pyridin-6-yl) -2-phenyl-ethylamine;
(1S) -benzyl-2- (3-pyridin-4-yl-1H-pyrazolo [3,4-b] pyridin-5-yloxy) -ethylamine;
2-Benzyl-3- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propylamine;
(1S)-(1H-indol-3-ylmethyl) -2- (2-pyridin-4-yl- [1,7] naphthyridin-5-yloxy) -ethylamine;
(1R)-(1H-indol-3-ylmethyl) -2- (2-pyridin-4-yl- [1,7] naphthyridin-5-yloxy) -ethylamine;
(1S)-(1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyridin-3-ylsulfanyl) -ethylamine;
(1S)-(1H-Indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-ylsulfanyl] -ethylamine;
(1S) -1- (4-Bromo-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (3-methyl-quinazolin-7-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (1H-indol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (1H-Indol-3-ylmethyl) -2- {5- [4- (1H-tetrazol-5-yl) -phenyl] -pyridin-3-yloxy} -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-pyrimidin-4-yloxy) -ethylamine;
(1S) -1-benzyl-2- [3- (3-methyl-1H-indazol-5-yl) -phenoxy] -ethylamine;
(1S) -1-benzyl-2- [6- (3-methyl-1H-indazol-5-yl) -pyridin-2-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-thiophen-3-yl-benzyl) -ethylamine;
(1S) -1- (4-Iodo-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
[4-((2S) -2-amino-3-phenyl-propoxy) -2- (3-methyl-1H-indazol-5-yl) -phenyl] -methanol;
(1S) -2- [5- (1H-benzotriazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -2- [5- (1H-benzotriazol-5-yl) -pyridin-3-yloxy] -1-benzyl-ethylamine;
(1S) -1-benzyl-2- [5- (3-morpholin-4-yl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1-benzyl-2- {5- [3- (4-methyl-piperazin-1-yl) -1H-indazol-5-yl] -pyridin-3-yloxy} -ethylamine;
(1S)-{5- [5- (2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl} -dimethyl-amine;
(1S)-{5- [5- (2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl}-(2-methoxy-ethyl) -amine;
{5- [5-((2S) -2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl}-(2-morpholin-4-yl-ethyl)- Amines;
5- [5-((2S) -2-amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-ylamine;
N- {5- [5-((2S) -2-amino-3-phenyl-propoxy) -pyridin-3-yl] -1H-indazol-3-yl} -2,2,2-trifluoro-acetamide ;
(2S) -2-amino-N- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -3-phenyl-propionamide;
(1S) -2- [5- (3-Benzyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -1-benzyl-2- [5- (3-benzyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Benzyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-methyl-ethylamine;
(6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -cinolin-4-yl) -phenyl-amine;
(1S) -2- [5- (1H-indazol-6-yl) -pyridin-3-yloxy]-(1H-indol-3-ylmethyl) -ethylamine;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -2,3-dihydro-isoindol-1-one;
6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-cinolin-4-one;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (4-phenyl-cinolin-6-yl) -pyridin-3-yloxy] -ethylamine;
(6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -cinolin-4-yl) -benzyl-amine;
(6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -cinolin-4-yl) -methyl-amine;
(6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -cinolin-4-ylamine;
[(3S) -3- (5-isoquinolin-6-yl-pyridin-3-yloxymethyl) -1,2,3,4-tetrahydro-b-carbolin-9-yl] -methanol;
3- (5-isoquinolin-6-yl-pyridin-3-yloxymethyl) -2,3,4,9-tetrahydro-1H- □ -carboline;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indazole-3-carboxylic acid;
5- {5-[(2S) -2-t-butoxycarbonylamino-3-hydroxy-propoxy) -pyridin-3-yl] -3-methyl-indazole-1-carboxylic acid t-butyl ester;
5- [5- (2S) -2-aziridin-2-ylmethoxy) -pyridin-3-yl] -3-methyl-1H-indazole;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (3-trifluoromethoxy-benzyl) -ethylamine;
(1S) -1- (3,5-dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,3-dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1-biphenyl-3-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3-Chloro-4-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-Chloro-3-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-trifluoromethoxy-benzyl) -ethylamine;
(1S) -1- (2-fluoro-4-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3-Fluoro-5-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2-methoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(3-{(2S) -2-amino-3- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propyl} -phenyl) -dimethyl-amine;
(1S) -1- (4-Chloro-2-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3-indole-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S)-(1S) -1- (3-fluoro-4-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3-Fluoro-4-methoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [6-chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (3,4-dichloro-benzyl) -ethylamine;
(1S) -1- (2-fluoro-6-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-Fluoro-3-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1-furan-2-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1-benzofuran-2-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3-Fluoro-4-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-Chloro-3-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1-furan-3-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2-fluoro-5-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3-chloro-5-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (3,4,5-trifluoro-benzyl) -ethylamine;
(1S) -1- (4-Fluoro-3-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,4-dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-Chloro-3-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2-trifluoromethoxy-benzyl) -ethylamine;
(1S) -1- (2,5-dimethoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-methylsulfanyl-benzyl) -ethylamine;
(1S) -1- (2-chlorohexyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,5-dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,5-dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,3-dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3,4-dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,4-dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3-Fluoro-4-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3,5-dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1-biphenyl-2-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3,4-dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,3-difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,5-difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,6-dichloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,4-difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,6-dimethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy ] -Ethylamine;
(1S) -1- (3,5-difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2,6-difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1-benzo [1,3] dioxol-5-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-Fluoro-3-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2,4,6-trimethyl-benzyl) -ethylamine;
(1S) -1- (2,4-dimethoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-trifluoromethyl-benzyl) -ethylamine;
(1S) -1- (5-Fluoro-2-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3,5-bis-trifluoromethyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-Fluoro-2-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (5-Fluoro-2-methoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2-methyl-naphthalen-1-ylmethyl) -ethylamine;
(1S) -1- (2,2-Difluoro-benzo [1,3] dioxol-4-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy ] -Ethylamine;
(1S) -1- (4-Fluoro-naphthalen-1-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2,2,3,3-tetrafluoro-2,3-dihydro- Benzo [1,4] dioxin-6-ylmethyl) -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (4-methyl-naphthalen-1-ylmethyl) -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2,4,6-trifluoro-benzyl) -ethylamine;
(1S) -2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2,3,4-trifluoro-benzyl) -ethylamine;
(1S) -1- (4-Bromo-2-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-Bromo-3-fluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2-bromo-4,6-difluoro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-Bromo-3-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -Bromo-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3-methoxy-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (3-Bromo-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (2-methoxy-naphthalen-1-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1R) -1- (4-chloro-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1R) -1-benzo [1,3] dioxol-5-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1R) -1- (3-Fluoro-4-methyl-benzyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1-benzyl-2- [6-chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-Bromo-benzyl) -2- [6-chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (4-chloro-benzyl) -2- [6-chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-cyclohexylmethyl-ethylamine;
(1S) -2- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (2,6-dimethyl-benzyl) -ethylamine;
(1S) -2- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -2-phenyl-propylamine;
(1S) -1- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -2,2-diphenyl-ethylamine;
(1S) -1- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -2-phenyl-propylamine;
(1S) -1- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -2,2-diphenyl-ethylamine;
(1S) -3-methyl-1- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxymethyl] -butylamine;
(1S) -2- [6-Chloro-5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -2- (6-chloro-5-thieno [2,3-c] pyridin-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine;
5-[(2S) -amino-3- (1H-indol-3-yl) -propoxy] -3-isoquinolin-6-yl-pyridin-2-carbonitrile;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (3-phenyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-Ethyl-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (3-pyridin-4-yl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (3-furan-2-yl-isoquinolin-6-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (3-phenylethynyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (3-prop-1-ynyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (3-vinyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -6- {5- [2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -isoquinoline-3-carbonitrile;
(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-6-vinyl-pyridin-3-yloxy) -ethylamine;
(1S) -2- (6-ethynyl-5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -2- (6-furan-2-yl-5-isoquinolin-6-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-6-phenylethynyl-pyridin-3-yloxy) -ethylamine;
6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -isoquinolin-5-ylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (8-methyl-isoquinolin-6-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (4-Chloro-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (4-phenyl-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (4-phenoxy-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (1H-indol-3-ylmethyl) -2- [5- (4-vinyl-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -2- [5- (4-Ethyl-thieno [2,3-c] pyridin-2-yl) -pyridin-3-yloxy] -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S)-(2- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -thieno [2,3-c] pyridin-2-yl ) -Phenyl-amine;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3,3-difluoro-1,3-dihydro-indole- 2-on;
6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3H-oxazolo [4,5-b] pyridine-2- on;
N1- (5-isoquinolin-6-yl-pyridin-3-yl) -ethane-1,2-diamine;
Naphthalene-2-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide;
Naphthalene-1-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide;
5-dimethylamino-naphthalene-1-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide;
Quinoline-5-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide;
Biphenyl-4-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide;
1-methyl-1H-imidazole-4-sulfonic acid (2-amino-ethyl)-(5-isoquinolin-6-yl-pyridin-3-yl) -amide;
3-amino-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] propan-1-ol;
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3-phenoxypropylamine;
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3- (naphthalen-2-yloxy) -propylamine;
3- (biphenyl-4-yloxy) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propylamine;
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3- (quinolin-7-yloxy) -propylamine;
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3- (pyridin-4-yloxy) -propylamine;
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -3- (naphthalen-1-yloxy) -propylamine;
3-{(2S) -2-amino-3- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propyl} -1H-indole-5-ol;
(1S) -1- (5-methoxy-1H-indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (5-Ethoxy-1H-indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (5-butoxy-1H-indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
(1S) -1- (5-isopropoxy-1H-indol-3-ylmethyl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
3- (1H-indol-3-yl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propan-1-ol;
3- (1H-indol-3-yl) -2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -propylamine;
Naphthalene-2-sulfonic acid (2-amino-ethyl)-[5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -amide;
Biphenyl-4-sulfonic acid (2-amino-ethyl)-[5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yl] -amide;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-isopropylidene-1,3-dihydro-indole-2 -ON;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (1H-imidazol-2-ylmethylene) -1, 3-dihydro-indol-2-one;
5- {5- [2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-pyridin-2-ylmethylene-1,3-dihydro-indole-2- on;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-furan-2-ylmethylene-1,3-dihydro- Indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (5-methyl-furan-2-ylmethylene)- 1,3-dihydro-indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (4,5-dimethyl-furan-2-ylmethylene ) -1,3-dihydro-indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-thiophen-2-ylmethylene-1,3-dihydro- Indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (1-methyl-1H-pyrrol-2-ylmethylene ) -1,3-dihydro-indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (1H-indol-3-ylmethylene) -1, 3-dihydro-indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (1-phenyl-1H-pyrrol-3-ylmethylene ) -1,3-dihydro-indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-pyridin-3-ylmethylene-1,3-dihydro- Indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (1H-pyrrol-3-ylmethylene) -1, 3-dihydro-indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (tetrahydro-pyran-4-ylidene) -1, 3-dihydro-indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3- (4-ethyl-3,5-dimethyl-1H -Pyrrol-2-ylmethylene) -1,3-dihydro-indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-cyclopropylmethylene-1,3-dihydro-indole- 2-on;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-pyrrolidin-2-ylmethylene-1,3-dihydro- Indol-2-one;
5- (5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -2-oxo-1,2-dihydro-indole -3-ylidenemethyl) -furan-2-carboxylic acid;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-benzylidene-1,3-dihydro-indole-2- on;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1H-indole-2,3-dione-3-oxime;
(1S) -2- (5-benzo [b] thiophen-2-yl-6-furan-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -2- (5-Benzo [b] thiophen-2-yl-6-vinyl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -2- (5-benzo [b] thiophen-2-yl-6-thiophen-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -2- (5-benzo [b] thiophen-2-yl-6-thiazol-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine;
(1S) -2- (5-benzo [b] thiophen-2-yl-6-pyrazin-2-yl-pyridin-3-yloxy) -1- (1H-indol-3-ylmethyl) -ethylamine;
{5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -3-benzo [b] thiophen-2-yl-pyridin-2-yl} -phenyl-amine;
{5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -3-benzo [b] thiophen-2-yl-pyridin-2-yl} -pyridine-3- Yl-amine;
6- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3H-benzoxazol-2-one;
1-benzimidazol-1-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
2- [5- (3-Methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -1-morpholin-4-ylmethyl-ethylamine;
5- [5-((2S) -2-amino-3-phenyl-propoxy) -pyridin-3-yl] -1,3-dihydro-indol-2-one;
5- [5-((2S) -2-Amino-3-phenyl-propoxy) -pyridin-3-yl] -3- (1H-pyrrol-2-ylmethylene) -1,3-dihydro-indole-2- on;
5- [5-((2S) -2-amino-3-phenyl-propoxy) -pyridin-3-yl] -3-furan-2-ylmethylene-1,3-dihydro-indol-2-one;
(1S) -1-Benzimidazol-1-ylmethyl-2- [5- (3-methyl-1H-indazol-5-yl) -pyridin-3-yloxy] -ethylamine;
3- {3-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -5-isoquinolin-6-yl-pyridin-4-yl} -acrylonitrile;
(1S) -1- (1H-indol-3-ylmethyl) -2- (5-isoquinolin-6-yl-4-methyl-pyridin-3-yloxy) -ethylamine;
5- {5-[(2S) -2-Amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-methyl-1,3-dihydro-indole-2- on;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3,3-dimethyl-1,3-dihydro-indole- 2-on;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -1,3,3-trimethyl-1,3-dihydro- Indol-2-one;
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-ethyl-1,3-dihydro-indole-2- On; and
5- {5-[(2S) -2-amino-3- (1H-indol-3-yl) -propoxy] -pyridin-3-yl} -3-benzyl-1,3-dihydro-indole-2- on
2. The compound of claim 1, selected from the group consisting of:   A pharmaceutical composition comprising a compound of claim 1 or a therapeutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.   A method of inhibiting protein kinases in a patient in need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of claim 1 or a therapeutically acceptable salt thereof.