JP2009521504A - Akt activity inhibitor - Google Patents

Abstract

  The present invention relates to novel thiophene compounds, the use of such compounds as protein kinase B activity inhibitors and the use in the treatment of cancer and arthritis.

Description

  The present invention relates to novel thiophene compounds, their use as inhibitors of protein kinase B (hereinafter referred to as PKB / Akt, PKB or Akt) activity and in the treatment of cancer and arthritis.

The present invention relates to thiophene-containing compounds that are inhibitors of the activity of one or more isoforms of one or more serine / threonine kinases, Akt (also known as protein kinase B). The present invention also relates to pharmaceutical compositions comprising such compounds and methods of using the compounds in the treatment of cancer and arthritis (Liu et al., Current Opin. Pharmacology 3: 317-22 (2003)).
Apoptosis (programmed cell death) plays an important role in the pathogenesis of various diseases such as embryonic development and degenerative neuronal diseases, cardiovascular diseases and cancer. Recent work has led to the identification of various pro- and anti-apoptotic gene products involved in the regulation or execution of programmed cell death. Expression of anti-apoptotic genes such as Bcl2 or Bcl-x _L inhibits apoptotic cell death induced by various stimuli. On the other hand, expression of pro-apoptotic genes such as Bax or Bad results in programmed cell death (Adams et al., Science, 281: 1322-1326 (1998)). The execution of programmed cell death is mediated by caspase-1-related proteinases including caspase-3, caspase-7, caspase-8 and caspase-9 (Thornberry et al., Science, 281: 1312-1316 (1998). )).

  The phosphatidylinositol 3′-OH kinase (PI3K) / Akt / PKB pathway appears to be important in the regulation of cell survival / death (Kulik et al., Mol. Cell. Biol. 17: 1595-1606 (1997); Franke Cell, 88: 435-437 (1997); Kauffmann-Zeh et al., Nature 385: 544-548 (1997) Hemmings Science, 275: 628-630 (1997); Dudek et al., Science, 275: 661-665 ( 1997)). Survival factors such as platelet-derived growth factor (PDGF), nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) promote cell survival under various conditions by inducing PI3K activity. (Kulik et al., 1997, Hemmings 1997). Activated PI3K induces the production of phosphatidylinositol (3,4,5) -triphosphate (PtdIns (3,4,5) -P3), which then converts the pleckstrin homology (PH) -domain. Binds to and promotes activation of the serine / threonine kinase Akt it contains (Franke et al., Cell, 81: 727-736 (1995); Hemmings Science, 277: 534 (1997); Downward, Curr. Opin. Cell Biol. 10: 262-267 (1998), Alessi et al., EMBO J. 15: 6541-6551 (1996)). Specific inhibitors of PI3K or dominant negative Akt / PKB mutants disrupt the survival promoting activity of these growth factors or cytokines. Inhibitors of PI3K (LY294002 or wortmannin) inhibited Akt / PKB activation by upstream kinases. Furthermore, the introduction of constitutively active PI3K or Akt / PKB mutants promotes cell survival under conditions where cells normally undergo apoptotic cell death (Kulik et al., 1997, Dudek et al., 1997).

  Analysis of Akt levels in human tumors has shown that Akt2 has a significant number of ovarian cancers (JQ Cheung et al., Proc. Natl. Acad. Sci. USA 89: 9267-9271 (1992)) and pancreatic cancer. (JQ Cheung et al., Proc. Natl. Acad. Sci. USA 93: 3636-3641 (1996)). Similarly, Akt3 was found to be overexpressed in breast and prostate cancer cell lines (Nakatani et al., J. Biol. Chem. 274: 21528-21532 (1999)). Akt-2 was overexpressed in 12% of ovarian carcinomas, and Akt amplification was found to be particularly frequent in 50% of undifferentiated tumors, suggesting that Akt may be associated with tumor challenge (Bellacosa et al., Int. J. Cancer, 64, pp. 280-285, 1995). Increased Akt1 kinase activity has been reported in breast, ovarian and prostate cancer (Sun et al., Am. J. Pathol. 159: 431-7 (2001)).

  The tumor suppressor PTEN, a protein and lipid phosphatase that specifically removes the 3 ′ phosphate of PtdIns (3,4,5) -P3, is a negative regulator of the PI3K / Akt pathway (Li et al., Science 275: 1943 -1947 (1997), Stambolic et al., Cell 95: 29-39 (1998), Sun et al., Proc. Nati. Acad. Sci. USA 96: 6199-6204 (1999)). Germline mutations in PTEN cause human cancer syndromes such as Cowden's disease (Liaw et al., Nature Genetics 16: 64-67 (1997)). PTEN is deleted in a large proportion of human tumors, and tumor cell lines that do not have functional PTEN display high levels of activated Akt (Li et al., Supra, Guldberg et al., Cancer Research 57: 3660. -3633 (1997), Risinger et al., Cancer Research 57: 4736-4738 (1997)).

These observations reveal that the PI3K / Akt pathway plays an important role in the regulation of cell survival or apoptosis in tumorigenesis.
Three members of the Akt / PKB subfamily of serine / threonine protein kinases regulated by second messengers have been identified and designated Akt1 / PKBα, Akt2 / PKBβ and Akt3 / PKBγ, respectively. The isoform is particularly homologous in the region encoding the catalytic domain. Akt / PKB is activated by phosphorylation events that occur in response to PI3K signaling. PI3K phosphorylates membrane inositol phospholipids, thereby producing second messenger phosphatidyl-inositol 3,4,5-triphosphate and phosphatidylinositol 3,4-bisphosphate, which are in the PH domain of Akt / PKB It turns out that they combine. The current model of Akt / PKB activation suggests that the enzyme is recruited to the membrane by 3'-phosphorylated phosphoinositides, where phosphorylation of the Akt / PKB regulatory site by upstream kinases occurs ( B.A. Hemmings, Science 275: 628-630 (1997); B.A. Hemmings, Science 276: 534 (1997); J. Downward, Science 279: 673-674 (1998)).

Phosphorylation of Akt1 / PKBα occurs at two regulatory sites, Thr ^3O8 in the catalytic domain activation loop and Ser ⁴⁷³ near the carboxy terminus (DR Alessi et al., EMBO J. 15: 6541-6551 (1996) and R. Meier et al., J. Biol. Chem. 272: 30491-30497 (1997)). Equivalent regulatory phosphorylation sites occur in Akt2 / PKBβ and Akt3 / PKBγ. An upstream kinase that phosphorylates Akt / PKB at the activation loop site has been cloned and named 3′-phosphoinositide-dependent protein kinase 1 (PDK1). PDK1 phosphorylates not only Akt / PKB but also p70 ribosomal S6 kinase, p90RSK, serum and glucocorticoid-regulated kinase (SGK), and protein kinase C. Upstream kinases that phosphorylate Akt / PKB regulatory sites near the carboxy terminus have not yet been identified, but recent reports have shown that integrin-linked kinase (ILK-1), serine / threonine protein kinases, or self A role for phosphorylation is suggested.

  Akt activation and inhibition of activity can be achieved by inhibiting PI3K with inhibitors such as LY294002 and wortmannin. However, PI3K inhibition is indiscriminate not only to all three Akt isoenzymes but also to other PH domain-containing signaling molecules that depend on PdtIns (3,4,5) -P3, such as the Tec family of tyrosine kinases. May be affected. Furthermore, it has been disclosed that Akt can be activated by growth signals independent of PI3K.

  Alternatively, Akt activity can be inhibited by blocking the activity of the upstream kinase PDK1. Compound UCN-01 is a reported inhibitor of PDK1 (Biochem. J. 375 (2): 255 (2003)). Also, inhibition of PDK1 will result in inhibition of multiple protein kinases whose activity depends on PDK1, such as atypical PKC isoforms, SGK and S6 kinase (Williams et al., Curr. Biol. 10: 439-). 448 (2000)).

  Akt small molecule inhibitors are useful in the treatment of tumors, particularly in the treatment of tumors with activated Akt (eg, tumors with PTEN null tumors and ras mutations). PTEN is an important negative regulator of Akt and its functions are breast and prostate carcinomas, glioblastoma, and Banyan-Zonana syndrome (Maehama, T. et al. Annual Review of Biochemistry, 70: 247 (2001). ), Cordon's disease (Parsons, R .; Simpson, L. Methods in Molecular Biology (Totowa, NJ, United States), 222 (Tumor Suppressor Genes, Volume 1): 147 (2003) te (L); S. et al., Current Opinion in Neurobiology, 12 (5): 516 (2002)). It has lost in many cancers including some cancer syndromes include. Akt3 is upregulated in estrogen receptor-deficient breast cancer and androgen independent prostate cancer lines, and Akt2 is overexpressed in pancreatic and ovarian carcinomas. Akt1 is amplified in gastric cancer (Staal, Proc. Natl. Acad. Sci. USA 84: 5034-7 (1987)) and is upregulated in breast cancer (Stal et al., Breast Cancer Res. 5: R37-R44 ( 2003)). Thus, small molecule Akt inhibitors are expected to be useful in the treatment of these types of cancer as well as other types of cancer. Akt inhibitors are also useful in combination with additional chemotherapeutic agents.

The object of the present invention is to provide novel compounds which are inhibitors of Akt / PKB.
It is also an object of the present invention to provide a pharmaceutical composition comprising a pharmaceutical carrier and a compound useful in the method of the present invention.
Another object of the present invention is to provide a method for treating cancer, which comprises administering such an inhibitor of Akt / PKB activity.
Another object of the present invention is to provide a method for treating arthritis, which comprises administering such an inhibitor of Akt / PKB activity.

［式中：
Ｖは、ＣＨおよびＮからなる群から選択され；
Ｚは、ＣＲ^７およびＮからなる群から選択され、ここに、Ｒ^７は、水素、−ＣＯ_２Ｒ^２０およびＣ_１−３アルキルから選択され、ここに、Ｒ^２０は、水素およびＣ_１−３アルキルから選択され；
Ｗ、ＸおよびＹは、ＣＲ^５、ＣＲ^１０およびＮからなる群から選択され、ここに、Ｒ^５は、水素、Ｃ_１−３アルキル、アリール、ヘテロアリール、−ＣＯ_２Ｒ^８、−ＣＮおよび−ＣＯＲ^８から選択され、Ｒ^１０は、式（Ｘ）：

（式中：
Ｒ^１およびＲ^２８は、独立して、水素、ハロゲン、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、Ｃ_１−３アルキル、−ＮＲ^１４Ｒ^１５、シアノおよび−ＯＲ^３０から選択され、
Ｌ^１は、−ＮＲ^６ＣＯ−、−ＣＯＮＲ^６−、−ＮＲ^６ＳＯ_２−、−ＳＯ_２ＮＲ^６−、−ＮＲ^６ＣＨ_２−、−ＣＨ_２ＮＲ^６−、−ＣＨ＝ＣＨ−、−ＣＦ＝ＣＨ−および−ＣＨ＝ＣＦ−から選択され、
Ｒ^２は、水素、−（ＣＨ_２）_ｍ−アリール、−（ＣＨ_２）_ｍ−Ｃ_３−７シクロアルキル、Ｃ_１−３アルキル、置換−（ＣＨ_２）_ｍ−アリール、置換−（ＣＨ_２）_ｍ−Ｃ_３−７シクロアルキルおよび置換Ｃ_１−３アルキルから選択され、ここに、ｍは０〜４であり、
Ｒ^２５は水素であるか、あるいはＲ^２５は、Ｒ^３またはＲ^４と一緒になって、１個のさらなるヘテロ原子を含有していてもよい４〜７員の炭素環を形成し、
Ｒ^３およびＲ^４は、独立して、水素およびＣ_１−５アルキルから選択されるか、あるいはＲ^３およびＲ^４は、それらが結合している窒素と一緒になって、１または２個のさらなるヘテロ原子を含有していてもよい４〜６員の炭素環を形成するか、あるいはＲ^３またはＲ^４は、Ｒ^２５と一緒になって、１個のさらなるヘテロ原子を含有していてもよい４〜７員の炭素環を形成し、
Ｑは、−（ＣＨ_２）_ｐアリール（ＣＨ_２）_ｐ−、置換−（ＣＨ_２）_ｐアリール（ＣＨ_２）_ｐ−および−（ＣＨ_２）_ｎ−から選択され、ここに、ｐは０〜４であり、ｎは０〜４であり、ｎが０以外である場合、−（ＣＨ_２）_ｎ−基はオキソにより置換されていてもよく、
ここに、Ｒ^６は、水素およびＣ_１−３アルキルからなる群から選択され、
Ｒ^３０は、水素、−（ＣＨ_２）_ｑＮＲ^２６Ｒ^２７およびＣ_１−３アルキルからなる群から選択され、ここに、ｑは０〜４であり、Ｒ^２６およびＲ^２７は、水素およびＣ_１−５アルキルから選択されるか、あるいはＲ^２６およびＲ^２７は、それらが結合している窒素と一緒になって、１または２個のさらなるヘテロ原子を含有していてもよい４〜６員の炭素環を形成し、
Ｒ^１４およびＲ^１５は、独立して、水素およびＣ_１−３アルキルから選択される）
で示される置換基であり；
ここに、Ｒ^８は、水素およびＣ_１−３アルキルから選択さる：
ただし、Ｗ、ＸおよびＹの１つはＣＲ^１０であり；Ｖ、Ｗ、Ｘ、ＹおよびＺの３個までがＮである］
で示される新規化合物および／またはその医薬上許容される塩，水和物、溶媒和物およびプロドラッグに関する。 The present invention relates to a compound of formula (I):

[Where:
V is selected from the group consisting of CH and N;
Z is selected from the group consisting of CR ⁷ and N, wherein R ⁷ is selected from hydrogen, —CO ₂ R ²⁰ and C _1-3 alkyl, wherein R ²⁰ is hydrogen and C _1- Selected from ₃ alkyls;
W, X and Y are selected from the group consisting of CR ⁵ , CR ¹⁰ and N, wherein R ⁵ is hydrogen, C _1-3 alkyl, aryl, heteroaryl, —CO ₂ R ⁸ , —CN and -COR ⁸ and R ¹⁰ is selected from the formula (X):

(Where:
R ¹ and R ²⁸ are independently selected from hydrogen, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C _1-3 alkyl, —NR ¹⁴ R ¹⁵ , cyano and —OR ³⁰ ;
L ¹ is —NR ⁶ CO—, —CONR ⁶ —, —NR ⁶ SO ₂ —, —SO ₂ NR ⁶ —, —NR ⁶ CH ₂ —, —CH ₂ NR ⁶ —, —CH═CH—, — Selected from CF═CH— and —CH═CF—
R ² is hydrogen, — (CH ₂ ) _m -aryl, — (CH ₂ ) _m —C _3-7 cycloalkyl, C _1-3 alkyl, substituted — (CH ₂ ) _m -aryl, substituted — (CH ₂ ) Selected from _m- C _3-7 cycloalkyl and substituted C _1-3 alkyl, wherein m is 0-4;
R ²⁵ is hydrogen or R ²⁵ together with R ³ or R ⁴ forms a 4-7 membered carbocyclic ring which may contain one additional heteroatom,
R ³ and R ⁴ are independently selected from hydrogen and C _1-5 alkyl, or R ³ and R ⁴ together with the nitrogen to which they are attached, 1 or 2 Forms a 4-6 membered carbocycle which may contain further heteroatoms, or R ³ or R ⁴ together with R ²⁵ may contain one further heteroatom Forming a good 4-7 membered carbocyclic ring,
Q is, - _{(CH 2) p} aryl _{(CH 2) p} -, substituted - _{(CH 2) p} aryl _{(CH 2) p} - and - _{(CH 2) n} - is selected from, where, p is 0 4 and n is 0 to 4 and when n is other than 0, the — (CH ₂ ) _n — group may be substituted by oxo,
Wherein R ⁶ is selected from the group consisting of hydrogen and C _1-3 alkyl;
R ³⁰ is selected from the group consisting of hydrogen, — (CH ₂ ) _q NR ²⁶ R ²⁷ and C _1-3 alkyl, wherein q is 0-4, R ²⁶ and R ²⁷ are hydrogen and C Selected from _1-5 alkyl, or R ²⁶ and R ²⁷ together with the nitrogen to which they are attached may contain 1 or 2 additional heteroatoms 4-6 members Form a carbocycle of
R ¹⁴ and R ¹⁵ are independently selected from hydrogen and C _1-3 alkyl)
A substituent represented by;
Wherein R ⁸ is selected from hydrogen and C _1-3 alkyl:
Where one of W, X and Y is CR ¹⁰ ; up to three of V, W, X, Y and Z are N]
And / or pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof.

The present invention relates to a method for treating cancer, comprising administering to a subject in need thereof an effective amount of an Akt / PKB inhibitor compound of formula (I).
The present invention relates to a method for treating arthritis, comprising administering to a subject in need thereof an effective amount of an Akt / PKB inhibitor compound of formula (I).

The invention also relates to the finding that the compounds of formula (I) are active as inhibitors of Akt / PKB.
In a further aspect of the present invention, novel processes and novel intermediates useful in the preparation of the Akt / PKB inhibitor compounds of the present invention are provided.

The present invention includes a pharmaceutical composition comprising a pharmaceutical carrier and a compound useful in the methods of the invention.
The present invention also includes a method of co-administering the Akt / PKB inhibitory compound of the present invention and a further active ingredient.

The present invention relates to a compound represented by the above formula (I).
The compound of the present invention represented by the formula (I) inhibits Akt / PKB activity. In particular, the compounds disclosed herein inhibit each of the three Akt / PKB isomers.

［式中：
ＺはＣＲ^７であり、ここに、Ｒ^７は、水素および−ＣＯ_２Ｒ^２０から選択され、ここに、Ｒ^２０は、水素およびＣ_１−３アルキルから選択され；
Ｗ、ＸおよびＹは、ＣＲ^５、ＣＲ^１０およびＮからなる群から選択され、ここに、Ｒ^５は、水素、Ｃ_１−３アルキル、アリール、ヘテロアリール、−ＣＯ_２Ｒ^８、−ＣＮおよび−ＣＯＲ^８から選択され、Ｒ^１０は、式（Ｘ）：

（式中：
Ｒ^１は、水素、ハロゲン、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、Ｃ_１−３アルキル、−ＮＲ^１４Ｒ^１５、シアノおよび−ＯＲ^６から選択され、
Ｌ^１は、−ＮＲ^６ＣＯ−、−ＣＯＮＲ^６−、−ＮＲ^６ＳＯ_２−、−ＳＯ_２ＮＲ^６−、−ＮＲ^６ＣＨ_２−、−ＣＨ_２ＮＲ^６−、−ＣＨ＝ＣＨ−、−ＣＦ＝ＣＨ−および−ＣＨ＝ＣＦ−から選択され、
Ｒ^２は、水素、−（ＣＨ_２）_ｍ−アリール、−（ＣＨ_２）_ｍ−Ｃ_３−７シクロアルキル、Ｃ_１−３アルキル、置換−（ＣＨ_２）_ｍ−アリール、置換−（ＣＨ_２）_ｍ−Ｃ_３−７シクロアルキルおよび置換Ｃ_１−３アルキルから選択され、ここに、ｍは０〜４であり、
Ｒ^２５は水素であるか、あるいは、Ｒ^２５は、Ｒ^３またはＲ^４と一緒になって、４〜７員の炭素環を形成し、
Ｒ^３およびＲ^４は、独立して、水素およびＣ_１−５アルキルから選択されるか、あるいはＲ^３およびＲ^４は、それらが結合している窒素と一緒になって、１または２個のさらなるヘテロ原子を含有していてもよい４〜６員の炭素環を形成するか、あるいはＲ^３またはＲ^４は、Ｒ^２５と一緒になって、４〜７員の炭素環を形成し、
Ｑは、−（ＣＨ_２）_ｐアリール（ＣＨ_２）_ｐ−、置換−（ＣＨ_２）_ｐアリール（ＣＨ_２）_ｐ−および−（ＣＨ_２）_ｎ−から選択され、ここに、ｐは０〜４であり、ｎは０〜４であり、ｎが０以外である場合、−（ＣＨ_２）_ｎ−器は、オキソにより置換されていてもよく、
ここに、Ｒ^６は、水素およびＣ_１−３アルキルからなる群から選択され、
Ｒ^３０は、水素、−（ＣＨ_２）_ｑＮＲ^２６Ｒ^２７およびＣ_１−３アルキルからなる群から選択され、ここに、ｑは０〜４であり、Ｒ^２６およびＲ^２７は、水素およびＣ_１−５アルキルから選択されるか、あるいはＲ^２６およびＲ^２７は、それらが結合している窒素と一緒になって、１または２個のさらなるヘテロ原子を含有していてもよい４〜６員の炭素環を形成し、
Ｒ^１４およびＲ^１５は、独立して、水素およびＣ_１−３アルキルから選択される）
で示される置換基であり、
ここに、Ｒ^８は、水素およびＣ_１−３アルキルから選択される：
ただし、Ｗ、ＸおよびＹの１つはＣＲ^１０であり；Ｗ、Ｘ、ＹおよびＺの３個まではＮである］
で示される化合物および／またはその医薬上許容される塩、水和物、溶媒和物およびプロドラッグを包含する。 The compound of the present invention represented by the formula (I) is represented by the formula (Ia):

[Where:
Z is CR ⁷ wherein R ⁷ is selected from hydrogen and —CO ₂ R ²⁰ , wherein R ²⁰ is selected from hydrogen and C _1-3 alkyl;
W, X and Y are selected from the group consisting of CR ⁵ , CR ¹⁰ and N, wherein R ⁵ is hydrogen, C _1-3 alkyl, aryl, heteroaryl, —CO ₂ R ⁸ , —CN and -COR ⁸ and R ¹⁰ is selected from the formula (X):

(Where:
R ¹ is selected from hydrogen, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C _1-3 alkyl, —NR ¹⁴ R ¹⁵ , cyano and —OR ⁶ ;
L ¹ is —NR ⁶ CO—, —CONR ⁶ —, —NR ⁶ SO ₂ —, —SO ₂ NR ⁶ —, —NR ⁶ CH ₂ —, —CH ₂ NR ⁶ —, —CH═CH—, — Selected from CF═CH— and —CH═CF—
R ² is hydrogen, — (CH ₂ ) _m -aryl, — (CH ₂ ) _m —C _3-7 cycloalkyl, C _1-3 alkyl, substituted — (CH ₂ ) _m -aryl, substituted — (CH ₂ ) Selected from _m- C _3-7 cycloalkyl and substituted C _1-3 alkyl, wherein m is 0-4;
R ²⁵ is hydrogen or R ²⁵ together with R ³ or R ⁴ forms a 4-7 membered carbocycle;
R ³ and R ⁴ are independently selected from hydrogen and C _1-5 alkyl, or R ³ and R ⁴ together with the nitrogen to which they are attached, 1 or 2 Forming a 4-6 membered carbocycle which may contain additional heteroatoms, or R ³ or R ⁴ together with R ²⁵ form a 4-7 membered carbocycle;
Q is, - _{(CH 2) p} aryl _{(CH 2) p} -, substituted - _{(CH 2) p} aryl _{(CH 2) p} - and - _{(CH 2) n} - is selected from, where, p is 0 4 and n is 0 to 4 and when n is other than 0, the — (CH ₂ ) _n — unit may be substituted by oxo,
Wherein R ⁶ is selected from the group consisting of hydrogen and C _1-3 alkyl;
R ³⁰ is selected from the group consisting of hydrogen, — (CH ₂ ) _q NR ²⁶ R ²⁷ and C _1-3 alkyl, wherein q is 0-4, R ²⁶ and R ²⁷ are hydrogen and C Selected from _1-5 alkyl, or R ²⁶ and R ²⁷ together with the nitrogen to which they are attached may contain 1 or 2 additional heteroatoms 4-6 members Form a carbocycle of
R ¹⁴ and R ¹⁵ are independently selected from hydrogen and C _1-3 alkyl)
A substituent represented by
Wherein R ⁸ is selected from hydrogen and C _1-3 alkyl:
Where one of W, X and Y is CR ¹⁰ ; up to three of W, X, Y and Z are N]
And / or pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof.

（式中：
Ｒ^１は、水素、ハロゲン、アリール、ヘテロアリールおよびシアノから選択され、
Ｌ^１は、−ＮＲ^６ＣＯ−および−ＣＯＮＲ^６−から選択され、
Ｒ^２は、水素、−（ＣＨ_２）_ｍ−アリール、置換−（ＣＨ_２）_ｍ−アリールから選択され、ここに、ｍは０〜４であり、
Ｒ^２５は水素であるか、あるいはＲ^２５は、Ｒ^３またはＲ^４と一緒になって、４〜７員の炭素環を形成し、
Ｒ^３およびＲ^４は、独立して、水素およびＣ_１−５アルキルから選択されるか、あるいはＲ^３およびＲ^４は、それらが結合している窒素と一緒になって、１または２個のさらなるヘテロ原子を含有していてもよい４〜６員の炭素環を形成するか、あるいはＲ^３またはＲ^４は、Ｒ^２５と一緒になって、４〜７員の炭素環を形成し、
Ｑは、−（ＣＨ_２）_ｐアリール（ＣＨ_２）_ｐ−および−（ＣＨ_２）_ｎ−から選択され、ここに、ｐは０〜４であり、ｎは０〜４であり、ｎが０以外である場合、−（ＣＨ_２）_ｎ−基は置換されていてもよい）
で示される置換基であり、
ここに、Ｒ^６は、水素およびＣ_１−３アルキルからなる群から選択される：
ただし、Ｗ、ＸおよびＹの１つはＣＲ^１０である、
式（Ｉａ）で示される化合物および／またはその医薬上許容される塩、水和物、溶媒和物およびプロドラッグを包含する。 The compounds of the present invention are:
Z is CR ⁷ , wherein R ⁷ is selected from hydrogen and —CO ₂ R ²⁰ , wherein R ²⁰ is selected from hydrogen and C _1-3 alkyl;
W, X and Y are selected from the group consisting of CR ⁵ and CR ¹⁰ , wherein R ⁵ is hydrogen and R ¹⁰ is of formula (X):

(Where:
R ¹ is selected from hydrogen, halogen, aryl, heteroaryl and cyano;
L ¹ is selected from —NR ⁶ CO— and —CONR ⁶ —,
R ² is selected from hydrogen, — (CH ₂ ) _m -aryl, substituted — (CH ₂ ) _m -aryl, where m is 0-4;
R ²⁵ is hydrogen, or R ²⁵ together with R ³ or R ⁴ forms a 4-7 membered carbocycle;
R ³ and R ⁴ are independently selected from hydrogen and C _1-5 alkyl, or R ³ and R ⁴ together with the nitrogen to which they are attached, 1 or 2 Forming a 4-6 membered carbocycle which may contain additional heteroatoms, or R ³ or R ⁴ together with R ²⁵ form a 4-7 membered carbocycle;
Q is, - _{(CH 2) p} aryl _{(CH 2) p} - and - _{(CH 2) n} - is selected from, where, p is 0 to 4, n is 0 to 4, n is 0 If other than, - _{(CH 2) n} - group may be substituted)
A substituent represented by
Wherein R ⁶ is selected from the group consisting of hydrogen and C _1-3 alkyl:
Where one of W, X and Y is CR ¹⁰ ;
It includes a compound of formula (Ia) and / or a pharmaceutically acceptable salt, hydrate, solvate and prodrug thereof.

  Novel compounds useful in the present invention are:
  3-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide;
  3-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide;
  4-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] butanamide;
  4-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] butanamide;
  3-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide;
  4-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide;
  N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  4-bromo-N- [2- (methylamino) -1-phenylethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- (3-amino-1-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (3-amino-1-phenylpropyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (3-amino-1-phenylpropyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (3-amino-1-phenylpropyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (4-amino-1-phenylbutyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (4-amino-1-phenylbutyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  3-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide;
  4-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide;
  N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] phenylalaninamide;
  2-Amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] acetamide;
  N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] phenylalaninamide;
  3-amino-2- (phenylmethyl) -N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide;
  3-amino-N- [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -2-phenylpropanamide;
  3-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thienyl] propanamide;
  4- [5-({[2- (dimethylamino) -1-phenylethyl] amino} carbonyl) -2-thienyl] -1H-pyrrolo [2,3-b] pyridine-2-carboxylate;
  N- [2- (dimethylamino) -1-phenylethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  4-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -4-piperidinecarboxamide;
  N-{[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} tyrosine amide;
  N- [2- (4-morpholinyl) -1-phenylethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-phenyl-2- (1-pyrrolidinyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(2-aminophenyl) methyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(3-aminophenyl) methyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-aminoethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -4- (3-pyridinyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -4- (1H-pyrazol-4-yl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -4-ethenyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -4-cyclopropyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  3-amino-N- [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylpropanamide;
  N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-phenyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  3-amino-N- [5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenylmethyl) propanamide;
  3-amino-2- (phenylmethyl) -N- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-furancarboxamide;
  3-amino-N- [5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylpropanamide;
  N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide;
  N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide;
  N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide;
  N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide;
  N-[(1S) -2-amino-1-phenylethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(1R) -2-amino-1-phenylethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-furancarboxamide;
  N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-furancarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-furancarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-furancarboxamide;
  (2-amino-1-phenylethyl) {[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] methyl} amine;
  N- (2-amino-1-phenylethyl) -4-phenyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -4-methyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-2-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-2-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  (3-amino-2-phenylpropyl) [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] amine;
  3-amino-3-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide;
  4-amino-3-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide;
  N- (2-amino-1-phenylethyl) -4-bromo-5- (3-phenyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  4-amino-4-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide;
  4-bromo-N- [2- (methylamino) -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophene Carboxamide;
  3-[(2-Aminoethyl) oxy] -N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -4-chloro-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-aminoethyl) -4-bromo-N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-aminoethyl) -4-bromo-N-phenyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-3-fluoro-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  4-Bromo-N- [2-[(1-methylethyl) amino] -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Thiophene carboxamide;
  4-bromo-N- [2- (ethylamino) -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  3-{[2-amino-1- (phenylmethyl) ethyl] oxy} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-N-methyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (6-amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  3-[(2-Aminoethyl) oxy] -N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Thiophene carboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {4- [5-({[2-amino-1- (phenylmethyl) ethyl] amino} carbonyl) -2-thienyl] -1H-pyrrolo [2,3-b] pyridin-3-yl}- 3-furancarboxamide;
  3-amino-N- [4- (2-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylpropanamide;
  N- (2-amino-1-phenylethyl) -4- [2- (3-furanyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thiophenecarboxamide;
  4-amino-N- [5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylbutanamide;
  3-amino-2- (phenylmethyl) -N- [5-phenyl-4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-chloro-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thiophenecarboxamide;
  N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-thiophenecarboxamide;
  N-[(1S) -2-amino-1- (cyclohexylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(1S) -2-amino-1- (cyclohexylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  3-Amino-N- [5- (3-furanyl) -4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenylmethyl) Propanamide;
  3-amino-2- (phenylmethyl) -N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -3,4-dibromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -3- (4-methylphenyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -3- (methyloxy) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  3-amino-N- [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -2- (phenylmethyl) propanamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -2-thiophenecarboxamide;
  2-amino-1- (phenylmethyl) ethyl [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbamate;
  4- [5-({[2-Amino-1- (phenylmethyl) ethyl] amino} carbonyl) -2-thienyl] -N- (2-furanylmethyl) -1H-pyrrolo [2,3-b] pyridine- 3-carboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- [2- (3-furanyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-N-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide
  N- [2-amino-1- (phenylmethyl) ethyl] -N-hydroxy-4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -N-hydroxy-3- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -N-[(phenylmethyl) oxy] -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide ;
  N- [2-amino-1- (phenylmethyl) ethyl] -N'-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboximidamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -N'-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboximidamide;
  3-amino-2- (phenylmethyl) -N- [5- (3-pyridinyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide;
  3-Amino-N- [5- (1,3-oxazol-2-yl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenyl Methyl) propanamide;
  N- {2-amino-1- [2- (methyloxy) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {2-amino-1- [3- (methyloxy) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {2-amino-1- [4- (methyloxy) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {2-amino-1- [2- (methyloxy) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {2-amino-1- [3- (methyloxy) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {2-amino-1- [4- (methyloxy) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-{(1R) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
  N-{(1S) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophenecarboxamide
  N- [1- (aminomethyl) -3-phenylpropyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-((1S) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) -2-thiophenecarboxamide;
  N-((1R) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) -2-thiophenecarboxamide;
  N-{(1S) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-((1R) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Thiophene carboxamide;
  N-((1S) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Thiophene carboxamide;
  N-{(1R) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-((1S) -2-amino-1-{[4- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-thiophenecarboxamide;
  N-((1S) -2-amino-1-{[4- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
  3-[(2-aminoethyl) oxy] -N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  3-[(2-aminoethyl) oxy] -N- (3-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  3-[(2-aminoethyl) oxy] -N- (2-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Furan carboxamide;
  N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-furancarboxamide;
  3-[(2-aminoethyl) oxy] -4-bromo-N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  3-[(2-aminoethyl) oxy] -4-bromo-N- (3-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  3-[(2-aminoethyl) oxy] -4-bromo-N- (2-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {2-amino-1- [3- (trifluoromethyl) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {2-amino-1- [3- (trifluoromethyl) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide ;
  4-Bromo-N-[(1S) -2-hydroxy-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(1S) -2-hydroxy-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {2-amino-1- [2- (trifluoromethyl) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {2-amino-1- [2- (trifluoromethyl) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide ;
  3-[(2-aminoethyl) oxy] -N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H- Pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3 -B] pyridin-4-yl) -2-thiophenecarboxamide;
  N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridine -4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(2S) -2-amino-3-phenylpropyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(2R) -2-amino-3-phenylpropyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(2S) -2-amino-3-phenylpropyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(2R) -2-amino-3-phenylpropyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- (3-amino-1-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (4-fluorophenyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (4-fluorophenyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (2-fluorophenyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (2-fluorophenyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (3-fluorophenyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (3-fluorophenyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
  N-[(2R) -2-amino-3- (3-fluorophenyl) propyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide
  N-{(1R) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
  N-{(1R) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
  N-{(1R) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-{(1S) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
  N-{(1S) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-{(1S) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-{(1R) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
  N-{(1R) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- [2-amino-1- (phenylmethyl) ethyl] -3-[(3-aminopropyl) oxy] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) -2-thiophenecarboxamide;
  N- {2-amino-1-[(2,6-difluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophene Carboxamide;
  N-{(1S) -2-amino-1-[(3,5-difluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N- {2-amino-1-[(3,5-difluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
  N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-thiophenecarboxamide;
  N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-thiophenecarboxamide;
  N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
  N- {2-amino-1-[(2,6-difluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(1S) -2-amino-1- (4-pyridinylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-[(1S) -2-amino-1- (4-pyridinylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
  N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Furan carboxamide;
  N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-furancarboxamide;
  N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3 -B] pyridin-4-yl) -2-furancarboxamide;
  3-[(2-Aminoethyl) oxy] -N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H- Pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide; and
  3-[(2-aminoethyl) oxy] -N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2, 3-b] pyridin-4-yl) -2-furancarboxamide;
And / or pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof.

  The compound of formula (I) is included in the pharmaceutical composition of the present invention and used in the method of the present invention.

  Certain compounds described herein may contain one or more chiral atoms or may exist separately as two enantiomers. Thus, the compounds of the invention can exist as mixtures of enantiomers as well as pure enantiomers or enantiomerically enriched mixtures. It is also understood that all tautomers and mixtures of tautomers are included within the scope of the compounds of formula I or Ia.

  As used herein, the term “aryl” and its derivatives, used alone or as part of a larger group such as “aralkyl”, “aralkoxy” or “aryloxyalkyl”, unless otherwise specified. , Monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring system is aromatic and the individual rings of the system are Contains 3 to 7 members and means, for example, phenyl, naphthalene, and temple hydronaphthalene and biphenyl.

  As used herein, the term “heteroaryl” used alone or as part of a larger group such as “heteroaralkyl”, “heteroaralkoxy”, or “heteroaryloxyalkyl” and its Derived terms mean monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 14 ring members, where at least one ring system is aromatic, unless otherwise specified. At least one ring of the system contains one or more heteroatoms and each ring of the system contains 3-7 members, such as 3,4-methylenedioxyphenyl, pyridine, quinoline, isoquinoline , Tetrahydroquinoline, tetrahydroisoquinoline, pyrimidine, quinazoline, thiophene, furan, pyrrole, pyrazole, imidazole, indole, indole 3 Yl means dihydroindole, indene, dihydro-indene, pyrazine, 1,3-dihydro -2H- benzimidazole, benzothiophene and tetrazole.

As used herein, the term “substituted”, unless stated otherwise, means that the subject compound moiety is —CO ₂ R ²⁰ , aryl, cycloalkyl, cycloalkyl containing 1-4 heteroatoms, hydroxy Alkyl, alkoxy, acyloxy, alkyl, amino, alkylamino, aminoalkyl, dialkylamino, acyloxy, N-acylamino, hydroxy, nitro, tetrazole, cyano, oxo, halogen and trifluoromethyl (where R ²⁰ is hydrogen, Means having 1 to 5 substituents, suitably 1 to 3 substituents, selected from the group consisting of C ₁ -C ₄ alkyl, selected from aryl and trifluoromethyl.

As used herein, the term “alkoxy” refers to —Oalkyl, wherein alkyl is as defined above, and includes —OCH ₃ and —OC (CH ₃ ) ₂ CH ₃ . .

As used herein, the term “cycloalkyl” means non-aromatic, unsaturated or saturated cyclic or polycyclic C ₃ -C ₁₂ unless otherwise specified.

  Examples of cycloalkyl and substituted cycloalkyl substituents as used herein include cyclohexyl, aminocyclohexyl, cyclobutyl, aminocyclobutyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4-methoxycyclohexyl, 4 -Methoxycyclohexyl, 4-carboxycyclohexyl, cyclopropyl, aminocyclopentyl, cyclopentyl.

  As used herein, the term “cycloalkyl containing 1 to 4 heteroatoms”, unless otherwise specified, is a non-aromatic containing 1 to 12 carbon atoms and 1 to 4 heteroatoms. Means a group, unsaturated or saturated, cyclic or polycyclic ring: provided that when the number of carbon atoms is 1, the aromatic ring contains at least 4 heteroatoms and the number of carbon atoms is 2. When the aromatic ring contains at least 3 heteroatoms and the number of carbon atoms is 3, the non-aromatic ring contains at least 2 heteroatoms and the number of carbon atoms is 4, The aromatic ring contains at least one heteroatom.

  Examples of cycloalkyl containing 1 to 4 heteroatoms and substituted cycloalkyl containing 1 to 4 heteroatoms as used herein include piperidyl, piperidine, pyrrolidine, 3-methylaminopyrrolidine , Piperazine, tetrazole, hexahydrodiazepine, azetidinyl, pyran, tetrahydropyran and morpholine.

As used herein, “acyloxy” refers to —OC (O) alkyl, wherein alkyl is as defined above. Examples of acyloxy substituents as used herein include —OC (O) CH ₃ , —OC (O) CH (CH ₃ ) ₂ and —OC (O) (CH ₂ ) ₃ CH _3. .

As used herein, the term “N-acylamino” refers to —N (H) C (O) alkyl, wherein alkyl is as defined above. As used herein, examples of N-acylamino substituents include —N (H) C (O) CH ₃ , —N (H) C (O) CH (CH ₃ ) ₂ and —N (H ) C (O) (CH ₂ ) ₃ CH ₃ .

  As used herein, “heteroatom” as used herein means oxygen, nitrogen or sulfur.

  As used herein, the term “halogen” refers to a substituent selected from bromide, iodide, chloride and fluoride.

As used herein, “alkyl” in all carbon chains, including alkyl chains defined by terms such as “— (CH ₂ ) _n ”, “— (CH ₂ ) _m ”, etc. By straight or branched chain, saturated or unsaturated hydrocarbon chain is meant, unless otherwise specified, a carbon chain will contain from 1 to 12 carbon atoms. Examples of alkyl and substituted alkyl substituents as used herein include —CH ₃ , —CH ₂ —CH ₃ , —CH ₂ —CH ₂ —CH ₃ , —CH (CH ₃ ) ₂ , —CH. _{2 -CH 2 -C (CH 3)} 3, -CH 2 -CF 3, -C≡C-C (CH 3) 3, -C≡C-CH 2 -OH, cyclopropylmethyl, _-CH 2 -C (CH ₃ ) ₂ —CH ₂ —NH ₂ , —C≡C—C ₆ H ₅ , —C≡C—C (CH ₃ ) ₂ —OH, —CH ₂ —CH (OH) —CH (OH) — _{CH (OH) -CH (OH)} -CH 2 -OH, piperidinylmethyl, methoxyphenyl _{ethyl, -C (CH 3) 3,} - (CH 2) 3 -CH 3, -CH 2 -CH (CH 3 _{) 2, -CH (CH 3)} -CH 2 -CH 3, -CH = CH 2, Oyo -C≡C-CH ₃ and the like.

  As used herein, the term “treatment” and its derivatives refer to prophylactic and therapeutic therapies.

  As used herein, the term “effective amount” and its derivatives refer to the biological or medical response of a tissue, system, animal or human being sought, for example, by a researcher or clinician. By the amount of drug or pharmaceutical that will be manifested. In addition, the term “therapeutically effective amount” and its derivatives refer to an improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a disease or relative to a corresponding subject not taking such an amount. Mean any amount that results in a decrease in the rate of progression of the disorder. The term also includes within its scope amounts effective to increase normal physiological function.

  The compound represented by the formula (I) is included in the pharmaceutical composition of the present invention and used in the method of the present invention. Where -COOH or -OH groups are present, pharmaceutically acceptable esters can be used, such as methyl, ethyl, pivaloyloxymethyl, etc. for -COOH, acetate, maleate, etc. for -OH. These esters are known in the art for use as sustained release or prodrug formulations to modify solubility or hydrolysis properties.

The novel compounds of formula I and Ia are prepared as shown in Schemes 1-6 below, or by analogous methods (where V, W, X, Y, Z, Q, L ¹ and R 'Substituents are as defined above for Formulas I and Ia, respectively: provided that the V, W, X, Y, Z, Q, L ¹ and R' substituents are the methods of Schemes 1-6. Is not included). All starting materials are commercially available or can be readily prepared by those skilled in the art from commercially available starting materials.

General scheme

Reagents: (a) DPPA, Et ₃ N, t-BuOH, 85 ° C .; (b) 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane— 2-yl)-1H-pyrrolo [2,3-b] _{pyridine, K 2 CO 3, Pd (} PPh 3) 4, dioxane _{/ H 2 O; (c)} HCl / dioxane; (d) PyBrop, (i- Pr) ₂ Net, 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid, DCM, RT; (e) 6N NaOH, MeOH, 50 ° C .; (f) HCl / dioxane

Commercially available carboxylic acid (I-1) is prepared according to J. Am. Med. Chem. Converted to the corresponding protected amine in one pot using the method described in 1991, 34, 1594-1605. The bromide (II-2) was converted to the aryl boronic acid ester [1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo. Coupled with [2,3-b] pyridine]. Typically, a palladium (0) catalyst, such as Pd (PPh ₃ ) _4, together with an inorganic base, such as K ₂ CO ₃ , Na ₂ CO ₃ or K ₃ PO ₄ , in an ether solvent such as DME, dioxane or Suzuki coupling is carried out in an aqueous mixture containing THF. The Boc protecting group of (I-3) is removed using a protic acid such as trifluoroacetic acid or HCl in a polar solvent such as methanol. A primary or secondary amine is converted to a carboxylic acid such as 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid and various amide coupling agents such as EDC, Coupling using PyBrop or the like, for example, amide (I-4) is obtained. Amide coupling reaction is conducted generally in a solvent such as DCM or DMF, with Et ₃ N or _(i-Pr) organic bases such as 2 NEt. The arylsulfonyl group of (I-4) is removed with aqueous NaOH and then treated with HCl or TFA to remove the Boc protecting group to give (I-5). One skilled in the art can utilize many different protecting groups and can be used as long as they do not interfere with the methods described below. Methods for protecting amines are described in standard materials such as Greene “Protective Groups in Organic Synthesis” (published by Wiley-Interscience).

Reagent: (a) 1- (Phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine , K ₂ CO ₃ , Pd (PPh ₃ ) ₄ , dioxane / H ₂ O; (b) H ₂ (1 atm), Pd / C, MeOH / THF, RT; (c) PyBrop, (i-Pr) ₂ Net 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid, DCM, RT; (d) 6N NaOH, MeOH, 50 ° C .; (e) HCl / dioxane

Commercially available bromide (II-1) was converted to arylboronic acid ester [1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H. Coupling with pyrrolo [2,3-b] pyridine] to give (II-2). Typically, palladium (0) catalyst, for example Pd _{(PPh 3) 4} an inorganic base, for example, with an _{K 2 CO 3, Na 2 CO} 3 or _K 3 PO _4, an ether solvent, for example DME, dioxane or THF Suzuki coupling is carried out in an aqueous mixture containing Reduction of the nitro group of (II-2) is carried out using a Pd / C catalyst in a polar solvent, such as MeOH, under a hydrogen atmosphere. Coupling of primary amines with carboxylic acids, such as 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid, with various amide coupling agents such as EDC, For example, amide (II-4) is obtained by using PyBrop or the like. Amide coupling reaction is carried out generally in a solvent such as DCM or DMF, with Et ₃ N or _(i-Pr) organic bases such as 2 NEt. The arylsulfonyl group of (II-4) is removed with aqueous NaOH and then treated with HCl or TFA to remove the Boc protecting group to give (II-5). One skilled in the art can utilize many different protecting groups and can be used as long as they do not interfere with the methods described below. Methods for protecting amines are described in standard materials such as Greene “Protective Groups in Organic Synthesis” (published by Wiley-Interscience).

Reagents: (a) phthalimide, PPh ₃ , DEAD, THF, RT; (b) CH ₃ NH ₂ / H ₂ O, MeOH, RT; (c) III-3, PyBrop, (i-Pr) ₂ Net, 3 -({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid, DCM, RT; (d) 1- (phenylsulfonyl) -4- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine, K ₂ CO ₃ , Pd (PPh ₃ ) ₄ , dioxane / H ₂ O; (e) 6N NaOH, MeOH, 50 ° C .; (f) HCl / dioxane

Aminoalcohol (III-1) was reacted under Mitsunobu conditions to give a separate protected diamine (III-2). The Mitsunobu reaction is a method known to those skilled in the art. Such conversion methods and reaction conditions are described in Synthesis 1981, 1-28. Selective deprotection of the phthalimide group of (III-2) is carried out with a nucleophilic amine such as hydrazine or methylamine in a polar solvent such as methanol to give amine (III-3). One skilled in the art can utilize many different protecting groups and can be used as long as they do not interfere with the methods described below. Methods for protecting amines are described in standard materials such as Greene “Protective Groups in Organic Synthesis” (published by Wiley-Interscience). Carboxylic acid (III-4) is reacted with amine (III-3) to form amide (III-5). Various amide coupling agents such as EDC and PyBrop are commercially available. Generally, it performed amide coupling reaction, in a solvent such as DCM or DMF, with Et ₃ N or _(i-Pr) organic bases such as 2 NEt. Dibromide (III-5) is regioselectively selected from aryl boronates, 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -1H-pyrrolo [2,3-b] pyridine was coupled with Suzuki coupling method. Typically, Suzuki coupling involves a palladium (0) catalyst, such as Pd (PPh ₃ ) _4, together with an inorganic base, such as K ₂ CO ₃ , Na ₂ CO ₃ or K ₃ PO ₄ , in an ether solvent, For example, using in an aqueous mixture containing DME, dioxane or THF. Palladium mediated coupling methods are described in standard materials such as Schlosser “Organometrics in Synthesis” (published by Wiley and sons). The arylsulfonyl group of (III-6) was removed with aqueous NaOH and then treated with HCl or TFA to remove the Boc protecting group to give (III-7).

Reagents: (a) (Boc) ₂ O, pyridine, NH ₄ HCO ₃ , 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid; (b) 1- ( Phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine, K ₂ CO ₃ , Pd ( PPh ₃ ) ₄ , dioxane / H ₂ O; (c) IV-2,1,2-diaminoethane, CuI, K ₂ CO ₃ , dioxane, 100 ° C .; (d) 6N NaOH, MeOH, 50 ° C .; e) HCl / dioxane

Carboxylic acid (IV-1) was converted to the corresponding primary amide (IV-2) in one pot according to the method of Pozdnev (Tet. Lett. 1995, 36 (39), 7115-7118). Dibromide (IV-3) is regioselectively selected from aryl boronates, 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -1H-pyrrolo [2,3-b] pyridine was coupled with Suzuki coupling method. Typically, palladium (0) catalyst, for example Pd _{(PPh 3) 4} an inorganic base, for example, with an _{K 2 CO 3, Na 2 CO} 3 or _K 3 PO _4, an ether solvent, for example DME, dioxane or THF Suzuki coupling is carried out in an aqueous mixture containing Palladium mediated coupling methods are described in standard materials such as Schlosser “Organometrics in Synthesis” (published by Wiley and sons). Bromide (IV-4) was coupled with amide (IV-2) by the method described in Buchwald (J. Amer. Chem. Soc. 2002, 124, 7421-7428). The arylsulfonyl group of (IV-5) is removed with aqueous NaOH and then treated with HCl or TFA to remove the Boc protecting group to give (IV-6). One skilled in the art can utilize many different protecting groups and can be used as long as they do not interfere with the methods described below. Methods for protecting amines are described in standard materials such as Greene “Protective Groups in Organic Synthesis” (published by Wiley-Interscience).

Reagents: (a) phthalimide, PPh ₃ , DEAD, THF, RT; (b) HCl, dioxane, RT; (c) III-4, PyBrop, (i-Pr) ₂ NEt, DCM, RT; (d) 1 -(Phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine, K ₂ CO ₃ , Pd (PPh ₃ ) ₄ , dioxane / H ₂ O; (e) 6N NaOH, MeOH, RT; (f) NH ₂ NH ₂ , MeOH, 50 ° C.

Amino alcohol (V-1) was reacted under Mitsunobu conditions to give a separate protected diamine (V-2). The Mitsunobu reaction is a method known to those skilled in the art. Such conversion methods and reaction conditions are described in Synthesis 1981, 1-28. Selective Boc deprotection was performed with anhydrous HCl in organic solvents. One skilled in the art can utilize many different protecting groups and can be used as long as they do not interfere with the methods described below. Methods for protecting amines are described in standard materials such as Greene “Protective Groups in Organic Synthesis” (published by Wiley-Interscience). Carboxylic acid (III-4) is reacted with amine (V-3) to form amide (V-4). Various amide coupling agents such as EDC and PyBrop are commercially available. Generally, it performed amide coupling reaction, in a solvent such as DCM or DMF, with Et ₃ N or _(i-Pr) organic bases such as 2 NEt. Dibromide (V-4) is regioselectively selected from aryl boronates, 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl. ) -1H-pyrrolo [2,3-b] pyridine and coupled using the Suzuki coupling method. Typically, Suzuki coupling involves a palladium (0) catalyst, such as Pd (PPh ₃ ) _4, together with an inorganic base, such as K ₂ CO ₃ , Na ₂ CO ₃ or K ₃ PO ₄ , in an ether solvent, For example, using in an aqueous mixture containing DME, dioxane or THF. Palladium mediated coupling methods are described in standard materials such as Schlosser “Organometrics in Synthesis” (published by Wiley and sons). The arylsulfonyl group of (V-5) is removed with aqueous NaOH at room temperature, then the phthalimide group is deprotected using a nucleophilic amine such as hydrazine or methylamine in a polar solvent such as methanol. Thus, amine (V-6) is obtained.

Reagents: (a) DPPA, Et ₃ N, t-BuOH, 85 ° C .; (b) Furan-3-boronic acid, K ₂ CO ₃ , Pd (PPh ₃ ) ₄ , dioxane / H ₂ O; (c) 1 -(Phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine, K ₂ CO ₃ , Pd (PPh ₃ ) ₄ , dioxane / H ₂ O; (d) HCl / dioxane; (e) PyBrop, (i-Pr) ₂ Net, 3-({[(1,1-dimethylethyl) oxy] carbonyl} (Amino) -2-phenylpropanoic acid, DCM, RT; (f) 6N NaOH, MeOH, 50 ° C .; (g) HCl / dioxane

Commercially available carboxylic acid (II-4) was prepared as described in J. Am. Med. Chem. Converted to the corresponding protected amine in one pot using the method described in 1991, 34, 1594-1605. Bromide (VI-1) is converted to furan-3-boronic acid, followed by arylboronic acid ester [1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane). Coupling with -2-yl) -1H-pyrrolo [2,3-b] pyridine]. Typically, palladium (0) catalyst, for example Pd _{(PPh 3) 4} an inorganic base, for example, with an _{K 2 CO 3, Na 2 CO} 3 or _K 3 PO _4, an ether solvent, for example DME, dioxane or THF Suzuki coupling is carried out in an aqueous mixture containing The Boc protecting group of (VI-3) is removed using a protic acid such as trifluoroacetic acid or HCl in a polar solvent such as methanol. A primary or secondary amine is converted to a carboxylic acid such as 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid and various amide coupling agents such as EDC, Coupling using PyBrop or the like, for example, amide (VI-4) is obtained. Amide coupling reaction is conducted generally in a solvent such as DCM or DMF, with Et ₃ N or _(i-Pr) organic bases such as 2 NEt. The arylsulfonyl group of (VI-4) is removed with aqueous NaOH and then treated with HCl or TFA to remove the Boc protecting group to give (VI-5). One skilled in the art can utilize many different protecting groups and can be used as long as they do not interfere with the methods described below. Methods for protecting amines are described in standard materials such as Greene “Protective Groups in Organic Synthesis” (published by Wiley-Interscience).

  One skilled in the art can use the intermediates known in the art and / or intermediates readily prepared from intermediates known in the art according to the above scheme and / or information known to those skilled in the art, Compounds of formula I can be synthesized. For example, a compound of formula I (Y═C—Ar, Z═CH or N) may be prepared using the intermediates described in Synthesis 2005, 5, 771-780 in the manner described in Scheme 3. Can do. Similarly, the compound of formula I (W = N) can be prepared according to the method described in Scheme 3, Bioorg. Med. Chem. Lett. It can be prepared using the intermediate described in 2004, 14, 5247-5250. In addition, the compound represented by the formula I (W = N, Z = N) is prepared by the method described in Scheme 3 according to J.P. Amer. Chem. Soc. 1956, 78, 784-790 can be used for the preparation.

  As used herein, the term “co-administration” and its derivatives are useful for the treatment of cancer, including the AKT inhibitor compounds described herein, and chemotherapy and radiotherapy. It is meant that the additional active ingredients known to be useful or useful for the treatment of arthritis are administered at the same time, or separately in any way and sequentially. As used herein, the term “further active ingredient” is known to exhibit or exhibit beneficial properties when administered to a patient in need of treatment for cancer or arthritis. Any compound or therapeutic agent that has been demonstrated to be included is included. Preferably, if not administered simultaneously, the compounds are administered in close time intervals. Furthermore, it does not matter whether the compounds are administered in the same dosage form, for example, one compound may be administered topically and the other compound administered orally.

  Typically, any anti-neoplastic agent having activity against the sensitive tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents are V. T.A. Devita and S.M. Can be found in Cancer Principles and Practice of Oncology, 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers by Hellman (editor). One skilled in the art will recognize which drug combinations are useful based on the drug involved and the characteristics of the cancer. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids, platinum coordination complexes, nitrogen mustards, oxazaphospholines, alkyl sulfonates, nitroso Alkylating agents such as urea and triazene, antibiotics such as anthracycline, actinomycin and bleomycin, topoisomerase II inhibitors such as epipodophyllotoxin, antimetabolites such as purine and pyrimidine analogs and antifolate compounds, camptothecin, etc. Topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, and cell cycle signaling inhibitors.

An example of a further active ingredient (anti-neoplastic agent) used in combination with or concurrently administered with an AKT inhibitor compound of the invention is a chemotherapeutic agent.
Anti-microtubules or anti-mitotic agents are cycle-specific agents that are active against the microtubules of tumor cells during the M or mitotic phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
Diterpenoids derived from natural resources are cycle-specific anticancer agents that operate in the G ₂ / M phase of the cell cycle. Diterpenoids are thought to stabilize the protein by binding to the microtubule β-tubulin subunit. The protein degradation then appears to be inhibited by mitosis being blocked and subsequent cell death. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.

Paclitaxel, 5β, 20-epoxy-1,2α, 4,7β, 10β, 13α-hexa-hydroxytax-11-en-9-one 4 with (2R, 3S) -N-benzoyl-3-phenylisoserine , 10- diacetate 2-benzoate 13-ester is a natural diterpene product from the tree Taxus brevifolia an isolated Taxus brevifolia and is commercially available as an injectable solution TAXOL ^R (registered trademark). It is a member of the taxane family of terpenes. It was first isolated by Wani et al. In 1971 (J. Am. Chem, Soc., 93: 2325.1971) and they characterized its structure by chemical and X-ray crystallographic methods. One mechanism of its activity is related to the ability of paclitaxel to bind to tubulin, thereby inhibiting cancer cell growth (Schiff et al., Proc. Natl, Acad, Sci. USA, 77: 1561-1565 ( 1980); Schiff et al., Nature, 277: 665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981)). For a review of the synthesis and anticancer activity of some paclitaxel derivatives, see D.C. G. I. Kingston et al., Studies in Organic Chemistry vol. 26, title “New trends in Natural Products Chemistry 1986”, Attaur-Rahman, P .; W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) See pp 219-235.

  Paclitaxel is a treatment for refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann. Lntem, Med., 111: 273, 1989), and breast cancer treatment. (Holmes et al., J. Nat. Cancer Inst., 83: 1797, 1991) is approved for clinical use. It has potential for the treatment of neoplasms in the skin (Einzig et al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinoma (Forastire et al., Sem. Oncol., 20:56, 1990). A candidate substance. The compounds also show potential for the treatment of polycystic kidney disease (Woo et al., Nature, 368: 750.1994), lung cancer and malaria. Treatment of patients with paclitaxel is associated with myelosuppression associated with a period of administration beyond a threshold concentration (50 nM) (Kearns, CM, et al., Seminars in Oncology, 3 (6) p. 16-23, 1995). Multicellular lineage, Ignoff, RJ et al., Cancer Chemotherapy Pocket Guide, 1998).

(2R, 3S) -N-carboxy-3 with docetaxel, 5β-20-epoxy-1,2α, 4,7β, 10β, 13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate - phenylisoserine, N-tert-butyl ester, 13-ester trihydrate is commercially available as an injectable solution TAXOTERE ^R. Docetaxel is required for the treatment of breast cancer. Docetaxel is a semi-synthetic derivative of paclitaxel (see above) prepared using the natural precursor 10-deacetyl-baccatin III extracted from the needles of European yew trees. The dose limiting toxicity of docetaxel is neutropenia.

  Vinca alkaloids are cycle-specific antineoplastic agents derived from periwinkle. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. As a result, bound tubulin molecules cannot polymerize into microtubules. Mitosis is thought to be arrested in metaphase, followed by cell death. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available as an injectable solution VELBAN ^R. It is primarily needed in the treatment of various lymphomas, including testicular cancer and Hodgkin's disease, and lymphocytic and histiocytic lymphomas, but it has shown potential as a secondary treatment for various solid tumors. It is. Myelosuppression is a dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo -, sulfate, is commercially available as an injectable solution ONCOVIN ^R. Vincristine is required for the treatment of acute leukemia and has found use in the treatment strategy for Hodgkin and non-Hodgkin malignant lymphoma. Alopecia and neurological effects are the most common side effects of vincristine, but to a lesser extent myelosuppression and gastrointestinal mucositis effects occur.

Vinorelbine, 3 ′, 4′-didehydro-4′-deoxy-C′-norvin calocoblastine [R- (R ^* , R ^* )-2,3-dihydroxybutanedioate (1: 2) (salt) ], commercially available as an injectable solution of vinorelbine tartrate (Navelbine ^R), is a semisynthetic vinca alkaloid. Vinorelbine is used as a single agent or in combination with other chemotherapeutic agents such as cisplastin in the treatment of various solid tumors, particularly non-small cell lung cancer, advanced breast cancer, and hormone-refractory prostate cancer Needed. Myelosuppression is the most common dose limiting side effect of vinorelbine.

  The platinum coordination complex is an aperiodic specific anticancer agent and interacts with DNA. Platinum complexes invade and aquatize tumor cells, forming intrastrand and interstrand crosslinks with DNA, thereby causing a detrimental biological effect on the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.

Cisplatin, cis - diamminedichloroplatinum, is commercially available as an injectable solution PLATINOL ^R. Cisplatin is mainly required for the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cisplatin are nephrotoxicity and inner ear neurotoxicity that can be controlled by hydration and diuresis.

Carboplatin, platinum diamine [1,1-cyclobutane - dicarboxylate (2 -) - O, O '] , is commercially available as an injectable solution PARAPLATIN ^R. Carboplatin is primarily required in primary and secondary treatment of advanced ovarian carcinoma. Myelosuppression is the dose limiting toxicity of carboplatin.

  Alkylating agents are aperiodic specific anticancer agents and are strong electrophiles. Typically, alkylating agents form covalent bonds to DNA via alkylation via nucleophilic groups of DNA molecules such as phosphate groups, amino groups, sulfhydryl groups, hydroxyl groups, carboxyl groups and imidazole groups. To do. Such alkylation disrupts nucleic acid function, thereby leading to cell death. Examples of alkylating agents include, but are not limited to, cyclophosphamide, nitrogen mustards such as melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, and triazenes such as dacarbazine. .

Cyclophosphamide, 2- [bis (2-chloroethyl) amino] tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, as an injectable solution or tablets, commercially available as CYTOXAN ^R ing. Cyclophosphamide is required in the treatment of malignant lymphoma, multiple myeloma and leukemia as a single agent or in combination with other chemotherapeutic agents. Hair loss, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.

Melphalan, 4- [bis (2-chloroethyl) amino] -L- phenylalanine, as an injectable solution or tablets, is commercially available as ALKERAN ^R. Melphalan is required for elective treatment of multiple myeloma and ovarian unresectable epithelial carcinoma. Myelosuppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4- [bis (2-chloroethyl) amino] benzenebutanoic acid, is commercially available as LEUKERAN ^R tablet. Chlorambucil is required for elective treatment of chronic lymphocytic leukemia and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma and Hodgkin's disease. Myelosuppression is the most common dose limiting side effect of chlorambucil.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available as MYLERAN ^R tablet. Busulfan is required for elective treatment of chronic myelogenous leukemia. Myelosuppression is the most common dose limiting side effect of busulfan.

Carmustine, 1,3- [bis (2-chloroethyl) -1-nitrosourea, is commercially available as BiCNU ^R as a single vial lyophilized product. Carmustine is required for elective treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphoma. Delayed myelosuppression is the most common dose limiting side effect of carmustine.

Dacarbazine, 5- (3,3-dimethyl-1-triazeno) -imidazole-4-carboxamide, is commercially available as DTIC-Dome ^R as a single vial product. Dacarbazine is required for the treatment of metastatic malignant melanoma and is used in combination with other drugs for secondary treatment of Hodgkin's disease. Nausea, vomiting and anorexia are the most common dose limiting side effects of dacarbazine.

  Antibiotic anti-neoplastic agents are cycle specific agents that bind to or mediate DNA. Typically, such action results in a stable DNA complex or strand break that disrupts the normal function of the nucleic acid, resulting in cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthracyclines such as daunorubicin and doxorubicin, and bleomycin.

Dactinomycin, also known as actinomycin D, is marketed in injectable form as COSMEGEN ^R. Dactinomycin is required for the treatment of Wilm tumor and rhabdomyosarcoma. Nausea, vomiting and anorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl) oxy] -7,8,9,10-tetrahydro- 6,8,11- trihydroxy-1-methoxy -5,12 naphthacene-dione hydrochloride, is commercially available as Cerubidine ^R as DaunoXome ^R or injection solution as a liposomal injectable form. Daunorubicin is required for mitigation induction in the treatment of acute nonlymphocytic leukemia and advanced HIV-related Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.

Doxorubicin (8S, 10S) -10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl) oxy] -8-glycoloyl, 7,8,9,10-tetrahydro-6 8,11-Trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride is commercially available as RUBEX ^R or ADRIAMYCIN RDF ^{R in} injectable form. Doxorubicin is primarily required for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of several solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.

Burenomaishin, mixtures of isolated cytotoxic glycopeptide antibiotics from a strain of Streptomyces verticillus, is commercially available as BLENOXANE ^R. Bleomycin is required as a palliative treatment for squamous cell carcinoma, lymphoma, and testicular carcinoma as a single agent or in combination with other agents. Lung and skin toxicity are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
Epipodophyllotoxins are cycle-specific antineoplastic agents derived from mandrake plants. Epipodophyllotoxins typically form topoisomerase II and DNA ternary complex, by causing DNA strand breaks affect cells in the S and G ₂ phases of the cell cycle. Strand breaks accumulate, followed by cell death. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

Etoposide, 4′-demethyl-epipodophyllotoxin 9 [4,6-0- (R) -ethylidene-β-D-glucopyranoside] is commercially available as VePESID ^R as an injection solution or capsule, It is known as VP-16. Etoposide is required in the treatment of testicular cancer and non-small cell lung cancer as a single agent or in combination with other chemotherapeutic agents. Myelosuppression is the most common dose limiting side effect of etoposide. The occurrence of leukopenia tends to be more severe than thrombocytopenia.

Teniposide, 4′-demethyl-epipodophyllotoxin 9 [4,6-0- (R) -tenylidene-β-D-glucopyranoside] is commercially available as VUMON ^R as an injectable solution. 26. Teniposide is required in the treatment of acute leukemia in children as a single drug or in combination with other chemotherapeutic agents. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.

  Antimetabolite anti-neoplastic agents are cycle specificities that affect the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby inhibiting DNA synthesis. It is an anti-neoplastic agent. As a result, the S phase does not proceed, resulting in cell death. Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mechatopurine, thioguanine, and gemcitabine.

  5-Fluorouracil, 5-fluoro-2,4- (1H, 3H) pyrimidinedione is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is incorporated into both RNA and DNA. As a result, cell death typically occurs. 5-Fluorouracil is required in the treatment of breast, colon, rectal, gastric and pancreatic carcinomas as a single agent or in combination with other chemotherapeutic agents. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

Cytarabine, 4-amino -1-beta-D-arabinofuranosyl -2 (1H) - pyrimidinone, is commercially available as ^{CYTOSAR-U R,} generally, are known as Ara-C. Cytarabine is thought to exhibit cell cycle specificity in S phase by inhibiting DNA strand elongation by terminal incorporation of cytarabine into the growing DNA strand. Cytarabine is required in the treatment of acute leukemia as a single agent or in combination with other chemotherapeutic agents. Other cytidine analogs include 5-azacytidine and 2 ', 2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia and mucositis.

Mercaptopurine, 1,7-dihydro--6H- purin-6-thione monohydrate, is commercially available as PURINETHOL® ^R. Mercaptopurine exhibits cell cycle specificity in S phase by inhibiting DNA synthesis by a mechanism not yet specified. Mercaptopurine is required in the treatment of acute leukemia as a single agent or in combination with other chemotherapeutic agents. Myelosuppression and gastrointestinal mucositis are the expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID ^R. Thioguanine exhibits cell cycle specificity in S phase by inhibiting DNA synthesis by a mechanism not yet identified. Thioguanine is required in the treatment of acute leukemia as a single agent or in combination with other chemotherapeutic agents. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and doses may be limited. Other purine analogs include pentostatin, erythrohydroxynonyl adenine, fludarabine phosphate, and cladribine.

Gemcitabine, 2'-deoxy-2 ', 2'-difluorocytidine monohydrochloride (beta-isomer), is commercially available as GEMZAR ^R. Gemcitabine exhibits cell cycle specificity in S phase by inhibiting cell progression through the G1 / S boundary. Gemcitabine is used in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and is used alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia and anemia, is the most common dose limiting side effect of gemcitabine administration.

  Methotrexate, N- [4 [[(2,4-diamino-6-pteridinyl) methyl] methylamino] benzoyl] -L-glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell cycle effects specifically in S phase by inhibiting DNA synthesis, repair and / or replication by inhibiting dihydrofolate reductase, which is required for the synthesis of purine nucleotides and thymidylates. Methotrexate is required as a single agent or in combination with other chemotherapeutic agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and breast, head, neck, ovarian and bladder carcinomas. Myelosuppression (leukopenia, thrombocytopenia and anemia) and mucositis are the expected side effects of methotrexate administration.

  Camptothecin, including camptothecin and camptothecin derivatives, is available as a topoisomerase I inhibitor or is under development. Camptothecin cytotoxic activity is thought to be related to its topoisomerase I inhibitory activity. Examples of camptothecin include, but are not limited to, irinotecan, topotecan, and various optical forms of 7- (4-methylpiperazino-methylene) -10,11-ethylenedioxy-20-camptothecin described below.

Irinotecin HCl, (4S) -4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy] -1H-pyrano [3 ′, 4 ′, 6,7] indolizino [ 1,2-b] quinoline--3,14 (4H, 12H) - dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR ^R.

  Irinotecan, along with its active metabolite SN-38, is a derivative of camptothecin that binds to the topoisomerase I-DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by the interaction of topoisomerase I: DNA: irinotecan or SN-38 triple complexes with replication enzymes. Irinotecan is required for the treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCl are myelosuppression, including neutropenia, and GI effects, including diarrhea.

Topotecan HCl, (S) -10-[(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1H-pyrano [3 ′, 4 ′, 6,7] indolidino [1,2-b] quinoline -3,14- (4H, 12H) - dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN ^R. Topotecan is a derivative of camptothecin that binds to the topoisomerase I-DNA complex and prevents religation of single strand breaks caused by topoisomerase I in response to torsional strains of the DNA molecule. Topotecan is required for secondary treatment of metastatic carcinomas of ovarian cancer and small cell lung cancer. The dose limiting side effect of topotecan HCl is myelosuppression, primarily neutropenia.

で示されるカンプトテシン誘導体は、化学名「７−（４−メチルピペラジノ−メチレン）−１０，１１−エチレンジオキシ−２０（Ｒ，Ｓ）−カンプトテシン（ラセミ混合物）」または「７−（４−メチルピペラジノ−メチレン）−１０，１１−エチレンジオキシ−２０（Ｒ）−カンプトテシン（Ｒエナンチオマー）」または「７−（４−メチルピペラジノ−メチレン）−１０，１１−エチレンジオキシ−２０（Ｓ）−カンプトテシン（Ｓエナンチオマー）によって知られている。かかる化合物ならびに関連化合物は、製造法も含め、米国特許第６，０６３，９２３号、第５，３４２，９４７号、第５，５５９，２３５号、第５，４９１，２３７号および出願中の米国特許出願第０８／９７７，２１７号（１９９７年１１月２４日出願）に記載されている。 In addition, the following formula A, currently under development, including the racemic mixture (R, S) form and the R and S enantiomers:

The camptothecin derivative represented by the formula "7- (4-methylpiperazino-methylene) -10,11-ethylenedioxy-20 (R, S) -camptothecin (racemic mixture)" or "7- (4-methylpiperazino- Methylene) -10,11-ethylenedioxy-20 (R) -camptothecin (R enantiomer) "or" 7- (4-methylpiperazino-methylene) -10,11-ethylenedioxy-20 (S) -camptothecin (S Such compounds as well as related compounds, including methods of preparation, are described in US Pat. Nos. 6,063,923, 5,342,947, 5,559,235, 5,491. 237, and pending US patent application Ser. No. 08 / 977,217 (filed Nov. 24, 1997). It is.

  Hormones and hormone analogs are compounds that are useful in the treatment of cancer where there is a relationship between hormones and the growth and / or undergrowth of cancer. Examples of hormones and hormone analogs useful for cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone useful for the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other Exemestane useful for the treatment of aromatase inhibitors such as anastrozole, letrazole, borazole, and adrenocortical carcinoma and hormone-dependent breast cancer containing estrogen receptors; progestrins such as hormone-dependent breast cancer and Megestrol acetate useful for the treatment of endometrial cancer; estrogen, androgen, and antiandrogens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5α useful for the treatment of prostate cancer and benign prostatic hypertrophy Reductases such as finasteride and dusteride; antiestrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, and iodoxifene useful for the treatment of hormone-dependent breast cancer and other sensitive cancers 681,835, 5,877,219 and 6,207,716, selective estrogen receptor modulators (SERMS); and gonadotropin-releasing hormone for the treatment of prostate cancer ( GnRH) and luteinizing hormone (LH) and / or its analogs that stimulate the release of follicle stimulating hormone (FSH), such as LHRH agonists and antagonists such as goserelin acetate and luprolide.

  Signal transduction pathway inhibitors are inhibitors that block or inhibit chemical processes that trigger intracellular conversion. As used herein, the change is cell proliferation or differentiation. Signal transduction inhibitors useful in the present invention include receptor tyrosine kinases, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphotidylinositol-3 kinase, myo-inositol signaling, and Ras oncogene. Inhibitors of

  Some protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.

  Receptor tyrosine kinases are transmembrane proteins that have an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are commonly referred to as growth factor receptors. Many inappropriate or unregulated activations of these kinases, eg, by overexpression or mutation, ie, abnormal kinase growth factor receptor activity, have been shown to result in unregulated cell growth. Thus, the abnormal activity of such kinases is associated with malignant tissue growth. As a result, inhibitors of such kinases could provide a cancer treatment. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), immunoglobulin-like and epidermal growth factor homology domains Tyrosine kinase (TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, kit, cmet, fibroblast growth factor (FGF) receptor, Trk receptor ( TrkA, TrkB and TrkC), the ephrin (eph) receptor, and the RET proto-oncogene. Several growth receptor inhibitors are in development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and antisense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described in, for example, Kath, John C. et al. , Exp. Opin. Ther. Patents (2000) 10 (6): 803-818; Shawver et al., DDT Vol 2, No. 2 February 1997; and Lofts, F .; J. et al. "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, Workingman, Paul and Kerr, edited by David, CRC press 1994, London.

  Tyrosine kinases that are not growth factor receptor kinases are termed non-receptor tyrosine kinases. Non-receptor tyrosine kinases useful in the present invention are anticancer drug targets or potential targets and include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Brutons tyrosine kinase, and Bcr- Includes Abl. Agents that inhibit such non-receptor kinase and non-receptor tyrosine kinase functions are described in Sinh, S .; And Corey, S .; J. et al. (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; and Bolen, J. et al. B. Brugge, J .; S. (1997) Annual review of Immunology. 15: 371-404.

  SH2 / SH3 domain blockers are SH2 or SH3 bound in various enzymes or adapter proteins including PI3-K p85 subunit, Src family kinase, adapter molecules (Shc, Crk, Nck, Grb2) and Ras-GAP. A drug that disrupts the domain. The SH2 / SH3 domain as a target for anticancer drugs is described in Smithgall, T .; E. (1995), Journal of Pharmacological and Toxicological Methods. 34 (3) 125-32.

  Inhibitors of serine / threonine kinases include MAP kinase cascade blockers, which include Raf kinases (rafk), mitogen or extracellular regulatory kinases (MEKs), and extracellular regulatory kinases (ERKs) blockers; and PKC (alpha , Beta, gamma, epsilon, mu, lambda, iota, zeta) blockers including protein kinase C family member blockers. Includes blockers of the IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, and TGF beta receptor kinases. Such serine / threonine kinases and inhibitors thereof are described in Yamamoto, T .; Taya, S .; Kaibuchi, K .; (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A .; , And Navab, R .; (2000), Biochemical Pharmacology, 60.1101-1107; Massague, J. et al. , Weis-Garcia, F .; (1996) Cancer Surveys. 27: 41-64; Philip, P .; A. , And Harris, A .; L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K.M. Bioorganic and Medicinal Chemistryletters, (10), 2000, 223-226; US Pat. No. 6,268,391; and Martinez-Iacaci, L. et al. Et al., Int. J. et al. Cancer (2000), 88 (1), 44-52.

  Inhibitors of members of the phosphotidylinositol-3 kinase family, including PI3-kinase, ATM, DNA-PK and Ku blockers may also be useful in the present invention. Such kinases are described in Abraham, R .; T.A. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.I. E. Lim, D .; S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S .; P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7): 935-8; and Zhong, H .; Et al., Cancer res, (2000) 60 (6), 1541-1545.

  The invention also relates to myo-inositol signaling inhibitors, such as phospholipase C blockers and myo-inositol analogs. Such signal inhibitors are described in Powis, G. et al. And Kozikowski A. (1994) New Molecular Targets for Cancer Chemotherapy ed. Paul Workman and David Kerr, CRC press 1994, London.

  Another group of signal transduction pathway inhibitors are inhibitors of Ras oncogene. Such inhibitors include farnesyl transferase, geranylgeranyl transferase and inhibitors of CAAX protease, as well as antisense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing the wild type mutant ras, thereby acting as an antiproliferative agent. Ras oncogene inhibition is described in Scharovsky, O .; G. Rozados, V .; R. Gervasoni, S .; I. Matar, P.M. (2000), Journal of Biomedical Science. 7 (4) 292-8; Ashby, M .; N. (1998), Current Opinion in Lipidology. 9 (2) 99-102; and BioChim. Biophys. Acta, (1989) 1423 (3): 19-30.

As noted above, antibody antagonists to receptor kinase ligand binding can also act as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example, Imclone C225 EGFR specific antibody (Green, M.C.. Et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat.Rev., (2000), 26 (4), see 269-286), Herceptin ^R (R ErbB2 antibody (see Tyrosine kinase Signaling in Breast cancer: erbB Family Receptor Tyrosine Kinases, Breast cancer Res., 2000, 2 (3), 176-183) Selective Inhibition of VEGFR2 Activity by a onoclonal Anti-VEGF antibody blocks tumor growth in mice, there is a Cancer Res. (2000) see 60,5117-5124).

Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention. Inhibitors of angiogenesis-related VEGFR and TIE2 have been discussed above with respect to signal transduction inhibitors (both receptors are receptor tyrosine kinases). In general, angiogenesis is associated with erbB2 / EGFR signaling, since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention. For example, which do not recognize VEGFR (the receptor tyrosine kinase), anti -VEGF antibody that binds to its ligand, it will inhibit angiogenesis integrin (alpha _v, beta ₃₎ small molecule inhibitors of endostatin and Angiostatin (non-RTK) also proves useful in combination with the disclosed compounds (Brunns CJ et al. (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME and Delynck R). (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).

  Agents used in immunotherapy methods may also be useful in combination with a compound of formula (I). There are many immunological strategies for generating an immune response. These strategies are generally in the area of tumor vaccination. The efficacy of immunological approaches can be greatly enhanced through the combined inhibition of signaling pathways using small molecule inhibitors. A discussion of immunological / tumor vaccine approaches to erbB2 / EGFR can be found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Elling DJ, Robbins J and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.

  Agents used in pro-apoptotic management (eg, bcl-2 antisense oligonucleotides) can also be used in the combinations of the present invention. Members of the Bcl-2 family of proteins inhibit apoptosis. Thus, bcl-2 up-regulation is associated with chemical resistance. Studies have shown that epidermal growth factor (EGF) stimulates bcl-2 family anti-apoptotic members (ie, mcl-1). Thus, a strategy planned to down-regulate bcl-2 expression in tumors, namely Genta's G3139 bcl-2 antisense oligonucleotide, has demonstrated clinical benefit and is currently in phase II / III In the exam. Such pro-apoptotic methods using the antisense oligonucleotide method for bcl-2 are described in Water JS et al. (2000), J. MoI. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994), Antisense Res. Dev. 4: 71-79.

  Cell cycle signaling inhibitors inhibit molecules involved in the regulation of the cell cycle. Their family of protein kinases, called cyclin-dependent kinases (CDKs), and their interactions with a family of proteins termed cyclins regulate eukaryotic cell cycle progression. Coordination activation and inactivation of various cyclin / CDK complexes is necessary for normal progression of the cell cycle. Several inhibitors of cell cycle signaling are under development. For example, examples of cyclin dependent kinases including CDK2, CDK4 and CDK6 and inhibitors thereof are described, for example, in Rosania et al., Exp. Opin. Ther. Patents (2000) 10 (2): 215-230.

  In one embodiment, the cancer treatment methods of the invention comprise a compound of Formula I and / or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and at least one antineoplastic agent, such as , Anti-microtubule agent, platinum coordination complex, alkylating agent, antibiotic agent, topoisomerase II inhibitor, antimetabolite, topoisomerase I inhibitor, hormone and hormone analog, signal transduction pathway inhibitor, non-receptor tyrosine kinase Co-administration with an antineoplastic agent selected from the group consisting of an angiogenesis inhibitor, an immunotherapeutic agent, a pro-apoptotic agent, and a cell cycle signaling inhibitor.

  Because the pharmaceutically active compounds of the present invention are active as AKT inhibitors, they exhibit therapeutic utility in the treatment of cancer and arthritis.

  Suitably, the present invention comprises a brain tumor (glioma), glioblastoma, Bannayan-Zonana syndrome, Corden's disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, The present invention relates to a method for treating or reducing the severity of a cancer selected from melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and thyroid cancer.

  Suitably, the present invention relates to the treatment of a cancer selected from ovarian cancer, breast cancer, pancreatic cancer and prostate cancer or a method for reducing the severity of such cancer.

His-tagged AKT1 (aa 136-480) Isolation and purification His-tagged AKT1 (aa 136-480) Insect cells 25 mM HEPES expressing the, 100 mM NaCl, the polytron in 20mM imidazole (pH 7.5) And lysed (5 mL lysis buffer / g cells). Cell debris was removed by centrifugation at 28,000 × g for 30 minutes. The supernatant was filtered through a 4.5 micron filter and then loaded onto a nickel-chelate column pre-equilibrated with lysis buffer. The column was washed with 5 column volumes (CV) of lysis buffer and then 5 CV of 20% buffer B, where buffer B is 25 mM HEPES, 100 mM NaCl, 300 mM imidazole, pH 7.5. His-tagged AKT1 (aa 136-480) was eluted with a 20-100% linear gradient of buffer B over 10 CV. His-tagged AKT1 (136-480) elution fractions were pooled and diluted with 3 volumes of buffer C (wherein buffer C is 25 mM HEPES, pH 7.5). The sample was then chromatographed on a Q-Sepharose HP column pre-equilibrated with buffer C. The column was washed with 5 CV Buffer C, then 5 CV 10% D, 5 CV 20% D, 5 CV 30% D, 5 CV 50% D and 5 CV 100% D (where Buffer D is Step elution with 25 mM HEPES, 1000 mM NaCl, pH 7.5). His-tagged AKT1 (aa 136-480) containing fractions were pooled and concentrated with a 10-kDa molecular weight cut-off concentrator. His-tagged AKT1 (aa 136-480) was chromatographed on a Superdex 75 gel filtration column pre-equilibrated with 25 mM HEPES, 200 mM NaCl, 1 mM DTT (pH 7.5). His-tagged AKT1 (aa 136-480) fractions were tested using SDS-PAGE and mass spectrometry. The proteins were pooled, concentrated and frozen at -80 ° C.
His-tagged AKT2 (aa 138-481) and His-tagged AKT3 (aa 135-479) were similarly isolated and purified.

His-tagged AKT enzyme assay Compounds of the present invention were tested for AKTl, 2 and 3 protein serine kinase inhibitory activity in substrate phosphorylation assays. The assay tests for the ability of small molecule organic compounds to inhibit serine phosphorylation of peptide substrates. Substrate phosphorylation assays utilize the catalytic domain of AKT1, 2 or 3. AKT1, 2 and 3 are also available from Upstate USA, Inc. Is available from The method measures the ability of the isolated enzyme to catalyze the transfer of ATP-derived gamma-phosphate onto the serine residue of biotinylated synthetic peptide SEQ ID NO: 1 (biotin-ahx-ARKRERAYSFGHHA-amide). Substrate phosphorylation was detected by the following procedure.
The assay was performed in 384 well U-bottom white plates. 1 μl of 10 nM activated AKT enzyme in 50 mM MOPS, pH 7.5, 20 mM MgCl ₂ , 4 μM ATP, 8 μM peptide, 0.04 μCi [g- ³³ P] ATP / well, 1 mM CHAPS, 2 mM DTT, and 100% DMSO Were incubated for 40 minutes at room temperature in an assay volume of 20 μl containing the test compounds. Reaction by addition of 50 μl SPA bead mix (Dulbecco PBS without Mg ²⁺ and Ca ²⁺ , 0.1% Triton X-100, 5 mM EDTA, 50 μM ATP, 2.5 mg / ml streptavidin coated SPA beads) Stopped. The plates were sealed and the beads were allowed to settle overnight, then the plates were counted in a Packard Topcount microplate scintillation counter (Packard Instrument Co., Meriden, CT).
Dose response data is converted into data conversion formula 100 ^* (U1-C2) / (C1-C2)
[Where U is an unknown value, C1 is the mean control value obtained for DMSO, and C2 is the mean control value obtained for 0.1M EDTA]
Plotted against compound concentration as% control calculated in Data
y = ((Vmax ^* x) / (K + x))
[Where Vmax is the upper asymptote and K is IC50]
Fit the curve represented by

Cloning of full- length human (FL) AKT1 The full-length human AKT1 gene was presented to a plasmid containing myristylated AKT1-ER (Robert T. Abraham, a gift from Duke University under MTA, Molecular and Cellular Biologic. ) To 5 ′ primer: SEQ ID NO: 2
5 'TATATAGGATCCATGAGCGACGTGGC 3'
And 3 ′ primer: SEQ ID NO: 3
AAATTTCTCGAGTCAGGCCGTGCTGCTGG 3 '
Was amplified by PCR. The 5 ′ primer contained a BamHI site and the 3 ′ primer contained an XhoI site for cloning purposes. The resulting PCR product was subcloned in pcDNA3 as a BamHI / XhoI fragment. Mutations in the sequence encoding the cysteine ²⁵ (T GC), by site-directed mutagenesis using the QuikChange ^R site-directed mutagenesis kit (Stratagene), wild-type AKT1 sequence encoding arginine ²⁵ (C GC ). AKT1 mutagenesis primer: SEQ ID NO: 4
5 'ACCTGGCGGCCACGCCTACTTCCTCC
And selection primer: SEQ ID NO: 5
5 'CTCGAGCATGCCAACTAGAGGGCC (designed to destroy the XbaI site in the multiple cloning site of pcDNA3)
Was used according to the manufacturer's instructions. For expression / purification purposes, AKT1 was isolated as a BamHI / XhoI fragment and cloned into the BamHI XhoI site of pFastbacHTb (Invitrogen).

Expression of FL human AKT1 was performed using Invitrogen's BAC-to-BAC baculovirus expression system (catalog number 10359-016). Briefly, 1) cDNA is transferred from the FastBac vector into bacmid DNA, 2) bacmid DNA is isolated and used to transfect Sf9 insect cells, 3) virus is produced in Sf9 cells, 4 ) T. ni cells were infected with the virus and subjected to purification.

Purification of FL human AKT1 For purification of full-length AKT1, 130 g sf9 cells (batch number 41646W02) were re-resuspended in lysis buffer (buffer A, 1 L, pH 7.5) containing 25 mM HEPES, 100 mM NaCl and 20 mM imidazole. Suspended. Cell lysis was performed by Avestin (2 times at 15K-20K psi). Cell debris was removed by centrifugation at 16K rpm for 1 hour, and the supernatant was batch bound to 10 ml nickel Sepharose HP beads overnight at 4 ° C. The beads were then transferred to the column and the bound material was eluted with buffer B (25 mM HEPES, 100 mM NaCl, 300 mM imidazole, pH 7.5). AKT elution fractions were pooled and diluted 3-fold with buffer C (25 mM HEPES, 5 mM DTT, pH 7.5). The sample was filtered and chromatographed at 2 mL / min on a 10 mL Q-HP column pre-equilibrated with buffer C.
The Q-HP column was washed with 3 column volumes (CV) of buffer C and then 5 CV 10% D, 5 CV 20% D, 5 CV 30% D, 5 CV 50% D and 5 CV 100% D ( Here, buffer D was step-eluted with 25 mM HEPES, 1000 mM NaCl, 5 mM DTT, pH 7.5). A 5 mL fraction was collected. AKT-containing fractions were pooled and concentrated to 5 ml. The protein was then loaded onto a 120 ml Superdex 75 sizing column pre-equilibrated with 25 mM HEPES, 200 mM NaCl, 5 mM DTT, pH 7.5. 2.5 mL fractions were collected.
AKT1 elution fractions were pooled, divided into aliquots (1 ml) and stored at −80 ° C. Mass spectrometry and SDS-PAGE analysis were used to confirm the purity and identity of the purified full-length AKT1.
Full length AKT2 and full length AKT3 were similarly cloned, expressed, isolated and purified.

AKT Enzyme Assay Compounds of the present invention are tested for AKT1, 2 and 3 protein serine kinase inhibitory activity in a substrate phosphorylation assay. The assay tests for the ability of small molecule organic compounds to inhibit serine phosphorylation of peptide substrates. Substrate phosphorylation assays utilize the catalytic domain of AKT1, 2 or 3. AKT1, 2 and 3 are available from Upstate USA, Inc. Commercially available. The method measures the ability of the isolated enzyme to catalyze the transfer of ATP-derived gamma-phosphate onto the serine residue of biotinylated synthetic peptide SEQ ID NO: 5 (Biotin-ahx-ARKRERAYSFGHHA-amide). Substrate phosphorylation is detected by the following procedure.
The assay is performed in 384 well U-bottom white plates. 1 μl of 10 nM activated AKT enzyme in 50 mM MOPS, pH 7.5, 20 mM MgCl ₂ , 4 μM ATP, 8 μM peptide, 0.04 μCi [g- ³³ P] ATP / well, 1 mM CHAPS, 2 mM DTT, and 100% DMSO Incubate for 40 minutes at room temperature in a 20 μl assay volume containing the test compound. Reaction by addition of 50 μl SPA bead mix (Dulbecco PBS without Mg ²⁺ and Ca ²⁺ , 0.1% Triton X-100, 5 mM EDTA, 50 μM ATP, 2.5 mg / ml streptavidin coated SPA beads) To stop. The plate is sealed and the beads are allowed to settle overnight, then the plate is counted in a Packard Topcount microplate scintillation counter (Packard Instrument Co., Meriden, CT).
Dose response data is converted into data conversion formula 100 ^* (U1-C2) / (C1-C2)
[Where U is an unknown value, C1 is the mean control value obtained for DMSO, and C2 is the mean control value obtained for 0.1M EDTA]
Plot against compound concentration as% control calculated in Data
y = ((Vmax ^* x) / (K + x))
[Where Vmax is the upper asymptote and K is IC50]
Fit the curve represented by

The compounds of the invention are tested for activity against AKT1, AKT2 and AKT3 in the above assay.
The compounds of Examples 5, 7, 43, 49, 53, 58, 76, 78, 104, 144, 174, 184 and 185 were tested in the above AKT enzyme assay and against AKT1, AKT2 and AKT3, respectively. An IC50 value of 0.5 uM or less was shown.

The pharmaceutically active compounds within the scope of the present invention are useful as AKT inhibitors in mammals, particularly humans, in need thereof.
Accordingly, the present invention provides cancer, arthritis, and AKT inhibition characterized by administering an effective compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. A method of treating other conditions in need is provided. The compounds of formula (I) are also provided in a method of treating the above-mentioned pathologies due to their apparent ability to act as Akt inhibitors. The drug may be administered to the patient in need by any convenient route of administration, including but not limited to intravenous, intramuscular, oral, subcutaneous, intradermal and parenteral.

The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are used. Solid carriers include starch, lactose, calcium sulfate dihydrate, clay, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent includes any sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax. The amount of solid carrier will vary widely but will preferably be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation is in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable solution such as an ampoule, or an aqueous or non-aqueous liquid suspension.

Pharmaceutical formulations include those in the pharmaceutical field that include mixing, granulating, and compressing (if necessary) the material, if appropriate in tablet form, or mixing, filling and dissolving to obtain the desired oral or parenteral product. Manufactured according to chemist's conventional technology.
The dose of the pharmaceutically active compound of the present invention in the above pharmaceutical dosage unit is preferably selected from 0.001 to 100 mg / kg, preferably 0.001 to 50 mg / kg of active compound amount. A non-toxic amount. When treating a human patient in need of an Akt inhibitor, the selected dose is preferably administered orally or parenterally 1-6 times daily. Preferred forms of parenteral administration include continuous administration by topical, rectal, transdermal, injection and infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration at low doses is preferred. However, parenteral administration at high doses can also be used if it is safe and convenient for the patient.

  The optimal dosage to be administered is readily determined by those skilled in the art and will vary with the particular Akt inhibitor used, the strength of the formulation, the mode of administration, and the degree of progression of the condition. Additional factors depending on the particular patient being treated, including patient age, weight, diet, and time of administration, will result in the need for dosage adjustments.

The method of the invention for inducing Akt inhibitory activity in mammals, including humans, is characterized by administering an effective Akt inhibitory amount of a pharmaceutically active compound of the invention to a subject in need of such activity. .
The present invention also provides the use of a compound of formula (I) in the manufacture of a medicament useful as an Akt inhibitor.

The present invention also provides the use of a compound of formula (I) in the manufacture of a medicament useful in therapy.
The present invention also provides the use of a compound of formula (I) in the manufacture of a medicament useful in the treatment of cancer.
The present invention also provides the use of a compound of formula (I) in the manufacture of a medicament useful in the treatment of arthritis.
The present invention also provides a pharmaceutical composition useful as an Akt inhibitor comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
The present invention also provides a pharmaceutical composition useful in the treatment of cancer comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
The present invention also provides a pharmaceutical composition useful in the treatment of arthritis comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

When the compounds of the invention are administered according to the invention, unacceptable toxicological effects are not expected.
Furthermore, the pharmaceutically active compounds of the present invention are known to be useful when used in combination with additional active ingredients such as other compounds known to treat cancer or arthritis, or Akt inhibitors. Can be co-administered with the compound.

  Without further modification, those skilled in the art, using the above description, are confident that the present invention can be utilized to its full scope. Accordingly, the following examples are to be construed as merely illustrative and are not intended to limit the scope of the invention in any way.

Experimental Details The compounds of Examples 1-191 were readily prepared according to Schemes 1-6 or by similar methods.

Preparation Example 1

ＤＣＭ（２１１ｍＬ）中の３−ヨウド−１Ｈ−ピロロ［２，３−ｂ］ピリジン（４２．４ｍｍｏｌ）［Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９９７４０，２４３０に従って調製した］、フェニルスルホニルクロライド（１１ｍＬ、８５．７ｍｍｏｌ）および硫酸水素テトラブチルアンモニウム（５７５ｍｇ、１．６９ｍｍｏｌ）の溶液に、２５℃で、６ＮのＮａＯＨ（２６ｍＬ）の溶液を滴下した。１２時間後、溶液を塩化アンモニウムの飽和溶液間で分配した。水相をＤＣＭで数回逆抽出し、合した有機フラクションを乾燥し（Ｎａ_２ＳＯ_４）、濃縮した。ついで、残渣をＭｅＯＨでトリチュレートし、濾過して、標題化合物（１３ｇ、８０％）を褐色固体として得た；ＬＣＭＳ（ｍ／ｅ）３８６（Ｍ＋Ｈ）^＋。 Preparation of 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine a) 3 -Iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine

3-iodo-1H-pyrrolo [2,3-b] pyridine (42.4 mmol) in DCM (211 mL) [J. Med. Chem. Prepared in accordance with 1997740, 2430], to a solution of phenylsulfonyl chloride (11 mL, 85.7 mmol) and tetrabutylammonium hydrogen sulfate (575 mg, 1.69 mmol) at 25 ° C., a solution of 6N NaOH (26 mL) was added dropwise. . After 12 hours, the solution was partitioned between saturated ammonium chloride solutions. The aqueous phase was back extracted several times with DCM and the combined organic fractions were dried (Na ₂ SO ₄ ) and concentrated. The residue was then triturated with MeOH and filtered to give the title compound (13 g, 80%) as a brown solid; LCMS (m / e) 386 (M + H) ⁺ .

b) 1- (Phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine DMF (40 mL) 3-iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (4.2 g, 10.9 mmol), bis-pinacolate diborane (5.6 g, 21.8 mmol), A solution of potassium acetate (3.2 g, 32.7 mmol) and Pd (dppf) Cl ₂ -complex was stirred with dichloromethane (788 mg, 0.982 mmol) in a sealed tube at 90 ° C. for 2 hours. The solution was cooled with ice and basified to pH 12-14 with 6N NaOH. The aqueous phase was then extracted with DCM and acidified to about pH 1 with 6N HCl. The aqueous phase was extracted several times with DCM and the combined fractions were dried (Na ₂ SO ₄ ) and concentrated to give the title compound (4.2 g, quantitative) as a brown solid that was used without further purification. LCMS (m / e) 386 (boronic acid ester M + H) ⁺ , 303 (boronic acid M + H) ⁺ .

Preparation Example 2

ＥｔＯＡＣ（５６ｍＬ）中のｍＣＰＢＡ（２３ｇ、０．１０３ｍｏｌ）の溶液を、ＥｔＯＡｃ（８４ｍＬ）中の７−アザインドール（１０ｇ、８４．６ｍｍｏｌ）の０℃溶液に滴下した。さらにＥｔＯＡｃ（５０ｍＬ）を撹拌の補助のために加え、溶液を２５℃に１２時間加温した。Ｋ_２ＣＯ_３の飽和溶液を加え、約ｐＨ９にし、溶液をＥｔＯＡｃで抽出して、標題化合物（６．７ｇ、５９％）を灰白色固体として得、これを直接用いた：ＬＣＭＳ（ｍ／ｅ）１３５（Ｍ＋Ｈ）^＋。 Preparation of 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine a) 7 -Azaindole-N-oxide

A solution of mCPBA (23 g, 0.103 mol) in EtOAC (56 mL) was added dropwise to a 0 ° C. solution of 7-azaindole (10 g, 84.6 mmol) in EtOAc (84 mL). Additional EtOAc (50 mL) was added to aid in stirring and the solution was warmed to 25 ° C. for 12 hours. A saturated solution of K ₂ CO ₃ was added to about pH 9 and the solution was extracted with EtOAc to give the title compound (6.7 g, 59%) as an off-white solid, which was used directly: LCMS (m / e) 135 (M + H) ⁺ .

ＤＭＦ（３７ｍＬ）中の７−アザインドール−Ｎ−オキシド（３ｇ、２２．４ｍｍｏｌ）およびテトラブチルアンモニウムブロマイド（１１ｇ、３３．６ｍｍｏｌ）の０℃の溶液に、ＤＭＦ（１０ｍＬ）中の無水メタンスルホン酸（５．９ｇ、３３．６ｍｍｏｌ）の溶液を滴下した。２５℃に４５分間加温した後、溶液をＨ_２Ｏ（５０ｍＬ）に加え、ついで、１ＮのＮａＯＨで中和した。得られた沈殿を濾過し、ＤＣＭ中０℃で０．５時間撹拌し、濾過して、標題化合物（１ｇ、２３％）を淡白色固体として得た：ＬＣＭＳ（ｍ／ｅ）１９８（Ｍ＋Ｈ）^＋。 b) 4-Bromo-1H-pyrrolo [2,3-b] pyridine

A solution of 7-azaindole-N-oxide (3 g, 22.4 mmol) and tetrabutylammonium bromide (11 g, 33.6 mmol) in DMF (37 mL) at 0 ° C. in anhydrous methanesulfonic acid in DMF (10 mL). A solution of (5.9 g, 33.6 mmol) was added dropwise. After warming to 25 ° C. for 45 min, the solution was added to H ₂ O (50 mL) and then neutralized with 1N NaOH. The resulting precipitate was filtered, stirred in DCM at 0 ° C. for 0.5 h and filtered to give the title compound (1 g, 23%) as a pale white solid: LCMS (m / e) 198 (M + H) ⁺ .

c) 1- (Phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine 3-iodo Preparation except that 4-bromo-1H-pyrrolo [2,3-b] pyridine (1 g, 5.08 mmol) was used instead of -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine. According to Example 1, the title compound was obtained as a brown solid: LCMS (m / e) 386 (boronic acid ester M + H) ⁺ , 303 (boronic acid M + H) ⁺ .

トルエンスルホニルクロライドの代わりにベンゼンスルホニルクロライドを用いること以外は、調製例２の方法に従って、標題化合物を褐色固体として得た（１．７ｇ、７７％）。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）ｐｐｍ １．３２（ｓ，１２Ｈ），２．３３（ｓ，３Ｈ），６．９５（ｄ，１Ｈ，Ｊ＝４．０Ｈｚ），７．４０（ｄ，２Ｈ，Ｊ＝８．１Ｈｚ），７．４７（ｄ，１Ｈ，Ｊ＝４．５Ｈｚ），７．９３−７．９８（ｍ，３Ｈ），８．３８（ｄ，１Ｈ，Ｊ＝４．５Ｈｚ）；ＬＣ／ＭＳ：ｍ／ｚ３９９（Ｍ＋１）＋ Preparation Example 3
1-[(4-Methylphenyl) sulfonyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine Preparation of

The title compound was obtained as a brown solid (1.7 g, 77%) according to the method of Preparation Example 2 except that benzenesulfonyl chloride was used in place of toluenesulfonyl chloride. ¹ H NMR (400 MHz, DMSO-d6) ppm 1.32 (s, 12H), 2.33 (s, 3H), 6.95 (d, 1H, J = 4.0 Hz), 7.40 (d, 2H, J = 8.1 Hz), 7.47 (d, 1H, J = 4.5 Hz), 7.93-7.98 (m, 3H), 8.38 (d, 1H, J = 4.5 Hz) LC / MS: m / z 399 (M + 1) +

ａ）５−ブロモ−Ｎ−｛［３−（メチルオキシ）フェニル］メチル｝−２−チオフェンカルボキサミド

Ｎ−［３−（ジメチルアミノ）プロピル］−Ｎ’−エチルカルボジイミド塩酸塩（３．１ｇ、１６．０ｍｍｏｌ）を、ＤＭＦ（１５０ｍＬ）中の５−ブロモ−２−チオフェンカルボン酸（３．０ｇ、１４．５ｍｍｏｌ）および｛［３−（メチルオキシ）フェニル］メチル｝アミン（２．０ｇ、１４．８ｍｍｏｌ）の溶液に加え、ついで、混合物を１時間室温で撹拌した。反応混合物をＮＨ_４Ｃｌ水溶液で希釈し、ＡｃＯＥｔで抽出した。溶媒を減圧下で除去して、５−ブロモ−Ｎ−｛［３−（メチルオキシ）フェニル］メチル｝−２−チオフェンカルボキサミドを白色固体として得た。 Preparation Example 4
Preparation of N-{[3- (methyloxy) phenyl] methyl} -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-thiophenecarboxamide

a) 5-Bromo-N-{[3- (methyloxy) phenyl] methyl} -2-thiophenecarboxamide

N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide hydrochloride (3.1 g, 16.0 mmol) was added to 5-bromo-2-thiophenecarboxylic acid (3.0 g, DMF (150 mL)). 14.5 mmol) and {[3- (methyloxy) phenyl] methyl} amine (2.0 g, 14.8 mmol) were added to the solution and then the mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with aqueous NH ₄ Cl and extracted with AcOEt. The solvent was removed under reduced pressure to give 5-bromo-N-{[3- (methyloxy) phenyl] methyl} -2-thiophenecarboxamide as a white solid.

b) N-{[3- (methyloxy) phenyl] methyl} -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-thiophenecarboxamide DMF ( 5-bromo-N-{[3- (methyloxy) phenyl] methyl} -2-thiophenecarboxamide (3.6 g, 10.9 mmol), 4,4,4 ′, 4 ′, 5,5 in 50 mL) , 5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (5.5 g, 21.7 mmol), KOAc (3.2 g, 32.7 mmol) and Pd (dppf) Cl ₂ (0.8 g, 1.1 mmol) was refluxed for 24 hours under an inert atmosphere. After cooling to room temperature, 1N aqueous NaOH was added until the aqueous layer was pH 10. The mixture was washed with CH ₂ Cl ₂ . The aqueous layer was then carefully acidified to pH 4 with 1N aqueous HCl. Extracted with CH ₂ Cl ₂ (20 mL × 3) and the organic layer was concentrated under reduced pressure to give the desired boronic ester as a brown solid (2.5 g, 61%). ¹ H NMR (400 MHz, DMSO-d6) ppm 1.29 (s, 12H), 3.73 (s, 3H), 4.42 (d, 2H, J = 6.1 Hz), 6.82 (ddd, 1H, J = 0.5, 2.5, 8.1 Hz), 6.86-6.89 (m, 2H), 7.25 (t, 1H, J = 8.1 Hz), 7.54 (d , 1H, J = 3.8 Hz), 7.84 (d, 1H, J = 3.8 Hz), 9.13 (t, 1H, J = 6.1 Hz); LC / MS: m / z 372 (M− 1)-, 374 (M + 1) +

｛［３−（メチルオキシ）フェニル］メチル｝アミンの代わりにＮ’，Ｎ’−ジメチル−１−フェニル−１，２−エタンジアミンを用いること以外は、調製例４（工程ａ）の方法に従って標題化合物を調製した。 Preparation Example 5
Preparation of 5-bromo-N- [2- (dimethylamino) -1-phenylethyl] -2-thiophenecarboxamide

According to the method of Preparation Example 4 (Step a) except that N ′, N′-dimethyl-1-phenyl-1,2-ethanediamine is used instead of {[3- (methyloxy) phenyl] methyl} amine. The title compound was prepared.

Preparation Example 6

ＴＨＦ（３５ｍＬ）中のベンゾイルアセトニトリル（２ｇ、１３．８ｍｍｏｌ）を、ＴＨＦ（３５ｍＬ）中のＬＡＨ（１．６ｇ、４１．３ｍｍｏｌ）の０℃の溶液に、滴下漏斗を用いて滴下した。得られた溶液を２５℃に加温し、ついで、６０℃にさらに２時間加熱した。０℃に冷却した後、飽和酒石酸ナトリウムカリウムの溶液を滴下し、溶液を数回ＤＣＭで抽出した。合した有機フラクションを乾燥し（Ｎａ_２ＳＯ_４）、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中５〜８％ＭｅＯＨ（１％ＮＨ_４ＯＨ））により精製して、アミノアルコール（１．４ｇ、６７％）を透明油として得た：ＬＣＭＳ（ＥＳ）ｍ／ｚ１５２（Ｍ＋Ｈ）^＋。 Preparation of 1,1-dimethylethyl (3-hydroxy-3-phenylpropyl) carbamate a) 3-Amino-1-phenyl-1-propanol

Benzoylacetonitrile (2 g, 13.8 mmol) in THF (35 mL) was added dropwise using a dropping funnel to a 0 ° C. solution of LAH (1.6 g, 41.3 mmol) in THF (35 mL). The resulting solution was warmed to 25 ° C. and then heated to 60 ° C. for an additional 2 hours. After cooling to 0 ° C., a solution of saturated sodium potassium tartrate was added dropwise and the solution was extracted several times with DCM. The combined organic fractions were dried (Na ₂ SO ₄ ), concentrated and purified by column chromatography (silica, 5-8% MeOH in DCM (1% NH ₄ OH)) to give amino alcohol (1.4 g, 67%) was obtained as a clear oil: LCMS (ES) m / z 152 (M + H) ⁺ .

b) 1,1-dimethylethyl (3-hydroxy-3-phenylpropyl) carbamate 3-Amino-1-phenyl-1-propanol (1.4 g, 9.27 mmol) was dissolved in THF (50 mL) and Boc. ₂ O (2.4 g, 11.1 mmol) was added in one portion. After 30 minutes, the solution was concentrated and the residue was purified by silica plug (0.5 to 1% MeOH in _{DCM (1% NH 4 OH)} ), the title compound (1.6 g, 69%) a pale white Obtained as a solid: LCMS (ES) m / z 152 (M + H) ⁺ .

Preparation Example 7

ＴＨＦ（７５ｍＬ）中の（Ｓ）−（−）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−３−フェニル−１−プロパノール（３．０ｇ、１１．９ｍｍｏｌ）、ＰＰｈ_３（３．７４ｇ、１４．４ｍｍｏｌ）およびフタルイミド（１．９３ｇ、１３．１ｍｍｏｌ）の溶液に、室温で、ＤＥＡＤ（２．８ｍＬ、１７．８ｍｍｏｌ）を５分にわたって加えた。室温で１．５時間後、反応溶液を濃縮し、シリカ（ヘキサン／ＥｔＯＡＣ、２：１）により精製して標題化合物を白色固体として得た（４．３ｇ、９５％）：ＬＣＭＳ（ＥＳ）ｍ／ｚ３８１（Ｍ＋Ｈ）^＋。 Preparation of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione a) 1,1-dimethylethyl [(1S) -2- (1, 3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) -1- (phenylmethyl) ethyl] carbamate

(S)-(−)-2- (tert-butoxycarbonylamino) -3-phenyl-1-propanol (3.0 g, 11.9 mmol), PPh ₃ (3.74 g, 14.14) in THF (75 mL). 4 mmol) and phthalimide (1.93 g, 13.1 mmol) at room temperature, DEAD (2.8 mL, 17.8 mmol) was added over 5 minutes. After 1.5 hours at room temperature, the reaction solution was concentrated and purified on silica (hexane / EtOAC, 2: 1) to give the title compound as a white solid (4.3 g, 95%): LCMS (ES) m / Z381 (M + H) ⁺ .

b) 2-[(2S) -2-Amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione 1,1-dimethylethyl in MeOH (100 mL) [(1S) -2 -(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1- (phenylmethyl) ethyl] carbamate (4.3 g, 11.3 mmol) in dioxane at room temperature. 4M HCl in (50 mL) was added. After stirring at room temperature for 3 hours, the reaction solution was concentrated to give a white solid (quantitative): LCMS (ES) m / z 281 (M + H) ⁺ .

Preparation Example 8

ＴＨＦ（２００ｍＬ）中のＮａＨ（２．２ｇ、５４ｍｍｏｌ）の懸濁液に、ジエチル ２−（フェニルメチル）ブタンジオエート（１２．５ｇ、４９．９ｍｍｏｌ）を加えた。室温で３０分後、ブロモメチルフタルイミドを反応混合物に加え、内容物を１４時間室温で撹拌した。反応をＨ_２Ｏ（１５ｍＬ）でクエンチし、Ｅｔ_２Ｏ（３００ｍＬ）で希釈し、層を分離した。有機層を減圧下で濃縮し、得られた残渣をＥｔＯＨ（０℃）から結晶化して、標題化合物（１３ｇ、６４％）を白色固体として得た：ＬＣＭＳ（ＥＳ）ｍ／ｚ４１０（Ｍ＋Ｈ）^＋。 Preparation of 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- (phenylmethyl) propanoic acid a) Diethyl 2-[(1,3-dioxo-1,3-dihydro-2H -Isoindol-2-yl) methyl] -2- (phenylmethyl) butanedioate

To a suspension of NaH (2.2 g, 54 mmol) in THF (200 mL) was added diethyl 2- (phenylmethyl) butanedioate (12.5 g, 49.9 mmol). After 30 minutes at room temperature, bromomethylphthalimide was added to the reaction mixture and the contents were stirred for 14 hours at room temperature. The reaction was quenched with H ₂ O (15 mL), diluted with Et ₂ O (300 mL) and the layers were separated. The organic layer was concentrated under reduced pressure and the resulting residue was crystallized from EtOH (0 ° C.) to give the title compound (13 g, 64%) as a white solid: LCMS (ES) m / z 410 (M + H) ⁺ .

濃ＨＣｌ（１２５ｍＬ）およびＨＯＡｃ（３０ｍＬ）中のジエチル ２−［（１，３−ジオキソ−１，３−ジヒドロ−２Ｈ−イソインドール−２−イル）メチル］−２−（フェニルメチル）ブタンジオエート（１３ｇ、３１．８ｍｍｏｌ）の溶液を、１Ｌのスクリューキャップ反応容器に入れて密閉し、内容物を１２０℃で４８時間加熱した。反応溶液を減圧下で濃縮し、得られた固体をＥｔ_２Ｏで洗浄して、標題化合物を得た（定量）を白色固体として得た：ＬＣＭＳ（ＥＳ）ｍ／ｚ１８１（Ｍ＋Ｈ）^＋。 b) 3-amino-2- (phenylmethyl) propanoic acid

Diethyl 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] -2- (phenylmethyl) butanedioate in concentrated HCl (125 mL) and HOAc (30 mL) The solution (13 g, 31.8 mmol) was placed in a 1 L screw cap reaction vessel and sealed, and the contents were heated at 120 ° C. for 48 hours. The reaction solution was concentrated under reduced pressure and the resulting solid was washed with Et ₂ O to give the title compound (quantitative) as a white solid: LCMS (ES) m / z 181 (M + H) ⁺ .

c) 3-({[(1,1-Dimethylethyl) oxy] carbonyl} amino) -2- (phenylmethyl) propanoic acid 3-amino-2- (in dioxane (100 mL) and H ₂ O (20 mL) To a solution of (phenylmethyl) propanoic acid (from the previous reaction) was added anhydrous Boc (10.1 g, 46.5 mmol) and 6M NaOH solution (26 mL). After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure, neutralized with 3M HCl, and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ and concentrated to give a viscous oil. The oil was washed with pentane and dried under high vacuum to give the title compound (5.0 g, 17.9 mmol, 58% over 2 steps) as a white solid: LCMS (ES) m / z 280 (M + H) ⁺ .

Preparation Example 9

ＡｃＯＨ中の２−（メチルオキシ）ベンズアルデヒド（７．７ｇ、５６．６ｍｍｏｌ）を、３０分にわたって、Ｅｔ_２Ｏ中のＫＣＮの激しく撹拌した混合物に０℃で滴下した。添加が完了した後、反応混合物を一晩室温に加温した。反応混合物を濾過してＫＯＡｃを除去し、Ｅｔ_２Ｏを除去して、生成物（８．５ｇ、９５％）を透明油として得、これをさらに精製することなく用いた：ＬＣＭＳ（ＥＳ）ｍ／ｚ１６４（Ｍ＋Ｈ）^＋。 Preparation of 1,1-dimethylethyl {2-amino-2- [2- (methyloxy) phenyl] ethyl} carbamate a) Hydroxy [2- (methyloxy) phenyl] acetonitrile

2- (Methyloxy) benzaldehyde (7.7 g, 56.6 mmol) in AcOH was added dropwise at 0 ° C. to a vigorously stirred mixture of KCN in Et ₂ O over 30 minutes. After the addition was complete, the reaction mixture was warmed to room temperature overnight. The reaction mixture was filtered to remove KOAc and Et ₂ O to give the product (8.5 g, 95%) as a clear oil that was used without further purification: LCMS (ES) m / Z 164 (M + H) ⁺ .

ＴＨＦ（１００ｍＬ）中のヒドロキシ［２−（メチルオキシ）フェニル］アセトニトリル（８．４ｇ、５２．３ｍｍｏｌ）を、ＴＨＦ（１００ｍＬ）中のＬＡＨ（１．６ｇ、４１．３ｍｍｏｌ）の２５℃溶液に滴下漏斗を用いて４５分にわたって、反応温度を６０℃に加温して、滴下した。アミンの滴下が完了した後、反応温度を室温に冷却し、反応が完了していることをＬＣＭＳにより確認した。０℃に冷却した後、酒石酸ナトリウムカリウムの飽和溶液を滴下し、溶液を数回ＤＣＭで抽出した。合した有機フラクションを乾燥し（Ｎａ_２ＳＯ_４）、濃縮して、アミノアルコール（７．７ｇ、８８％）を透明油として得、これをさらに精製することなく用いた：ＬＣＭＳ（ＥＳ）ｍ／ｚ１６７（Ｍ＋Ｈ）^＋。 b) 2-Amino-1- [2- (methyloxy) phenyl] ethanol

Hydroxy [2- (methyloxy) phenyl] acetonitrile (8.4 g, 52.3 mmol) in THF (100 mL) was added dropwise to a 25 ° C. solution of LAH (1.6 g, 41.3 mmol) in THF (100 mL). The reaction temperature was warmed to 60 ° C. over 45 minutes using a funnel and added dropwise. After the addition of the amine was completed, the reaction temperature was cooled to room temperature, and it was confirmed by LCMS that the reaction was complete. After cooling to 0 ° C., a saturated solution of potassium sodium tartrate was added dropwise and the solution was extracted several times with DCM. The combined organic fractions were dried (Na ₂ SO ₄ ) and concentrated to give the amino alcohol (7.7 g, 88%) as a clear oil that was used without further purification: LCMS (ES) m / z167 (M + H) ^<+> .

２−アミノ−１−［２−（メチルオキシ）フェニル］エタノール（７．７ｇ、４６．０ｍｍｏｌ）をＴＨＦ（５０ｍＬ）中に溶解し、Ｂｏｃ_２Ｏ（２．４ｇ、１１．１ｍｍｏｌ）を一度に加えた。３０分後、溶液を濃縮し、残渣をシリカプラグ（ＤＣＭ中５％ＭｅＯＨ（０．５％ＮＨ_４ＯＨ））により精製して、標題化合物（１０．０ｇ、８１％）を淡白色固体として得た：ＬＣＭＳ（ＥＳ）ｍ／ｚ２６８（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl {2-hydroxy-2- [2- (methyloxy) phenyl] ethyl} carbamate

2-Amino-1- [2- (methyloxy) phenyl] ethanol (7.7 g, 46.0 mmol) was dissolved in THF (50 mL) and Boc ₂ O (2.4 g, 11.1 mmol) was added in one portion. added. After 30 minutes, the solution was concentrated and the residue was purified by silica plug (5% MeOH in DCM (0.5% NH ₄ OH)) to give the title compound (10.0 g, 81%) as a pale white solid. LCMS (ES) m / z 268 (M + H) ⁺ .

ＴＨＦ（２０ｍＬ）中の１，１−ジメチルエチル ｛２−ヒドロキシ−２−［２−（メチルオキシ）フェニル］エチル｝カルバメート（１．０ｇ、４．０ｍｍｏｌ）、ＰＰｈ_３（１．６ｇ、６．１ｍｍｏｌ）およびフタルイミド（０．５９ｇ、４．０ｍｍｏｌ）の溶液に、室温で、ＤＥＡＤ（０．９６ｍＬ、６．１ｍｍｏｌ）を５分にわたって加えた。室温で０．５時間後、反応溶液を濃縮し、シリカ（ヘキサン／ＥｔＯＡＣ、２：１）により精製して、標題化合物を白色固体として得た（０．８ｇ、４９％）：ＬＣＭＳ（ＥＳ）ｍ／ｚ３９７（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl {2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -2- [2- (methyloxy) phenyl] ethyl} carbamate

1,1-Dimethylethyl {2-hydroxy-2- [2- (methyloxy) phenyl] ethyl} carbamate (1.0 g, 4.0 mmol), PPh ₃ (1.6 g, 6. 5) in THF (20 mL). DEAD (0.96 mL, 6.1 mmol) was added to a solution of 1 mmol) and phthalimide (0.59 g, 4.0 mmol) at room temperature over 5 minutes. After 0.5 h at room temperature, the reaction solution was concentrated and purified on silica (hexane / EtOAC, 2: 1) to give the title compound as a white solid (0.8 g, 49%): LCMS (ES) m / z 397 (M + H) ⁺ .

e) 1,1-dimethylethyl {2-amino-2- [2- (methyloxy) phenyl] ethyl} carbamate NH ₂ NH ₂ (0.7 mL, 22.3 mmol) was replaced with 1,1-dimethylethyl {2 -(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -2- [2- (methyloxy) phenyl] ethyl} carbamate (0.8 g, 1.97 mmol) in THF / Added to MeOH (8 mL / 8 mL) solution and stirred overnight. After 12 hours, the solution was concentrated and purified by column chromatography using 5% MeOH in CHCl ₃ containing 0.5% NH ₄ OH to give the title compound (328 mg, 30%) as a white solid: LC-MS (ES) m / z = 267 (M + H) ^<+> .

Preparation Example 10

３−クロロベンゼン過カルボン酸（１２．１ｇ、５４．０ｍｍｏｌ）を、ＣＨ_２Ｃｌ_２中の３−ブテン−１−イルベンゼン（７．１５ｇ、５４．１ｍｍｏｌ）の溶液に、０℃で一度に加え、ついで、２５℃に一晩加温した。飽和ＮａＨＣＯ_３を加え、混合物を分離し、得られた透明油（８．０ｇ、定量）を、さらに精製することなく次に用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝１４９（Ｍ＋Ｈ）^＋。 Preparation of 1,1-dimethylethyl (2-amino-4-phenylbutyl) carbamate a) 2- (2-Phenylethyl) oxirane

3-Chlorobenzenepercarboxylic acid (12.1 g, 54.0 mmol) is added in one portion to a solution of 3-buten-1-ylbenzene (7.15 g, 54.1 mmol) in CH ₂ Cl ₂ at 0 ° C. Then, it was heated to 25 ° C. overnight. Saturated NaHCO ₃ was added, the mixture was separated and the resulting clear oil (8.0 g, quantitative) was then used without further purification: LC-MS (ES) m / z = 149 (M + H) ⁺ .

２−（２−フェニルエチル）オキシラン（８．０ｇ、５４ｍｍｏｌ）を、７ＮのＮＨ_３−ＭｅＯＨ（１３０ｍＬ）とシールしたチューブに入れ、７０℃で２時間撹拌し、ついで、濃縮して、透明油を得、これをさらに精製することなく次の工程に用いた。 b) 1-amino-4-phenyl-2-butanol

2- (2-Phenylethyl) oxirane (8.0 g, 54 mmol) was placed in a tube sealed with 7N NH ₃ -MeOH (130 mL), stirred at 70 ° C. for 2 h, then concentrated to a clear oil This was used in the next step without further purification.

１−アミノ−４−フェニル−２−ブタノール（７．４ｇ、５０．０ｍｍｏｌ）をＴＨＦ（５０ｍＬ）中に溶解し、Ｂｏｃ_２Ｏ（１３ｇ、５９．６ｍｍｏｌ）を一度に加えた。３０分後、溶液を濃縮し、残渣をシリカプラグ（ＤＣＭ中５％ＭｅＯＨ（０．５％ＮＨ_４ＯＨ））により精製して、標題化合物（１３．１ｇ、９１％）を透明黄色油として得た：ＬＣＭＳ（ＥＳ）ｍ／ｚ２６６（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl (2-hydroxy-4-phenylbutyl) carbamate

1-Amino-4-phenyl-2-butanol (7.4 g, 50.0 mmol) was dissolved in THF (50 mL) and Boc ₂ O (13 g, 59.6 mmol) was added in one portion. After 30 minutes, the solution was concentrated and the residue was purified by silica plug (5% MeOH in DCM (0.5% NH ₄ OH)) to give the title compound (13.1 g, 91%) as a clear yellow oil. LCMS (ES) m / z 266 (M + H) ⁺ .

ＴＨＦ（６０ｍＬ）中の１，１−ジメチルエチル （２−ヒドロキシ−４−フェニルブチル）カルバメート（３．０ｇ、１１．４ｍｍｏｌ）、ＰＰｈ_３（３．６ｇ、１３．７ｍｍｏｌ）およびフタルイミド（１．８４ｇ、１２．５ｍｍｏｌ）の溶液に、室温で、ＤＥＡＤ（１．８ｍＬ、１１．４ｍｍｏｌ）を５分にわたって加えた。室温で０．５時間後、反応溶液を濃縮し、シリカ（ヘキサン／ＥｔＯＡＣ、２：１）により精製して、標題化合物を白色固体として得た（３．１ｇ、６９％）：ＬＣＭＳ（ＥＳ）ｍ／ｚ３９５（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -4-phenylbutyl] carbamate

1,1-dimethylethyl (2-hydroxy-4-phenylbutyl) carbamate (3.0 g, 11.4 mmol), PPh ₃ (3.6 g, 13.7 mmol) and phthalimide (1.84 g) in THF (60 mL). DEAD (1.8 mL, 11.4 mmol) was added to a solution of 12.5 mmol) at room temperature over 5 minutes. After 0.5 h at room temperature, the reaction solution was concentrated and purified on silica (hexane / EtOAC, 2: 1) to give the title compound as a white solid (3.1 g, 69%): LCMS (ES) m / z 395 (M + H) ⁺ .

e) 1,1-dimethylethyl (2-amino-4-phenylbutyl) carbamate NH ₂ NH ₂ (2.5 mL, 79.6 mmol) was replaced with 1,1-dimethylethyl (2-amino-4-phenylbutyl) Carbamate (3.1 g, 7.83 mmol) was added to a THF / MeOH (40 mL / 40 mL) solution and stirred overnight. After 12 hours, the solution was concentrated and purified by column chromatography using 5% MeOH in CHCl ₃ containing 0.5% NH ₄ OH to give the title compound (1.4 mg, 66%) as a white solid. Obtained: LC-MS (ES) m / z = 265 (M + H) ⁺ .

Preparation Example 11

ＴＨＦ（４７ｍＬ、４７ｍｍｏｌ）中の１ＭのＢＨ_３を、Ｎ−｛［（１，１−ジメチルエチル）オキシ］カルボニル｝−Ｏ−メチル−Ｌ−チロシン（２．７ｇ、９．４ｍｍｏｌ）のＴＨＦ（３５ｍＬ）溶液に、０℃で加え、２時間撹拌し、ついで、一晩冷凍庫に置いた。反応混合物を、ＭｅＯＨ（３０ｍＬ）中のＡｃＯＨ（１５ｍＬ）の溶液を、０℃で１時間ゆっくりと添加してクエンチした。混合物を室温に加温し、飽和ＮａＨＣＯ_３（１００ｍＬ）を加えた。層を分離し、有機層を蒸発させて、透明油を得（１．９２ｇ、７８％）、これをさらに精製することなく次に用いた：ＬＣＭＳ（ＥＳ）ｍ／ｚ２６６（Ｍ＋Ｈ）^＋。 Preparation of 2-{(2S) -2-amino-3- [4- (methyloxy) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione a) 1,1-dimethylethyl (( 1S) -2-Hydroxy-1-{[4- (methyloxy) phenyl] methyl} ethyl) carbamate

1M BH ₃ in THF (47 mL, 47 mmol) was added to N-{[(1,1-dimethylethyl) oxy] carbonyl} -O-methyl-L-tyrosine (2.7 g, 9.4 mmol) in THF ( 35 mL) solution was added at 0 ° C. and stirred for 2 hours, then placed in the freezer overnight. The reaction mixture was quenched by slowly adding a solution of AcOH (15 mL) in MeOH (30 mL) at 0 ° C. for 1 h. The mixture was warmed to room temperature and saturated NaHCO ₃ (100 mL) was added. The layers were separated and the organic layer was evaporated to give a clear oil (1.92 g, 78%) which was then used without further purification: LCMS (ES) m / z 266 (M + H) ⁺ .

ＴＨＦ（３６ｍＬ）中の１，１−ジメチルエチル （（１Ｓ）−２−ヒドロキシ−１−｛［４−（メチルオキシ）フェニル］メチル｝エチル）カルバメート（１．９ｇ、７．２ｍｍｏｌ）、ＰＰｈ_３（２．９ｇ、１１．０ｍｍｏｌ）およびフタルイミド（１．１ｇ、７．２ｍｍｏｌ）の溶液に、室温で、ＤＥＡＤ（４．３ｍＬ、１０．９ｍｍｏｌ）を５分にわたって加えた。室温で０．５時間後、反応溶液を濃縮し、シリカ（ヘキサン／ＥｔＯＡＣ、２：１）で精製して、標題化合物を白色固体として得た（２．７ｇ、８３％）：ＬＣＭＳ（ＥＳ）ｍ／ｚ３９５（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl ((1S) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1-{[4- (methyloxy) phenyl] Methyl} ethyl) carbamate

1,1-dimethylethyl ((1S) -2-hydroxy-1-{[4- (methyloxy) phenyl] methyl} ethyl) carbamate (1.9 g, 7.2 mmol) in THF (36 mL), PPh ₃ To a solution of (2.9 g, 11.0 mmol) and phthalimide (1.1 g, 7.2 mmol) at room temperature was added DEAD (4.3 mL, 10.9 mmol) over 5 minutes. After 0.5 h at room temperature, the reaction solution was concentrated and purified on silica (hexane / EtOAC, 2: 1) to give the title compound as a white solid (2.7 g, 83%): LCMS (ES) m / z 395 (M + H) ⁺ .

c) 2-{(2S) -2-amino-3- [4- (methyloxy) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione CHCl ₃ (40 mL) and MeOH (2 mL) 1,1-dimethylethyl ((1S) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1-{[4- (methyloxy) phenyl] To a solution of (methyl} ethyl) carbamate (2.7 g, 6.0 mmol) was added 4M HCl in dioxane (20 mL) at room temperature. After stirring at room temperature overnight, the reaction solution was concentrated to give a white solid (quantitative): LCMS (ES) m / z 295 (M + H) ⁺ .

Example 1

ｔ−ＢｕＯＨ（２０ｍＬ）中の５−ブロモチオフェンカルボン酸（２４．２ｍｍｏｌ、５．０ｇ）の混合物に、ＤＰＰＡ（３１．４ｍｍｏｌ、６．８ｍＬ）およびトリエチルアミン（７２．６ｍｍｏｌ、１０．１ｍＬ）を加えた。混合物を、Ｎ_２雰囲気下で８５℃に１５時間加熱した。室温に冷却した後、反応物を減圧下で濃縮した。フラッシュクロマトグラフィー（シリカゲル、ヘキサン／ＥｔＯＡｃ、４：１））に付して、標題化合物（４．０ｇ、６０％）を淡黄色泡沫体として得た。ＬＣＭＳ（ＥＳ）ｍ／ｚ２７８（Ｍ＋Ｈ）^＋ Preparation of 3-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide a) 1,1-dimethylethyl (4- Bromo-2-thienyl) carbamate

To a mixture of 5-bromothiophenecarboxylic acid (24.2 mmol, 5.0 g) in t-BuOH (20 mL) was added DPPA (31.4 mmol, 6.8 mL) and triethylamine (72.6 mmol, 10.1 mL). It was. The mixture was heated to 85 ° C. for 15 hours under N ₂ atmosphere. After cooling to room temperature, the reaction was concentrated under reduced pressure. Flash chromatography (silica gel, hexane / EtOAc, 4: 1)) gave the title compound (4.0 g, 60%) as a pale yellow foam. LCMS (ES) m / z 278 (M + H) ⁺

ジオキサン（４０ｍＬ）およびＨ_２Ｏ（８ｍＬ）中の１，１−ジメチルエチル （４−ブロモ−２−チエニル）カルバメート（１．２６ｇ、５．５８ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（２．３１ｇ、１６．７４ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．６５ｇ、０．５６ｍｍｏｌ）、および１−（フェニルスルホニル）−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（２．１５ｇ、５．５８ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で７０℃に４時間加熱した。反応溶液をＨ_２Ｏ（１００ｍＬ）に注ぎ、ＤＣＭで抽出した。有機層を乾燥し（Ｎａ_２ＳＯ_４）、減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、１：１）で精製して、標題化合物（１．９０ｇ、７５％）を黄褐色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４５６。 b) 1,1-dimethylethyl {4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} carbamate

To a solution of 1,1-dimethylethyl (4-bromo-2-thienyl) carbamate (1.26 g, 5.58 mmol) in dioxane (40 mL) and H ₂ O (8 mL) was added K ₂ CO ₃ (2.31 g). 16.74 mmol), tetrakistriphenylphosphine Pd (0) (0.65 g, 0.56 mmol), and 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (2.15 g, 5.58 mmol) was added. The reaction mixture was heated to 70 ° C. for 4 hours in a sealed tube. The reaction solution was poured into H ₂ O (100 mL) and extracted with DCM. The organic layer was dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and purified on silica gel (hexane / EtOAc, 1: 1) to give the title compound (1.90 g, 75%) as a tan foam. LC: MS-ES (ES) m / z = 456.

メタノール（２０ｍＬ）中の１，１−ジメチルエチル ｛４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−２−チエニル｝カルバメート（１．０ｇ、２．２ｍｍｏｌ）の溶液に、ジオキサン中４ＭのＨＣｌ（５ｍＬ）を加えた。反応物を室温で４時間撹拌し、ついで、減圧下で濃縮して固体を得た。
ＤＣＭ（５０ｍＬ）中の３−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−２−フェニルプロパン酸（０．８７ｇ、３．３ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（１．５４ｇ、３．３ｍｍｏｌ）およびＨｕｎｉｇ塩基（１．９ｍＬ、１１．０ｍｍｏｌ）を加えた。１５分後、残りのアミンを、ＤＣＭ（１０ｍＬ）中の反応混合物に加え、室温で１２時間撹拌した。反応溶液を減圧下で濃縮し、シリカゲル（ＤＣＭ／ＭｅＯＨ、９５：５）で精製して、標題化合物（１．０ｇ、７６％）を黄褐色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６０３。 c) 1,1-dimethylethyl [3-oxo-2-phenyl-3-({4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2- Thienyl} amino) propyl] carbamate

1,1-dimethylethyl {4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} carbamate (1.0 g, in methanol (20 mL)) 2.2 mmol) was added 4M HCl in dioxane (5 mL). The reaction was stirred at room temperature for 4 hours and then concentrated under reduced pressure to give a solid.
To a solution of 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid (0.87 g, 3.3 mmol) in DCM (50 mL) was added PyBrop (1.54 g, 3.3 mmol) and Hunig base (1.9 mL, 11.0 mmol) were added. After 15 minutes, the remaining amine was added to the reaction mixture in DCM (10 mL) and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and purified on silica gel (DCM / MeOH, 95: 5) to give the title compound (1.0 g, 76%) as a tan foam: LC-MS (ES) m / Z = 603.

d) 3-Amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide in THF (10 mL) and MeOH (20 mL) 1,1-dimethylethyl [3-oxo-2-phenyl-3-({4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} To a solution of (amino) propyl] carbamate (1.0 g, 1.66 mmol) was added 6N NaOH (3 mL). After 1 hour at 55 ° C., the reaction mixture was neutralized with 1M aqueous HCl and extracted with DCM. The DCM solution was dried over _Na 2 SO _4, concentrated under reduced pressure, silica gel (DCM / MeOH, 95: 5 ) to afford a tan solid: LC-MS (ES) m / z = 463 (M + H) ⁺ .
The solid material from above was dissolved in MeOH (15 mL) and added to a solution of 4M HCl in dioxane (5 mL). After 2 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound (289 mg, 48%) as a yellow solid: LC-MS (ES) m / z = 363 (M + H) ⁺ . ¹ H NMR (d6-DMSO, 400 MHz) δ 8.68 (d, J = 7.9 Hz, 1H), 8.43 (d, J = 5.3 Hz, 1H), 8.29 (brs, 2H), 7 .90 (s, 1H), 7.35-7.47 (m, 5H), 7.32 (m2H), 7.12 (s, 1H), 4.32 (m, 1H), 3.06 ( m, 2H).

Example 2

ジオキサン（４０ｍＬ）およびＨ_２Ｏ（８ｍＬ）中の％−ブロモ−２−ニトロチオフェン（１．０８ｇ、５．２ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（２．１５ｇ、１６．７４ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．６０ｇ、０．５２ｍｍｏｌ）、および１−（フェニルスルホニル）−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（２．０ｇ、５．２ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で８０℃に１２時間加熱した。反応溶液をＨ_２Ｏ（１００ｍＬ）に注ぎ、ＤＣＭで抽出した。有機層を乾燥し（Ｎａ_２ＳＯ_４）、減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、１：１）により精製して、標題化合物（１．１ｇ、５５％）を黄褐色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３８６。 Preparation of 3-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide a) 3- (5-Nitro-2- Thienyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine

Dioxane (40 mL) and _H 2 O (8mL)% in - bromo-2-nitro-thiophene (1.08 g, 5.2 mmol) to a solution _{of, K 2 CO 3 (2.15g,} 16.74mmol), Tetorakisutori Phenylphosphine Pd (0) (0.60 g, 0.52 mmol), and 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (2.0 g, 5.2 mmol) was added. The reaction mixture was heated to 80 ° C. for 12 hours in a sealed tube. The reaction solution was poured into H ₂ O (100 mL) and extracted with DCM. The organic layer was dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and purified by silica gel (hexane / EtOAc, 1: 1) to give the title compound (1.1 g, 55%) as a tan foam. : LC-MS (ES) m / z = 386.

ＴＨＦ（３０ｍＬ）およびＭｅＯＨ（３０ｍＬ）中の３−（５−ニトロ−２−チエニル）−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．９０ｇ、２．３４ｍｍｏｌ）の溶液に、１０％Ｐｄ／Ｃを加えた。反応混合物をＨ_２雰囲気下に置き、６時間激しく撹拌した。反応溶液をセライト（ＴＨＦ／ＭｅＯＨ）により濾過し、減圧下で濃縮して、褐色固体を得、これをさらに精製することなく用いた。
ＤＣＭ（１５ｍＬ）中の上記からの粗褐色固体（０．５ｇ、１．４ｍｍｏｌ）を、３−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−２−フェニルプロパン酸（０．５６ｇ、２．１ｍｍｏｌ）、ＰｙＢｒｏｐ（０．９８ｇ、２．１ｍｍｏｌ）およびＨｕｎｉｇ塩基（０．７３ｍＬ、４．２ｍｍｏｌ）のＤＣＭ（５０ｍＬ）溶液に加えた。室温で１２時間後、反応溶液を減圧下で濃縮し、シリカゲル（ＤＣＭ／ＭｅＯＨ、９７：３）により精製して、標題化合物（０．５５ｇ、６５％）を黄褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６０３。 b) 1,1-dimethylethyl [3-oxo-2-phenyl-3-({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2- Thienyl} amino) propyl] carbamate

3- (5-Nitro-2-thienyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.90 g, 2.34 mmol) in THF (30 mL) and MeOH (30 mL). 10% Pd / C was added to the solution. The reaction mixture was placed under H ₂ atmosphere and stirred vigorously for 6 hours. The reaction solution was filtered through celite (THF / MeOH) and concentrated under reduced pressure to give a brown solid that was used without further purification.
The crude brown solid from above (0.5 g, 1.4 mmol) in DCM (15 mL) was dissolved in 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid (0 .56 g, 2.1 mmol), PyBrop (0.98 g, 2.1 mmol) and Hunig base (0.73 mL, 4.2 mmol) in DCM (50 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel (DCM / MeOH, 97: 3) to give the title compound (0.55 g, 65%) as a tan solid: LC- MS (ES) m / z = 603.

c) 3-Amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide in THF (10 mL) and MeOH (20 mL) 1,1-dimethylethyl [3-oxo-2-phenyl-3-({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} To a solution of (amino) propyl] carbamate (0.5 g, 0.83 mmol) was added 6N NaOH (3 mL). After 1 hour at 55 ° C., the reaction mixture was neutralized with 1M HCl and extracted with DCM. The DCM solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The solid residue was dissolved in MeOH (15 mL) and added to a 4M HCl solution in dioxane (5 mL). The reaction solution was concentrated under reduced pressure and purified by reverse phase HPLC (C18 column: H ₂ O / CH ₃ CN gradient) to give the title compound (72 mg, 24%) as a yellow solid: LC-MS (ES ) M / z = 363 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 8.29 (d, J = 5.3 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H) 7.95 (brs, 4H), 7.72 (s, 1H), 7.35-7.51 (m, 4H), 7.29 (m1H), 7.12 (s, 1H), 6. 68 (s, 1H), 4.05 (m, 1H), 3.55 (m, 2H).

Example 3

Preparation of 4-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] butanamide 3-({[(1,1-dimethylethyl ) Oxy] carbonyl} amino) -2-phenylpropanoic acid instead of 4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylbutanoic acid (0.82 g, 2.97 mmol) The title compound was obtained as a tan solid according to the method of Example 1 except using: LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ8 .61 (d, J = 7.9 Hz, 1H), 8.43 (d, J = 5.3 Hz, 1H), 8.14 (brs, 2H), 7.90 (s, 1H), 7.35 -7.45 (m, 5H), 7.3 0 (m2H), 7.12 (s, 1H), 4.00 (m, 1H), 2.74 (m, 1H), 2.65 (m, 1H), 2.44 (m, 1H), 2.09 (m, 1H).

Example 4

Preparation of 4-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] butanamide 3-({[(1,1-dimethylethyl ) Oxy] carbonyl} amino) -2-phenylpropanoic acid instead of 4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylbutanoic acid (0.83 g, 2.98 mmol) The title compound was obtained as a tan solid according to the method of Example 1 except using: LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ8 .29 (d, J = 5.1 Hz, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.82 (brs, 2H), 7.71 (s, 1H), 7.40 (M, 3H), 7.35 (m, 1 H), 7.25 (m, 1H), 7.19 (m, 1H), 7.09 (m, 1H), 6.68 (d, J = 3.9 Hz, 1H), 3.79 (m) , 1H), 2.72 (m, 2H), 2.32 (m, 1H), 2.03 (m, 1H).

Example 5

Preparation of 3-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide 1- (phenylsulfonyl) -3- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine instead of 1- (phenylsulfonyl) -4- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (2 g, 5.29 mmol) according to Example 2, except that The title compound was obtained as a yellow solid.

The final step for deprotection was modified to remove the sulfonamide group under basic conditions and the solution was neutralized with 6N HCl and then extracted with DCM. The combined fractions were dried (Na ₂ SO ₄ ) and concentrated to give a residue that was immediately treated with TFA / DCM (0.1 M, 1: 2). After 0.5 h, the solution was concentrated by toluene azeotrope and the residue was neutralized with 3-10% MeOH solution in DCM (1% NH ₄ OH). The neutralized compound was then dissolved in DCM (0.1 M), treated with a 2M solution of HCl in Et ₂ O (7 eq) and concentrated to give the title compound (195 mg) as the diHCl salt. : LC-MS (ES) m / z = 363 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 8.39 (d, J = 6 Hz, 1H), 8.16 (bs, 2H), 7 80-80.82 (m, 1H), 7.62-7.68 (m, 1H) 7.50-7.52 (m, 1H), 7.31-7.48 (m, 5H), 6.9-7.03 (m, 1H), 6.91 (d, J = 4.2 Hz, 1H), 4.21-4.28 (m, 1H), 3.52-3.61 (m , 1H), 3.10-3.17 (m, 1H).

The racemate is subjected to racemic resolution using a ChiralPak AD-H column to give GSK1155572A (labeled E1, 86 mg, 99% ee) as the first eluting enantiomer and then GSK1155573A (labeled E2, as the later eluting enantiomer). 89 mg, 98.5% ee), and LCMS and ¹ H NMR data were identical to the parent racemic compound GSK1070771A.

Example 6

Preparation of 4-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide 3-({[(1,1-dimethylethyl ) Oxy] carbonyl} amino) -2-phenylpropanoic acid instead of 4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylbutanoic acid (0.813 mg, 2.91 mmol) The title compound was obtained as an orange solid as described in Example 5 except using: LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ8. 29 (d, J = 5.9 Hz, 1H), 8.00 (bs, 2H), 8.7 (d, J = 2.2 Hz, 1H), 7.7 (s, 1H), 7.53 ( d, J = 5.4 Hz, 1H), 7. 29-7.43 (m, 5H), 7.00 (s, 1H), 6.99 (d, J = 1.0 Hz, 1H), 4.00-4.09 (m, 1H), 2. 64-2-2.79 (m, 2H), 2.31-2.41 (m, 1H), 2.06-2.14 (m, 1H).

Example 7

ＴＨＦ（１８２ｍＬ）中の２−アミノ−１−フェニルエタノール（５ｇ、３６．４ｍｍｏｌ）の溶液に、２５℃で、Ｂｏｃ_２Ｏ（８．７ｇ、４０．１ｍｍｏｌ）を一度に加えた。０．５時間後、溶液を濃縮し、残渣をさらに精製することなく直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝２３８（Ｍ＋Ｈ）^＋。 Preparation of N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 1,1-dimethylethyl (2- Hydroxy-2-phenylethyl) carbamate

To a solution of 2-amino-1-phenylethanol (5 g, 36.4 mmol) in THF (182 mL) at 25 ° C. was added Boc ₂ O (8.7 g, 40.1 mmol) in one portion. After 0.5 h, the solution was concentrated and the residue was used directly without further purification: LC-MS (ES) m / z = 238 (M + H) ⁺ .

ＴＨＦ（３５ｍＬ）中の１，１−ジメチルエチル （２−ヒドロキシ−２−フェニルエチル）カルバメート（２ｇ、８．４４ｍｍｏｌ）、フタルイミド（１ｇ、７．０３ｍｍｏｌ）およびトリフェニルホスフィン（２．７６ｇ、１０．５ｍｍｏｌ）の溶液に、２５℃で、ＤＥＡＤ（１．７ｍＬ、１０．５ｍｍｏｌ）を滴下した。０．５時間後、溶液を濃縮し、カラムクロマトグラフィー（シリカ、ヘキサン中１５％ＥｔＯＡｃ）により精製して、標題化合物（２ｇ、８０％）を白色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３６７（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -2-phenylethyl] carbamate

1,1-dimethylethyl (2-hydroxy-2-phenylethyl) carbamate (2 g, 8.44 mmol), phthalimide (1 g, 7.03 mmol) and triphenylphosphine (2.76 g, 10.5 g) in THF (35 mL). DEAD (1.7 mL, 10.5 mmol) was added dropwise to the solution of 5 mmol) at 25 ° C. After 0.5 h, the solution was concentrated and purified by column chromatography (silica, 15% EtOAc in hexane) to give the title compound (2 g, 80%) as a white foam: LC-MS (ES) m / z = 367 (M + H) ⁺ .

ＭｅＯＨ（０．５Ｍ、１０ｍＬ）中の１，１−ジメチルエチル ［２−（１，３−ジオキソ−１，３−ジヒドロ−２Ｈ−イソインドール−２−イル）−２−フェニルエチル］カルバメート（２ｇ、５．４６ｍｍｏｌ）およびＭｅＮＨ_２（Ｈ_２Ｏ中４０ｗｔ％、１０当量）またはＮＨ_２ＮＨ_２（１０当量）のいずれかの溶液を、シールしたチューブ中で６０℃に加熱した。１２時間後、溶液を濃縮し、カラムクロマトグラフィー（シリカ−乾燥充填、ＤＣＭ中２％ＭｅＯＨ（１％ＮＨ_４ＯＨ））により精製して、標題化合物（１．１ｇ、８５％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝２３７（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl (2-amino-2-phenylethyl) carbamate

1,1-dimethylethyl [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -2-phenylethyl] carbamate (2 g in MeOH (0.5 M, 10 mL) 5.46 mmol) and either MeNH ₂ (40 wt% in H ₂ O, 10 eq) or NH ₂ NH ₂ (10 eq) were heated to 60 ° C. in a sealed tube. After 12 h, the solution was concentrated and purified by column chromatography (silica - dry loaded, DCM in _{2% MeOH (1% NH 4} OH)) to give the title compound (1.1 g, 85%) as a white solid Obtained: LC-MS (ES) m / z = 237 (M + H) ⁺ .

ＤＣＭ（１１ｍＬ）中の５−ブロモ−２−チオフェンカルボン酸（０．７２３ｍｇ、３．４９ｍｍｏｌ）、ＰｙＢｒＯＰ（１．６２ｇ、３．４９ｍｍｏｌ）およびジイソプロピルエチルアミン（１．２ｍＬ、６．９９ｍｍｏｌ）の溶液に、２５℃で、１，１−ジメチルエチル （２−アミノ−２−フェニルエチル）カルバメート（５００ｍｇ、２．１２ｍｍｏｌ）を加えた。１２時間後、溶液をＨ_２Ｏで分配し、ＤＣＭで洗浄した。合した有機フラクションを乾燥し（Ｎａ_２ＳＯ_４）、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中０．５％ＭｅＯＨ）により精製して、標題化合物（７３０ｍｇ、８１％）を白色粉末として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４２６（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl (2-{[(5-bromo-2-thienyl) carbonyl] amino} -2-phenylethyl) carbamate

To a solution of 5-bromo-2-thiophenecarboxylic acid (0.723 mg, 3.49 mmol), PyBrOP (1.62 g, 3.49 mmol) and diisopropylethylamine (1.2 mL, 6.99 mmol) in DCM (11 mL). At 25 ° C., 1,1-dimethylethyl (2-amino-2-phenylethyl) carbamate (500 mg, 2.12 mmol) was added. After 12 hours, the solution was partitioned with H ₂ O and washed with DCM. The combined organic fractions were dried (Na ₂ SO ₄ ), concentrated and purified by column chromatography (silica, 0.5% MeOH in DCM) to give the title compound (730 mg, 81%) as a white powder. : LC-MS (ES) m / z = 426 (M + H) ⁺ .

ジオキサン／Ｈ_２Ｏ（５：１、８．６ｍＬ）中の１，１−ジメチルエチル （２−｛［（５−ブロモ−２−チエニル）カルボニル］アミノ｝−２−フェニルエチル）カルバメート（３５６ｍｇ、０．８５９ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（４７４ｍｇ、３．４４ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（５０ｍｇ、４２．９ｕｍｏｌ）および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（３９６ｍｇ、１．０３ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で８０℃に１２時間加熱した。反応溶液をＨ_２Ｏ（１００ｍＬ）に注ぎ、ＤＣＭで抽出した。有機層を乾燥し（Ｎａ_２ＳＯ_４）、減圧下で濃縮し、シリカゲル（ＤＣＭ中の１％ＭｅＯＨ）により精製して、標題化合物（４９６ｍｇ、９６％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６０３。 e) 1,1-dimethylethyl {2-phenyl-2-[({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbonyl ) Amino] ethyl} carbamate

1,1-dimethylethyl (2-{[(5-bromo-2-thienyl) carbonyl] amino} -2-phenylethyl) carbamate (356 mg, in dioxane / H ₂ O (5: 1, 8.6 mL) 0.859 mmol) was added to a solution of K ₂ CO ₃ (474 mg, 3.44 mmol), tetrakistriphenylphosphine Pd (0) (50 mg, 42.9 umol) and 1- (phenylsulfonyl) -4- (4,4,4). 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (396 mg, 1.03 mmol) was added. The reaction mixture was heated to 80 ° C. for 12 hours in a sealed tube. The reaction solution was poured into H ₂ O (100 mL) and extracted with DCM. The organic layer was dried (Na ₂ SO ₄ ), concentrated under reduced pressure and purified by silica gel (1% MeOH in DCM) to give the title compound (496 mg, 96%) as a yellow solid: LC-MS (ES) m / z = 603.

ＴＨＦ／ＭｅＯＨ（８ｍＬ）中の１，１−ジメチルエチル ｛２−フェニル−２−［（｛５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］エチル｝カルバメート（４９６ｍｇ、０．８２４ｍｍｏｌ）の溶液を、６ＮのＮａＯＨ（８ｍＬ）で処理し、２５〜５０℃で２時間撹拌した。ついで、溶液を６ＮのＨＣｌで中和し、ＤＣＭで抽出した。合した有機フラクションを乾燥し（Ｎａ_２ＳＯ_４）、濃縮し、カラムクロマトグラフィー（シリカ−乾燥充填、ＤＣＭ中の２％ＭｅＯＨ）により精製して、標題化合物（１２３ｍｇ、３２％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４６４（Ｍ＋Ｈ）^＋。 f) 1,1-dimethylethyl [2-phenyl-2-({[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} amino) ethyl] carbamate

1,1-dimethylethyl {2-phenyl-2-[({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] in THF / MeOH (8 mL) A solution of -2-thienyl} carbonyl) amino] ethyl} carbamate (496 mg, 0.824 mmol) was treated with 6N NaOH (8 mL) and stirred at 25-50 ° C. for 2 hours. The solution was then neutralized with 6N HCl and extracted with DCM. The combined organic fractions were dried (Na ₂ SO ₄ ), concentrated and purified by column chromatography (silica-dry packed, 2% MeOH in DCM) to give the title compound (123 mg, 32%) as a yellow solid Obtained: LC-MS (ES) m / z = 464 (M + H) ⁺ .

g) N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide (GSK 1229745A)
1,1-dimethylethyl [2-phenyl-2-({[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} amino) ethyl] carbamate (123 mg, 0.266 mmol) was dissolved in MeOH (3 mL) and treated with 4M HCl in dioxane (465 uL, 1.86 mmol). After 12 hours, the solution was concentrated to give the diHCl salt of the title compound (102 mg, 34% 2 steps) as a yellow solid: LC-MS (ES) m / z = 364 (M + H) ⁺ ; ¹ H NMR (D6-DMSO, 400 MHz) δ 9.47 (d, J = 8.2 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.24 (bs, 2H), 7.95 ( d, J = 4.0 Hz, 1H), 7.69-7.70 (m, 1H), 7.51-7.60 (m, 1H), 7.46-7.52 (m, 2H), 7.38-7.42 (m, 2H), 7.32-7.34 (m, 1H), 6.93-6.95 (m, 1H), 5.31-5.38 (m, 1H) ), 3.38-3.42 (m, 1H), 3.18-3.22 (m, 1H).

Example 8

Preparation of N- (2-amino-1-phenylethyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide instead of 5-bromo-2-thiophenecarboxylic acid The title compound was obtained as a yellow solid according to Example 7 except that 4-bromo-2-thiophenecarboxylic acid (723 mg, 3.49 mmol) was used for: LC-MS (ES) m / z = 364 (M + H ) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 9.90-9.93 (m, 1H), 9.01-9.05 (m, 1H), 8.64-8.69 (m, 1H) ), 8.52-8.54 (m, 1H), 8.38-8.45 (bs, 2H), 7.81-7.84 (m, 1H), 7.72-7.75 (m , 1H), 7.49-7.52 (m, 2H), 7. 28-7.41 (m, 4H), 5.30-5.35 (m, 1H), 3.45-3.51 (m, 1H), 3.11-3.21 (m, 1H).

Example 9

Preparation of N- (2-amino-1-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 5-Bromo-2-thiophene The title compound was obtained as a yellow solid according to Example 7 except that 4,5-dibromo-2-thiophenecarboxylic acid (2.2 g, 7.69 mmol) was used instead of carboxylic acid: LC-MS (ES ) M / z = 442 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 9.55-9.59 (m, 1H), 8.34-8.37 (m, 2H), 8.27 (Bs, 2H), 7.64-7.66 (m, 1H), 7.47-7.49 (m, 2H), 7.41-7.43 (m, 2H), 7.32-7 .39 (m, 2H), 6.53-6.54 (m, 1H) , 5.29-5.34 (m, 1H), 3.32-3.39 (m, 1H), 3.22-3.25 (m, 1H).

Example 10

Preparation of 4-bromo-N- [2- (methylamino) -1-phenylethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 5-bromo- Instead of 2-thiophenecarboxylic acid, 4,5-dibromo-2-thiophenecarboxylic acid (1.89 g, 6.6 mmol) was used instead of 1,1-dimethylethyl (2-hydroxy-2-phenylethyl) carbamate. The title compound was obtained as a yellow solid according to Example 7, except that 1,1-dimethylethyl (2-hydroxy-2-phenylethyl) methylcarbamate (2 g, 8 mmol) was used: LC-MS (ES) m ^{/ z = 456 (M + H} ) +; 1 H NMR (d6-DMSO, 400MHz) δ9.65 (d, J = 8.2Hz, 1H), 8.95-9 02 (m, 2H), 8.36-8.38 (m, 2H), 7.63-7.65 (m, 1H), 7.48-7.50 (m, 2H), 7.39- 7.43 (m, 2H), 7.32-7.36 (m, 2H), 6.53-6.55 (m, 1H), 5.37-5.43 (m, 1H), 3. 49-3.57 (m, 1H), 3.30-3.36 (m, 1H), 2.64 (s, 3H).

Example 11

Preparation of N- (2-amino-1-phenylethyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 1- (phenylsulfonyl) -4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine instead of 1- (phenylsulfonyl) -3- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (450 mg, 1.17 mmol) with 5-bromo-2-thiophenecarboxylic acid. The title compound was obtained as a yellow solid according to Example 7 except that 4-bromo-2-thiophenecarboxylic acid (415 mg, 0.976 mmol) was used instead of.

Alternatively, the Boc protecting group was removed using TFA-DCM (1: 2, 0.1 M) at 25 ° C. for 1 hour. The resulting solution was concentrated using toluene azeotrope and the residue was neutralized with a silica plug (2-10% MeOH in DCM (1% NH ₄ OH)) to give a neutral compound. The compound in DCM was then treated with excess HCl in diethyl ether to give the diHCl salt of the title compound: LC-MS (ES) m / z = 363 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 9.17 (d, J = 8.4 Hz, 1H), 8.45-8.48 (m, 1H), 8.30-8.34 (m, 1H), 8.15 ( bs, 2H), 7.99 (s, 1H), 7.88 (s, 1H), 7.41-7.49 (m, 5H), 7.32-7.39 (m, 1H), 7 20-7.23 (m, 1H), 3.28-3.58 (m, 2H).

Example 12

Preparation of N- (2-amino-1-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 1- (phenylsulfonyl)- 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine instead of 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (289 mg, 0.751 mmol) was replaced with 5-bromo-2 -The title compound was obtained as a yellow solid according to Example 7, except that 4,5-dibromo-2-thiophenecarboxylic acid (2.2 g, 7.69 mmol) was used instead of thiophenecarboxylic acid.

Alternatively, the Boc protecting group was removed using TFA-DCM (1: 2, 0.1 M) at 25 ° C. for 0.5 h. The resulting solution was concentrated using toluene azeotrope and the residue was neutralized with a silica plug (2-10% MeOH in DCM (1% NH ₄ OH)) to give a neutral compound. The compound in DCM was then treated with excess HCl in diethyl ether to give the diHCl salt of the title compound: LC-MS (ES) m / z = 442 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 9.30 (d, J = 8.2 Hz, 1H), 8.35-8.37 (m, 1H), 8.20 (bs, 2H), 8.12-8.19 ( m, 1H), 7.37-7.47 (m, 5H), 7.31-7.35 (m, 1H), 7.23-7.26 (m, 1H), 5.27-5. 33 (m, 1H), 3.17-3.37 (m, 2H).

Example 13

Preparation of N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide in THF (3 mL) cooled to 78 ° C N- (2-amino-1-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide (120 mg, 0.273 mmol) [ NBuLi (2.5 M hexane, 765 uL, 1.91 mmol) was added dropwise to the solution prepared in Example 7. After 0.5 hours, the same amount of nBuLi was added and the solution was stirred for another 2 hours. The solution was then quenched with H ₂ O and extracted several times with DCM. The combined extracts were dried (Na ₂ SO ₄ ), concentrated and purified by silica chromatography (5% MeOH in DCM (1% NH ₄ OH)) to give the neutralized compound. The compound in DCM was treated with excess HCl in diethyl ether to give the diHCl salt of the title compound: LC-MS (ES) m / z = 363 (M + H) ⁺ ; ¹ H NMR (d6-DMSO , 400 MHz) δ 9.01-9.04 (m, 1H), 8.32-8.35 (m, 2H), 8.12 (bs, 2H), 8.03-8.04 (m, 2H) 7.46-7.50 (m, 5H), 7.38-7.44 (m, 1H), 7.22-7.34 (m, 1H), 5.29-5.35 (m, 1H), 3.17-3.41 (m, 2H).

Example 14

Preparation of N- (2-amino-1-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 1- (phenylsulfonyl)- 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine instead of 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (289 mg, 0.751 mmol) was replaced with 5-bromo-2 -Instead of thiophenecarboxylic acid, 4,5-dibromo-2-thiophenecarboxylic acid (315 mg, 0.626 mmol) was replaced with 1,1-dimethylethyl (2-hydroxy-2-phenylethyl) carbamate The title compound was obtained as a yellow solid according to Example 7 except that 1,1-dimethylethyl (2-hydroxy-2-phenylethyl) methylcarbamate (2 g, 8 mmol) was used instead of ES) m / z = 456 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 9.48 (d, J = 7.3 Hz, 1H), 9.01 (bs, 2H), 8.36− 8.38 (m, 1H), 8.33-8.35 (m, 1H), 8.22-8.27 (m, 1H), 8.19-8.21 (m, 1H), 7. 31-7.48 (m, 5H), 7.24-7.27 (m, 1H), 5.37-5.42 (m, 1H), 3.47-3.54 (m, 1H), 3.31-3.34 (m, 1H), 2.50 (s, 3H).

Example 15

ジオキサン／Ｈ_２Ｏ（５：１、６ｍＬ）中の５−ブロモ−２−チオフェンカルボン酸（１０４ｍｇ、０．５ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（３２８ｍｇ、２．３８ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（３４ｍｇ、６０ｕｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（２３１ｍｇ、０．６ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で８０℃に１２時間加熱した。混合物を６ＮのＮａＯＨ水溶液でｐＨ１３に塩基性化し、ジクロロメタンで洗浄した。ついで、水層をｐＨ４に酸性化し、ジクロロメタンで抽出した。有機フラクションをプールし、Ｎａ_２ＳＯ_４で乾燥し、濃縮して、標題化合物（１９０ｍｇ、定量）を褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３８５（Ｍ＋Ｈ）^＋。 Preparation of N- (3-amino-1-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylic acid

To a solution of 5-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) in dioxane / H ₂ O (5: 1, 6 mL) was added K ₂ CO ₃ (328 mg, 2.38 mmol), tetrakistriphenylphosphine. Pd (0) (34 mg, 60 umol) and 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2 , 3-b] pyridine (231 mg, 0.6 mmol) was added. The reaction mixture was heated to 80 ° C. for 12 hours in a sealed tube. The mixture was basified to pH 13 with 6N aqueous NaOH and washed with dichloromethane. The aqueous layer was then acidified to pH 4 and extracted with dichloromethane. The organic fractions were pooled, dried over Na ₂ SO ₄ and concentrated to give the title compound (190 mg, quantitative) as a brown solid: LC-MS (ES) m / z = 385 (M + H) ⁺ .

ＤＣＭ（３ｍＬ）中の５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸（９５ｍｇ、０．２５ｍｍｏｌ）、ＰｙＢｒＯＰ（１１６．６ｍｇ、０．２５ｍｍｏｌ）およびジイソプロピルエチルアミン（０．０８７ｍＬ、０．５ｍｍｏｌ）の溶液に、２５℃で、１，１−ジメチルエチル （３−アミノ−３−フェニルプロピル）カルバメート［１，１−ジメチルエチル （３−ヒドロキシ−３−フェニルプロピル）カルバメート［調製例６に記載］から、実施例７に従って調製した］（４０ｍｇ、０．１５ｍｍｏｌ）を加えた。１２時間後、溶液を水で分配し、ＤＣＭで洗浄した。合した有機フラクションを乾燥し（Ｎａ_２ＳＯ_４）、濃縮し、カラムクロマトグラフィー（シリカ、ヘキサン中０〜５０％酢酸エチル）により精製して、標題化合物（８２．１ｍｇ、５２％）を黄色油として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６１７（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl {3-phenyl-3-[({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbonyl ) Amino] propyl} carbamate

5- [1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylic acid (95 mg, 0.25 mmol), PyBrOP (116. 6 mg, 0.25 mmol) and diisopropylethylamine (0.087 mL, 0.5 mmol) at 25 ° C. and 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate [1,1-dimethylethyl (3-Hydroxy-3-phenylpropyl) carbamate [prepared according to example 7 from Preparation 6] (40 mg, 0.15 mmol) was added. After 12 hours, the solution was partitioned with water and washed with DCM. The combined organic fractions were dried (Na ₂ SO ₄ ), concentrated and purified by column chromatography (silica, 0-50% ethyl acetate in hexanes) to give the title compound (82.1 mg, 52%) as a yellow oil Obtained as: LC-MS (ES) m / z = 617 (M + H) ^<+> .

ＭｅＯＨ（２ｍＬ）中の１，１−ジメチルエチル ｛３−フェニル−３−［（｛５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］プロピル｝カルバメート（８２ｍｇ、０．１３ｍｍｏｌ）の溶液を、６ＮのＮａＯＨ（０．５５ｍＬ、１．３ｍｍｏｌ）で処理し、２５〜５０℃で０．５時間撹拌した。ついで、溶液を６ＮのＨＣｌで中和し、ＤＣＭで抽出した。合した有機フラクションを乾燥し（Ｎａ_２ＳＯ_４）、濃縮し、カラムクロマトグラフィー（シリカ−乾燥充填、ＤＣＭ中３％ＭｅＯＨ）により精製して、標題化合物（３９．２ｍｇ、６２％）を黄色油として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４７７（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl [3-phenyl-3-({[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} amino) propyl] carbamate

1,1-Dimethylethyl {3-phenyl-3-[({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2 in MeOH (2 mL) A solution of -thienyl} carbonyl) amino] propyl} carbamate (82 mg, 0.13 mmol) was treated with 6N NaOH (0.55 mL, 1.3 mmol) and stirred at 25-50 ° C. for 0.5 h. The solution was then neutralized with 6N HCl and extracted with DCM. The combined organic fractions were dried (Na ₂ SO ₄ ), concentrated and purified by column chromatography (silica-dry packed, 3% MeOH in DCM) to give the title compound (39.2 mg, 62%) as a yellow oil Obtained as: LC-MS (ES) m / z = 477 (M + H) ^<+> .

d) N- (3-amino-1-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1-dimethylethyl [3-phenyl- 3-({[5- (1H-pyrrolo [2,3-b] pyridine-4-yl) -2-thienyl] carbonyl} amino) propyl] carbamate (39 mg, 0.08 mmol) was added to TFA-DCM (1 : 2, 0.1M) and stirred at 25 ° C. After 0.5 h, the solution was concentrated using toluene azeotrope and the residue was neutralized with a silica plug (2-10% MeOH (1% NH ₄ OH) in DCM) to give the neutralized compound. The compound in DCM was then treated with excess HCl in diethyl ether to give the diHCl salt of the title compound as a yellow solid: LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (d4-MeOH, 400 MHz) δ 8.43 (d, J = 6.1 Hz, 1H), 8.03-8.08 (m, 2H), 7.86-7.94 (m, 1H), 7 .78-7.85 (m, 1H), 7.48-7.55 (m, 2H), 7.40-7.47 (m, 2H), 7.33-7.39 (m, 1H) , 7.28-7.33 (m, 1H), 5.22-5.32 (m, 1H), 3.07-3.15 (m, 1H), 2.92-3.02 (m, 1H), 2.28-2.43 (m, 2H).

Example 16

Preparation of N- (3-amino-1-phenylpropyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide instead of 5-bromo-2-thiophenecarboxylic acid The title compound was obtained as a white solid according to Example 15 except that 4-bromo-2-thiophenecarboxylic acid (95 mg, 0.25 mmol) was used for: LC-MS (ES) m / z = 377 (M + H ^{) +; 1 H NMR (d4} -MeOH, 400MHz) δ8.57 (s, 1H), 8.47 (s, 1H), 8.4-8.44 (m, 1H), 7.68-7. 18 (m, 2H), 7.48-7.55 (m, 2H), 7.40-7.46 (m, 2H), 7.31-7.38 (m, 1H), 7.18- 7.22 (m, 1H), 5.23-5.32 (m, 1 H), 3.07-3.16 (m, 1H), 2.95-3.04 (m, 1H), 2.28-2.45 (m, 2H).

Example 17

Preparation of N- (3-amino-1-phenylpropyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 5-Bromo-2-thiophene The title compound was obtained as a yellow solid according to Example 15, except that 4,5-dibromo-2-thiophenecarboxylic acid (116 mg, 0.25 mmol) was used instead of carboxylic acid: LC-MS (ES) m ^{/ z = 456 (M + H} ) +; 1 H NMR (d4-MeOH, 400MHz) δ8.38 (s, 1H), 7.95-7.97 (m, 1H), 7.58-7.67 (m , 1H), 7.48-7.58 (m, 3H), 7.41-7.47 (m, 2H), 7.31-7.39 (m, 1H), 6.68-6.79. (M, 1H), 5.2-5.29 (m, 1H ), 3.07-3.17 (m, 1H), 2.93-3.03 (m, 1H), 2.25-2.43 (m, 2H).

Example 18

Preparation of N- (3-amino-1-phenylpropyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1-dimethylethyl ( 1,1-dimethylethyl (4-amino-4-phenylbutyl) carbamate (40 mg, 0.25 mmol) [1,1-dimethylethyl (4-hydroxy-4) instead of 3-amino-3-phenylpropyl) carbamate The title compound was obtained as a yellow solid according to Example 15, except using -phenylbutyl) carbamate (prepared by Marshall, DRJ Chem. Soc., Perkin Trans. 21977, 1898 and Preparation 6). ^{: LC-MS (ES) m} / z = 391 (M + H) +; 1 H NMR (d4-MeO , 400 MHz) δ 8.33 (d, J = 5.2 Hz, 1H), 7.89-7.96 (m, 2H), 7.63-7.69 (m, 2H), 7.44-7. 51 (m, 2H), 7.36-7.43 (m, 2H), 7.26-7.34 (m, 1H), 7.06-7.13 (m, 1H), 5.13- 5.23 (m, 1H), 2.97-3.08 (m, 2H), 2.0-2.15 (m, 2H), 1.69-1.90 (m, 2H).

Example 19

Preparation of N- (4-amino-1-phenylbutyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1-dimethylethyl (3-amino- 1,1-dimethylethyl (4-amino-4-phenylbutyl) carbamate (38 mg, 0.15 mmol) [1,1-dimethylethyl (4-hydroxy-4-phenylbutyl) instead of 3-phenylpropyl) carbamate Carbamate (prepared from Marshall, DRJ Chem. Soc., Perkin Trans. 21977, 1898 and Preparation Example 6) was prepared from 4-dibromo-2-thiophenecarboxylic acid instead of 5-dibromo-2-thiophenecarboxylic acid. According to Example 15, except that the acid (95 mg, 0.25 mmol) is used. The title compound was obtained as a yellow ^{solid: LC-MS (ES) m} / z = 391 (M + H) +; 1 H NMR (d4-MeOH, 400MHz) δ8.67 (s, 1H), 8.59 (s, 1H), 8.44-8.50 (m, 1H), 7.84-7.90 (m, 1H), 7.79-7.84 (m, 1H), 7.48-7.55 ( m, 2H), 7.35-7.43 (m, 2H), 7.26-7.34 (m, 2H), 5.12-5.20 (m, 1H), 2.98-3. 07 (m, 2H), 2.13-2.24 (m, 1H), 2.01-2.11 (m, 1H), 1.82-1.95 (m, 1H), 1.68- 1.81 (m, 1H).

Example 20

Preparation of N- (4-amino-1-phenylbutyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1-dimethylethyl ( 1,1-dimethylethyl (4-amino-4-phenylbutyl) carbamate (38 mg, 0.15 mmol) [1,1-dimethylethyl (4-hydroxy-4) instead of 3-amino-3-phenylpropyl) carbamate -Phenylbutyl) carbamate (prepared from Marshall, DRJ. Chem. Soc., PerkinTrans. 21977, 1898. and Preparation 6)] in place of 5-dibromo-2-thiophenecarboxylic acid. Example 1 except that 2-thiophenecarboxylic acid (116 mg, 0.25 mmol) was used According, the title compound was obtained as a brown ^{solid: LC-MS (ES) m} / z = 470 (M + H) +; 1 H NMR (d4-MeOH, 400MHz) δ8.40-8.50 (m, 1H), 8.0 (s, 1H), 7.63-7.74 (m, 2H), 7.42-7.5 (m, 2H), 7.34-7.42 (m, 2H), 7. 25-7.33 (m, 1H), 6.81-6.89 (m, 1H), 5.10-5.14 (m, 1H), 2.96-3.08 (m, 2H), 1.98-2.15 (m, 2H), 1.80-1.92 (m, 1H), 1.67-1.79 (m, 1H).

Example 21

ジオキサン（１５ｍＬ）およびＨ_２Ｏ（２ｍＬ）中の１，１−ジメチルエチル （４−ブロモ−２−チエニル）カルバメート（０．５ｇ、１．８０ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（１．０ｇ、７．２ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．１０４ｇ、０．０９ｍｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．６９ｇ、１．８ｍｍｏｌ）を加えた。反応混合物を、シールしたチューブ中で４時間７０℃に加熱した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、２：１）により精製して、標題化合物（５６０ｍｇ、７０％）を褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４５６（Ｍ＋１）^＋。 Preparation of 3-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide a) 1,1-dimethylethyl {4- [1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate

To a solution of 1,1-dimethylethyl (4-bromo-2-thienyl) carbamate (0.5 g, 1.80 mmol) in dioxane (15 mL) and H ₂ O (2 mL) was added K ₂ CO ₃ (1.0 g 7.2 mmol), tetrakistriphenylphosphine Pd (0) (0.104 g, 0.09 mmol), and 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (0.69 g, 1.8 mmol) was added. The reaction mixture was heated to 70 ° C. for 4 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by silica gel (hexane / EtOAc, 2: 1) to give the title compound (560 mg, 70%) as a brown solid: LC-MS (ES) m / z = 456. (M + 1) ⁺ .

塩化メチレン（５ｍＬ）中の１，１−ジメチルエチル ｛４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルバメート（２３０ｍｇ、０．５１ｍｍｏｌ）の溶液に、室温でＴＦＡ（２ｍＬ）を加えた。反応物を室温で１時間撹拌し、ついで、減圧下で濃縮して固体を得た。
ＤＣＭ（４ｍＬ）中の３−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−２−フェニルプロパン酸（０．２３ｇ、０．８５ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（０．４ｇ、０．９０ｍｍｏｌ）およびＨｕｎｉｇ塩基（１．９ｍＬ、１１．０ｍｍｏｌ）を加えた。１５分後、残ったアミンをＤＣＭ中の反応混合物（２ｍＬ）に加えて、１２時間室温で撹拌した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、２：１〜１：１）で精製して、標題化合物（９７ｍｇ、２工程で３２％）を黄褐色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６０３（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl {4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate

1,1-dimethylethyl {4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate (230 mg, 0 in methylene chloride (5 mL) .51 mmol) was added TFA (2 mL) at room temperature. The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give a solid.
To a solution of 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid (0.23 g, 0.85 mmol) in DCM (4 mL) was added PyBrop (0.4 g, 0.90 mmol) and Hunig's base (1.9 mL, 11.0 mmol) were added. After 15 minutes, the remaining amine was added to the reaction mixture in DCM (2 mL) and stirred for 12 hours at room temperature. The reaction solution was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 2: 1 to 1: 1) to give the title compound (97 mg, 32% over 2 steps) as a tan foam: LC- MS (ES) m / z = 603 (M + H) ^<+> .

d) 3-Amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide 1,1-dimethyl in MeOH (3 mL) To a solution of ethyl {4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate (0.097 g, 0.16 mmol) was added 6N NaOH. (1.5 mL) was added. After 5 hours at 55 ° C., the reaction mixture was neutralized with 1M aqueous HCl and extracted with DCM. The DCM solution was dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel (DCM / MeOH, 95: 5) to give a tan solid: LC-MS (ES) m / z = 463 (M + H) ⁺ .

The solid material from above was dissolved in MeOH (1 mL) and to this solution was added 1M HCl in dioxane (2 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound (31 mg, 53% over 2 steps) as a green solid: LC-MS (ES) m / z = 363 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.39 (d, J = 6.1 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J = 3.5 Hz, 1H), 7 .71 (d, J = 6.3 Hz, 1H), 7.49-7.39 (m, 5H), 7.36 (bs, 1H), 7.15 (d, J = 1.5 Hz, 1H) , 4.24 (m, 1H), 3.70 (m, 1H), and 3.32 (m, 1H).

Example 22

Preparation of 4-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide 3-({[(1,1-dimethylethyl Example 21 except that 4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylbutanoic acid is used instead of) oxy] carbonyl} amino) -2-phenylpropanoic acid. To give the title compound as a brown solid: LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.38 (d, J = 6. 3 Hz, 1 H), 7.86 (d, J = 1.8 Hz, H), 7.75 (d, J = 3.5 Hz, 1 H), 7.70 (d, J = 6.3 Hz, 1 H), 7.49-7.32 (m, 6H), 7.16 ( = 3.85 Hz, 1 H), 3.90 (dd, J = 7.3, 7.3 Hz, 1 H), 2.98 (m, 1 H), 2.88 (m, 1 H), 2.48 (m , 1H) and 2.20 (m, 1H).

Example 23

Preparation of N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] phenylalaninamide 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) The title compound was obtained as a green solid according to the method of Example 21 except that N-{[(1,1-dimethylethyl) oxy] -carbonyl} phenylalanine was used instead of 2-phenylpropanoic acid: LC -MS (ES) m / z = 363 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.42 (d, J = 6.3 Hz, 1H), 7.94 (d, J = 1 .8 Hz, H), 7.79 (d, J = 3.5 Hz, 1H), 7.74 (d, J = 6.3 Hz, 1H), 7.40-7.32 (m, 6H), 7 .17 (d, J = 3.8 Hz, 1H), 4 34 (dd, J = 7.3, 7.6 Hz, 1H), 3.37 (dd, J = 7.1, 13.9 Hz, 1H) and 3.23 (dd, J = 7.6, 13. 9Hz, 1H).

Example 24

Preparation of 2-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] acetamide 3-({[(1,1-dimethylethyl )] Oxy] carbonyl} amino) -2-phenylpropanoic acid instead of ({[(1,1-dimethylethyl) oxy] -carbonyl} amino)-(phenyl) acetic acid. To give the title compound as a green solid: LC-MS (ES) m / z = 349 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.39 (d, J = 6.3 Hz, 1H), 7.93 (d, J = 1.8 Hz, H), 7.76 (d, J = 3.8 Hz, 1H), 7.73 (d, J = 6.3 Hz, 1H), 7. 66-7.54 (m, 2H), 7.57-7.5 (M, 3H), 7.40 (d, J = 1.8Hz, 1H), 7.16 (d, J = 3.8Hz, 1H), and 5.29 (s, 1H).

Example 25

ジオキサン（９ｍＬ）およびＨ_２Ｏ（１．８ｍＬ）中の２−ブロモ−５−ニトロチオフェン（０．２３ｇ、１．０８ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（０．４０ｇ、４．３３ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．０６ｇ、０．０５６ｍｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．５ｇ、１．２９ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で４時間７０℃に加熱した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、３：１）により精製して、標題化合物（４００ｍｇ、８０％）を褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３８６（Ｍ＋１）^＋。 Preparation of N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] phenylalaninamide a) 4- (5-Nitro-2-thienyl) -1- (phenylsulfonyl) ) -1H-pyrrolo [2,3-b] pyridine

To a solution of 2-bromo-5-nitrothiophene (0.23 g, 1.08 mmol) in dioxane (9 mL) and H ₂ O (1.8 mL) was added K ₂ CO ₃ (0.40 g, 4.33 mmol), Tetrakistriphenylphosphine Pd (0) (0.06 g, 0.056 mmol), and 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) -1H-pyrrolo [2,3-b] pyridine (0.5 g, 1.29 mmol) was added. The reaction mixture was heated to 70 ° C. for 4 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by silica gel (hexane / EtOAc, 3: 1) to give the title compound (400 mg, 80%) as a brown solid: LC-MS (ES) m / z = 386 (M + 1) ⁺ .

ＭｅＯＨ（１７ｍＬ）中の４−（５−ニトロ−２−チエニル）−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．７０ｇ、１．８２ｍｍｏｌ）の溶液に、触媒Ｐｄ（ＯＨ）_２を加えた。反応混合物をＨ_２雰囲気下に置き、１０時間激しく撹拌した。反応溶液をセライトにより濾過し（ＥｔＯＡｃ／ＭｅＯＨ）、減圧下で濃縮して褐色固体を得、これをさらに精製することなく用いた。
ＤＣＭ（５ｍＬ）中の上記からの粗褐色固体（０．１８ｇ、０．５１ｍｍｏｌ）を、３−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−２−フェニルプロパン酸（０．２２ｇ、０．８５ｍｍｏｌ）、ＰｙＢｒｏｐ（０．３９ｇ、０．８５ｍｍｏｌ）およびＨｕｎｉｇ塩基（０．３ｍＬ、１．７ｍｍｏｌ）のＤＣＭ（５ｍＬ）溶液に加えた。室温で１２時間後、反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、１：１）により精製して、標題化合物（７８ｍｇ、６５％）を黄褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６０３（Ｍ＋１）^＋。 b) N-{[(1,1-dimethylethyl) oxy] carbonyl} -N- {5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2 -Thienyl} phenylalaninamide

To a solution of 4- (5-nitro-2-thienyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.70 g, 1.82 mmol) in MeOH (17 mL) was added the catalyst. Pd (OH) ₂ was added. The reaction mixture was placed under H ₂ atmosphere and stirred vigorously for 10 hours. The reaction solution was filtered through celite (EtOAc / MeOH) and concentrated under reduced pressure to give a brown solid which was used without further purification.
The crude brown solid from above (0.18 g, 0.51 mmol) in DCM (5 mL) was converted to 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid (0 .22 g, 0.85 mmol), PyBrop (0.39 g, 0.85 mmol) and Hunig base (0.3 mL, 1.7 mmol) in DCM (5 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel (hexane / EtOAc, 1: 1) to give the title compound (78 mg, 65%) as a tan solid: LC-MS ( ES) m / z = 603 (M + 1) ⁺ .

c) N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] phenylalaninamide N-{[(1,1-dimethylethyl) oxy in MeOH (2 mL) ] Of carbonyl} -N- {5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} phenylalaninamide (0.16 g, 0.27 mmol) To the solution was added 6N NaOH (2 mL). After 0.5 h at 55 ° C., the reaction mixture was neutralized with 1M HCl and extracted with DCM. DCM solution was dried over _Na 2 SO _4, concentrated under reduced pressure, silica gel (DCM / MeOH, 95: 5 ) to afford a tan solid: LC-MS (ES) m / z = 463 (M + H) ⁺ .

The solid material from above was dissolved in MeOH (2 mL) and to this solution was added 1 M HCl in dioxane (1 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound (30 mg, 31% over 2 steps) as a green solid: LC-MS (ES) m / z = 363 (M + H) ⁺ ; ¹ 1 H NMR (d ₄ -MeOH, 400 MHz) δ 8.31 (d, J = 6.6 Hz, 1H), 8.00 (d, J = 4.3 Hz, H), 7.80 (d, J = 6. 3 Hz, 1 H), 7.75 (d, J = 3.5 Hz, 1 H), 7.40-7.32 (m, 5 H), 7.29 (d, J = 3.7 Hz, 1 H), 6. 95 (d, J = 4.3 Hz, 1H), 4.33 (dd, J = 7.3, 7.6 Hz, 1H), 3.36 (dd, J = 7.0, 13.9 Hz, 1H) And 3.23 (dd, J = 7.6, 13.9 Hz, 1H).

Example 26

４−ブロモ−２−チオフェンカルボン酸の代わりに５−ブロモ−２−チオフェンカルボン酸を用いること以外は、実施例１の方法に従って、標題化合物を黄褐色固体として得た；ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝２７９（Ｍ＋Ｈ）^＋。 Preparation of 3-amino-2- (phenylmethyl) -N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide a) 1,1-dimethylethyl (5-Bromo-2-thienyl) carbamate

The title compound was obtained as a tan solid according to the method of Example 1 except that 5-bromo-2-thiophenecarboxylic acid was used instead of 4-bromo-2-thiophenecarboxylic acid; LC-MS (ES) m / z = 279 (M + H) ⁺ .

１，１−ジメチルエチル （４−ブロモ−２−チエニル）カルバメートの代わりに１，１−ジメチルエチル （５−ブロモ−２−チエニル）カルバメートを用いること以外は、実施例２１の方法に従って、標題化合物を黄褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４５６（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl {5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate

The title compound was prepared according to the method of Example 21 except that 1,1-dimethylethyl (5-bromo-2-thienyl) carbamate was used instead of 1,1-dimethylethyl (4-bromo-2-thienyl) carbamate. Was obtained as a tan solid: LC-MS (ES) m / z = 456 (M + H) ⁺ .

塩化メチレン（５ｍＬ）中の１，１−ジメチルエチル ｛５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルバメート（４００ｍｇ、０．８８ｍｍｏｌ）の溶液に、室温でＴＦＡ（３ｍＬ）を加えた。反応物を室温で１時間撹拌し、ついで、減圧下で濃縮して固体を得た。
ＤＣＭ（４ｍＬ）中の３−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−２−（フェニルメチル）プロパン酸（０．５ｇ、１．７６ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（０．８４ｇ、１．７６ｍｍｏｌ）およびＨｕｎｉｇ塩基（３ｍＬ、１７．０ｍｍｏｌ）を加えた。１５分後、残ったアミンを、ＤＣＭ（２ｍＬ）中の反応混合物に加え、室温で１２時間撹拌した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、１：１）により精製して、標題化合物（８０ｍｇ、２工程で１５％）を黄色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６１７（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl [3-oxo-2- (phenylmethyl) -3-({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} amino) propyl] carbamate

1,1-dimethylethyl {5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate (400 mg, 0 in methylene chloride (5 mL) .88 mmol) was added TFA (3 mL) at room temperature. The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give a solid.
To a solution of 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- (phenylmethyl) propanoic acid (0.5 g, 1.76 mmol) in DCM (4 mL) was added PyBrop (0 .84 g, 1.76 mmol) and Hunig base (3 mL, 17.0 mmol) were added. After 15 minutes, the remaining amine was added to the reaction mixture in DCM (2 mL) and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel (hexane / EtOAc, 1: 1) to give the title compound (80 mg, 15% over 2 steps) as a yellow foam: LC-MS (ES) m / Z = 617 (M + H) ⁺ .

d) 3-Amino-2- (phenylmethyl) -N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide 1, in MeOH (2 mL). 1-dimethylethyl [3-oxo-2- (phenylmethyl) -3-({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl } Amino) propyl] carbamate (80 mg, 0.13 mmol) was added 6N NaOH (2 mL). After 0.5 h at 55 ° C., the reaction mixture was neutralized with 1M HCl and extracted with DCM. The DCM solution was dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified on silica gel (DCM / MeOH, 95: 5) to give a tan solid (30 mg): LC-MS (ES) m / z. = 477 (M + H) ^<+> .

The solid material from above was dissolved in MeOH (2 mL) and to this solution was added 1 M HCl in dioxane (1 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound (20 mg, 32% over 2 steps) as a yellow solid: LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.26 (d, J = 6.6 Hz, 1H), 7.94 (d, J = 4.3 Hz, 1H), 7.75 (d, J = 6. 6 Hz, 1 H), 7.70 (d, J = 3.5 Hz, 1 H), 7.31-7.20 (m, 6 H), 6.94 (d, J = 4.0 Hz, 1 H), 3. 40-3.29 (m, 2H), 3.19-3.11 (m, 2H) and 3.01 (dd, J = 7.3, 13.6 Hz, 1H).

Example 27

ｔ−ＢｕＯＨ（２０ｍＬ）中の４，５−ジブロモチオフェンカルボン酸（９．８ｍｍｏｌ、２．８ｇ）の混合物に、ＤＰＰＡ（１２．５ｍｍｏｌ、２．７ｍＬ）およびトリエチルアミン（２９ｍｍｏｌ、４．２ｍＬ）を加えた。混合物をＮ_２雰囲気下で１２時間８５℃に加熱した。室温に冷却した後、反応物を減圧下で濃縮した。フラッシュクロマトグラフィー（シリカゲル、ヘキサン／ＥｔＯＡｃ、１０：１））に付して、標題化合物（２．６ｇ、７４％）を白色固体として得た。ＬＣＭＳ（ＥＳ）ｍ／ｚ３５７（Ｍ＋Ｈ）^＋ Preparation of 3-amino-N- [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -2-phenylpropanamide a) 1,1-dimethyl Ethyl (4,5-dibromo-2-thienyl) carbamate

To a mixture of 4,5-dibromothiophenecarboxylic acid (9.8 mmol, 2.8 g) in t-BuOH (20 mL) was added DPPA (12.5 mmol, 2.7 mL) and triethylamine (29 mmol, 4.2 mL). It was. The mixture was heated to 85 ° C. under N ₂ atmosphere for 12 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. Flash chromatography (silica gel, hexane / EtOAc, 10: 1)) gave the title compound (2.6 g, 74%) as a white solid. LCMS (ES) m / z 357 (M + H) ⁺

ジオキサン（１０ｍＬ）およびＨ_２Ｏ（２ｍＬ）中の１，１−ジメチルエチル （４，５−ジブロモ−２−チエニル）カルバメート（１．３ｇ、３．６４ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（２．０ｇ、１４．５ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．２１０ｇ、０．１８ｍｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１．５４ｇ、４．０ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で４時間７０℃に加熱した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、３：１）により精製して、標題化合物（６００ｍｇ、４０％、８０％変換率）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５３５（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl {4-bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate

To a solution of 1,1-dimethylethyl (4,5-dibromo-2-thienyl) carbamate (1.3 g, 3.64 mmol) in dioxane (10 mL) and H ₂ O (2 mL) was added K ₂ CO ₃ (2 0.0 g, 14.5 mmol), tetrakistriphenylphosphine Pd (0) (0.210 g, 0.18 mmol), and 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (1.54 g, 4.0 mmol) was added. The reaction mixture was heated to 70 ° C. for 4 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by silica gel (hexane / EtOAc, 3: 1) to give the title compound (600 mg, 40%, 80% conversion) as a yellow solid: LC-MS (ES) m / z = 535 (M + H) ⁺ .

塩化メチレン（３ｍＬ）中の１，１−ジメチルエチル ｛４−ブロモ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルバメート（２５０ｍｇ、０．４６ｍｍｏｌ）の溶液に、ＴＦＡ（３ｍＬ）を室温で加えた。反応物を室温で１時間撹拌し、ついで、減圧下で濃縮して固体を得た。 c) 1,1-dimethylethyl [3-({4-bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} amino) -3-Oxo-2-phenylpropyl] carbamate

1,1-dimethylethyl {4-bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate in methylene chloride (3 mL) To a solution of (250 mg, 0.46 mmol) was added TFA (3 mL) at room temperature. The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give a solid.

To a solution of 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid (0.182 g, 0.69 mmol) in DCM (3 mL) was added PyBrop (0.32 g, 0.69 mmol) and Hunig base (3 mL, 17.0 mmol) were added. After 15 minutes, the remaining amine above was added to the reaction mixture in DCM (2 mL) and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel (hexane / EtOAc, 2: 1 to 1: 1) to give the title compound (220 mg, 70% over 2 steps) as a yellow foam: LC-MS (ES) m / z = 681 (M ^<+> ).

d) 3-Amino-N- [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -2-phenylpropanamide 1 in MeOH (3 mL) , 1-Dimethylethyl [3-({4-Bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} amino) -3- To a solution of oxo-2-phenylpropyl] carbamate (0.18 g, 0.26 mmol) was added 6N NaOH (2.5 mL). After 0.5 h at 55 ° C., the reaction mixture was neutralized with 1M HCl and extracted with DCM. The DCM solution was dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel (DCM / MeOH, 95: 5) to give a tan solid (78 mg, 50%): LC-MS (ES ) M / z = 542 (M + H) ⁺ .

The solid material from above was dissolved in MeOH (2 mL) and to this solution was added 4M HCl in dioxane (2.5 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound (61 mg, 96%): LC-MS (ES) m / z = 442 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) [delta] 8.43 (d, J = 6.3 Hz, 1H), 7.90 (d, J = 6.3 Hz, 1H), 7.78 (d, J = 3.5 Hz, 1H), 7.50-7.41 (m, 5H), 7.71 (d, J = 3.5 Hz, 1H), 6.90 (s, 1H), 4.23 (dd, J = 8.8, 5 .6 Hz, 1H) and 3.7-3.59 (m, 2H).

Example 28

ジオキサン（１０ｍＬ）およびＨ_２Ｏ（２ｍＬ）中の２，４−ジブロモチオフェン（０．５７ｇ、２．３５ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（０．８ｇ、５．８ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．１４ｇ、０．１７ｍｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１．０ｇ、２．６ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で４時間７０℃に加熱した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、５：１）により精製して、標題化合物（５２０ｍｇ、５３％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４２０（Ｍ＋Ｈ）^＋。 Preparation of 3-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thienyl] propanamide a) 4- (4-Bromo-2- Thienyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine

To a solution of 2,4-dibromothiophene (0.57 g, 2.35 mmol) in dioxane (10 mL) and H ₂ O (2 mL) was added K ₂ CO ₃ (0.8 g, 5.8 mmol), tetrakistriphenylphosphine. Pd (0) (0.14 g, 0.17 mmol), and 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -Pyrrolo [2,3-b] pyridine (1.0 g, 2.6 mmol) was added. The reaction mixture was heated to 70 ° C. for 4 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by silica gel (hexane / EtOAc, 5: 1) to give the title compound (520 mg, 53%) as a white solid: LC-MS (ES) m / z = 420. (M + H) ⁺ .

ジオキサン（５ｍＬ）中の４−（４−ブロモ−２−チエニル）−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（３００ｍｇ、７．２ｍｍｏｌ），３−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−２−フェニルプロパン酸（３１０ｍｇ、０．４１ｍｍｏｌ）、ＣｕＩ（２ｍｇ、０．０１ｍｍｏｌ）、Ｋ_２ＣＯ_３（３００ｍｇ、２．２ｍｍｏｌ）、Ｎ，Ｎ−ジメチルエチレンジアミン（１３μＬ、０．１３ｍｍｏｌ）の混合物を、シールしたチューブ中、Ｎ_２雰囲気下で１１０℃で１２時間加熱した。室温に冷却した後、懸濁液をＥｔＯＡｃで希釈し、濾過し、濃縮した。粗物質をシリカゲル（ヘキサン／ＥｔＯＡｃ、１：１）により精製して、標題化合物（１３２ｍｇ、３１％）を褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６０３（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl [3-oxo-2-phenyl-3-({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -3- Thienyl} amino) propyl] carbamate

4- (4-Bromo-2-thienyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (300 mg, 7.2 mmol), 3-({[( 1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid (310 mg, 0.41 mmol), CuI (2 mg, 0.01 mmol), K ₂ CO ₃ (300 mg, 2.2 mmol), N, A mixture of N-dimethylethylenediamine (13 μL, 0.13 mmol) was heated in a sealed tube at 110 ° C. for 12 hours under N ₂ atmosphere. After cooling to room temperature, the suspension was diluted with EtOAc, filtered and concentrated. The crude material was purified by silica gel (hexane / EtOAc, 1: 1) to give the title compound (132 mg, 31%) as a brown solid: LC-MS (ES) m / z = 603 (M + H) ⁺ .

c) 3-Amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thienyl] propanamide 1,1-dimethyl in MeOH (3 mL) Ethyl [3-oxo-2-phenyl-3-({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -3-thienyl} amino) propyl] carbamate To a solution of (0.132 g, 0.22 mmol) was added 6N NaOH (2.5 mL). After 0.5 h at 55 ° C., the reaction mixture was neutralized with 1M HCl and extracted with DCM. The DCM solution was dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel (DCM / MeOH, 95: 5) to give a tan solid; LC-MS (ES) m / z = 463 (M + H) ⁺ .
The solid material from above was dissolved in MeOH (2 mL) and to this solution was added 4M HCl in dioxane (2.5 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound as a green solid (90 mg, 94%): LC-MS (ES) m / z = 363) ⁺ ; ¹ H NMR (d _4- MeOH, 400 MHz) δ 8.38 (d, J = 6.3 Hz, 1H), 8.11 (d, J = 1.3 Hz, H), 8.06 (d, J = 1.3 Hz, 1H) , 7.78 (brs, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.52-7.37 (m, 5H), 7.24 (d, J = 3.5 Hz, 1H), 4.21 (dd, J = 8.8 Hz, 1H), and 3.77-3.59 (m, 2H).

Example 29

ＷＯ２００００４４７５３に従って調製した１Ｈ−ピロロ［２，３−ｂ］ピリジン−２−カルボン酸エチル７−オキシド（１．０ｇ、５．０ｍｍｏｌ）およびテトラメチルアンモニウムブロマイド（１．２ｇ、７．５ｍｍｏｌ）を、ＤＭＦ（５０ｍＬ）に加えた。混合物を０℃に冷却し、無水メタンスルホン酸（１．７ｇ、１０ｍｍｏｌ）を滴下した。得られた懸濁液を室温に加温し、６時間撹拌した。混合物を水（１００ｍＬ）に注ぎ、溶液を５０％ＮａＯＨ水溶液で中和した。得られた溶液をＡｃＯＥｔで抽出し、ついで、有機層を水およびブラインで洗浄した。減圧下で濃縮して残渣をＳＣＸカートリッジにより精製して、所望の化合物を淡黄色固体として得た（１．０ｇ、７７％）。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）ｐｐｍ １．３５（ｔ，３Ｈ，Ｊ＝７．１Ｈｚ），４．３６（ｑ，２Ｈ，Ｊ＝７．１Ｈｚ），７．０５（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ），７．４８（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），８．２８（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），１２．９５（ｂｒｓ，１Ｈ）；ＬＣ／ＭＳ：ｍ／ｚ２６９，２７１（Ｍ＋１）＋。 Preparation of ethyl 4- [5-({[2- (dimethylamino) -1-phenylethyl] amino} carbonyl) -2-thienyl] -1H-pyrrolo [2,3-b] pyridine-2-carboxylate a ) Ethyl 4-bromo-1H-pyrrolo [2,3-b] pyridine-2-carboxylate

1H-Pyrrolo [2,3-b] pyridine-2-carboxylate 7-oxide (1.0 g, 5.0 mmol) and tetramethylammonium bromide (1.2 g, 7.5 mmol) prepared according to WO2000044753 were added to DMF. (50 mL). The mixture was cooled to 0 ° C. and methanesulfonic anhydride (1.7 g, 10 mmol) was added dropwise. The resulting suspension was warmed to room temperature and stirred for 6 hours. The mixture was poured into water (100 mL) and the solution was neutralized with 50% aqueous NaOH. The resulting solution was extracted with AcOEt and then the organic layer was washed with water and brine. Concentrated under reduced pressure and the residue was purified by SCX cartridge to give the desired compound as a pale yellow solid (1.0 g, 77%). ¹ H NMR (400 MHz, DMSO-d6) ppm 1.35 (t, 3H, J = 7.1 Hz), 4.36 (q, 2H, J = 7.1 Hz), 7.05 (d, 1H, J = 2.0 Hz), 7.48 (d, 1H, J = 5.1 Hz), 8.28 (d, 1H, J = 5.1 Hz), 12.95 (brs, 1H); LC / MS: m / Z 269, 271 (M + 1) +.

ＤＭＦ（２０ｍＬ）中の４−ブロモ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２−カルボン酸エチル（１．０ｇ、３．９ｍｍｏｌ）、４，４，４’，４’，５，５，５’，５’−オクタメチル−２，２’−ビ−１，３，２−ジオキサボロラン（２．１ｇ、７．８ｍｍｏｌ）、ＫＯＡｃ（１．２ｇ、１１．７ｍｍｏｌ）およびＰｄ（ｄｐｐｆ）Ｃｌ_２（０．３ｇ、０．４ｍｍｏｌ）を、不活性雰囲気下で４８時間９０℃で加熱した。室温に冷却した後、反応をＮＨ_４Ｃｌ水溶液でクエンチした。得られた混合物をＡｃＯＥｔで抽出した。有機層を水、ブラインで洗浄し、硫酸ナトリウムで乾燥した。減圧下で濃縮して、残渣をＹＡＭＡＺＥＮ Ｆａｓｔ Ｆｌｏｗ 液体クロマトグラフィー（シリカゲル、ＥｔＯＡｃ：ヘキサン、１：１）により精製して、所望の生成物を白色固体として得た（０．８ｇ、６８％）。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）ｐｐｍ １．３３−１．３７（ｍ，１５Ｈ），４．３７（ｑ，２Ｈ，Ｊ＝７．１Ｈｚ），７．２９（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ），７．４０（ｄ，１Ｈ，Ｊ＝４．５Ｈｚ），８．４４（ｄ，１Ｈ，Ｊ＝４．３Ｈｚ），１２．５５（ｂｒｓ，１Ｈ）．ＬＣ／ＭＳ：ｍ／ｚ３１５（Ｍ−１）−，３１７（Ｍ＋１）＋ b) 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
-1H-pyrrolo [2,3-b] pyridine-2-carboxylate ethyl

Ethyl 4-bromo-1H-pyrrolo [2,3-b] pyridine-2-carboxylate (1.0 g, 3.9 mmol), 4,4,4 ′, 4 ′, 5,5 in DMF (20 mL) , 5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.1 g, 7.8 mmol), KOAc (1.2 g, 11.7 mmol) and Pd (dppf) Cl ₂ (0.3 g, 0.4 mmol) was heated at 90 ° C. for 48 hours under inert atmosphere. After cooling to room temperature, the reaction was quenched with aqueous NH ₄ Cl. The resulting mixture was extracted with AcOEt. The organic layer was washed with water, brine and dried over sodium sulfate. Concentrated under reduced pressure and the residue was purified by YAMAZEN Fast Flow liquid chromatography (silica gel, EtOAc: hexanes, 1: 1) to give the desired product as a white solid (0.8 g, 68%). ¹ H NMR (400 MHz, DMSO-d6) ppm 1.33-1.37 (m, 15H), 4.37 (q, 2H, J = 7.1 Hz), 7.29 (d, 1H, J = 2) .0Hz), 7.40 (d, 1H, J = 4.5Hz), 8.44 (d, 1H, J = 4.3Hz), 12.55 (brs, 1H). LC / MS: m / z 315 (M−1) −, 317 (M + 1) +

c) Ethyl 4- [5-({[2- (dimethylamino) -1-phenylethyl] amino} carbonyl) -2-thienyl] -1H-pyrrolo [2,3-b] pyridine-2-carboxylate 5 -Bromo-N- [2- (dimethylamino) -1-phenylethyl] -2-thiophenecarboxamide (35.3 mg, 0.1 mmol) and 4- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine-2-carboxylate (31.6 mg, 0.1 mmol) was added to DME (2 mL) and aqueous Na ₂ CO ₃ (2M , 0.2 mL). The resulting solution and Pd (PPh ₃ ) ₄ (11.6 mg, 0.01 mmol) were placed in a microwave vessel. After sealing, the mixture was heated with a Smith Synthesizer at 120 ° C. for 60 minutes. The mixture was filtered and washed with MeOH. After purification by SCX cartridge with capture-and-release, the residue was purified by LC / MS purification to give the desired compound. ¹ H NMR (400 MHz, d6-DMSO) ppm 1.36 (d, 3H, J = 7.1 Hz), 2.23 (s, 6H), 4.38 (q, 2H, J = 7.1 Hz), 5.14-5.22 (m, 1H), 7.25 (dd, 1H, J = 1.3, 7.1 Hz), 7.33-7.37 (m, 2H), 7.42 (s , 2H), 7.48 (s, 1H), 7.50 (d, 1H, J = 5.1 Hz), 7.93 (d, 1H, J = 4.0 Hz), 8.04 (d, 1H) , J = 4.0 Hz), 8.46 (d, 1H, J = 5.1 Hz), 8.92 (d, 1H, J = 8.3 Hz), 12.82 (brs, 1H). LC / MS: m / z 461 (M-1)-, 463 (M + 1) +.

ａ）Ｎ−［２−（ジメチルアミノ）−１−フェニルエチル］−５−｛１−［（４−メチルフェニル）スルホニル］−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル｝−２−チオフェンカルボキサミド

４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２−カルボン酸エチルの代わりに、１−［（４−メチルフェニル）スルホニル］−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（調製例３）を用いること以外は、実施例２９の方法に従って、標題化合物を調製した。 Example 30
Preparation of N- [2- (dimethylamino) -1-phenylethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

a) N- [2- (Dimethylamino) -1-phenylethyl] -5- {1-[(4-methylphenyl) sulfonyl] -1H-pyrrolo [2,3-b] pyridin-4-yl}- 2-thiophenecarboxamide

Instead of ethyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine-2-carboxylate, [(4-Methylphenyl) sulfonyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (Preparation The title compound was prepared according to the method of Example 29 except using Example 3).

b) N- [2- (Dimethylamino) -1-phenylethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide (title compound)
To a solution of the above residue in a mixture of CH ₂ Cl ₂ and MeOH was added 6N NaOH and stirred at room temperature for 3 hours. The reaction was neutralized with 1N aqueous HCl and purified on a capture and release SCX cartridge. Concentrated under reduced pressure and purified by LC / MS to give the desired compound. ¹ H NMR (400 MHz, DMSO-d6) ppm 2.30 (s, 6H), 2.54 (br, 1H), 2.89 (br, 1H), 5.22 (br, 1H), 6.84 −6.85 (m, 1H), 7.24-7.45 (m, 6H), 7.62-7.64 (m, 1H), 7.85 (d, 1H, J = 3.8 Hz) , 8.03 (d, 1H, J = 3.8 Hz), 8.27 (d, 1H, J = 5.1 Hz), 8.92 (d, 1H, J = 7.6 Hz), 11.94 ( s, 1H). LC / MS: m / z 389 (M-1)-, 391 (M + 1) +

ａ）１−［（４−メチルフェニル）スルホニル］−４−（５−ニトロ−２−チエニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン

１−［（４−メチルフェニル）スルホニル］−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（８８０ｍｇ、２．２ｍｍｏｌ）および２−ブロモ−５−ニトロチオフェン（４１６ｍｇ、２ｍｍｏｌ）をＤＭＥ（１０ｍＬ）およびＮａ_２ＣＯ_３水溶液（２Ｍ、２ｍＬ）中に溶解した。得られた溶液およびＰｄ（ＰＰｈ_３）_４（１００ｍｇ、０．０８７ｍｍｏｌ）を、マイクロ波容器に加えた。シールした後、混合物をＣｒｅａｔｏｒで６０分間１２０℃で加熱した。粗物質をＣＨ_２Ｃｌ_２で抽出し、ＮＨ_４Ｃｌ水溶液で洗浄した。溶媒を除去した後、残渣を次の工程に直接用いた。 Example 31
Preparation of 4-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -4-piperidinecarboxamide

a) 1-[(4-Methylphenyl) sulfonyl] -4- (5-nitro-2-thienyl) -1H-pyrrolo [2,3-b] pyridine

1-[(4-Methylphenyl) sulfonyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine was dissolved (880 mg, 2.2 mmol) and 2-bromo-5-nitro-thiophene (416 mg, 2 mmol) and DME (10 mL) and aqueous _Na 2 CO ₃ (2M, 2 mL) in. The resulting solution and Pd (PPh ₃ ) ₄ (100 mg, 0.087 mmol) were added to the microwave vessel. After sealing, the mixture was heated in a creator for 60 minutes at 120 ° C. The crude material was extracted with CH ₂ Cl ₂ and washed with aqueous NH ₄ Cl. After removing the solvent, the residue was used directly in the next step.

b) (5- {1-[(4-Methylphenyl) sulfonyl] -1H-pyrrolo [2,3-b] pyridin-4-yl} -2-thienyl) amine 1-[(in 5 mL) 4-methylphenyl) sulfonyl] -4- (5-nitro-2-thienyl) -1H-pyrrolo [2,3-b] pyridine (52 mg, 0.13 mmol) was added to a catalytic amount of 10% Pd / C. And stirred at room temperature for 3 hours under H ₂ atmosphere (H ₂ balloon). The catalyst was removed by filtration through celite and washed with MeOH. After purification by SCX cartridge by capture-and-release, the corresponding title compound was obtained and used directly without further purification. ¹ H NMR (400 MHz, d6-DMSO) ppm 2.34 (s, 3H), 5.98 (d, 1H, J = 3.8 Hz), 6.36 (s, 2H), 7.06 (d, 1H, J = 4.0 Hz), 7.20 (d, 1H, J = 5.3 Hz), 7.40-7.44 (m, 3H), 7.86 (d, 1H, J = 4.0 Hz) ), 7.9 (d, 2H, J = 8.6 Hz), 8.15 (d, 1H, J = 5.3 Hz); LC / MS: m / z 368 (M−1) −, 370 (M + 1) +

（５−｛１−［（４−メチルフェニル）スルホニル］−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル｝−２−チエニル）アミン（３７ｍｇ、０．１ｍｍｏｌ）、１−｛［（１，１−ジメチルエチル）オキシ］カルボニル｝−４−フェニル−４−ピペラジンカルボン酸（３７ｍｇ、０．１２ｍｍｏｌ）および１−（メチルスルホニル）−１Ｈ−１，２，３−ベンゾトリアゾール（２４ｍｇ、０．１２ｍｍｏｌ）を、無水ＴＨＦ（１ｍＬ）およびＥｔ_３Ｎ（２０ｍｇ、０．２ｍｍｏｌ）中に、マイクロ波容器中で溶解した。混合物を、マイクロ波照射により、１６０℃で１５分間加熱した。溶媒を除去した後、残渣を分取ＬＣ／ＭＳにより精製して、標題化合物を得、収率の計算はしなかった。 c) 4-{[(5- {1-[(4-Methylphenyl) sulfonyl] -1H-pyrrolo [2,3-b] pyridin-4-yl} -2-thienyl) amino] carbonyl} -4- 1,1-dimethylethyl phenyl-1-piperazinecarboxylate

(5- {1-[(4-Methylphenyl) sulfonyl] -1H-pyrrolo [2,3-b] pyridin-4-yl} -2-thienyl) amine (37 mg, 0.1 mmol), 1-{[ (1,1-dimethylethyl) oxy] carbonyl} -4-phenyl-4-piperazinecarboxylic acid (37 mg, 0.12 mmol) and 1- (methylsulfonyl) -1H-1,2,3-benzotriazole (24 mg, 0.12 mmol) was dissolved in anhydrous THF (1 mL) and Et ₃ N (20 mg, 0.2 mmol) in a microwave vessel. The mixture was heated at 160 ° C. for 15 minutes by microwave irradiation. After removal of the solvent, the residue was purified by preparative LC / MS to give the title compound and the yield was not calculated.

d) 4-Phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -4-piperidinecarboxamide The residue was MeOH (3 mL) in a microwave vessel. ) And concentrated HCl (0.5 mL). The mixture was heated at 80 ° C. for 30 minutes by microwave irradiation. After concentration under reduced pressure, the residue was dissolved in MeOH (2 mL) and 6N KOH (0.5 mL). The mixture was heated at 55 ° C. for 12 hours. After removal of the solvent, the residue was purified by preparative LC / MS to give the title compound and the yield was not calculated. ¹ H NMR (400 MHz, DMSO-d6) ppm 1.90-3.17 (m, 8H), 6.78-6.80 (m, 1H), 6.87 (d, 1H, J = 4.0 Hz) ), 7.23 (d, 1H, J = 5.0 Hz), 7.25-7.29 (m, 1H), 7.36-7.43 (m, 4H), 7.51-7.54. (M, 2H), 8.16 (d, 1H, J = 5.0 Hz), 10.84 (br, 1H), 11.75 (s, 1H). LC / MS: m / z 401 (M-1)-, 403 (M + 1) +.

ａ）５−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）−２−チオフェンカルボン酸

１−［（４−メチルフェニル）スルホニル］−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１．２ｇ、３ｍｍｏｌ）、５−ブロモ−２−チオフェンカルボン酸（７４５ｍｇ、３．６ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（３５０ｍｇ、０．３ｍｍｏｌ）、２ＭのＮａ_２ＣＯ_３水溶液（６ｍＬ）およびＤＭＦ（１５ｍＬ）の混合物を、８０℃で１６時間加熱した。冷却した後、反応混合物を濾過チューブ（５．０μｍ細孔経）により濾過し、ＭｅＯＨで洗浄した。６ＮのＮａＯＨ水溶液（１００ｍＬ）を濾液に加え、混合物を５０℃で１〜２時間加熱した。混合物を２ＮのＨＣｌで酸性化し、ＳＣＸにより精製した。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）ｐｐｍ ６．８３−６．８６（ｍ，１Ｈ），７．４３（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），７．６４−７．６７（ｍ，１Ｈ），７．８２（ｄ，１Ｈ，Ｊ＝３．９Ｈｚ），７．８５（ｄ，１Ｈ，Ｊ＝３．９Ｈｚ），８．２８（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），１１．９９（ｂｒ，１Ｈ），１３．３７（ｂｒ，１Ｈ）．ＬＣ／ＭＳ：ｍ／ｚ２４３（Ｍ−１）−，２４５（Ｍ＋１）＋ Example 32
Preparation of N-{[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} tyrosine amide

a) 5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxylic acid

1-[(4-Methylphenyl) sulfonyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (1.2 g, 3 mmol), 5-bromo-2-thiophenecarboxylic acid (745 mg, 3.6 mmol), Pd (PPh ₃ ) ₄ (350 mg, 0.3 mmol), 2M aqueous Na ₂ CO ₃ (6 mL) and A mixture of DMF (15 mL) was heated at 80 ° C. for 16 hours. After cooling, the reaction mixture was filtered through a filter tube (5.0 μm pore size) and washed with MeOH. 6N aqueous NaOH (100 mL) was added to the filtrate and the mixture was heated at 50 ° C. for 1-2 h. The mixture was acidified with 2N HCl and purified by SCX. ¹ H NMR (400 MHz, DMSO-d6) ppm 6.83-6.86 (m, 1H), 7.43 (d, 1H, J = 5.1 Hz), 7.64-7.67 (m, 1H) ), 7.82 (d, 1H, J = 3.9 Hz), 7.85 (d, 1H, J = 3.9 Hz), 8.28 (d, 1H, J = 5.1 Hz), 11.99 (Br, 1H), 13.37 (br, 1H). LC / MS: m / z 243 (M-1)-, 245 (M + 1) +

b) N-{[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} tyrosinamide 5- (1H-pyrrolo [2,3] in DMF (2 mL) -B] To a solution of pyridin-4-yl) -2-thiophenecarboxylic acid (30 mg, 0.12 mmol) was added tyrosine amide (45 mg, 0.25 mmol) and HBTU (76 mg, 0.2 mmol) and the mixture was allowed to come to room temperature. For 16 hours. The mixture was then concentrated under reduced pressure and purified by preparative LC / MS. ¹ H NMR (400 MHz, DMSO-d6) ppm 2.79-2.91 (m, 1H), 2.94-3.05 (m, 1H), 4.49-4.59 (m, 1H), 6.63 (d, 2H, J = 8.6 Hz), 6.83 (d, 1H, J = 3.5 Hz), 7.11 (br, 1H), 7.13 (d, 2H, J = 8) .6 Hz), 7.37 (d, 1 H, J = 5.0 Hz), 7.57 (br, 1 H), 7.62 (d, 1 H, J = 3.5 Hz), 7.80 (d, 1 H) , J = 4.0 Hz), 7.96 (d, 1H, J = 4.0 Hz), 8.25 (d, 1H, J = 5.0 Hz), 8.66 (d, 1H, J = 8. 6 Hz), 9.16 (br, 1H), 11.93 (br, 1H); LC / MS: m / z 405 (M−1) −, 407 (M + 1) +

チロシンアミドの代わりに２−（４−モルホリニル）−１−フェニルエタンアミンを用いること以外は、実施例３２の方法に従って標題化合物を調製した。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）ｐｐｍ ２．４１−２．５９（ｍ，５Ｈ），２．８５（ｄｄ，１Ｈ，Ｊ＝１２．６，９．９Ｈｚ），３．５０−３．６１（ｍ，４Ｈ），５．２０−５．２８（ｍ，１Ｈ），６．８４（ｄ，１Ｈ，Ｊ＝３．３Ｈｚ），７．２３−７．２８（ｍ，１Ｈ），７．３２−７．４０（ｍ，３Ｈ），７．４１−７．４６（ｍ，２Ｈ），７．６１−７．６５（ｍ，１Ｈ），７．８５（ｄ，１Ｈ，Ｊ＝４．０Ｈｚ），８．０２（ｄ，１Ｈ，Ｊ＝４．０Ｈｚ），８．２６（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），８．９０（ｄ，１Ｈ，Ｊ＝８．３Ｈｚ），１１．９３（ｂｒ，１Ｈ）．ＬＣ／ＭＳ：ｍ／ｚ４３１（Ｍ−１）−，４３３（Ｍ＋１）＋ Example 33
Preparation of N- [2- (4-morpholinyl) -1-phenylethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

The title compound was prepared according to the method of Example 32 except using 2- (4-morpholinyl) -1-phenylethanamine instead of tyrosine amide. ¹ H NMR (400 MHz, DMSO-d6) ppm 2.41-2.59 (m, 5H), 2.85 (dd, 1H, J = 12.6, 9.9 Hz), 3.50-3.61 (M, 4H), 5.20-5.28 (m, 1H), 6.84 (d, 1H, J = 3.3 Hz), 7.23-7.28 (m, 1H), 7.32 -7.40 (m, 3H), 7.41-7.46 (m, 2H), 7.61-7.65 (m, 1H), 7.85 (d, 1H, J = 4.0 Hz) , 8.02 (d, 1H, J = 4.0 Hz), 8.26 (d, 1H, J = 5.1 Hz), 8.90 (d, 1H, J = 8.3 Hz), 11.93 ( br, 1H). LC / MS: m / z 431 (M−1) −, 433 (M + 1) +

チロシンアミドの代わりに２−フェニル−２−（１−ピロリジニル）エタナミンを用いること以外は、実施例３２の方法に従って標題化合物を調製した。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）ｐｐｍ １．５９−１．７０（ｍ，４Ｈ），２．３１−２．４１（ｍ，２Ｈ），２．５０−２．５８（ｍ，２Ｈ），３．３８−３．５５（ｍ，２Ｈ），３．７６−３．８６（ｍ，１Ｈ），６．８２（ｄ，１Ｈ，Ｊ＝３．６Ｈｚ），７．２１−７．２７（ｍ，１Ｈ），７．２９−７．３２（ｍ，４Ｈ），７．３５（ｄ，１Ｈ，Ｊ＝４．８Ｈｚ），７．６０−７．６４（ｍ，１Ｈ），７．７１（ｄ，１Ｈ，Ｊ＝４．０Ｈｚ），７．７６（ｄ，１Ｈ，Ｊ＝４．０Ｈｚ），８．２５（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），８．４１（ｔ，１Ｈ，Ｊ＝５．８Ｈｚ），１１．９２（ｂｒ，１Ｈ）．ＬＣ／ＭＳ：ｍ／ｚ４１５（Ｍ−１）−，４１７（Ｍ＋１）＋ Example 34
Preparation of N- [2-phenyl-2- (1-pyrrolidinyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

The title compound was prepared according to the method of Example 32 except that 2-phenyl-2- (1-pyrrolidinyl) ethanamine was used instead of tyrosine amide. ¹ H NMR (400 MHz, DMSO-d6) ppm 1.59-1.70 (m, 4H), 2.31-2.41 (m, 2H), 2.50-2.58 (m, 2H), 3.38-3.55 (m, 2H), 3.76-3.86 (m, 1H), 6.82 (d, 1H, J = 3.6 Hz), 7.21-7.27 (m , 1H), 7.29-7.32 (m, 4H), 7.35 (d, 1H, J = 4.8 Hz), 7.60-7.64 (m, 1H), 7.71 (d , 1H, J = 4.0 Hz), 7.76 (d, 1H, J = 4.0 Hz), 8.25 (d, 1H, J = 5.1 Hz), 8.41 (t, 1H, J = 5.8 Hz), 11.92 (br, 1H). LC / MS: m / z 415 (M−1) −, 417 (M + 1) +

チロシンアミドの代わりに２−（アミノメチル）アニリンを用いること以外は、実施例３２の方法に従って標題化合物を調製した。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）ｐｐｍ ４．３３（ｄ，２Ｈ，Ｊ＝６．１Ｈｚ），５．１５（ｂｒ，２Ｈ），６．５０−６．５６（ｍ，１Ｈ），６．６１−６．６６（ｍ，１Ｈ），６．８５（ｄｄ，１Ｈ，Ｊ＝３．５，１．８Ｈｚ），６．９５−７．０１（ｍ，１Ｈ），７．０３−７．０８（ｍ，１Ｈ），７．３９（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），７．６３（ｄｄ，１Ｈ，Ｊ＝３．５，２．５Ｈｚ），７．８３（ｄ，１Ｈ，Ｊ＝３．８Ｈｚ），７．９１（ｄ，１Ｈ，Ｊ＝４．０Ｈｚ），８．２６（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），９．０７（ｔ，１Ｈ，Ｊ＝６．０Ｈｚ），１１．９４（ｂｒ，１Ｈ）．ＬＣ／ＭＳ：ｍ／ｚ３４７（Ｍ−１）−，３４９（Ｍ＋１）＋ Example 35
Preparation of N-[(2-aminophenyl) methyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

The title compound was prepared according to the method of Example 32 except that 2- (aminomethyl) aniline was used instead of tyrosine amide. ¹ H NMR (400 MHz, DMSO-d6) ppm 4.33 (d, 2H, J = 6.1 Hz), 5.15 (br, 2H), 6.50-6.56 (m, 1H), 6. 61-6.66 (m, 1H), 6.85 (dd, 1H, J = 3.5, 1.8 Hz), 6.95-7.01 (m, 1H), 7.03-7.08 (M, 1H), 7.39 (d, 1H, J = 5.1 Hz), 7.63 (dd, 1H, J = 3.5, 2.5 Hz), 7.83 (d, 1H, J = 3.8 Hz), 7.91 (d, 1 H, J = 4.0 Hz), 8.26 (d, 1 H, J = 5.1 Hz), 9.07 (t, 1 H, J = 6.0 Hz), 11.94 (br, 1H). LC / MS: m / z 347 (M-1)-, 349 (M + 1) +

チロシンアミドの代わりに３−（アミノメチル）アニリンを用いること以外は、実施例３２の方法に従って標題化合物を調製した。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）ｐｐｍ ４．３５（ｄ，２Ｈ，Ｊ＝５．８Ｈｚ），５．０６（ｂｒ，２Ｈ），６．４１−６．４９（ｍ，２Ｈ），６．５１−６．５５（ｍ，１Ｈ），６．８５（ｄｄ，１Ｈ，Ｊ＝３．５，１．８Ｈｚ），６．９７（ｔ，１Ｈ，Ｊ＝７．７Ｈｚ），７．３９（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），７．６３（ｄｄ，１Ｈ，Ｊ＝３．３，２．５Ｈｚ），７．８２（ｄ，１Ｈ，Ｊ＝４．０Ｈｚ），７．９３（ｄ，１Ｈ，Ｊ＝４．０Ｈｚ），８．２６（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），９．０９（ｔ，１Ｈ，Ｊ＝５．９Ｈｚ），１１．９３（ｂｒ，１Ｈ）．ＬＣ／ＭＳ：ｍ／ｚ３４７（Ｍ−１）−，３４９（Ｍ＋１）＋ Example 36
Preparation of N-[(3-aminophenyl) methyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

The title compound was prepared according to the method of Example 32 except that 3- (aminomethyl) aniline was used instead of tyrosine amide. ¹ H NMR (400 MHz, DMSO-d6) ppm 4.35 (d, 2H, J = 5.8 Hz), 5.06 (br, 2H), 6.41-6.49 (m, 2H), 6. 51-6.55 (m, 1H), 6.85 (dd, 1H, J = 3.5, 1.8 Hz), 6.97 (t, 1H, J = 7.7 Hz), 7.39 (d , 1H, J = 5.1 Hz), 7.63 (dd, 1H, J = 3.3, 2.5 Hz), 7.82 (d, 1H, J = 4.0 Hz), 7.93 (d, 1H, J = 4.0 Hz), 8.26 (d, 1H, J = 5.1 Hz), 9.09 (t, 1H, J = 5.9 Hz), 11.93 (br, 1H). LC / MS: m / z 347 (M-1)-, 349 (M + 1) +

チロシンアミドの代わりに１，１−ジメチルエチル （２−アミノエチル）カルバメートを用い、ＴＦＡを用いてＢｏｃ脱保護すること以外は、実施例３２の方法に従って標題化合物を調製した。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）ｐｐｍ ２．８０（ｔ，２Ｈ，Ｊ＝６．４Ｈｚ），３．３４−３．３９（ｍ，２Ｈ），６．８５（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ），７．３９（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），７．６３（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ），７．８２（ｄ，１Ｈ，Ｊ＝４．０Ｈｚ），７．８８（ｄ，１Ｈ，Ｊ＝４．０Ｈｚ），８．２６（ｄ，１Ｈ，Ｊ＝５．１Ｈｚ），８．８２（ｔ，１Ｈ，Ｊ＝５．４Ｈｚ），１１．９４（ｂｒ，１Ｈ）．ＬＣ／ＭＳ：ｍ／ｚ２８５（Ｍ−１）−，２８７（Ｍ＋１）＋ Example 37
Preparation of N- (2-aminoethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

The title compound was prepared according to the method of Example 32 except that 1,1-dimethylethyl (2-aminoethyl) carbamate was used in place of tyrosine amide and Boc deprotected with TFA. ¹ H NMR (400 MHz, DMSO-d6) ppm 2.80 (t, 2H, J = 6.4 Hz), 3.34-3.39 (m, 2H), 6.85 (d, 1H, J = 3) .5 Hz), 7.39 (d, 1 H, J = 5.1 Hz), 7.63 (d, 1 H, J = 3.5 Hz), 7.82 (d, 1 H, J = 4.0 Hz), 7 .88 (d, 1H, J = 4.0 Hz), 8.26 (d, 1H, J = 5.1 Hz), 8.82 (t, 1H, J = 5.4 Hz), 11.94 (br, 1H). LC / MS: m / z 285 (M−1) −, 287 (M + 1) +

Example 38

スクリューキャップでシールしたフラスコ中のジオキサン（２５ｍＬ）およびＨ_２Ｏ（５ｍＬ）中の１，１−ジメチルエチル ｛２−［（｛４−ブロモ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］−２−フェニルエチル｝カルバメート（０．６０ｇ、０．８８ｍｍｏｌ）の溶液に、ピリジン−３−ボロン酸（０．２２ｇ、１．７６ｍｍｏｌ）、Ｋ_２ＣＯ_３（０．３６ｇ、２．６４ｍｍｏｌ）およびＰｄ（ＰＰｈ_３）_４（０．１０ｇ、０．０９ｍｍｏｌ）を加えた。８０℃に１６時間加熱した後、反応溶液を減圧下で濃縮し、シリカ（ＤＣＭ／ＭｅＯＨ；９５：５）で精製して、明黄色固体を得た（０．４０ｇ、６７％）：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６８１（Ｍ＋Ｈ）^＋。 Preparation of N- (2-amino-1-phenylethyl) -4- (3-pyridinyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 1 , 1-dimethylethyl [2-phenyl-2-({[5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -4- (3-pyridinyl)- 2-thienyl] carbonyl} amino) ethyl] carbamate

Dioxane in a sealed flask with a screw cap (25 mL) and _H 2 O (5 mL) solution of 1,1-dimethylethyl {2 - [({4-bromo-5- [1- (phenylsulfonyl)-1H-pyrrolo To a solution of [2,3-b] pyridin-4-yl] -2-thienyl} carbonyl) amino] -2-phenylethyl} carbamate (0.60 g, 0.88 mmol) was added pyridine-3-boronic acid (0 .22 g, 1.76 mmol), K ₂ CO ₃ (0.36 g, 2.64 mmol) and Pd (PPh ₃ ) ₄ (0.10 g, 0.09 mmol) were added. After heating to 80 ° C. for 16 hours, the reaction solution was concentrated under reduced pressure and purified on silica (DCM / MeOH; 95: 5) to give a light yellow solid (0.40 g, 67%): LC- MS (ES) m / z = 681 (M + H) ^<+> .

b) N- (2-Amino-1-phenylethyl) -4- (3-pyridinyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide MeOH (3 mL ) 1,1-dimethylethyl [2-phenyl-2-({[5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -4- (3 To a solution of -pyridinyl) -2-thienyl] carbonyl} amino) ethyl] carbamate (0.40 g, 0.59 mmol) was added 6N NaOH (1 mL). After 1 hour at room temperature, the reaction mixture was neutralized with 1M HCl and extracted with DCM. The DCM solution was dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified on silica (DCM / MeOH; 95: 5) to give a light yellow solid (0.27 g, 85%): LC-MS (ES) m / z = 541 (M + H) ⁺ .

The solid material from above was dissolved in MeOH (2 mL) and to this solution was added 4M HCl in dioxane (3 mL). After 6 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound (quantitative) as a light yellow solid: LC-MS (ES) m / z = 441 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 9.91 (d, J = 9.1 Hz, 1H), 8.87 (s, 1H), 8.78 (m, 2H), 8.48 (brs, 2H), 8.31 (D, J = 5.1 Hz, 1H), 8.20 (m, 1H), 7.86 (m, 1H), 7.53 (m, 2H), 7.40 (m, 2H), 7. 32 (m, 1H), 7.15 (d, J = 5.1 Hz, 1H), 6.21 (m, 1H), 5.39 (m, 1H), 3.48 (m, 2H), and 3.34 (m, 1H).

Example 39

Of N- (2-amino-1-phenylethyl) -4- (1H-pyrazol-4-yl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide The title compound was obtained as a light yellow solid according to the method of Example 38 except that 4-pyrazoleboronic acid (0.34 g, 1.76 mmol) was used in place of the prepared pyridine-3-boronic acid: LC-MS (ES) m / z = 430 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 9.13 (d, J = 9.4 Hz, 1H), 8.29 (d, J = 5.0 Hz, 1H), 8.19 (s, 1H), 8.12 (brs, 2H), 7.4-7.52 (m, 5H), 7.37 (m, 1H), 7.10 (d, J = 5.0 Hz, 1H), 6.19 (s, 1H), 5.35 (M, 1H), and 3.31 (m, 2H).

Example 40

Preparation of N- (2-amino-1-phenylethyl) -4-ethenyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide of pyridine-3-boronic acid The title compound was obtained as a light yellow solid according to the method of Example 38 except that 2,4,6-trivinylcyclotriboroxan-pyridine complex (85 mg, 0.35 mmol) was used instead: LC- MS (ES) m / z = 390 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 9.72 (d, J = 8.1 Hz, 1H), 8.82 (s, 1H), 8. 39 (m, 2H), 7.69 (m, 1H), 7.50 (m, 2H), 7.41 (m, 2H), 7.32 (m, 1H), 7.21 (m, 1H) ), 6.63 (m, 1H), 6.55 (m, 1H) ), 5.95 (d, J = 17.4 Hz, 1H), 5.39 (d, J = 12.0 Hz, 1H), 5.30 (m, 1H), 3.48 (m, 1H), And 3.21 (m, 1H).

Example 41

Preparation of N- (2-amino-1-phenylethyl) -4-cyclopropyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Pyridine-3-boronic acid The title compound was obtained as a light yellow solid according to the method of Example 38, except that cyclopropaneboronic acid (0.13 g, 1.47 mmol) was used instead of LC: MS-ES (ES) m / z = 403 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 9.01 (d, J = 9.0 Hz, 1H), 8.32 (d, J = 5.0 Hz, 1H), 8.12 (brs , 2H), 7.61 (m, 1H), 7.45 (m, 3H), 7.36 (m, 1H), 7.36 (d, J = 5.0 Hz, 1H), 6.57 ( m, 1H), 5.33 (m, 1H), 3.31 ( m, 2H), 1.97 (m, 1H), 1.02 (m, 2H) and 0.79 (m, 2H).

Example 42

Preparation of 3-amino-N- [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylpropanamide 1- (phenylsulfonyl)- 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine instead of 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (0.09 g, 0.35 mmol) was replaced with 5-bromo. The title compound was obtained as a light yellow solid according to the method of Example 7 except that 4,5-dibromo-2-thiophenecarboxylic acid (0.79 g, 2.78 mmol) was used instead of 2-thiophenecarboxylic acid. : LC-MS ^{ES) m / z = 441 (} M + H) +; 1 H NMR (d6-DMSO, 400MHz) δ8.41 (d, J = 4.1Hz, 1H), 8.25 (m, 3H), 7.46 ( m, 1H), 7.38 (m, 3H), 6.82 (s, 1H), 4.30 (m, 1H), 3.69 (m, 1H), 3.51 (m, 1H), And 3.11 (m, 1H).

Example 43

ジオキサン（５０ｍＬ）およびＨ_２Ｏ（８ｍＬ）中の４，５−ジブロモ−２−チオフェンカルボン酸（１．２６ｇ、４．４ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（１．８２ｇ、１３．２ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．５１ｇ、０．４４ｍｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１．７ｇ、４．４ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で８０℃に１２時間加熱した。反応溶液をＨ_２Ｏ（１００ｍＬ）に注ぎ、ＤＣＭで抽出した。有機層を乾燥し（Ｎａ_２ＳＯ_４）、減圧下で濃縮し、シリカゲル（ＤＣＭ中の１％ＭｅＯＨ）で精製して、標題化合物（１．０ｇ，５０％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４６４。 Preparation of N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 4-Bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylic acid

To a solution of 4,5-dibromo-2-thiophenecarboxylic acid (1.26 g, 4.4 mmol) in dioxane (50 mL) and H ₂ O (8 mL) was added K ₂ CO ₃ (1.82 g, 13.2 mmol). , Tetrakistriphenylphosphine Pd (0) (0.51 g, 0.44 mmol), and 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) -1H-pyrrolo [2,3-b] pyridine (1.7 g, 4.4 mmol) was added. The reaction mixture was heated to 80 ° C. for 12 hours in a sealed tube. The reaction solution was poured into H ₂ O (100 mL) and extracted with DCM. The organic layer was dried (Na ₂ SO ₄ ), concentrated under reduced pressure and purified on silica gel (1% MeOH in DCM) to give the title compound (1.0 g, 50%) as a yellow solid: LC -MS (ES) m / z = 464.

ＤＣＭ（５０ｍＬ）中の４−ブロモ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸（０．５１ｇ，１．１ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（０．６４ｇ、１．３８ｍｍｏｌ）、Ｈｕｎｉｇ塩基（０．８ｍＬ、４．６ｍｍｏｌ）および２−［（２Ｓ）−２−アミノ−３−フェニルプロピル］−１Ｈ−イソインドール−１，３（２Ｈ）−ジオン（０．３６ｇ、０．９２ｍｍｏｌ）を加えた。室温で１８時間後、反応溶液を減圧下で濃縮し、シリカゲル（ＤＣＭ／ＭｅＯＨ９５：５）で精製して、標題化合物（０．６０ｇ、７５％）を白色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝７２６（Ｍ＋Ｈ）。 b) 4-Bromo-N-[(1S) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1- (phenylmethyl) ethyl] -5- [ 1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxamide

4-Bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylic acid (0.51 g, 1.1 mmol) in DCM (50 mL) ) Solution of PyBrop (0.64 g, 1.38 mmol), Hunig base (0.8 mL, 4.6 mmol) and 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole- 1,3 (2H) -dione (0.36 g, 0.92 mmol) was added. After 18 hours at room temperature, the reaction solution was concentrated under reduced pressure and purified on silica gel (DCM / MeOH 95: 5) to give the title compound (0.60 g, 75%) as a white foam: LC-MS ( ES) m / z = 726 (M + H).

c) N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 4-Bromo-N-[(1S) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1- (phenylmethyl) ethyl] in MeOH (20 mL) A solution of -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxamide (0.5 g, 0.66 mol) at room temperature with hydrazine ( 0.41 mL, 13.3 mmol) was added. After stirring at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure and used directly in the next reaction.

The residue from above was dissolved in THF (10 mL) and MeOH (10 mL) and 6M NaOH (2 mL) was added. After 1 hour at room temperature, the reaction solution was neutralized with 1M HCl and extracted with DCM. The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification on silica (DCM / MeOH / NH ₄ OH, 94: 5: 1) gave the title compound (120 mg) as a yellow solid: LC-MS (ES) m / z = 455 (M + H) ⁺ ; ¹ 1 H NMR (CD ₃ OD, 400 MHz) δ 8.79 (s, 1H), 8.55 (m, 1H), 7.97 (m, 1H), 7.85 (brs, 1H), 7.65 (m , 2H), 7.31 (m, 3H), 7.26 (m, 1H), 7.00 (m, 1H), 4.61 (m, 1H), 3.24 (m, 2H), and 3.05 (m, 2H).

Example 44

Preparation of N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 2-[(2R) -2-amino-3-phenylpropyl] -1 instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione The title compound was obtained as a light yellow solid according to the method of Example 43 except that 1H-isoindole-1,3 (2H) -dione (0.36 g, 0.92 mmol) was used: LC-MS (ES ) M / z = 455 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.79 (s, 1 H), 8.55 (m, 1 H), 7.97 (m, 1 H), 7. 85 (brs, 1H), 7.65 ( , 2H), 7.31 (m, 3H), 7.26 (m, 1H), 7.00 (m, 1H), 4.61 (m, 1H), 3.24 (m, 2H), and 3.05 (m, 2H).

Example 45

Preparation of N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 4,5- The title compound was obtained as a light yellow solid according to the method of Example 43 except that 5-bromo-2-thiophenecarboxylic acid (0.79 g, 3.8 mmol) was used instead of dibromo-2-thiophenecarboxylic acid. : LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.43 (m, 1H), 8.09 (m, 1H), 7.93 (m , 1H), 7.89 (s, 1H), 7.82 (m, 1H), 7.30 (m, 5H), 7.22 (m, 1H), 4.61 (m, 1H), 3 .24 (m, 2H), and 3.06 (m, 2H).

Example 46

Preparation of N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 2-[( 2S) -2-Amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-[(2R) -2-amino-3-phenylpropyl] -1H-isoindole -1,3 (2H) -dione (0.36 g, 0.92 mmol) was replaced with 5-bromo-2-thiophenecarboxylic acid (0.79 g, 3.2 mmol) instead of 4,5-dibromo-2-thiophenecarboxylic acid. The title compound was obtained as a light yellow solid according to the method of Example 43 except using 8 mmol): LC-MS (ES) m / z = 376 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 M Hz) δ 8.43 (m, 1H), 8.09 (m, 1H), 7.93 (m, 1H), 7.89 (s, 1H), 7.82 (m, 1H), 7.30 (M, 5H), 7.22 (m, 1H), 4.61 (m, 1H), 3.24 (m, 2H), and 3.06 (m, 2H).

Example 47

ジオキサン（６０ｍＬ）およびＨ_２Ｏ（６ｍＬ）中の４−ブロモ−３−ヨウド−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（２．０ｇ、４．３ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（１．７９ｇ、１３．０ｍｍｏｌ）、フェニルボロン酸（０．５３ｇ、４．３３ｍｍｏｌ）およびテトラキストリフェニルホスフィンＰｄ（０）（０．５０ｇ、０．４３ｍｍｏｌ）を加えた。Ｎ_２雰囲気下７５℃で１６時間撹拌した後、反応内容物を減圧下で濃縮し、シリカ（ヘキサン／ＥｔＯＡｃ、２：１）で精製して、標題化合物（１．２ｇ、６７％）を橙色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４１４（Ｍ＋Ｈ）^＋。 Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-phenyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 4- Bromo-3-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine

Solution of dioxane (60 mL) and _H 2 O (6 mL) solution of 4-bromo-3-iodo-1- (phenylsulfonyl)-1H-pyrrolo [2,3-b] pyridine (2.0 g, 4.3 mmol) To was added K ₂ CO ₃ (1.79 g, 13.0 mmol), phenylboronic acid (0.53 g, 4.33 mmol) and tetrakistriphenylphosphine Pd (0) (0.50 g, 0.43 mmol). After stirring at 75 ° C. for 16 hours under N ₂ atmosphere, the reaction contents were concentrated under reduced pressure and purified on silica (hexane / EtOAc, 2: 1) to give the title compound (1.2 g, 67%) as orange. Obtained as a solid: LC-MS (ES) m / z = 414 (M + H) ⁺ .

ＤＭＦ（３ｍＬ）中の１，１−ジメチルエチル （２−｛［（５−ブロモ−２−チエニル）カルボニル］アミノ｝−３−フェニルプロピル）カルバメート（０．８０ｇ、１．８２ｍｍｏｌ）の溶液に、ＫＯＡｃ（０．５４ｇ、５．５ｍｍｏｌ）、ビス（ピノコラート）ジボラン（０．９２ｇ、３．６４ｍｍｏｌ）およびＰｄ（ｄｐｐｆ）Ｃｌ_２（０．１５ｇ、０．１８ｍｍｏｌ）を加えた。反応物を、シールしたチューブ中８０℃で１８時間加熱した。反応溶液を減圧下で濃縮して固体を得、次の反応に直接用いた。 b) 1,1-dimethylethyl [3-phenyl-2-({[5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-thienyl] carbonyl } Amino) propyl] carbamate

To a solution of 1,1-dimethylethyl (2-{[(5-bromo-2-thienyl) carbonyl] amino} -3-phenylpropyl) carbamate (0.80 g, 1.82 mmol) in DMF (3 mL), KOAc (0.54 g, 5.5 mmol), bis (pinocolato) diborane (0.92 g, 3.64 mmol) and Pd (dppf) Cl ₂ (0.15 g, 0.18 mmol) were added. The reaction was heated in a sealed tube at 80 ° C. for 18 hours. The reaction solution was concentrated under reduced pressure to give a solid that was used directly in the next reaction.

ジオキサン（１５ｍＬ）およびＨ_２Ｏ（３ｍＬ）中の４−ブロモ−３−フェニル−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．２２ｇ、０．５３ｍｍｏｌ）の溶液に、１，１−ジメチルエチル ［３−フェニル−２−（｛［５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−２−チエニル］カルボニル｝アミノ）プロピル］カルバメート（０．２５ｇ、０．５３ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（６１ｍｇ、０．０５ｍｍｏｌ）およびＫ_２ＣＯ_３（０．２２ｇ、１．６ｍｍｏｌ）を加えた。Ｎ_２雰囲気下、８０℃で１８時間加熱した後、反応溶液を減圧下で濃縮し、シリカ（ＤＣＭ／ＭｅＯＨ、９５：５）で精製して、標題化合物（０．１０ｇ、２７％）を明黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６９３（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl {3-phenyl-2-[({5- [3-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2 -Thienyl} carbonyl) amino] propyl} carbamate

A solution of 4-bromo-3-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.22 g, 0.53 mmol) in dioxane (15 mL) and H ₂ O (3 mL). And 1,1-dimethylethyl [3-phenyl-2-({[5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-thienyl] carbonyl } Amino) propyl] carbamate (0.25 g, 0.53 mmol), Pd (PPh ₃ ) ₄ (61 mg, 0.05 mmol) and K ₂ CO ₃ (0.22 g, 1.6 mmol) were added. After heating at 80 ° C. under N ₂ atmosphere for 18 hours, the reaction solution was concentrated under reduced pressure and purified on silica (DCM / MeOH, 95: 5) to give the title compound (0.10 g, 27%). as a yellow solid: LC-MS (ES) m / z = 693 (M + H) +.

ＴＨＦ（４ｍＬ）およびＭｅＯＨ（４ｍＬ）中の１，１−ジメチルエチル ｛３−フェニル−２−［（｛５−［３−フェニル−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］プロピル｝カルバメート（１００ｍｇ、０．１４ｍｍｏｌ）の溶液を、６ＮのＮａＯＨ（１ｍＬ）で処理し、室温で２時間撹拌した。ついで、溶液を６ＮのＨＣｌで中和し、ＤＣＭで抽出した。合した有機フラクションを乾燥し（Ｎａ_２ＳＯ_４）、濃縮し、シリカ（ＤＣＭ中５％ＭｅＯＨ）で精製して、標題化合物（４５ｍｇ、５８％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５５３（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl [3-phenyl-2-({[5- (3-phenyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} amino) Propyl]

1,1-dimethylethyl {3-phenyl-2-[({5- [3-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] in THF (4 mL) and MeOH (4 mL) A solution of] pyridin-4-yl] -2-thienyl} carbonyl) amino] propyl} carbamate (100 mg, 0.14 mmol) was treated with 6N NaOH (1 mL) and stirred at room temperature for 2 hours. The solution was then neutralized with 6N HCl and extracted with DCM. The combined organic fractions were dried (Na ₂ SO ₄ ), concentrated and purified on silica (5% MeOH in DCM) to give the title compound (45 mg, 58%) as a yellow solid: LC-MS (ES ) M / z = 553 (M + H) ⁺ .

g) N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-phenyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1- Dimethylethyl [3-phenyl-2-({[5- (3-phenyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} amino) propyl] (45 mg, 0 0.08 mmol) was dissolved in MeOH (3 mL) and treated with 4 M HCl in dioxane (2 mL). After 1 h, the solution was concentrated to give the diHCl salt of the title compound (21 mg) as a yellow solid: LC-MS (ES) m / z = 453 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.35 (d, J = 5.2 Hz, 1H), 7.62 (s, 1H), 7.33 (m, 7H), 7.24 (m, 1H), 7.17 (m, 2H), 7.10 (m, 2H), 6.51 (d, J = 5.0 Hz, 1H), 4.51 (m, 1H), 3.23 (m, 1H), 3.14 (m , 1H) and 3.06 (m, 2H).

Example 48

Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 1,1-dimethylethyl (2 -{[(5-bromo-2-thienyl) carbonyl] amino} -2-phenylethyl) carbamate instead of 1,1-dimethylethyl (2-{[(4-bromo-2-thienyl) carbonyl] amino} -3-phenylpropyl) carbamate (0.30 g, 0.68 mmol) was converted to 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl. ) -1H-pyrrolo [2,3-b] pyridine instead of 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -1H-pyrrolo [2,3-b] pyridine (0.29 g, 0.76 mmol) was used to give the title compound as a light yellow solid according to the method of Example 7: LC-MS (ES ) M / z = 377 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 9.13 (d, J = 7.2 Hz, 1H), 8.51 (d, J = 5.5 Hz, 1H) , 8.32 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.21 (m, 1H), 7.38 (m, 1H), 7.31 ( m, 2H), 7.23 (m, 1H), 4.61 (m, 1H), 3.25 (m, 2H), 3.13 (m, 1H) and 3.05 (m, 1H).

Example 49

ジオキサン（５０ｍＬ）およびＨ_２Ｏ（８ｍＬ）中の１，１−ジメチルエチル （４，５−ジブロモ−２−チエニル）カルバメート（１．０ｇ、２．８ｍｍｏｌ）の溶液に、フラン−３−ボロン酸（０．３１ｇ、２．８ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（３２０ｍｇ、０．２８ｍｍｏｌ）およびＫ_２ＣＯ_３（１．２ｇ、８．４ｍｍｏｌ）を加えた。Ｎ_２雰囲気下、８０℃で１８時間加熱した後、反応溶液を減圧下で濃縮し、シリカ（ＤＣＭ／ＭｅＯＨ、９５：５）で精製して、標題化合物（０．５５ｇ、５７％）を白色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３４５（Ｍ＋Ｈ）^＋。 Preparation of 3-amino-N- [5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenylmethyl) propanamide a) 1,1-Dimethylethyl [4-bromo-5- (3-furanyl) -2-thienyl] carbamate

To a solution of 1,1-dimethylethyl (4,5-dibromo-2-thienyl) carbamate (1.0 g, 2.8 mmol) in dioxane (50 mL) and H ₂ O (8 mL) was added furan-3-boronic acid. (0.31 g, 2.8 mmol), Pd (PPh ₃ ) ₄ (320 mg, 0.28 mmol) and K ₂ CO ₃ (1.2 g, 8.4 mmol) were added. After heating at 80 ° C. for 18 hours under N ₂ atmosphere, the reaction solution was concentrated under reduced pressure and purified on silica (DCM / MeOH, 95: 5) to give the title compound (0.55 g, 57%) as white Obtained as a foam: LC-MS (ES) m / z = 345 (M + H) ⁺ .

ジオキサン（５０ｍＬ）およびＨ_２Ｏ（６ｍＬ）中の１，１−ジメチルエチル ［４−ブロモ−５−（３−フラニル）−２−チエニル］カルバメート（０．５５ｇ、１．６ｍｍｏｌ）の溶液に、１−（フェニルスルホニル）−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．６８ｇ、１．７６ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（１９０ｍｇ、０．１６ｍｍｏｌ）およびＫ_２ＣＯ_３（０．６６ｇ、４．８ｍｍｏｌ）を加えた。Ｎ_２雰囲気下、８０℃で１８時間加熱した後、反応溶液を減圧下で濃縮し、シリカ（ヘキサン／ＥｔＯＡｃ、１：１）で精製して、標題化合物（０．６０ｇ、６３％）を明黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５２２（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl {5- (3-furanyl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} carbamate

To a solution of 1,1-dimethylethyl [4-bromo-5- (3-furanyl) -2-thienyl] carbamate (0.55 g, 1.6 mmol) in dioxane (50 mL) and H ₂ O (6 mL), 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (0.68 g, 1.76 mmol), Pd (PPh ₃ ) ₄ (190 mg, 0.16 mmol) and K ₂ CO ₃ (0.66 g, 4.8 mmol) were added. After heating at 80 ° C. under N ₂ atmosphere for 18 hours, the reaction solution was concentrated under reduced pressure and purified on silica (hexane / EtOAc, 1: 1) to give the title compound (0.60 g, 63%). Obtained as a yellow solid: LC-MS (ES) m / z = 522 (M + H) ⁺ .

ＭｅＯＨ（５ｍＬ）中の１，１−ジメチルエチル ｛５−（３−フラニル）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−２−チエニル｝カルバメート（０．６０ｇ，１．０ｍｍｏｌ）の溶液に、ジオキサン中の４ＭのＨＣｌ（１０ｍＬ）を加えた。室温で６時間撹拌した後、反応溶液を減圧下で濃縮して、褐色固体を得、これを次の工程に直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４２２（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl [3-({5- (3-furanyl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2- Thienyl} amino) -3-oxo-2- (phenylmethyl) propyl] carbamate

1,1-dimethylethyl in MeOH (5 mL) {5- (3-furanyl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2- To a solution of thienyl} carbamate (0.60 g, 1.0 mmol) was added 4M HCl in dioxane (10 mL). After stirring at room temperature for 6 hours, the reaction solution was concentrated under reduced pressure to give a brown solid, which was used directly in the next step: LC-MS (ES) m / z = 422 (M + H) ⁺ .

Amine hydrochloride (1 mmol) from above was dissolved in DCM (50 mL) and to this solution was added PyBrop (0.70 g, 1.5 mmol), (iPr) ₂ NEt (0.87 mL, 5.0 mmol) and 3 -({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- (phenylmethyl) propanoic acid (0.41 g, 1.5 mmol) was added. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure and purified on silica (DCM / MeOH, 97: 3) to give the title compound (0.30 g, 44%) as an off-white solid: LC -MS (ES) m / z = 683 (M + H) ^<+> .

ＴＨＦ／ＭｅＯＨ（１０ｍＬ／１０ｍＬ）中の１，１−ジメチルエチル ［３−（｛５−（３−フラニル）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−２−チエニル｝アミノ）−３−オキソ−２−（フェニルメチル）プロピル］カルバメート（３００ｍｇ、０．４４ｍｍｏｌ）の溶液を、６ＮのＮａＯＨ（１ｍＬ）で処理し、室温で２時間撹拌した。溶液を６ＮのＨＣｌで中和し、ＤＣＭで抽出した。合した有機フラクションを乾燥し（Ｎａ_２ＳＯ_４）、濃縮し、シリカ（ＤＣＭ中５％ＭｅＯＨ）で精製して、標題化合物（２００ｍｇ、８４％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５４３（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl [3-{[5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] amino} -3- Oxo-2- (phenylmethyl) propyl] carbamate

1,1-dimethylethyl [3-({5- (3-furanyl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine in THF / MeOH (10 mL / 10 mL) A solution of -3-yl] -2-thienyl} amino) -3-oxo-2- (phenylmethyl) propyl] carbamate (300 mg, 0.44 mmol) was treated with 6N NaOH (1 mL) and 2 at room temperature. Stir for hours. The solution was neutralized with 6N HCl and extracted with DCM. The combined organic fractions were dried (Na ₂ SO ₄ ), concentrated and purified on silica (5% MeOH in DCM) to give the title compound (200 mg, 84%) as a yellow solid: LC-MS (ES ) M / z = 543 (M + H) ⁺ .

e) 3-Amino-N- [5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenylmethyl) propanamide 1,1-dimethylethyl [3-{[5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] amino} -3-oxo- 2- (Phenylmethyl) propyl] carbamate (200 mg, 0.37 mmol) was dissolved in MeOH (3 mL) and treated with 4M HCl in dioxane (4 mL). The solution was concentrated to give the diHCl salt of the title compound (125 mg) as a light green solid: LC-MS (ES) m / z = 443 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ8 .43 (d, J = 5.6 Hz, 1H), 8.33 (d, J = 6.7 Hz, 1H), 7.74 (s, 1H), 7.53 (m, 1H), 7.49 (M, 1H), 7.43 (m, 1H), 7.31 (m, 4H), 7.27 (m, 1H), 6.85 (s, 1H), 6.26 (m, 1H) 3.38 (m, 1H), 3.24 (m, 1H), 3.13 (m, 2H), and 2.99 (m, 1H).

Example 50

Preparation of 3-amino-2- (phenylmethyl) -N- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide 3-({[(1, 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- (phenylmethyl) propanoic acid (0 instead of 1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid The title compound was obtained as a tan solid according to the method of Example 1 except using .74 g, 2.6 mmol): LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 9.03 (d, J = 8.0 Hz, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.93 (s, 1H), 7.68 (m, 1H), 7.32 (m, 5H), 7 27 (m, 1H), 7.13 (s, 1H), 3.35 (m, 1H), 3.24 (m, 1H), 3.15 (m, 2H) and 2.97 (m, 1H) ).

Example 51

Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide 1,1-dimethylethyl (2 -{[(5-Bromo-2-thienyl) carbonyl] amino} -2-phenylethyl) carbamate instead of 1,1-dimethylethyl (2-{[(5-bromo-2-furanyl) carbonyl] amino} The title compound was obtained as a light yellow solid according to the method of Example 7 except that 3-phenylpropyl) carbamate (0.35 g, 0.83 mmol) was used: LC-MS (ES) m / z = 361 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.77 (d, J = 8.7 Hz, 1H), 8.46 (d, J = 6.3 Hz, 1H), 8.17 (d , = 6.3 Hz, 1H), 7.83 (d, J = 3.5 Hz, 1H), 7.74 (d, J = 3.5 Hz, 1H), 7.66 (m, 1H), 7.58 (M, 1H), 7.43 (m, 1H), 7.32 (m, 6H), 7.23 (m, 1H), 4.69 (m, 1H), 3.31 (m, 2H) , And 3.06 (m, 2H).

Example 52

Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-furancarboxamide 1,1-dimethylethyl (2 -{[(5-bromo-2-thienyl) carbonyl] amino} -2-phenylethyl) carbamate instead of 1,1-dimethylethyl (2-{[(5-bromo-2-furanyl) carbonyl] amino} -3-phenylpropyl) carbamate (0.35 g, 0.83 mmol) was converted to 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl. ) -1H-Pyrrolo [2,3-b] pyridine instead of 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The title compound was obtained as a light yellow solid according to the method of Example 7 except that 1H-pyrrolo [2,3-b] pyridine (0.35 g, 0.91 mmol) was used: LC-MS (ES) m / Z = 361 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 9.16 (d, J = 7.9 Hz, 1H), 8.55 (d, J = 5.4 Hz, 1H), 8 .39 (s, 1H), 7.73 (m, 1H), 7.37 (m, 1H), 7.32 (m, 4H), 7.24 (m, 1H), 7.01 (m, 1H), 4.62 (m, 1H), 3.29 (m, 2H), and 3.07 (m, 2H).

Example 53

N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-furancarboxamide Preparation of 2-{(2S) -2 instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione -Amino-3- [2- (trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (0.104 g, 0.3 mmol) [N-{[(1,1- The title compound was obtained as a yellow solid according to the method of Example 43, except using [dimethylethyl) oxy] carbonyl} -2- (trifluoromethyl) -L-phenylalanine according to Preparation 7. ^{-MS (ES) m / z =} 508 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.48 (brs, 1H), 8.25 (m, 1H), 7.77 (m, 1H ), 7.74 (m, 1H), 7.57 (m, 3H), 7.45 (m, 1H), 7.31 (m, 1H), 4.73 (m, 1H) and 3.22. (M, 4H).

Example 54

Preparation of 3-amino-N- [5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylpropanamide 3- ( {[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- (phenylmethyl) propanoic acid instead of 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- The title compound was obtained as a light yellow solid according to the method of Example 49 except using (phenylmethyl) propanoic acid (0.34 g, 1.3 mmol): LC-MS (ES) m / z = 429 ( M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.33 (m, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.57 (s, 1H), 7.48 (M, 6H), 7.42 (m, H), 7.29 (m, 1H), 6.81 (s, 1H), 6.26 (m, 1H), 4.17 (m, 1H), 3.69 (m, 1H), and 3 .30 (m, 1H).

Example 55

Preparation of N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide 2-[( 2S) -2-Amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-[(2R) -2-amino-3-phenylpropyl] -1H-isoindole -1,3 (2H) -dione (0.45 g, 1.1 mmol), except that 5-bromofuran-2-carboxylic acid was used instead of 4,5-dibromo-2-thiophenecarboxylic acid. 43 gave the title compound as a light yellow solid: LC-MS (ES) m / z = 361 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.37 (d, J = 5 .8Hz, 1 ), 7.89 (d, J = 5.8 Hz, 1H), 7.71 (m, 1H), 7.55 (d, J = 3.7 Hz, 1H), 7.36 (m, 4H), 7.25 (m, 1H), 7.19 (m, 1H), 6.61 (m, 1H), 4.65 (m, 1H), 3.27 (m, 2H), and 3.08 ( m, 2H).

Example 56

Preparation of N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide 4,5- The title compound was obtained as a light yellow solid according to the method of Example 43 except that 5-bromofuran-2-carboxylic acid was used instead of dibromo-2-thiophenecarboxylic acid: LC-MS (ES) m / z = 361 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.37 (d, J = 5.8 Hz, 1H), 7.89 (d, J = 5.8 Hz, 1H), 7.71 (M, 1H), 7.55 (d, J = 3.7 Hz, 1H), 7.36 (m, 4H), 7.25 (m, 1H), 7.19 (m, 1H), 6. 61 (m, 1H), 4.65 (m, 1H), 3.27 (m, 2H), Preliminary 3.08 (m, 2H).

Example 57

Preparation of N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide 2-[(2R) -2-amino-3-phenylpropyl] -1 instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione 1H-isoindole-1,3 (2H) -dione (0.45 g, 1.1 mmol) was replaced with 4,5-dibromofuran-2-carboxylic acid ( The title compound was obtained as a light yellow solid according to the method of Example 43 except using 1.52 g, 5.6 mmol): LC-MS (ES) m / z = 440 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.38 (d, J = 5.8 Hz, 1H), 8.01 (d, J = 5.8 Hz, 1H), 7.67 (m, 1H), 7.39 (s, 1H), 7.36 (m, 4H), 7.25 (m, 1H), 7.08 (m, 1H), 4.62 (m, 1H), 3.25 (m, 2H), and 3.08 ( m, 2H).

Example 58

Preparation of N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide According to the method of Example 43, except that 4,5-dibromofuran-2-carboxylic acid (1.52 g, 5.6 mmol) was used instead of 4,5-dibromo-2-thiophenecarboxylic acid, the title compound was Obtained as a light yellow solid: LC-MS (ES) m / z = 440 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.38 (d, J = 5.8 Hz, 1H), 8. 01 (d, J = 5.8 Hz, 1H), 7.67 (m, 1H), 7.39 (s, 1H), 7.36 (m, 4H), 7.25 (m, 1H), 7 .08 (m, 1H), 4.62 (m, 1H), 3.25 (m 2H), and 3.08 (m, 2H).

Example 59

Preparation of N-[(1S) -2-amino-1-phenylethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1 -Dimethylethyl (2-amino-2-phenylethyl) carbamate instead of 1,1-dimethylethyl [(2S) -2-amino-2-phenylethyl] carbamate (0.60 g, 2.54 mmol) -The title compound was converted to a light yellow solid according to the method of Example 7 except that 4,5-dibromothiophene-2-carboxylic acid (1.08 g, 3.81 mmol) was used instead of bromo-2-thiophenecarboxylic acid. ^{and-obtained: LC-MS (ES) m} / z = 441 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ9.32 (d, J = 8.3Hz, 1H , 8.53 (d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 7.83 (m, 2H), 7.44 (m, 2H), 7.47 (m, 1H) ), 7.39 (m, 1H), 6.98 (m, 1H), 5.48 (m, 1H), 3.62 (m, 1H), and 3.48 (m, 1H).

Example 60

Preparation of N-[(1R) -2-amino-1-phenylethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1 1-Diethylethyl (2-amino-2-phenylethyl) carbamate instead of 1,1-dimethylethyl [(2R) -2-amino-2-phenylethyl] carbamate (0.60 g, 2.54 mmol) -The title compound was converted to a light yellow solid according to the method of Example 7 except that 4,5-dibromothiophene-2-carboxylic acid (1.08 g, 3.81 mmol) was used instead of bromo-2-thiophenecarboxylic acid. ^{and-obtained: LC-MS (ES) m} / z = 440 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ9.32 (d, J = 8.3Hz, 1H , 8.53 (d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 7.83 (m, 2H), 7.44 (m, 2H), 7.47 (m, 1H) ), 7.39 (m, 1H), 6.98 (m, 1H), 5.48 (m, 1H), 3.62 (m, 1H), and 3.48 (m, 1H).

Example 61

Preparation of N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3- furancarboxamide instead of 5-bromo-2-thiophenecarboxylic acid 2-bromofuran-4-carboxylic acid (0.75 g, 3.92 mmol) [J. Org. Chem. 1976, 41, 2350] according to the method of Example 7 to give the title compound as a light yellow solid: LC-MS (ES) m / z = 347 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.65 (s, 1H), 8.43 (d, J = 6.3 Hz, 1H), 8.27 (s, 1H), 7.91 (d, J = 6.3 Hz, 1H), 7.80 (m, 1H), 7.57 (m, 2H), 7.42 (m, 4H), 5.53 (m, 1H), 3.65 (m, 1H), and 3 .48 (m, 1H).

Example 62

Preparation of N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3- furancarboxamide instead of 5-bromo-2-thiophenecarboxylic acid 2-bromofuran-4-carboxylic acid (0.75 g, 3.92 mmol) [J. Org. Chem. 1976, 41, 2350] to 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3- b] 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] instead of pyridine The title compound was obtained as a light yellow solid according to the method of Example 7 except using pyridine (0.39 g, 1.0 mmol): LC-MS (ES) m / z = 347 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 9.12 (d, J = 7.8 Hz, 1H), 8.54 (m, 1H), 8.32 (s, 1H), 8.10 (s, 1H) , 7.72 (m, 1H), 7.57 (m, 1H), .45 (m, 4H), 7.39 (m, 1H), 5.50 (m, 1H), 3.65 (m, 1H), and 3.48 (m, 1H).

Example 63

Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-furancarboxamide 1,1-dimethylethyl (2 -{[(5-Bromo-2-thienyl) carbonyl] amino} -2-phenylethyl) carbamate instead of 1,1-dimethylethyl (2-{[(5-bromo-3-furanyl) carbonyl] amino} The title compound was obtained as a light yellow solid according to the method of Example 7 except that 3-phenylpropyl) carbamate (0.50 g, 1.22 mmol) was used: LC-MS (ES) m / z = 361 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.50 (s, 1H), 8.43 (d, J = 6.3 Hz, 1H), 8.11 (s, 1H), 7. 88 d, J = 6.3 Hz, 1H), 7.80 (m, 1H), 7.36 (m, 2H), 7.22 (m, 1H), 4.62 (m, 1H), 3.61 (M, 1H), 3.25 (m, 1H), and 3.07 (m, 7H).

Example 64

Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-furancarboxamide 1,1-dimethylethyl (2 -{[(5-Bromo-2-thienyl) carbonyl] amino} -2-phenylethyl) carbamate instead of 1,1-dimethylethyl (2-{[(5-bromo-3-furanyl) carbonyl] amino} -3-phenylpropyl) carbamate (0.50 g, 1.22 mmol) was converted to 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl. ) -1H-pyrrolo [2,3-b] pyridine instead of 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The title compound was obtained as a light yellow solid according to the method of Example 7 except that 1H-pyrrolo [2,3-b] pyridine (0.39 g, 1.0 mmol) was used: LC-MS (ES) m / Z = 361 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 9.09 (d, J = 7.7 Hz, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8 .19 (s, 1H), 8.10 (s, 1H), 7.72 (m, 1H), 7.80 (m, 1H), 7.31 (m, 4H), 7.23 (m, 1H), 4.61 (m, 1H), 3.62 (m, 1H), 3.26 (m, 1H) and 3.07 (m, 2H).

Example 65

ＤＣＭ／ＭｅＯＨ（６ｍＬ、１：１）中の５−ブロモ−２−チオフェンカルボアルデヒド（１３１μＬ、１．１ｍｍｏｌ）、１，１−ジメチルエチル （２−アミノ−２−フェニルエチル）カルバメート（２６０ｍｇ、１．１ｍｍｏｌ）［実施例７に従って調製した］およびＮａ_２ＳＯ_４（３１３ｍｇ、２．２ｍｍｏｌ）の溶液を、室温で１２時間撹拌した。溶液を０℃に冷却し、ＮａＢＨ_４（１２５ｍｇ、３．３ｍｍｏｌ）を一度に加えた。３０分後、イミン還元が完了し、溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中１％ＭｅＯＨ）により精製して、標題化合物（５０６ｍｇ、９０％）を褐色油として得た：ＬＣＭＳｍ／ｚ４１２（Ｍ＋Ｈ）^＋。 Preparation of (2-amino-1-phenylethyl) {[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] methyl} amine a) 1,1-dimethylethyl ( 2-{[(5-Bromo-2-thienyl) methyl] amino} -2-phenylethyl) carbamate

5-bromo-2-thiophenecarbaldehyde (131 μL, 1.1 mmol), 1,1-dimethylethyl (2-amino-2-phenylethyl) carbamate (260 mg, 1 mL) in DCM / MeOH (6 mL, 1: 1). 0.1 mmol) [prepared according to Example 7] and Na ₂ SO ₄ (313 mg, 2.2 mmol) were stirred at room temperature for 12 hours. The solution was cooled to 0 ° C. and NaBH ₄ (125 mg, 3.3 mmol) was added in one portion. After 30 minutes, imine reduction was complete and the solution was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1% MeOH in DCM) to give the title compound (506 mg, 90% ) Was obtained as a brown oil: LCMS m / z 412 (M + H) ⁺ .

ジオキサン／Ｈ_２Ｏ（６ｍＬ、５：１）中の１，１−ジメチルエチル （２−｛［（５−ブロモ−２−チエニル）メチル］アミノ｝−２−フェニルエチル）カルバメート（５０６ｍｇ、１．２３ｍｍｏｌ）、１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（５２１ｍｇ、１．４ｍｍｏｌ）［調製例２において調製した］、Ｋ_２ＣＯ_３（６８０ｍｇ、４．９２ｍｍｏｌ）およびＰｄ（ＰＰｈ_３）_４（７１ｍｇ、６１．６μｍｏｌ）の溶液を、シールしたチューブ中に合し、８０℃で２時間撹拌した。ついで、溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中１％ＭｅＯＨ）により精製して、標題化合物（５９３ｍｇ、７４％）を黄色泡沫体として得た：ＬＣＭＳｍ／ｚ５８９（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl {2-phenyl-2-[({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} methyl ) Amino] ethyl} carbamate

1,1-Dimethylethyl (2-{[(5-bromo-2-thienyl) methyl] amino} -2-phenylethyl) carbamate (506 mg, 1.N) in dioxane / H ₂ O (6 mL, 5: 1). 23 mmol), 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (521 mg) 1.4 mmol) [prepared in Preparation Example 2], a solution of K ₂ CO ₃ (680 mg, 4.92 mmol) and Pd (PPh ₃ ) ₄ (71 mg, 61.6 μmol) was combined in a sealed tube. And stirred at 80 ° C. for 2 hours. The solution was then partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1% MeOH in DCM) to give the title compound (593 mg, 74% ) Was obtained as a yellow foam: LCMS m / z 589 (M + H) ⁺ .

c) (2-Amino-1-phenylethyl) {[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] methyl} amine THF-MeOH (9 mL, 1: 1) ) And 6-N NaOH (9 mL) 1,1-dimethylethyl {2-phenyl-2-[({5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-4- Yl] -2-thienyl} methyl) amino] ethyl} carbamate (539 mg, 0.917 mmol) was stirred at room temperature for 2 hours. The solution was then cooled with ice and neutralized with 6N HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly.

1,1-dimethylethyl [2-phenyl-2-({[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] methyl} amino) ethyl] carbamate (from above Of crude material) was dissolved in TFA / MeOH (1: 2, 9 mL) and stirred at room temperature for 30 min. The solution was then concentrated azeotropically with toluene and neutralized with a silica plug (3% MeOH in DCM (1% NH ₄ OH)) to give the title compound as the free base (200 mg, 63% over 2 steps). ).

The free base as a solution in MeOH was then treated with excess HCl in dioxane to give the title compound as the HCl salt: LC-MS (ES) m / z 349 (M + H) ⁺ ; ¹ H NMR ( d6-DMSO, 400 MHz) δ 8.34 (bs, 2H), 8.31 (d, J = 5.3 Hz, 1H), 7.82 (d, J = 2.7 Hz, 1H), 7.71-7 .73 (m, 3H), 7.52-7.68 (m, 3H), 7.42-7.45 (m, 2H), 6.88 (s, 1H), 4.68 (bs, 1H) ), 4.34-4.39 (m, 1H), 4.10-4.14 (m, 1H), 3.73-3.78 (m, 1H), 3.38-3.44 (m) , 1H).

Example 66

１，１−ジメチルエチル ｛２−［（｛４−ブロモ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］−２−フェニルエチル｝カルバメート（２２５ｍｇ、０．３３ｍｍｏｌ）［実施例９で調製］、フェニルボロン酸（４８ｍｇ、０．３９ｍｍｏｌ）、Ｋ_２ＣＯ_３（１８２ｍｇ、１．３２ｍｍｏｌ）およびジオキサン／Ｈ_２Ｏ（３ｍＬ、５：１）中のＰｄ（ＰＰｈ_３）_４（１９ｍｇ、１６．５μｍｏｌ）をシールしたチューブに合し、８０℃で２時間撹拌した。ついで、得られた溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中の１％ＭｅＯＨ）により精製して、標題化合物（１６０ｍｇ、７１％）を褐色泡沫体として得た：ＬＣＭＳｍ／ｚ６８０（Ｍ＋Ｈ）^＋。 Preparation of N- (2-amino-1-phenylethyl) -4-phenyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 1,1-dimethyl Ethyl {2-phenyl-2-[({4-phenyl-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbonyl) amino] Ethyl} carbamate

1,1-dimethylethyl {2-[({4-bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbonyl) amino ] -2-Phenylethyl} carbamate (225 mg, 0.33 mmol) [prepared in Example 9], phenylboronic acid (48 mg, 0.39 mmol), K ₂ CO ₃ (182 mg, 1.32 mmol) and dioxane / H ₂ Pd (PPh ₃ ) ₄ (19 mg, 16.5 μmol) in O (3 mL, 5: 1) was combined into a sealed tube and stirred at 80 ° C. for 2 hours. The resulting solution was then partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1% MeOH in DCM) to give the title compound (160 mg, 71 %) Was obtained as a brown foam: LCMS m / z 680 (M + H) ⁺ .

b) N- (2-Amino-1-phenylethyl) -4-phenyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide THF-MeOH (2 mL, 1 1) and 1,1-dimethylethyl {2-phenyl-2-[({4-phenyl-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3- b] Pyridin-4-yl] -2-thienyl} carbonyl) amino] ethyl} carbamate (160 mg, 0.236 mmol) was stirred at room temperature for 2 hours. The solution was then cooled with ice and neutralized with 6N HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly.

Boc-amine (crude material from above) was dissolved in TFA / MeOH (1: 2, 3 mL) and stirred at room temperature for 30 min. The solution was then azeotroped with toluene, concentrated and neutralized with a silica plug (3% MeOH in DCM (1% NH ₄ OH)) to give the title compound as the free base (50 mg, 48% -2 Process).

The free base as a solution in MeOH was then treated with excess HCl in dioxane to give the title compound as the HCl salt: LC-MS (ES) m / z 440 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 9.49 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 8.26 (bs, 2H), 8.21-8.23 (m, 1H) , 7.43-7.50 (m, 3H), 7.39-7.41 (m, 2H), 7.30-7.35 (m, 1H), 7.25-7.29 (m, 4H), 6.98 (d, J = 5.1 Hz, 1H), 6.18 (dd, J = 3.4, 1.9 Hz, 1H), 5.32-5.38 (m, 1H), 3.37-3.42 (m, 1H), 3.17-3.26 (m, 1H).

Example 67

Preparation of N- (2-amino-1-phenylethyl) -4-methyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Trimethyl instead of phenylboronic acid The title compound was obtained as a yellow solid according to Example 66 except using boroxine (55 μL, 0.396 mmol): LC-MS (ES) m / z 378 (M + H) ⁺ ; ¹ H NMR (d6-DMSO , 400 MHz) δ 9.41 (d, J = 8.2 Hz, 1H), 8.30 (s, 1H), 8.29 (bs, 2H), 8.12 (s, 1H), 7.66 (dd , J = 3.1, 3.1 Hz, 1H), 7.42-7.48 (m, 2H), 7.38-7.40 (m, 2H), 7.31-7.34 (m, 1H), 7.26-7.28 (m, 1H), 6. 0 (s, 1H), 5.30-5.35 (m, 1H), 3.37-3.43 (m, 1H), 3.17-3.23 (m, 1H).

Example 68

Preparation of N- (2-amino-2-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1-dimethylethyl ( 1,1-dimethylethyl (2-amino-1-phenylethyl) carbamate (172 mg, 0.729 mmol) instead of 2-amino-2-phenylethyl) carbamate and 5-bromo-2-thiophenecarboxylic acid The title compound was obtained as a yellow solid according to Example 7 except that 4,5-dibromo-2-thiophenecarboxylic acid (344 mg, 1.20 mmol) was used for: LC-MS (ES) m / z 442 (M + H ^{) +; 1 H NMR (d6} -DMSO, 400MHz) δ9.30 (dd, 5.5,5.5Hz, 1H), 8.80 (bs, H), 8.37 (d, J = 5.1 Hz, 1H), 8.16 (s, 1H), 7.66-7.67 (m, 1H), 7.56-7.58 (m, 2H), 7.38-7.47 (m, 2H), 7.34-7.36 (d, J = 5.1 Hz, 1H), 6.56 (s, 1H), 4.53-4. 57 (m, 1H), 3.80-3.86 (m, 1H), 3.72-3.77 (m, 1H).

Example 69

Preparation of N- (2-amino-2-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1-dimethylethyl (2-amino- The title compound as a yellow solid according to Example 7, except that 1,1-dimethylethyl (2-amino-1-phenylethyl) carbamate (172 mg, 0.729 mmol) was used instead of 2-phenylethyl) carbamate. Obtained: LC-MS (ES) m / z 363 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 9.19 (dd, J = 5.5, 5.5 Hz, 1H), 8.83 ( bs, 2H), 8.35 (d, J = 5.5 Hz, 1H), 8.05 (d, J = 4.0 Hz, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.72 ( d, J = 3.1, 3.1 Hz, 1H), 7.54-7.58 (m, 2H), 7.37-7.46 (m, 3H), 6.97 (s, 1H), 4.56-4.58 (m, 1H), 3.80-3.86 (m, 1H), 3.71-3.76 (m, 1H).

Example 70

１，１−ジメチルエチル （５−ブロモ−２−チエニル）カルバメート（１ｇ、３．５９ｍｍｏｌ）［４−ブロモチオフェン−２−カルボン酸の代わりに５−ブロモチオフェン−２−カルボン酸（５ｇ、２４．１ｍｍｏｌ）を用いること以外は実施例１の方法に従って調製した］、１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１．７ｇ、４．３２ｍｍｏｌ）、Ｋ_２ＣＯ_３（１．９８ｇ、１４．４ｍｍｏｌ）およびジオキサン／Ｈ_２Ｏ（１８ｍＬ、５：１）中のＰｄ（ＰＰｈ_３）_４（２０７ｍｇ、０．１７９ｍｍｏｌ）をシールしたチューブ中に合し、８０℃で２時間撹拌した。ついで、得られた溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中０．５％ＭｅＯＨ）により精製して、標題化合物（１ｇ、６１％）を橙色泡沫体として得た：ＬＣＭＳｍ／ｚ４５７（Ｍ＋Ｈ）^＋。 Preparation of (3-amino-2-phenylpropyl) [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] amine a) 1,1-dimethylethyl {5- [ 1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate

1,1-dimethylethyl (5-bromo-2-thienyl) carbamate (1 g, 3.59 mmol) [5-bromothiophene-2-carboxylic acid instead of 4-bromothiophene-2-carboxylic acid (5 g, 24. Prepared according to the method of Example 1 except using 1 mmol)], 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- pyrrolo [2,3-b] pyridine _{(1.7g, 4.32mmol), K 2} CO 3 (1.98g, 14.4mmol) and dioxane _{/ H 2 O (18mL, 5} : 1) solution of Pd (PPh ₃ ) ₄ (207 mg, 0.179 mmol) was combined in a sealed tube and stirred at 80 ° C. for 2 hours. The resulting solution was then partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 0.5% MeOH in DCM) to give the title compound (1 g, 61%) was obtained as an orange foam: LCMS m / z 457 (M + H) ⁺ .

ｉ）ＤＣＭ（１６４ｍＬ）中の２−フェニル−１，３−プロパンジオール（５ｇ、３２．９ｍｍｏｌ）およびＥｔ_３Ｎ（５．５ｍＬ、３９．５ｍｍｏｌ）の溶液に、０℃で、トシルクロライド（６．３ｇ、３２．９ｍｍｏｌ）およびＤＭＡＰ（４００ｍｇ、３．２９ｍｍｏｌ）を加えた。３０分後、溶液を濃縮し、カラムクロマトグラフィー（シリカ、０．５−ＤＣＭ中２％ＭｅＯＨ）により精製して、３−ヒドロキシ−２−フェニルプロピル ４−メチルベンゼンスルホネート（３．５ｇ、３５％）を白色固体として得た：ＬＣＭＳｍ／ｚ３０７（Ｍ＋Ｈ）^＋。 b) 3- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) -2-phenylpropyl 4-methylbenzenesulfonate

i) Tosyl chloride (6) at 0 ° C. in a solution of 2-phenyl-1,3-propanediol (5 g, 32.9 mmol) and Et ₃ N (5.5 mL, 39.5 mmol) in DCM (164 mL). .3 g, 32.9 mmol) and DMAP (400 mg, 3.29 mmol) were added. After 30 minutes, the solution was concentrated and purified by column chromatography (silica, 2% MeOH in 0.5-DCM) to give 3-hydroxy-2-phenylpropyl 4-methylbenzenesulfonate (3.5 g, 35% ) Was obtained as a white solid: LCMS m / z 307 (M + H) ⁺ .

ii) 3-hydroxy-2-phenylpropyl 4-methylbenzenesulfonate (1.5 g, 4.9 mmol), phthalimide (600 mg, 4.1 mmol), triphenylphosphine (1.6 g, 6. 5 mL) in THF (20 mL). To the 1 mmol) solution, DEAD (965 μL, 6.1 mmol) was added in one portion at room temperature. After 30 minutes, the solution was concentrated and purified by column chromatography (silica, DCM) to give the title compound (1.52 g, 83%) as a white foam: LCMS m / z 436 (M + H) ⁺ .

ＤＭＦ（５ｍＬ）中の１，１−ジメチルエチル ｛５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルバメート（２２８ｍｇ、０．５０ｍｍｏｌ）、３−（１，３−ジオキソ−１，３−ジヒドロ−２Ｈ−イソインドール−２−イル）−２−フェニルプロピル４−メチルベンゼンスルホネート（２４０ｍｇ、０．５５ｍｍｏｌ）およびＣｓ_２ＣＯ_３（３２６ｍｇ、１．０ｍｍｏｌ）を、シールしたチューブで合し、７０℃で撹拌した。１０時間後、溶液を濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中０．５％ＭｅＯＨ）により精製して、標題化合物（２１７ｍｇ、６０％）を黄色泡沫体として得た：ＬＣＭＳｍ／ｚ７１９（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl [3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -2-phenylpropyl] {5- [1- (phenylsulfonyl)- 1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate

1,1-dimethylethyl {5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate (228 mg, 0. 1) in DMF (5 mL). 50 mmol), 3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -2-phenylpropyl 4-methylbenzenesulfonate (240 mg, 0.55 mmol) and Cs ₂ CO ₃ ( 326 mg, 1.0 mmol) were combined in a sealed tube and stirred at 70 ° C. After 10 hours, the solution was concentrated and purified by column chromatography (silica, 0.5% MeOH in DCM) to give the title compound (217 mg, 60%) as a yellow foam: LCMS m / z 719 (M + H) ⁺ .

ＴＨＦ／ＭｅＯＨ（３．６ｍＬ、１：１）中の１，１−ジメチルエチル ［３−（１，３−ジオキソ−１，３−ジヒドロ−２Ｈ−イソインドール−２−イル）−２−フェニルプロピル］｛５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルバメート（２５３ｍｇ、０．３５２ｍｍｏｌ）およびヒドラジン（２１９μＬ、７．０ｍｍｏｌ）を室温で撹拌した。１２時間後、溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回抽出し、合した有機フラクションを乾燥（Ｎａ_２ＳＯ_４）し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中の２％ＭｅＯＨ（１％ＮＨ_４ＯＨ））により精製して、標題化合物（１１０ｍｇ、５３％）を黄色油として得た：ＬＣＭＳｍ／ｚ５８９（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl (3-amino-2-phenylpropyl) {5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} Carbamate

1,1-dimethylethyl [3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -2-phenylpropyl in THF / MeOH (3.6 mL, 1: 1) ] {5- [1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbamate (253 mg, 0.352 mmol) and hydrazine (219 μL, 7.0 mmol) Was stirred at room temperature. After 12 hours, the solution was partitioned between H ₂ O / DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na ₂ SO ₄ ), concentrated and purified by column chromatography (silica, 2% MeOH in DCM (1% NH ₄ OH)). Gave the title compound (110 mg, 53%) as a yellow oil: LCMS m / z 589 (M + H) ⁺ .

e) (3-Amino-2-phenylpropyl) [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] amine THF-MeOH (2 mL, 1: 1) and 6N 1,1-dimethylethyl (3-amino-2-phenylpropyl) {5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] in NaOH (2 mL) -2-thienyl} carbamate (110 mg, 0.187 mmol) was stirred at room temperature for 2 hours. The solution was then cooled with ice and neutralized with 6N HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly.

Boc-amine (crude material from above) was dissolved in TFA / MeOH (1: 2, 3 mL) and stirred at room temperature for 30 min. The solution was then azeotroped with toluene, concentrated and neutralized with a silica plug (2% MeOH in DCM (1% NH ₄ OH)) to give the title compound as the free base (45 mg, 69% -2 Process).

The free base as a solution in MeOH was then treated with excess HCl in dioxane to give the title compound as the HCl salt: LC-MS (ES) m / z 349 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.02 (d, J = 6.7 Hz, 1H), 7.93 (d, J = 4.5 Hz, 1H), 7.53 (d, J = 3.7 Hz, 1H), 7 .35-7.50 (m, 6H), 7.12 (d, J = 3.7 Hz, 1H), 6.28 (d, J = 3.5 Hz, 1H), 3.66-3.71 ( m, 1H), 3.55-3.60 (m, 1H), 3.48-3.50 (m, 2H), 3.37-3.40 (m, 1H).

Example 71

Preparation of 3-amino-3-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide instead of 4-bromothiophenecarboxylic acid 5- Bromothiophenecarboxylic acid (5 g, 24.1 mmol) was converted to 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo. 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo instead of [2,3-b] pyridine [2 , 3-b] pyridine (1.6 g, 4.32 mmol) instead of 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid. (1,1-dimension Ruethyl) oxy] carbonyl} amino) -3-phenylpropanoic acid (226 mg, 0.852 mmol) was used according to Example 1 to give the title compound as a yellow solid: LC-MS (ES) m / z = 363 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.27 (d, J = 6.5 Hz, 1H), 7.97 (d, J = 4.4 Hz, 1H), 7.60 (D, J = 6.4 Hz, 1H), 7.73 (d, J = 3.6 Hz, 1H), 7.45-7.56 (m, 5H), 7.28 (d, J = 3. 7 Hz, 1H), 6.92 (d, J = 3.3 Hz, 1H), 4.91-4.97 (m, 1H), 3.42-3.49 (m, 1H), 3.22- 3.27 (m, 1H).

Example 72

Preparation of 4-amino-3-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide 5-bromo instead of 4-bromothiophenecarboxylic acid Thiophenecarboxylic acid (5 g, 24.1 mmol) was added to 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [ 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2, instead of 2,3-b] pyridine 3-b] pyridine (1.6 g, 4.32 mmol) is replaced with 4-({[([(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid instead of 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid. 1,1-dimethyl Ethyl) oxy] carbonyl} amino) -3-phenylbutanoic acid (238 mg, 0.852 mmol) was used according to Example 1 to give the title compound as a yellow solid: LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 8.29 (d, J = 6.1 Hz, 1H), 8.06 (bs, 2H), 7.88 (d, J = 4) .2 Hz, 1 H), 7.70 (dd, J = 3.0 Hz, 1 H), 7.56 (d, 6.1 Hz, 1 H), 7.35-7.37 (m, 4 H), 7.25 −7.33 (m, 1H), 7.03 (s, 1H), 6.86 (d, J = 4.8 Hz, 1H), 3.54-3.57 (m, 1H), 3.17 -3.22 (m, 1H), 3.03-3.12 (m, 2H), 2.80-2.8 (M, 1H).

Example 73

ジオキサン（９ｍＬ）およびＨ_２Ｏ（１．７ｍＬ）中の４−ブロモ−３−ヨウド−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１ｇ、２．１６ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（１．２ｇ、８．６４ｍｍｏｌ）、フェニルボロン酸（２６３ｍｇ、２．１６ｍｍｏｌ）およびテトラキストリフェニルホスフィンＰｄ（０）（１２５ｍｇ、０．１０８ｍｍｏｌ）を加えた。８０℃で１２時間後、反応物をＨ_２Ｏ／ＤＣＭで分配した。水相をＤＣＭで数回抽出し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、０．ＤＣＭ中５％ＭｅＯＨ）により精製して、標題化合物（４７０ｍｇ、５３％）を黄褐色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４１４（Ｍ＋Ｈ）^＋。 Preparation of N- (2-amino-1-phenylethyl) -4-bromo-5- (3-phenyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 4 -Bromo-3-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine

A solution of 4-bromo-3-iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (1 g, 2.16 mmol) in dioxane (9 mL) and H ₂ O (1.7 mL). To was added K ₂ CO ₃ (1.2 g, 8.64 mmol), phenylboronic acid (263 mg, 2.16 mmol) and tetrakistriphenylphosphine Pd (0) (125 mg, 0.108 mmol). After 12 hours at 80 ° C., the reaction was partitioned with H ₂ O / DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 0. 5% MeOH in DCM) to give the title compound (470 mg, 53%) was obtained as a tan foam: LC-MS (ES) m / z = 414 (M + H) ⁺ .

３−ヨウド−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジンの代わりに４−ブロモ−３−フェニル−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（４７０ｍｇ、１．１４ｍｍｏｌ）を用いること以外は、調製例１に従って、標題化合物を褐色油として得た：ＬＣＭＳ（ＥＳ）ｍ／ｚ＝４６１（Ｍ＋Ｈ）^＋。 b) 3-Phenyl-1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] Pyridine

4-Bromo-3-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] instead of 3-iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine The title compound was obtained as a brown oil according to Preparation 1 except using pyridine (470 mg, 1.14 mmol): LCMS (ES) m / z = 461 (M + H) ⁺ .

ジオキサン（７．１ｍＬ）およびＨ_２Ｏ（１．４ｍＬ）中の３−フェニル−１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（３９２ｍｇ、０．８５２ｍｍｏｌ）の溶液に、１，１−ジメチルエチル （２−｛［（４，５−ジブロモ−２−チエニル）カルボニル］アミノ｝−２−フェニルエチル）カルバメート（４２８ｍｇ、０．８５２ｍｍｏｌ）［実施例１２で調製］、Ｐｄ（ＰＰｈ_３）_４（４９ｍｇ、４２．６μｍｏｌ）およびＫ_２ＣＯ_３（４７０ｍｇ、３．４１ｍｍｏｌ）を加えた。８０℃で４時間後、反応物をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中１％ＭｅＯＨ）により精製して、標題化合物（４８５ｍｇ、７５％）を黄褐色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝７５８（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl {2-[({4-bromo-5- [3-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2 -Thienyl} carbonyl) amino] -2-phenylethyl} carbamate

3-Phenyl-1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- in dioxane (7.1 mL) and H ₂ O (1.4 mL) To a solution of 2-yl) -1H-pyrrolo [2,3-b] pyridine (392 mg, 0.852 mmol) was added 1,1-dimethylethyl (2-{[(4,5-dibromo-2-thienyl) carbonyl. Amino} -2-phenylethyl) carbamate (428 mg, 0.852 mmol) [prepared in Example 12], Pd (PPh ₃ ) ₄ (49 mg, 42.6 μmol) and K ₂ CO ₃ (470 mg, 3.41 mmol) Was added. After 4 hours at 80 ° C., the reaction was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1% MeOH in DCM) to give the title compound (485 mg, 75% ) Was obtained as a tan foam: LC-MS (ES) m / z = 758 (M + H) ⁺ .

d) N- (2-amino-1-phenylethyl) -4-bromo-5- (3-phenyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide THF-MeOH 1,6-Dimethylethyl {2-[({4-Bromo-5- [3-phenyl-1- (phenylsulfonyl)-in 6.5 mL, 1: 1) and 6N NaOH (6.5 mL). 1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbonyl) amino] -2-phenylethyl} carbamate (485 mg, 0.641 mmol) was stirred at room temperature for 2 hours. The solution was then cooled with ice and neutralized with 6N HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly.

Boc-amine (crude material from above) was dissolved in TFA / MeOH (1: 2, 3 mL) and stirred at room temperature for 30 min. The solution was then concentrated azeotropically with toluene and neutralized with a silica plug (3% MeOH in DCM (1% NH ₄ OH)) to give the title compound as the free base (60 mg, 18% -2 Process).

The free base as a solution in MeOH was then treated with excess HCl in dioxane to give the title compound as the HCl salt: LC-MS (ES) m / z 518 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 9.32 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 4.9 Hz, 1H), 8.26 (bs, 2H), 7.92 (s, 1H), 7.72 (d, J = 2.6 Hz, 1H), 7.44-7.46 (m, 4H), 7.34-7.42 (m, 1H), 7.01-7. 11 (m, 5H), 5.23-5.28 (m, 1H), 3.22-3.33 (m, 1H), 3.17-3.21 (m, 1H).

Example 74

Preparation of 4-amino-4-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide 5-bromo instead of 4-bromothiophenecarboxylic acid Thiophenecarboxylic acid (5 g, 24.1 mmol) was added to 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [ 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2, instead of 2,3-b] pyridine 3-b] pyridine (1.6 g, 4.32 mmol) is replaced with 4-({[([(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid 1,1-dimethyl Ethyl) oxy] carbonyl} amino) -4-phenylbutanoic acid (200 mg, 0.747 mmol) was used according to Example 1 to give the title compound as a yellow solid: LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 8.50 (bs, 2H), 8.25 (d, J = 5.6 Hz, 1H), 7.77 (bs, 1H), 7.65 (bs, 1H), 7.42-7.53 (m, 6H), 6.93 (bs, 1H), 6.78 (d, J = 4.1 Hz, 1H), 4.30- 4.35 (m, 1H), 2.28-2.38 (m, 3H), 2.12-2.20 (m, 1H).

Example 75

ＭｅＮＨ_２（ＭｅＯＨ中の２Ｍ溶液、１００ｍＬ）中の２−（フェニルメチル）オキシラン（５ｇ、３６．５ｍｍｏｌ）の溶液を、シールしたチューブ中、２５℃で撹拌した。１２時間後、溶液を濃縮し、直接用いた：ＬＣＭＳ（ＥＳ）ｍ／ｅ１６６（Ｍ＋Ｈ）^＋。 Preparation of 4-bromo-N- [2- (methylamino) -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a ) 1- (Methylamino) -3-phenyl-2-propanol

A solution of 2- (phenylmethyl) oxirane (5 g, 36.5 mmol) in MeNH ₂ (2M solution in MeOH, 100 mL) was stirred at 25 ° C. in a sealed tube. After 12 hours, the solution was concentrated and used directly: LCMS (ES) m / e 166 (M + H) ⁺ .

b) 4-Bromo-N- [2- (methylamino) -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide ( GSK 1347675A)
Instead of 2-amino-1-phenylethanol, 1- (methylamino) -3-phenyl-2-propanol (6.2 g, 36.5 mmol) was replaced with 1- (phenylsulfonyl) -3- (4, 4, Instead of 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine, 1- (phenylsulfonyl) -4- (4,4,5,5) 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (172 mg, 0.407 mmol) instead of 5-bromo-2-thiophenecarboxylic acid The title compound was obtained as a yellow solid according to Example 7, except that 4,5-dibromo-2-thiophenecarboxylic acid (387 mg, 1.35 mmol) was used.

Alternatively, the Boc protecting group was removed using TFA-DCM (1: 2, 0.1 M) at 25 ° C. for 0.5 h. The resulting solution was concentrated using toluene azeotrope and the residue was neutralized with a silica plug (2-10% MeOH in DCM (1% NH ₄ OH)) to give the neutralized compound. The compound in DCM was then treated with excess HCl in diethyl ether to give the diHCl salt of the title compound: LC-MS (ES) m / z = 470 (M + H) ⁺ ; ¹ H NMR (d6 −DMSO, 400 MHz) δ 9.00 (d, J = 8.6 Hz, 1H), 8.71-8.89 (m, 2H), 8.35 (d, J = 5.1 Hz, 1H), 8. 11 (s, 1H), 7.64 (dd, J = 2.0, 2.0 Hz, 1H), 7.28-7.31 (m, 4H), 7.22-7.24 (m, 1H) ), 6.50 (dd, J = 1.8, 3.4 Hz, 1H), 4.45-4.51 (m, 1H), 3.13-3.15 (m, 2H), 2.93. -2.95 (m, 2H), 2.51 (s, 3H).

Example 76

ＮＨ_４ＯＨ（１００ｍＬ）中の２−（フェニルメチル）オキシラン（７．５ｇ、５６．３ｍｍｏｌ）の溶液を、シールしたチューブ中、２５℃で撹拌した。１２時間後、溶液を濃縮し、直接用いた：ＬＣＭＳ（ＥＳ）ｍ／ｅ１５２（Ｍ＋Ｈ）^＋。 Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 1- Amino-3-phenyl-2-propanol

A solution of 2- (phenylmethyl) oxirane (7.5 g, 56.3 mmol) in NH ₄ OH (100 mL) was stirred at 25 ° C. in a sealed tube. After 12 hours, the solution was concentrated and used directly: LCMS (ES) m / e 152 (M + H) ⁺ .

b) N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 2-amino- Instead of 1-phenylethanol, 1-amino-3-phenyl-2-propanol (8.5 g, 56.3 mmol) was replaced with 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl- Instead of 1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine, 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (336 mg, 0.873 mmol) was replaced with 4,5-dibromo-2 instead of 5-bromo-2-thiophenecarboxylic acid. -Chi The title compound was obtained as a yellow solid according to Example 7 except that offenecarboxylic acid (376 mg, 1.32 mmol) was used.

Alternatively, the Boc protecting group was removed using TFA-DCM (1: 2, 0.1 M) at 25 ° C. for 0.5 h. The resulting solution was concentrated using toluene azeotrope, and the residue was neutralized with a silica plug (2-10% MeOH (1% NH ₄ OH) in DCm) to give a neutralized compound. The compound in DCM was then treated with excess HCl in diethyl ether to give the diHCl salt of the title compound: LC-MS (ES) m / z = 456 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.78 (d, J = 8.6 Hz, 1H), 8.54 (d, 6.1 Hz, 1H), 7.95 (s, 1H), 7.85-7.88 ( m, 2H), 7.33-7.37 (m, 3H), 7.24-7.30 (m, 1H), 7.00 (d, J = 3.6 Hz, 1H), 4.56- 4.59 (m, 1H), 3.20-3.27 (m, 2H), 3.03-3.05 (m, 2H).

Example 77

４，５−ジブロモ−３−ヒドロキシ−２−チオフェンカルボン酸メチル（５００ｍｇ、１．５９ｍｍｏｌ）、１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（６１１ｍｇ、０．１．５９ｍｍｏｌ）［調製例２で調製した］、Ｐｄ（ＰＰｈ_３）_４（９２ｍｇ、７９．４μｍｏｌ）およびジオキサン（１３ｍＬ）およびＨ_２Ｏ（２．６ｍＬ）中のＫ_２ＣＯ_３（８７６ｍｇ、６．３５ｍｍｏｌ）を、シールしたチューブ中で合した。８０℃で１２時間後、反応物をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中１％ＭｅＯＨ）により精製して、標題化合物（４２０ｍｇ、５４％）を褐色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４９５（Ｍ＋Ｈ）^＋。 N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophene Preparation of carboxamide a) methyl 4-bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (500 mg, 1.59 mmol), 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (611 mg, 0.1.59 mmol) [prepared in Preparation Example 2], Pd (PPh ₃ ) ₄ (92 mg, 79.4 μmol) And K ₂ CO ₃ (876 mg, 6.35 mmol) in dioxane (13 mL) and H ₂ O (2.6 mL) were combined in a sealed tube. After 12 hours at 80 ° C., the reaction was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1% MeOH in DCM) to give the title compound (420 mg, 54% ) Was obtained as a brown foam: LC-MS (ES) m / z = 495 (M + H) ⁺ .

ＴＨＦ（５ｍＬ）中の４−ブロモ−３−ヒドロキシ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（２６２ｍｇ、０．５３０ｍｍｏｌ）、ＭｅＯＨ（２６μＬ、０．５３０ｍｍｏｌ）、ＰＰｈ_３（２０９ｍｇ、０．７９６ｍｍｏｌ）の溶液に、２５℃で、ＤＥＡＤ（１２５μＬ、０．７９６ｍｍｏｌ）を一度で加えた。３０分後、反応物をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中０．５％ＭｅＯＨ）により精製して、標題化合物（１５５ｍｇ、５８％）を透明な泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５０９（Ｍ＋Ｈ）^＋。 b) Methyl 4-bromo-3- (methyloxy) -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4-bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate (262 mg, in THF (5 mL) 0.530 mmol), MeOH (26 μL, 0.530 mmol), PPh ₃ (209 mg, 0.796 mmol), at 25 ° C., DEAD (125 μL, 0.796 mmol) was added in one portion. After 30 minutes, the reaction was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 0.5% MeOH in DCM) to give the title compound (155 mg, 58%) was obtained as a clear foam: LC-MS (ES) m / z = 509 (M + H) ⁺ .

ｉ）１ＮのＮａＯＨ（３ｍＬ）およびＴＨＦ（３ｍＬ）中の４−ブロモ−３−（メチルオキシ）−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（１５５ｍｇ、０．３０５ｍｍｏｌ）の溶液を、シールしたチューブ中、８０℃で撹拌した。２時間後、溶液を、１ＮのＨＣｌを用いてｐＨ３に酸性化し、ＤＣＭで数回抽出した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３５３（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl [2-({[4-Bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl } Amino) -3-phenylpropyl] carbamate

i) 4-Bromo-3- (methyloxy) -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-4-in in 1N NaOH (3 mL) and THF (3 mL) A solution of methyl yl] -2-thiophenecarboxylate (155 mg, 0.305 mmol) was stirred at 80 ° C. in a sealed tube. After 2 hours, the solution was acidified to pH 3 with 1N HCl and extracted several times with DCM. The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z = 353 (M + H) ⁺ .

ii) Crude acid, 1,1-dimethylethyl (2-amino-3-phenylpropyl) carbamate (85 mg, 0.340 mmol) [prepared in Example 76], diisopropylethylamine (302 μL) in DCM (3.4 mL) PyBrop (206 mg, 0.442 mmol) was added in one portion to a solution of 1.7 mmol). After 12 hours, the reaction was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 2% MeOH in DCM) to give the title compound (199 mg, 92% ) Was obtained as a clear foam: LC-MS (ES) m / z = 586 (M + H) ⁺ .

d) N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophencarboxamide 1,1-dimethylethyl in TFA-DCM (3 mL, 1: 2) [2-({[4-Bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3-b ] A solution of pyridin-4-yl) -2-thienyl] carbonyl} amino) -3-phenylpropyl] carbamate (199 mg, 0.340 mmol) was stirred at 25 ° C. After 30 minutes, the solution was concentrated by azeotroping with toluene and the residue was neutralized with a silica plug (3% MeOH in DCM (1% NH ₄ OH)) to give the free base of the title compound.

The free base as a solution in MeOH was then treated with excess HCl in dioxane to give the title compound as the HCl salt: LC-MS (ES) m / z 486 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 8.34 (d, J = 5.0 Hz, 1H), 8.09 (bs, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.65 (dd, 3.2, 3.2 Hz, 1H), 7.22-7.35 (m, 5H), 6.53 (dd, J = 1.9, 3.5 Hz, 1H), 4.55-4.57 (M, 1H), 3.83 (s, 3H), 3.15-3.18 (m, 1H), 2.99-3.05 (m, 3H).

Example 78

3-[(2-Aminoethyl) oxy] -N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) Preparation of 2-thiophenecarboxamide The title compound was obtained as a yellow solid according to Example 77 except that 1,1-dimethylethyl (2-hydroxyethyl) carbamate (300 mg, 0.607 mmol) was used instead of MeOH. LC: MS (ES) m / z 616 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 8.58 (bs, 2H), 8.37 (d, J = 5.1 Hz, 1H), 8.22-8.24 (m, 2H), 7.68 (dd, J = 3.0, 3.0 Hz, 1H), 7.21-7.35 (m, 6H), 6.58 (dd , J = 1.7,3. Hz, 1H), 4.50-4.56 (m, 1H), 4.41-4.49 (m, 1H), 4.30-4.36 (m, 1H), 3.34-3. 36 (m, 1H), 3.24-3.32 (m, 2H), 2.97-3.17 (m, 3H).

Example 79

ＣＨＣｌ_３（５０ｍＬ）中の１−（２−チエニル）エタノン（５ｇ、３９．６ｍｍｏｌ）の溶液に、０℃で、ＡｌＣｌ_３（１６ｇ、０．１１９）を滴下した。３０分後、ＣＣｌ_４（０．４Ｍ）中のＣｌ_２の溶液を滴下漏斗で滴下した。得られた溶液を１２時間にわたって２５℃に加温し、氷Ｈ_２Ｏ／ＤＣＭ間で分配した。有機フラクションを１ＮのＮａＯＨで洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ヘキサン中０．５ＥｔＯＡｃ）により精製して、標題化合物（２．３ｇ、３６％）を黄色油として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝１６１（Ｍ＋Ｈ）^＋。 Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -4-chloro-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 1- (4-Chloro-2-thienyl) ethanone

To a solution of 1- (2-thienyl) ethanone (5 g, 39.6 mmol) in CHCl ₃ (50 mL) at 0 ° C., AlCl ₃ (16 g, 0.119) was added dropwise. After 30 minutes, a solution of Cl ₂ in CCl ₄ (0.4M) was added dropwise with a dropping funnel. The resulting solution was warmed to 25 ° C. over 12 hours and partitioned between ice H ₂ O / DCM. The organic fraction was washed with 1N NaOH, dried over Na ₂ SO ₄ , concentrated, and purified by column chromatography (silica, 0.5 EtOAc in hexanes) to give the title compound (2.3 g, 36%) as yellow Obtained as an oil: LC-MS (ES) m / z = 161 (M + H) ⁺ .

ＣＨＣｌ_３（２９ｍＬ）中の１−（４−クロロ−２−チエニル）エタノン（２．３ｇ、１４．０ｍｍｏｌ）の溶液に、ＡｌＣｌ_３（５．５ｇ、４１．０ｍｍｏｌ）を滴下した。１０分後、ＣＨＣｌ_３（１０ｍＬ）中のＢｒ_２（１ｍＬ、２０．１ｍｍｏｌ）の溶液を滴下漏斗により滴下し、溶液を２時間還流し、２５℃に冷却し、さらに１２時間撹拌した。得られた溶液を氷Ｈ_２Ｏ／ＤＣＭ間で分配した。有機フラクションを１ＮのＮａＯＨで洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝２３９（Ｍ＋Ｈ）^＋。 b) 1- (5-Bromo-4-chloro-2-thienyl) ethanone

To a solution of 1- (4-chloro-2-thienyl) ethanone (2.3 g, 14.0 mmol) in CHCl ₃ (29 mL) was added dropwise AlCl ₃ (5.5 g, 41.0 mmol). After 10 minutes, a solution of Br ₂ (1 mL, 20.1 mmol) in CHCl ₃ (10 mL) was added dropwise via a dropping funnel and the solution was refluxed for 2 hours, cooled to 25 ° C. and stirred for an additional 12 hours. The resulting solution was partitioned between ice H ₂ O / DCM. The organic fraction was washed with 1N NaOH, dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z = 239 (M + H) ⁺ .

１ＮのＮａＯＨ（２００ｍＬ）中の（５−ブロモ−４−クロロ−２−チエニル）エタノン（３．４ｇ、１４．３ｍｍｏｌ）の溶液に、Ｂｒ_２（２．４ｍＬ、４７．１ｍｍｏｌ）を０℃で滴下した。１２時間後、塩基性溶液をＤＣＭで抽出した。水相をｐＨ１に調節し、ＤＣＭで数回抽出した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮して、標題化合物（１．５ｇ、４４％）を白色粉末として得た。 c) 5-Bromo-4-chloro-2-thiophenecarboxylic acid

To a solution of (5-bromo-4-chloro-2-thienyl) ethanone (3.4 g, 14.3 mmol) in 1N NaOH (200 mL) was added Br ₂ (2.4 mL, 47.1 mmol) at 0 ° C. It was dripped. After 12 hours, the basic solution was extracted with DCM. The aqueous phase was adjusted to pH 1 and extracted several times with DCM. The combined organic fractions were dried over Na ₂ SO ₄ and concentrated to give the title compound (1.5 g, 44%) as a white powder.

d) N- [2-amino-1- (phenylmethyl) ethyl] -4-chloro-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 2-amino- 1-Amino-3-phenyl-2-propanol (394 mg, 1.65 mmol) [prepared in Example 76] instead of 1-phenylethanol was replaced with 1- (phenylsulfonyl) -3- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine instead of 1- (phenylsulfonyl) -4- (4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (450 mg, 1.17 mmol) instead of 5-bromo-2-thiophenecarboxylic acid The title compound was obtained as a yellow solid according to Example 7 except that 5-bromo-4-chloro-2-thiophenecarboxylic acid (394 mg, 1.64 mmol) was used.

Alternatively, the Boc protecting group was removed using TFA-DCM (1: 2, 0.1 M) at 25 ° C. for 0.5 h. The resulting solution was concentrated using toluene azeotrope and the residue was neutralized with a silica plug (2-10% MeOH in DCM (1% NH ₄ OH)) to give a neutralized compound. The compound in DCM was then treated with excess HCl in diethyl ether to give the diHCl salt of the title compound: LC-MS (ES) m / z = 411 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 9.03 (d, J = 8.5 Hz, 1H), 8.36 (d, J = 5.1 Hz, 1H), 8.13 (bs, 2H), 7.66 (dd, 3.2, 3.2 Hz, 1H), 7.29-7.36 (m, 5H), 7.20-7.28 (m, 1H), 6.56 (dd, J = 1.8, 3 .4 Hz, 1H), 4.39-4.40 (m, 1H), 3.01-3.09 (m, 2H), 2.93-2.99 (m, 2H).

Example 80

Preparation of N- (2-aminoethyl) -4-bromo-N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1- Instead of dimethylethyl (2-amino-2-phenylethyl) carbamate, 1,1-dimethylethyl {2-[(phenylmethyl) amino] ethyl} carbamate-HCl (300 mg, 1.05 mmol) was replaced with 1- (phenyl 1- (phenylsulfonyl) instead of sulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (468 mg, 1.22 mm l) was prepared according to Example 7 except that 4,5-dibromo-2-thiophenecarboxylic acid (495 mg, 1.73 mmol) was used instead of 5-bromo-2-thiophenecarboxylic acid. Got as.

Alternatively, the Boc protecting group was removed using TFA-DCM (1: 2, 0.1 M) at 25 ° C. for 0.5 h. The resulting solution was concentrated using toluene azeotrope and the residue was neutralized with a silica plug (2-10% MeOH in DCM (1% NH ₄ OH)) to give the neutralized compound. The compound in DCM was then treated with excess HCl in diethyl ether to give the diHCl salt of the title compound: LC-MS (ES) m / z = 411 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 8.38 (d, J = 5.0 Hz, 1H), 8.24 (bs, 1H), 7.67 (s, 1H), 7.32-7.44 (m, 7H) 6.56 (bs, 1H), 4.93 (bs, 2H), 3.65-3.69 (m, 2H), 3.09-3.11 (m, 2H).

Example 81

Preparation of N- (2-aminoethyl) -4-bromo-N-phenyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1-dimethylethyl ( Instead of 2-amino-2-phenylethyl) carbamate, 1,1-dimethylethyl [2- (phenylamino) ethyl] carbamate (300 mg, 1.27 mmol) was replaced with 1- (phenylsulfonyl) -3- (4 Instead of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine, 1- (phenylsulfonyl) -4- (4,4,4) 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (587 mg, 1.52 mmol) was added to 5-bromo-2-thio Fen 4,5-dibromo-2-thiophenecarboxylic acid in place of the carboxylic acid (600 mg, 2.1 mmol) except using, according to Example 7 to give the title compound as a yellow solid.

Alternatively, the Boc protecting group TFA-DCM (1: 2, 0.1 M) was removed using 25 hours at 25 ° C. The resulting solution was concentrated using toluene azeotrope and the residue was neutralized with a silica plug (2-10% MeOH in DCM (1% NH ₄ OH)) to give the neutralized compound. The compound in DCM was then treated with excess HCl in diethyl ether to give the diHCl salt of the title compound: LC-MS (ES) m / z = 411 (M + H) ⁺ ; ¹ H NMR (d6 −DMSO, 400 MHz) δ 8.30 (d, J = 5.1 Hz, 1H), 8.09 (bs, 1H), 7.55-7.63 (m, 6H), 7.21 (d, J = 5.1 Hz, 1H), 6.51 (s, 1H), 6.35 (dd, J = 1.8, 3.4 Hz, 1H), 4.05-4.09 (m, 2H), 3. 02-3.04 (m, 2H).

Example 82

ジオキサン（１２ｍＬ）およびＨ_２Ｏ（２．３ｍＬ）中の４，５−ジブロモ−３−フルオロ−２−チオフェンカルボン酸メチル（４５４ｍｇ、１．４３ｍｍｏｌ）［Ｋｉｒｙａｎｏｖ，Ａ．Ａ．ら、ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．２００１，４２，５０，８７９７に従って調製した］、１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（６０７ｍｇ、０．１．５８ｍｍｏｌ）［調製例２で調製した］、Ｐｄ（ＰＰｈ_３）_４（８３ｍｇ、７１．６μｍｏｌ）およびＫ_２ＣＯ_３（７９０ｍｇ、５．７３ｍｍｏｌ）をシールしたチューブ中で合した。８０℃で１２時間後、反応物をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、０．ＤＣＭ中５％ＭｅＯＨ）により精製して、標題化合物（２６０ｍｇ、３７％）を褐色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４９５（Ｍ＋Ｈ）^＋。 Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-3-fluoro-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) Methyl 4-bromo-3-fluoro-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4,5-dibromo-3-fluoro-2-thiophenecarboxylate (454 mg, 1.43 mmol) in dioxane (12 mL) and H ₂ O (2.3 mL) [Kyryanov, A. et al. A. Et al., Tetrahedron Lett. 2001, 42, 50, 8797], 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [ 2,3-b] pyridine (607 mg, 0.1.58 mmol) [prepared in Preparation Example 2], Pd (PPh ₃ ) ₄ (83 mg, 71.6 μmol) and K ₂ CO ₃ (790 mg, 5.73 mmol) Were combined in a sealed tube. After 12 hours at 80 ° C., the reaction was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 0. 5% MeOH in DCM) to give the title compound (260 mg, 37%) was obtained as a brown foam: LC-MS (ES) m / z = 495 (M + H) ⁺ .

ｉ）１ＮのＮａＯＨ（５ｍＬ）およびＴＨＦ（５ｍＬ）中の４−ブロモ−３−フルオロ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（２６０ｍｇ、０．５２６ｍｍｏｌ）の溶液を、シールしたチューブ中、８０℃で撹拌した。２時間後、溶液を、１ＮのＨＣｌを用いてｐＨ３に酸性化し、ついで、ＤＣＭで数回抽出した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３４２（Ｍ＋Ｈ）^＋。 b) 1,1-Dimethylethyl [2-({[4-Bromo-3-fluoro-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} amino) -3-Phenylpropyl] carbamate

i) 4-Bromo-3-fluoro-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl]-in 1N NaOH (5 mL) and THF (5 mL) A solution of methyl 2-thiophenecarboxylate (260 mg, 0.526 mmol) was stirred at 80 ° C. in a sealed tube. After 2 hours, the solution was acidified to pH 3 with 1N HCl and then extracted several times with DCM. The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z = 342 (M + H) ⁺ .

ii) Crude acid in DCM (5 mL), 1,1-dimethylethyl (2-amino-3-phenylpropyl) carbamate (132 mg, 0.528 mmol) [prepared in Example 76], diisopropylethylamine (469 μL, 2 PyBrop (320 mg, 0.686 mmol) was added in one portion to a solution of .64 mmol). After 12 hours, the reaction was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1% MeOH in DCM) to give the title compound (100 mg, 33% ) Was obtained as a yellow solid: LC-MS (ES) m / z = 574 (M + H) ⁺ .

c) N- [2-Amino-1- (phenylmethyl) ethyl] -4-bromo-3-fluoro-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1-Dimethylethyl [2-({[4-Bromo-3-fluoro-5- (1H-pyrrolo [2,3-b] pyridin-4-yl] in TFA-DCM (3 mL, 1: 2) A solution of) -2-thienyl] carbonyl} amino) -3-phenylpropyl] carbamate (100 mg, 0.175 mmol) was stirred at 25 ° C. After 30 minutes, the solution was concentrated by azeotroping with toluene and the residue was neutralized with a silica plug (3% MeOH in DCM (1% NH ₄ OH)) to give the free base of the title compound.

The free base as a solution in MeOH was then treated with excess HCl in dioxane to give the title compound as the HCl salt: LC-MS (ES) m / z 474 (M + H) ⁺ ; ¹ H NMR (d6- DMSO, 400 MHz) δ 8.36 (d, J = 5.0 Hz, 1H), 8.15-8.18 (m, 1H), 8.02 (bs, 2H), 7.67 (dd, J = 3 .1, 3.1 Hz, 1H), 7.23-7.32 (m, 5H), 6.54 (dd, J = 1.9, 3.5 Hz, 1H), 4.49-4.51 ( m, 1H), 3.15-3.17 (m, 2H), 2.91-2.96 (m, 2H).

Example 83

ｉＰｒＮＨ_２（１５ｍＬ）中の２−（フェニルメチル）オキシラン（７．５ｇ、５６．３ｍｍｏｌ）の溶液を、シールしたチューブ中、２５℃で１２時間撹拌した。得られた溶液を濃縮し、ＴＨＦ（１００ｍＬ）中に再び溶解し、Ｂｏｃ_２Ｏ（８．９５ｇ、４１．０４ｍｍｏｌ）を一度に加えた。さらに３０分後、溶液を濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中１％ＭｅＯＨ）により精製して、標題化合物（１０ｇ、９１％）を透明油として得た：ＬＣＭＳ（ＥＳ）ｍ／ｅ２９４（Ｍ＋Ｈ）^＋。 4-Bromo-N- [2-[(1-methylethyl) amino] -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Preparation of thiophene carboxamide a) 1,1-dimethylethyl (2-hydroxy-3-phenylpropyl) (1-methylethyl) carbamate

A solution of 2- (phenylmethyl) oxirane (7.5 g, 56.3 mmol) in iPrNH ₂ (15 mL) was stirred at 25 ° C. for 12 hours in a sealed tube. The resulting solution was concentrated, redissolved in THF (100 mL) and Boc ₂ O (8.95 g, 41.04 mmol) was added in one portion. After an additional 30 minutes, the solution was concentrated and purified by column chromatography (silica, 1% MeOH in DCM) to give the title compound (10 g, 91%) as a clear oil: LCMS (ES) m / e 294 ( M + H) ⁺ .

ＤＣＭ（３８ｍＬ）中の１，１−ジメチルエチル （２−ヒドロキシ−３−フェニルプロピル）（１−メチルエチル）カルバメート（１．１ｇ、３．７５ｍｍｏｌ）の溶液に、２５℃で、ＰＣＣ（８９０ｍｇ、４．１３ｍｍｏｌ）を加えた。１２時間後、溶液をセライト（登録商標）により濾過し、濃縮した。残渣を、シリカプラグ（０．ＤＣＭ中５％ＭｅＯＨ）により精製して、標題化合物（７８０ｍｇ、７１％）を黄色油として得た：ＬＣＭＳ（ＥＳ）ｍ／ｅ２９２（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl (1-methylethyl) (2-oxo-3-phenylpropyl) carbamate

To a solution of 1,1-dimethylethyl (2-hydroxy-3-phenylpropyl) (1-methylethyl) carbamate (1.1 g, 3.75 mmol) in DCM (38 mL) at 25 ° C., PCC (890 mg, 4.13 mmol) was added. After 12 hours, the solution was filtered through Celite® and concentrated. The residue was purified by silica plug (0. 5% MeOH in DCM) to give the title compound (780 mg, 71%) as a yellow oil: LCMS (ES) m / e 292 (M + H) ⁺ .

ＭｅＯＨ（３．３ｍＬ）およびＨ_２Ｏ（３８０μＬ）中の１，１−ジメチルエチル （１−メチルエチル）（２−オキソ−３−フェニルプロピル）カルバメート（３６５ｍｇ、１．２５ｍｍｏｌ）、ギ酸アンモニウム（８７ｍｇ、１．３８ｍｍｏｌ）およびＰｄ（ＯＨ）_２（３７ｍｇ、１０ｗｔ．％）を、シールしたチューブ中、７０℃で撹拌した。１２時間後、さらにギ酸アンモニウムおよびＰｄ（ＯＨ）_２を加え、溶液をさらに１２時間撹拌し、セライト（登録商標）により濾過し、濃縮し、シリカプラグ（ＤＣＭ中２％ＭｅＯＨ（１％ＮＨ_４ＯＨ））により精製して、標題化合物（１４０ｍｇ、１９％）を透明油として得た：ＬＣＭＳ（ＥＳ）ｍ／ｅ２９２（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl (2-amino-3-phenylpropyl) (1-methylethyl) carbamate

1,1-dimethylethyl (1-methylethyl) (2-oxo-3-phenylpropyl) carbamate (365 mg, 1.25 mmol), ammonium formate (87 mg) in MeOH (3.3 mL) and H ₂ O (380 μL). , 1.38 mmol) and Pd (OH) ₂ (37 mg, 10 wt.%) Were stirred at 70 ° C. in a sealed tube. After 12 hours, more ammonium formate and Pd (OH) ₂ were added and the solution was stirred for an additional 12 hours, filtered through Celite®, concentrated and silica plug (2% MeOH in DCM (1% NH ₄ OH). )) To give the title compound (140 mg, 19%) as a clear oil: LCMS (ES) m / e 292 (M + H) ⁺ .

d) 4-Bromo-N- [2-[(1-methylethyl) amino] -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl)- 2-thiophenecarboxamide Instead of 2-amino-1-phenylethanol, 1,1-dimethylethyl (2-amino-3-phenylpropyl) (1-methylethyl) carbamate (140 mg, 0.479 mmol) was replaced with 1- ( 1- (phenylsulfonyl) instead of phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine ) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (194 mg, 0.420 mmo) The title compound as a yellow solid according to Example 7 except that 4,5-dibromo-2-thiophenecarboxylic acid (226 mg, 0.791 mmol) is used instead of 5-bromo-2-thiophenecarboxylic acid. Obtained.

Alternatively, the Boc protecting group TFA-DCM (1: 2, 0.1M) was removed using 25 hours at 25 ° C. The resulting solution was concentrated using toluene azeotrope and the residue was neutralized with a silica plug (2-10% MeOH in DCM (1% NH ₄ OH)) to give the neutralized compound. The compound in DCM was then treated with excess HCl in diethyl ether to give the diHCl salt of the title compound: LC-MS (ES) m / z = 498 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 9.10 (d, J = 8.5 Hz, 1H), 8.89 (bs, 1H), 8.75 (bs, 1H), 8.36 (d, J = 5.1 Hz, 1H), 8.18 (s, 1H), 7.65 (dd, J = 3.0, 3.0 Hz, 1H), 7.30-7.33 (m, 4H), 7.20-7. 28 (m, 1H), 6.53 (dd, J = 1.8, 3.5 Hz, 1H), 4.49-4.51 (m, 1H), 3.33-3.37 (m, 1H) ), 3.21-3.23 (m, 1H), 3.12-3.19 (m, 1H), 2.97-2.99 (m, 2H), 1.26. (D, J = 4.6 Hz, 6H).

Example 84

Preparation of 4-bromo-N- [2- (ethylamino) -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide i The title compound was obtained as a yellow solid according to Example 83, except that ethylamine (7 mL) was used instead of -PrNH ₂ : LC-MS (ES) m / z = 484 (M + H) ⁺ ; ¹ H NMR ( d6-DMSO, 400 MHz) δ 9.06 (d, J = 8.5 Hz, 1H), 8.83 (bs, 2H), 8.35 (d, J = 5.0 Hz, 1H), 8.15 (s) , 1H), 7.64 (dd, J = 3.1, 3.1 Hz, 1H), 7.28-7.32 (m, 4H), 7.22-7.26 (m, 1H), 6 .53 (dd, J = 1.7, 3.4 Hz, 1H), 4.10-4 14 (m, 1H), 3.13-3.17 (m, 2H), 2.93-3.00 (m, 4H), 1.19-1.23 (m, 3H).

Example 85

ＭｅＯＨの代わりに１，１−ジメチルエチル （２−ヒドロキシ−３−フェニルプロピル）カルバメート（４９０ｍｇ、０．９９４ｍｍｏｌ）を用いること以外は、実施例７７に従って橙色泡沫体として標題化合物を調製した：ＬＣＭＳ（ＥＳ）ｍ／ｅ７２７（Ｍ＋Ｈ）^＋。 Preparation of 3-{[2-amino-1- (phenylmethyl) ethyl] oxy} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a ) 4-Bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -1- (phenylmethyl) ethyl] oxy} -5- [1- (phenylsulfonyl)- Methyl 1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate

The title compound was prepared as an orange foam according to Example 77 except that 1,1-dimethylethyl (2-hydroxy-3-phenylpropyl) carbamate (490 mg, 0.994 mmol) was used instead of MeOH: LCMS ( ES) m / e 727 (M + H) ⁺ .

７ＮのＮＨ_３−ＭｅＯＨ（１０ｍＬ）およびＴＨＦ（２ｍＬ）中の４−ブロモ−３−｛［２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−１−（フェニルメチル）エチル］オキシ｝−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（６８５ｍｇ、０．９４４ｍｍｏｌ）の溶液を、シールしたチューブで合し、７０℃で撹拌した。１２時間後、溶液を濃縮し、シリカクロマトグラフィー（ＤＣＭ中３％ＭｅＯＨ（１％ＮＨ_４ＯＨ））により精製して、標題化合物（３８７ｍｇ、５８％）を黄色油として得た：ＬＣＭＳ（ＥＳ）ｍ／ｅ７１２（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl (2-{[2- (aminocarbonyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thienyl] oxy} -3-Phenylpropyl) carbamate

7N of _NH 3 -MeOH (10 mL) and THF (2 mL) in 4-bromo-3 - {[2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -1- (phenylmethyl) A solution of methyl [ethyl] oxy} -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate (685 mg, 0.944 mmol) was sealed. The tubes were combined and stirred at 70 ° C. After 12 hours, the solution was concentrated and purified by silica chromatography (3% MeOH in DCM (1% NH ₄ OH)) to give the title compound (387 mg, 58%) as a yellow oil: LCMS (ES) m / e 712 (M + H) ⁺ .

c) 3-{[2-Amino-1- (phenylmethyl) ethyl] oxy} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide THF 1,1-dimethylethyl (2-{[2- (aminocarbonyl) -4-bromo-5- (1H-pyrrolo [2,3] in iPrOH (5 mL, 1: 1) and 6N NaOH (5 mL) -B] pyridin-4-yl) -3-thienyl] oxy} -3-phenylpropyl) carbamate (387 mg, 0.544 mmol) was stirred at 50 <0> C. After 12 hours, the solution was cooled with ice and neutralized with 6N HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly.

Boc-amine (crude material from above) was dissolved in TFA / MeOH (1: 2, 5.4 mL) and stirred at room temperature for 30 minutes. The solution was then concentrated azeotropically with toluene and purified by silica plug (4% MeOH in DCM (1% NH ₄ OH)) to give the title compound as the free base (76 mg, 30% -2 steps). ).
The free base as a solution in MeOH was then treated with excess HCl in dioxane to give the title compound as the HCl salt: LC-MS (ES) m / z 471 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 8.50 (s, 3H), 8.37 (d, J = 5.1 Hz, 1H), 7.99 (bs, 1H), 7.68 (s, 1H), 7.62 (S, 1H), 7.16-7.28 (m, 4H), 6.54 (d, J = 1.8, 3.2 Hz, 1H), 5.22-5.23 (m, 1H) 3.27-3.34 (m, 1H), 3.05-3.17 (m, 3H).

Example 86

Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-N-methyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 2- [2- (methylamino) -3-phenylpropyl] -1H instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione -Isoindole-1,3 (2H) -dione-HCl (131 mg, 0.396 mmol) [1,1-dimethylethyl [2-hydroxy-1- (phenylmethyl) ethyl] methylcarbamate was prepared according to Method 7. ] but using, according to example 43, the title compound was obtained as a yellow solid: LC-MS (ES) m / z470 (M + H) +; 1 H NMR (d6-DM O, 400 MHz) δ 9.20-9.26 (m, 2H), 8.38 (d, J = 5.1 Hz, 1H), 8.23 (s, 1H), 7.68 (dd, J = 2) .9, 2.9 Hz, 1H), 7.33-7.38 (m, 4H), 7.27-7.29 (m, 1H), 6.57 (dd, 1.6, 3.4 Hz, 1H), 3.59-3.61 (m, 1H), 3.51-3.54 (m, 2H), 3.21-3.22 (m, 1H), 2.88-2.94 ( m, 1H), 2.68 (s, 3H).

Example 87

ＤＣＭ（１００ｍＬ）中の４−ブロモ−１Ｈ−ピロロ［２，３−ｂ］ピリジン（４ｇ、２０．３ｍｍｏｌ）の溶液に、０℃で、ｍＣＰＢＡ（６．８ｇ、３０．５ｍｍｏｌ）を加えた。２５℃に加温して１２時間後、溶液を飽和ＮａＨＣＯ_３／ＤＣＭ間で分配した。有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮して、標題化合物を淡黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ２１４（Ｍ＋Ｈ）^＋。 Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (6-amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 4- Bromo-1H-pyrrolo [2,3-b] pyridine 7-oxide

To a solution of 4-bromo-1H-pyrrolo [2,3-b] pyridine (4 g, 20.3 mmol) in DCM (100 mL) at 0 ° C. was added mCPBA (6.8 g, 30.5 mmol). After 12 hours warming to 25 ° C., the solution was partitioned between saturated NaHCO ₃ / DCM. The organic fraction was dried over Na ₂ SO ₄ and concentrated to give the title compound as a pale yellow solid: LC-MS (ES) m / z 214 (M + H) ⁺ .

ピリジン（７０ｍＬ）中の４−ブロモ−１Ｈ−ピロロ［２，３−ｂ］ピリジン７−オキシド（１ｇ、４．７ｍｍｏｌ）の溶液に、２５℃で、塩化トシル（１．２ｇ、６．１ｍｍｏｌ）を加えた。１２時間後、溶液を濃縮し、エタノールアミン（２０ｍＬ）に溶解し、２５℃で１時間撹拌した。得られた溶液を、Ｈ_２Ｏ／ＤＣＭ間で分配し、水相をＤＣＭで数回洗浄した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中２％ＭｅＯＨ）により精製して、標題化合物（３７０ｍｇ、３７％）を淡黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ２１３（Ｍ＋Ｈ）^＋。 b) 4-Bromo-1H-pyrrolo [2,3-b] pyridin-6-amine

Tosyl chloride (1.2 g, 6.1 mmol) in a solution of 4-bromo-1H-pyrrolo [2,3-b] pyridine 7-oxide (1 g, 4.7 mmol) in pyridine (70 mL) at 25 ° C. Was added. After 12 hours, the solution was concentrated, dissolved in ethanolamine (20 mL) and stirred at 25 ° C. for 1 hour. The resulting solution was partitioned between H ₂ O / DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 2% MeOH in DCM) to give the title compound (370 mg, 37%) as a pale yellow solid: LC -MS (ES) m / z 213 (M + H) ^<+> .

３−ヨウド−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジンの代わりに４−ブロモ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−６−アミン（３７０ｍｇ、１．７５ｍｍｏｌ）を用いること以外は調製例１に従って、標題化合物を褐色油として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ２６０（Ｍ＋Ｈ）^＋。 c) 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridin-6-amine

4-bromo-1H-pyrrolo [2,3-b] pyridin-6-amine (370 mg, 1.75 mmol) instead of 3-iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine ) Was used to give the title compound as a brown oil according to Preparation 1: LC-MS (ES) m / z 260 (M + H) ⁺ .

ジオキサン（９．４ｍＬ）およびＨ_２Ｏ（１．９ｍＬ）中の４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−６−アミン（２００ｍｇ、０．１．１３ｍｍｏｌ）の溶液に、１，１−ジメチルエチル （２−｛［（５−ブロモ−２−チエニル）カルボニル］アミノ｝−３−フェニルプロピル）カルバメート（４９７ｍｇ、０．１．１３ｍｍｏｌ）［実施例７６で調製した］、Ｐｄ（ＰＰｈ_３）_４（６５ｍｇ、５６．５μｍｏｌ）およびＫ_２ＣＯ_３（６２４ｍｇ、４．５２ｍｍｏｌ）を加えた。８０℃で４時間後、反応物をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中３％ＭｅＯＨ）により精製して、標題化合物（５９ｍｇ、１０％）を黄褐色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４９３（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl [2-({[5- (6-amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} amino) -3-phenylpropi Le] Carbamate

Dioxane (9.4 mL) and _H 2 O (1.9 mL) solution of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo [2, To a solution of 3-b] pyridin-6-amine (200 mg, 0.1.13 mmol) was added 1,1-dimethylethyl (2-{[(5-bromo-2-thienyl) carbonyl] amino} -3-phenylpropylene. G) Carbamate (497 mg, 0.1.13 mmol) [prepared in Example 76], Pd (PPh ₃ ) ₄ (65 mg, 56.5 μmol) and K ₂ CO ₃ (624 mg, 4.52 mmol) were added. After 4 hours at 80 ° C., the reaction was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 3% MeOH in DCM) to give the title compound (59 mg, 10% ) Was obtained as a tan foam: LC-MS (ES) m / z = 493 (M + H) ⁺ .

e) N- [2-amino-1- (phenylmethyl) ethyl] -5- (6-amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1- Dimethylethyl [2-({[5- (6-Amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} amino) -3-phenylpropyl] carbamate (59 mg, 0.120 mmol) was dissolved in TFA / MeOH (1: 2, 3 mL) and stirred at room temperature for 30 min. The solution was then azeotroped with toluene and concentrated to give the title compound as a TFA salt (64 mg): LC-MS (ES) m / z 393 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ11 .62 (bs, 1H), 8.59 (d, J = 8.5 Hz, 1H), 7.90 (bs, 2H), 7.82 (d, J = 4.0 Hz, 1H), 7.75 (D, J = 4.0 Hz, 1H), 7.26-7.32 (m, 3H), 7.17-7.23 (m, 2H), 6.67 (d, J = 4.8 Hz, 1H), 4.38-4.39 (m, 1H), 2.92-3.03 (m, 2H), 2.88-2.90 (m, 2H).

Example 88

ＭｅＯＨ（９ｍＬ）中の４−ブロモ−３−｛［２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）エチル］オキシ｝−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（５６５ｍｇ、０．８８７ｍｍｏｌ）［実施例７８で調製した］およびＰｄ（ＯＨ）_２（２８０ｍｇ、５０ｗｔ％）の溶液を、１気圧下で水素化した。１２時間後、溶液をセライト（登録商標）により濾過し、濃縮し、直接用いた：ＬＣＭＳ（ＥＳ）ｍ／ｅ５６０（Ｍ＋Ｈ）^＋。 3-[(2-Aminoethyl) oxy] -N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Preparation of thiophenecarboxamide a) 3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b] Methyl pyridin-4-yl] -2-thiophenecarboxylate

4-Bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [1- (phenylsulfonyl) -1H- in MeOH (9 mL). A solution of methyl pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate (565 mg, 0.887 mmol) [prepared in Example 78] and Pd (OH) ₂ (280 mg, 50 wt%) Was hydrogenated under 1 atm. After 12 hours, the solution was filtered through Celite®, concentrated and used directly: LCMS (ES) m / e 560 (M + H) ⁺ .

b) 3-[(2-Aminoethyl) oxy] -N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl)- 2-thiophenecarboxamide 1,1-dimethylethyl [2-({[4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl ] Instead of carbonyl} amino) -3-phenylpropyl] carbamate 3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [1- (phenyl The title compound is prepared according to Example 77 except that methyl (sulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate (about 490 mg, 0.887 mmol) is used. Was obtained as a color ^{solid: LC-MS (ES) m} / z438 (M + H) +; 1 H NMR (d6-DMSO, 400MHz) δ8.29 (d, J = 5.1Hz, 1H), 8.17 (bs , 2H), 7.91 (bs, 2H), 7.78 (s, 1H), 7.67 (dd, J = 3.3, 3.3 Hz, 1H), 7.42-7.449m, 2H ), 7.32-7.36 (m, 2H), 7.23-7.27 (m, 2H), 6.85 (dd, J = 1.8, 3.5 Hz, 1H), 4.49. -4.56 (m, 3H), 3.29-3.31 (m, 2H), 3.02-3.03 (m, 1H), 2.95-3.01 (m, 3H).

Example 89

Ｈ_２ＳＯ_４（５０ｍＬ）中の４−ブロモ−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１１ｇ、５５．８ｍｍｏｌ）［調製例２に従って調製した］の０℃に冷却した溶液に、Ｈ_２ＳＯ_４（３．５ｍＬ）中のＨＮＯ_３（５．１ｍＬ）の予め冷却した溶液を加えた。１時間後、溶液を氷に注ぎ、沈殿物を濾過し、乾燥して、標題化合物（１１．４ｇ、８４％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ２４３（Ｍ＋Ｈ）^＋。 Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 4- Bromo-3-nitro-1H-pyrrolo [2,3-b] pyridine

To a solution of 4-bromo-1H-pyrrolo [2,3-b] pyridine (11 g, 55.8 mmol) [prepared according to Preparative Example 2] cooled to 0 ° C. in H ₂ SO ₄ (50 mL) was added H _2. A pre-cooled solution of HNO ₃ (5.1 mL) in SO ₄ (3.5 mL) was added. After 1 hour, the solution was poured onto ice and the precipitate was filtered and dried to give the title compound (11.4 g, 84%) as a yellow solid: LC-MS (ES) m / z 243 (M + H) ⁺ .

ＳｎＣｌ_２（４．４ｇ、２３．０ｍｍｏｌ）を、濃ＨＢｒ（７ｍＬ）中の４−ブロモ−３−ニトロ−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１ｇ、４．１２ｍｍｏｌ）の７０℃溶液に滴下した。１時間後、この溶液を氷に加え、ｐＨを約１２に調節した。沈殿物を濾過し、水性残渣を過剰のＤＣＭで洗浄した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ２１３（Ｍ＋Ｈ）^＋。 b) 4-Bromo-1H-pyrrolo [2,3-b] pyridin-3-amine

SnCl ₂ (4.4 g, 23.0 mmol) was added to a 70 ° C. solution of 4-bromo-3-nitro-1H-pyrrolo [2,3-b] pyridine (1 g, 4.12 mmol) in concentrated HBr (7 mL). It was dripped in. After 1 hour, the solution was added to ice and the pH was adjusted to about 12. The precipitate was filtered and the aqueous residue was washed with excess DCM. The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z 213 (M + H) ⁺ .

ジオキサン（２．５ｍＬ）およびＨ_２Ｏ（０．５ｍＬ）中の４−ブロモ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−アミン（６３ｍｇ、０．２９８ｍｍｏｌ）の溶液に、１，１−ジメチルエチル ［３−フェニル−２−（｛［５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−２−チエニル］カルボニル｝アミノ）プロピル］カルバメート（１４５ｍｇ、０．２９８ｍｍｏｌ）［実施例８７で調製した］、Ｐｄ（ＰＰｈ_３）_４（１７ｍｇ、１４．９μｍｏｌ）およびＫ_２ＣＯ_３（１６４ｍｇ、１．１９ｍｍｏｌ）を加えた。シールしたチューブ中、８０℃で１２時間加熱した後、反応溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中３％ＭｅＯＨ）を用いて精製して、標題化合物（６０ｍｇ、４１％）を橙色油として得た。ｌ：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４９２（Ｍ＋Ｈ）^＋ c) 1,1-dimethylethyl [2-({[5- (3-amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} amino) -3-phenylpropi Le] Carbamate

To a solution of 4-bromo-1H-pyrrolo [2,3-b] pyridin-3-amine (63 mg, 0.298 mmol) in dioxane (2.5 mL) and H ₂ O (0.5 mL) was added 1,1 -Dimethylethyl [3-phenyl-2-({[5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-thienyl] carbonyl} amino) propyl] Carbamate (145 mg, 0.298 mmol) [prepared in Example 87], Pd (PPh ₃ ) ₄ (17 mg, 14.9 μmol) and K ₂ CO ₃ (164 mg, 1.19 mmol) were added. After heating at 80 ° C. for 12 hours in a sealed tube, the reaction solution was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified using column chromatography (silica, 3% MeOH in DCM) to give the title compound (60 mg, 41%) as an orange oil. l: LC-MS (ES) m / z = 492 (M + H) ⁺

d) N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1- Dimethylethyl [2-({[5- (3-Amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} amino) -3-phenylpropyl] carbamate (60 mg, 0.122 mmol) was dissolved in TFA / MeOH (1: 2, 3 mL) and stirred at room temperature for 30 minutes. The solution was then concentrated azeotropically with toluene and neutralized with a silica plug (3-5% MeOH in DCM (1% NH ₄ OH)) to give the title compound as the free base (21 mg, 44% ).
The free base as a solution in MeOH was then treated with excess HCl in dioxane to give the title compound as the HCl salt: LC-MS (ES) m / z 392 (M + H) ⁺ ; ¹ H NMR (d6 −DMSO, 400 MHz) δ 10.14 (bs, 2H), 8.98 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 4.9 Hz, 1H), 8.24 (bs, 2H), 8.07 (d, J = 3.9 Hz, 1H), 7.82 (d, J = 2.7 Hz, 1H), 7.73 (d, J = 3.9 Hz, 1H), 7. 28-7.32 (m, 3H), 7.18-7.24 (m, 2H), 4.42-4.45 (m, 1H), 2.91-3.08 (m, 4H).

Example 90

ＤＣＭ（１０ｍＬ）中の４−ブロモ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−アミン（２２０ｍｇ、１．０４ｍｍｏｌ）［実施例８９に従って調製した］、３−フロ酸（１２８ｍｇ、１．１４ｍｍｏｌ）およびジイソプロピルエチルアミン（５９５μＬ、３．４２ｍｍｏｌ）の溶液に、２５℃で、ＰｙＢｒｏｐ（５８０ｍｇ、１．２５ｍｍｏｌ）を一度で加えた。１２時間後、溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中３％ＭｅＯＨ）を用いて精製して、標題化合物（２９０ｍｇ、９１％）を橙色油として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３０７（Ｍ＋Ｈ）^＋。 N- {4- [5-({[2-amino-1- (phenylmethyl) ethyl] amino} carbonyl) -2-thienyl] -1H-pyrrolo [2,3-b] pyridin-3-yl}- Preparation of 3-furancarboxamide a) N- (4-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -3-furancarboxamide

4-Bromo-1H-pyrrolo [2,3-b] pyridin-3-amine (220 mg, 1.04 mmol) [prepared according to Example 89], 3-furoic acid (128 mg, 1.mg) in DCM (10 mL). 14 mmol) and diisopropylethylamine (595 μL, 3.42 mmol) at 25 ° C. was added PyBrop (580 mg, 1.25 mmol) in one portion. After 12 hours, the solution was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified using column chromatography (silica, 3% MeOH in DCM) to give the title compound (290 mg, 91%) was obtained as an orange oil: LC-MS (ES) m / z = 307 (M + H) ⁺ .

b) N- {4- [5-({[2-amino-1- (phenylmethyl) ethyl] amino} carbonyl) -2-thienyl] -1H-pyrrolo [2,3-b] pyridin-3-yl } -3-furancarboxamide Instead of 4-bromo-1H-pyrrolo [2,3-b] pyridin-3-amine, N- (4-bromo-1H-pyrrolo [2,3-b] pyridine-3- Yl) -3-furancarboxamide (112 mg, 0.366 mmol) according to Example 89 to give the title compound as an orange solid: LC-MS (ES) m / z 485 (M + H) ⁺ ; ¹ H NMR (D6-DMSO, 400 MHz) δ 9.47 (s, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.30 (d, J = 5.0 Hz, 1H), 8.17 ( s, 1H), 8.06 (b , 2H), 7.74 (dd, J = 1.6, 1.6 Hz, 1H), 7.66 (dd, J = 4.2, 4.2 Hz, 2H), 7.40 (d, J = 3.9 Hz, 1 H), 7.16-7.30 (m, 5 H), 6.81 (d, J = 1.2 Hz, 1 H), 4.31-4.36 (m, 1 H), 2. 88-2.98 (m, 2H).

Example 91

ＴＨＦ（２．６ｍＬ）中の３−ヨウド−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１ｇ、２．６ｍｍｏｌ）［調製例１で調製した］を、ＬＤＡ［ｎＢｕＬｉ（１．１ｍＬ、２．８６ｍｍｏｌ）を、ＴＨＦ（５ｍＬ）中のジイソプロピルアミン（４００μＬ、２．８６ｍｍｏｌ）の−７８℃溶液に添加することにより調製した］の−７８℃溶液に滴下した。１時間後、ＴＨＦ（５ｍＬ）中のＰｈＳＯ_２Ｃｌ（３７２μＬ、２．８６ｍｍｏｌ）を滴下し、溶液を２５℃に加温し、１２時間後、溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮した。残渣を、ＭｅＯＨを用いてトリチュレートし、得られた褐色固体を濾過し、乾燥して、標題化合物（６００ｍｇ、５５％）を得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４１９（Ｍ＋Ｈ）^＋。 Preparation of 3-amino-N- [4- (2-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylpropanamide a) 2-Chloro-3 -Iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine

3-Iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (1 g, 2.6 mmol) [prepared in Preparation 1] in THF (2.6 mL) was converted to LDA [nBuLi (1.1 mL, 2.86 mmol) was added dropwise to a −78 ° C. solution of diisopropylamine (400 μL, 2.86 mmol) in THF (5 mL) added to a −78 ° C. solution. After 1 hour, PhSO ₂ Cl (372 μL, 2.86 mmol) in THF (5 mL) was added dropwise, the solution was warmed to 25 ° C., and after 12 hours, the solution was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ and concentrated. The residue was triturated with MeOH and the resulting brown solid was filtered and dried to give the title compound (600 mg, 55%): LC-MS (ES) m / z = 419 (M + H) ⁺ .

ジオキサン（５ｍＬ）およびＨ_２Ｏ（１ｍＬ）中の２−クロロ−３−ヨウド−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（２５７ｍｇ、０．６１５ｍｍｏｌ）の溶液に、１，１−ジメチルエチル ［４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−２−チエニル］カルバメート（２００ｍｇ、０．６１５ｍｍｏｌ）［１，１−ジメチルエチル （２−｛［（５−ブロモ−２−チエニル）カルボニル］アミノ｝−３−フェニルプロピル）カルバメートの代わりに１，１−ジメチルエチル （４−ブロモ−２−チエニル）カルバメート（１ｇ、３．６ｍｍｏｌ、実施例１で調製した）を用いること以外は、実施例４７に従って調製した］、Ｐｄ（ＰＰｈ_３）_４（３６ｍｇ、３０．８μｍｏｌ）およびＫ_２ＣＯ_３（３４０ｍｇ、２．５ｍｍｏｌ）を加えた。シールしたチューブで８０℃に１２時間加熱した後、反応溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中３％ＭｅＯＨ）を用いて精製し、標題化合物（１４８ｍｇ、４９％）を灰白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４９０（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl [4- (2-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] carbamate

To a solution of 2-chloro-3-iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (257 mg, 0.615 mmol) in dioxane (5 mL) and H ₂ O (1 mL), 1,1-dimethylethyl [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-thienyl] carbamate (200 mg, 0.615 mmol) [1,1 1,1-dimethylethyl (4-bromo-2-thienyl) carbamate (1 g, instead of 2-dimethylethyl (2-{[(5-bromo-2-thienyl) carbonyl] amino} -3-phenylpropyl) carbamate 3.6 mmol, except using prepared) in example 1 was prepared according to example _{47], Pd (PPh 3)} 4 (36mg, 30.8 mol) and _{K 2 CO 3 (340mg, 2.5mmol} ) was added. After heating in a sealed tube to 80 ° C. for 12 hours, the reaction solution was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified using column chromatography (silica, 3% MeOH in DCM) to give the title compound (148 mg, 49 %) Was obtained as an off-white solid: LC-MS (ES) m / z = 490 (M + H) ⁺ .

c) 3-Amino-N- [4- (2-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylpropanamide 1,1-dimethylethyl { Instead of 4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} carbamate, 1,1-dimethylethyl [4- (2-chloro-1H -The title compound was obtained as a yellow solid according to Example 1 except that pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] carbamate (148 mg, 0.302 mmo) was used: MS (ES) m / z 398 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 8.27 (dd, J = 1.4, 4.7 Hz, 1H), 8.07-8.12 (m , 3H), 7. 31-7.43 (m, 5H), 7.16-7.29 (m, 2H), 4.19-4.38 (m, 1H), 3.54-3.58 (m, 2H), 3.08-3.17 (m, 2H).

Example 92

ジオキサン（５ｍＬ）およびＨ_２Ｏ（１ｍＬ）中の１，１−ジメチルエチル （３−｛［４−（２−クロロ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル）−２−チエニル］アミノ｝−３−オキソ−２−フェニルプロピル）カルバメート（１００ｍｇ、０．２０１ｍｍｏｌ）［実施例９１で調製した］の溶液に、３−フランボロン酸（２３ｍｇ、０．２０１ｍｍｏｌ）、Ｐｄ（ＰｔＢｕ_３）_２（５ｍｇ、１０．１μｍｏｌ）およびＣｓ_２ＣＯ_３（２６２ｍｇ、０．８０５ｍｍｏｌ）を加えた。マイクロ波で２０分間１５０℃で加熱した後、反応溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５２９（Ｍ＋Ｈ）^＋。 Preparation of N- (2-amino-1-phenylethyl) -4- [2- (3-furanyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thiophenecarboxamide a) 1 , 1-dimethylethyl [3-({4- [2- (3-furanyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} amino) -3-oxo-2 -Phenylpropyl] carbamate

1,1-dimethylethyl (3-{[4- (2-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-in dioxane (5 mL) and H ₂ O (1 mL) To a solution of thienyl] amino} -3-oxo-2-phenylpropyl) carbamate (100 mg, 0.201 mmol) [prepared in Example 91] was added 3-furanboronic acid (23 mg, 0.201 mmol), Pd (PtBu ₃ ) ₂ (5 mg, 10.1 μmol) and Cs ₂ CO ₃ (262 mg, 0.805 mmol) were added. After heating in the microwave for 20 minutes at 150 ° C., the reaction solution was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z = 529 (M + H) ⁺ .

b) N- (2-amino-1-phenylethyl) -4- [2- (3-furanyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thiophenecarboxamide 1,1 -Dimethylethyl [3-({4- [2- (3-furanyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} amino) -3-oxo-2-phenylpropi L] carbamate (crude material from above) was dissolved in TFA-DCM (1: 2, 3 mL). After 30 minutes, the solution was concentrated by azeotroping with toluene, then neutralized with a silica plug (3% MeOH in DCM (1% NH ₄ OH)) to give the title compound as the free base (12 mg, 14 % -2 step).
The free base as a solution in MeOH was then treated with excess HCl in dioxane to give the title compound as the HCl salt: LC-MS (ES) m / z 429 (M + H) ⁺ ; ¹ H NMR (d6 -DMSO, 400 MHz) δ 8.27 (dd, J = 1.2, 1.2 Hz, 1H), 8.09 (bs, 2H), 8.03 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.75 (dd, J = 1.3, 3.2 Hz, 1H), 7.40-7.42 (m, 4H), 7.33-7.35 (m, 1H) ), 7.15 (dd, J = 4.9, 7.8 Hz, 1H), 7.04 (d, J = 1.4 Hz, 1H), 6.75 (d, J = 1.6 Hz, 1H) 6.64 (d, J = 1.1 Hz, 1H), 4.13-4.17 (m, 1H), 3.51-3.62 (m, 1 H), 3.16-3.18 (m, 1H).

Example 93

Preparation of 4-amino-N- [5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylbutanamide 3- ( {[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- (phenylmethyl) propanoic acid instead of 4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- The title compound was obtained as an orange solid according to Example 49 except using phenylbutanoic acid (134 mg, 0.480 mmol): LC-MS (ES) m / z 444 (M + H) ⁺ ; ¹ H NMR (d6-DMSO , 400 MHz) δ 8.26 (dd, J = 1.2, 4.8 Hz, 1H), 7.90 (bs, 2H), 7.66 (d, J = 7.4 Hz, 1H), 7.63 ( s, 1H), 7.5 7 (dd, J = 1.7, 1.7 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.39-7.41 (m, 4H), 7.29-7 .36 (m, 1H), 7.08 (dd, J = 4.9, 7.9 Hz, 1H), 6.78 (s, 1H), 6.25 (s, 1H), 3.85-3 .89 (m, 1H), 2.75-2.78 (m, 1H), 2.67-2.73 (m, 1H), 2.33-2.34 (m, 1H), 2.03 -2.06 (m, 1H).

Example 94

ジオキサン（１２ｍＬ）およびＨ_２Ｏ（２ｍＬ）中の４，５−ジブロモ−２−チオフェンカルボン酸（１ｇ、３．５ｍｍｏｌ）の溶液に、フェニルボロン酸（５５２ｍｇ、４．６ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（２０２ｍｇ、０．１７５ｍｍｏｌ）およびＫ_２ＣＯ_３（１．９ｇ、１４．０ｍｍｏｌ）を加えた。シールしたチューブで１２時間８０℃で加熱した後、反応溶液を６ＮのＮａＯＨ／ＤＣＭ間で分配した。水相のｐＨを約３に調節し、ＤＣＭで数回洗浄した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝２８４（Ｍ＋Ｈ）^＋。 Preparation of 3-amino-2- (phenylmethyl) -N- [5-phenyl-4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide a) 4- Bromo-5-phenyl-2-thiophenecarboxylic acid

To a solution of 4,5-dibromo-2-thiophenecarboxylic acid (1 g, 3.5 mmol) in dioxane (12 mL) and H ₂ O (2 mL) was added phenylboronic acid (552 mg, 4.6 mmol), Pd (PPh ₃ ) ₄ (202 mg, 0.175 mmol) and K ₂ CO ₃ (1.9 g, 14.0 mmol) were added. After heating in a sealed tube for 12 hours at 80 ° C., the reaction solution was partitioned between 6N NaOH / DCM. The pH of the aqueous phase was adjusted to about 3 and washed several times with DCM. The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z = 284 (M + H) ⁺ .

ジオキサン（１４．６ｍＬ）およびＨ_２Ｏ（２．９ｍＬ）中の４−ブロモ−５−フェニル−２−チオフェンカルボン酸（上記からの粗物質）の溶液に、１−（フェニルスルホニル）−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１．４ｇ、３．５ｍｍｏｌ）［調製例１に従って調製した］、Ｐｄ（ＰＰｈ_３）_４（２０２ｍｇ、０．１７５ｍｍｏｌ）およびＫ_２ＣＯ_３（１．９ｇ、１４．０ｍｍｏｌ）を加えた。シールしたチューブで１２時間８０℃で加熱した後、反応溶液を６ＮのＮａＯＨ／ＤＣＭ間で分配した。水相のｐＨを約３に調節し、ＤＣＭで数回洗浄した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４６１（Ｍ＋Ｈ）^＋。 b) 5-Phenyl-4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thiophenecarboxylic acid

To a solution of 4-bromo-5-phenyl-2-thiophenecarboxylic acid (crude material from above) in dioxane (14.6 mL) and H ₂ O (2.9 mL) was added 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (1.4 g, 3.5 mmol) [according to Preparation Example 1 Prepared], Pd (PPh ₃ ) ₄ (202 mg, 0.175 mmol) and K ₂ CO ₃ (1.9 g, 14.0 mmol) were added. After heating in a sealed tube for 12 hours at 80 ° C., the reaction solution was partitioned between 6N NaOH / DCM. The pH of the aqueous phase was adjusted to about 3 and washed several times with DCM. The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z = 461 (M + H) ⁺ .

５−フェニル−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−２−チオフェンカルボン酸（上記からの粗物質）、ｔ−ＢｕＯＨ（１８ｍＬ）、Ｅｔ_３Ｎ（１．５ｍＬ）およびジフェニルホスホリルアジド（９８６ｍｇ、４．５６ｍｍｏｌ）の溶液を、８０℃で撹拌した。１２時間後、溶液を濃縮し、カラムクロマトグラフィー（シリカ、ヘキサン中１０〜４０％ＥｔＯＡｃ）により精製して、標題化合物を得た（１６０ｍｇ、１０％−３工程）：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５３２（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl {5-phenyl-4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} carbamate

5-Phenyl-4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thiophenecarboxylic acid (crude material from above), t-BuOH (18 mL) , Et ₃ N (1.5 mL) and diphenylphosphoryl azide (986 mg, 4.56 mmol) were stirred at 80 ° C. After 12 hours, the solution was concentrated and purified by column chromatography (silica, 10-40% EtOAc in hexanes) to give the title compound (160 mg, 10% -3 steps): LC-MS (ES) m / Z = 532 (M + H) ⁺ .

メタノール（３ｍＬ）中の１，１−ジメチルエチル ｛５−フェニル−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−２−チエニル｝カルバメート（１６０ｍｇ、０．３０１ｍｍｏｌ）の溶液に、ジオキサン（１．５ｍＬ）中の４ＭのＨＣｌを加えた。反応物を室温で１２時間撹拌し、ついで、減圧下で濃縮して固体を得た。
ＤＣＭ（３ｍＬ）およびジイソプロピルエチルアミン（２６３μＬ、１．５１ｍｍｏｌ）中の粗残渣、３−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−２−フェニルプロパン酸（９２ｍｇ、０．３３１ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（１５４ｍｇ、０．３３１ｍｍｏｌ）を加えた。１２時間後、反応溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をＤＣＭで数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、ＤＣＭ中１％ＭｅＯＨ）により精製して、標題化合物（１４０ｍｇ、６７％）を得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６９２（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl [3-oxo-2- (phenylmethyl) -3-({5-phenyl-4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine- 3-yl] -2-thienyl} amino) propyl] carbamate

1,1-dimethylethyl {5-phenyl-4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} carbamate (3 mL) in methanol (3 mL) To a solution of 160 mg, 0.301 mmol) was added 4M HCl in dioxane (1.5 mL). The reaction was stirred at room temperature for 12 hours and then concentrated under reduced pressure to give a solid.
Crude residue in DCM (3 mL) and diisopropylethylamine (263 μL, 1.51 mmol), 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid (92 mg, 0.331 mmol) ) Was added PyBrop (154 mg, 0.331 mmol). After 12 hours, the reaction solution was partitioned between H ₂ O / DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1% MeOH in DCM) to give the title compound (140 mg, 67% ) Was obtained: LC-MS (ES) m / z = 692 (M + H) ⁺ .

e) 3-Amino-2- (phenylmethyl) -N- [5-phenyl-4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide i) THF ( 1,1-dimethylethyl [3-oxo-2- (phenylmethyl) -3-({5-phenyl-4- [1- (phenylsulfonyl) -1H-pyrrolo [2]) in 1 mL) and iPrOH (1 mL) , 3-b] pyridin-3-yl] -2-thienyl} amino) propyl] carbamate (140 mg, 0.202 mmol) was added 6N NaOH (2 mL). After 1 hour at 55 ° C., the reaction mixture was neutralized with 1M HCl and extracted with DCM. The DCM solution was dried over Na ₂ SO ₄ , concentrated under reduced pressure and used directly: LC-MS (ES) m / z = 553 (M + H) ⁺ .
ii) Boc-amine (crude material from above) was dissolved in TFA / MeOH (1: 2, 3 mL) and stirred at room temperature for 30 min. The solution was then concentrated azeotropically with toluene and neutralized with a silica plug (4% MeOH in DCM (1% NH ₄ OH)) to give the title compound.

The free base as a solution in MeOH was then treated with excess HCl in dioxane to give the title compound (38 mg, 42% -2 steps) as the HCl salt: LC-MS (ES) m / z 453 ( ¹ H NMR (d6-DMSO, 400 MHz) δ 8.25 (dd, J = 1.1, 2.8 Hz, 1H), 8.06 (bs, 2H), 7.47-7.51 (M + H) ⁺ ; m, 2H), 7.19-7.35 (m, 10H), 7.00-7.35 (m, 1H), 6.88 (s, 1H), 3.21-3.25 (m, 1H), 3.05-3.17 (m, 2H), 2.80-2.89 (m, 2H).

Example 95

ＴＨＦ（２５ｍＬ）中の４−ブロモ−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１ｇ、５．１ｍｍｏｌ）［調製例２に従って調製した］の溶液に、０℃で、ＮＣＳ（７４２ｍｇ、５．６ｍｍｏｌ）を一度で加えた。２５℃に加温した後、溶解度のためＭｅＯＨ（２ｍＬ）を加え、溶液をさらに１２時間撹拌した。ついで、反応混合物をＨ_２Ｏ／ＤＣＭ間で分配し、水相をＤＣＭで数回洗浄した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ２３４（Ｍ＋Ｈ）^＋。 Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-chloro-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 4- Bromo-3-chloro-1H-pyrrolo [2,3-b] pyridine

To a solution of 4-bromo-1H-pyrrolo [2,3-b] pyridine (1 g, 5.1 mmol) [prepared according to Preparation 2] in THF (25 mL) at 0 ° C., NCS (742 mg, 5. 6 mmol) was added in one portion. After warming to 25 ° C., MeOH (2 mL) was added for solubility and the solution was stirred for an additional 12 hours. The reaction mixture was then partitioned between H ₂ O / DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z 234 (M + H) ⁺ .

b) N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-chloro-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 4-bromo- Implemented except using 4-bromo-3-chloro-1H-pyrrolo [2,3-b] pyridine (113 mg, 0.411 mmol) instead of 1H-pyrrolo [2,3-b] pyridin-3-amine The title compound was obtained as a yellow solid according to Example 89: LC-MS (ES) m / z 411 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 8.69 (d, J = 8.5 Hz, 1H) ), 8.32 (d, J = 4.9 Hz, 1H), 8.00 (bs, 2H), 7.88 (d, J = 3.8 Hz, 1H), 7.78 (d, J = 2) .8 Hz, 1 H), 7.39 (d, J = 3 9Hz, 1H), 7.28-7.33 (m, 3H), 7.20-7.23 (m, 1H), 7.14 (d, J = 4.9Hz, 1H), 4.37- 4.40 (m, 1H), 2.92-3.17 (m, 4H).

Example 96

Preparation of N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thiophenecarboxamide instead of 5-bromo-2-thiophenecarboxylic acid 5-bromo-3-thiophenecarboxylic acid (1 g, 4.85 mmol) [J. Org. Chem. 1976, 41, 2350] according to the method of Example 7 to give the title compound as a yellow solid: LC-MS (ES) m / z = 364 (M + H) ⁺ ; ¹ H NMR (d6- DMSO, 400 MHz) δ 9.15 (d, J = 8.3 Hz, 1H), 8.50 (dd, J = 7.2, 8.0 Hz, 1H), 8.36 (dd, J = 3.4) 3.4 Hz, 1H), 8.25 (bs, 2H), 7.95-7.98 (m, 2H), 7.37-7.48 (m, 2H), 7.30-7.33 ( m, 2H), 7.26-7.29 (m, 2H), 5.32-5.38 (m, 1H), 3.38-3.45 (m, 1H), 3.17-3. 24 (m, 1H).

Example 97

Preparation of N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-thiophenecarboxamide instead of 5-bromo-2-thiophenecarboxylic acid 2-bromofuran-4-carboxylic acid (1 g, 4.85 mmol) [J. Org. Chem. 1976, 41, 2350] to 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3- b] 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] instead of pyridine The title compound was obtained as a yellow solid according to the method of Example 7 except using pyridine (228 mg, 0.590 mmol): LC-MS (ES) m / z = 364 (M + H) ⁺ ; ¹ H NMR ( d6-DMSO, 400 MHz) δ 9.28-9.31 (m, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 3.34 (d, J = 5.4 Hz, 1H) ), 8.26 (bs, 2H), 7.6 2 (s, 1H), 7.53-7.56 (m, 1H), 7.48-7.50 (m, 1H), 7.38-7.41 (m, 2H), 7.29- 7.31 (m, 1H), 7.05 (s, 1H), 5.31-5.36 (m, 1H), 3.35-3.42 (m, 1H), 3.18-3. 22 (m, 1H).

Example 98

Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thiophenecarboxamide 1,1-dimethylethyl (2 -{[(5-Bromo-2-thienyl) carbonyl] amino} -2-phenylethyl) carbamate instead of 1,1-dimethylethyl (2-{[(5-bromo-3-thienyl) carbonyl] amino} The title compound was obtained as a yellow solid according to the method of Example 7 except that 3-phenylpropyl) carbamate (250 mg, 0.568 mmol) was used: LC-MS (ES) m / z = 378 (M + H) ^{+; 1 H NMR (d6-} DMSO, 400MHz) δ8.69 (d, J = 8.3Hz, 1H), 8.39 (d, J = 1.0Hz, 1H), 8.33 d, J = 5.3 Hz, 1H), 8.29 (s, 1H), 8.10 (bs, 2H), 7.71 (dd, J = 3.1, 3.1 Hz, 1H), 7. 47 (d, J = 5.4 Hz, 1H), 7.21-7.31 (m, 1H), 7.19-7.20 (m, 1H), 7.01 (s, 1H), 4. 41-4.48 (m, 1H), 2.87-3.02 (m, 4H).

Example 99

Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-thiophenecarboxamide 1,1-dimethylethyl (2 -{[(5-Bromo-2-thienyl) carbonyl] amino} -2-phenylethyl) carbamate instead of 1,1-dimethylethyl (2-{[(5-bromo-3-thienyl) carbonyl] amino} -3-phenylpropyl) carbamate (250 mg, 0.568 mmol) was converted to 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- Instead of 1H-pyrrolo [2,3-b] pyridine, 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- L) -1H-pyrrolo [2,3-b] pyridine (219 mg, 0.568 mmol) was used to give the title compound as a yellow solid according to the method of Example 7: LC-MS (ES) m / Z = 378 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 8.57 (d, J = 8.5 Hz, 1 H), 8.48 (dd, J = 1.1, 8.0 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.12 (bs, 2H), 8.06 (d, J = 1.3 Hz, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.20-7.31 (m, 4H), 7.19-7.20 (m, 1H), 4. 35-4.40 (m, 1H), 2.82-3.11 (m, 4H).

Example 100

Preparation of N-[(1S) -2-amino-1- (cyclohexylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione, 2-[(2S) -2-amino-3-cyclohexylpropyl]- The title compound was obtained as a yellow solid according to Example 43 except using 1H-isoindole-1,3 (2H) -dione-HCl (177 mg, 0.540 mmol) [prepared according to Method 7]: LC -MS (ES) m / z = 462 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 8.70 (d, J = 8.7 Hz, 1H), 8.36 (d, J = 5. 0, 5.0 Hz, 1H), 8.14 (s, 1H), 8.04 (bs, 2H), 7.65 (d, J = 3.2 Hz, 1H), 7.31 (d, J = 5.1 Hz, 1H), 6.54 (dd, J = 1.8, 3.5 Hz, 1H), 4.31-4.44 (m, 1H), 2.80-3.01 (m, 2H) ), 1.71-1.82 (m, 1H), 1.52-1.71 (m, 5H), 1.22-1.41 (m, 2H), 1.12-1.20 (m) , 3H), 0.88-1.01 (m, 2H).

Example 101

Preparation of N-[(1S) -2-amino-1- (cyclohexylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 2-[( 2-[(2S) -2-amino-3-cyclohexylpropyl] -1H-isoindole instead of 2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione -1,3 (2H) -dione-HCl (177 mg, 0.540 mmol) [prepared according to Method 7] was prepared from 4-bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] Instead of pyridin-4-yl] -2-thiophenecarboxylic acid, 5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxyl (250 mg, 0.649 mmol) except using, according to Example 43, the title compound was obtained as a yellow ^{solid: LC-MS (ES) m} / z = 384 (M + H) +; 1 H NMR (d6-DMSO , 400 MHz) δ 8.48-8.51 (m, 1H), 8.28 (d, J = 5.1 Hz, 1H), 7.87-7.96 (m, 4H), 7.66 (dd, J = 3.0, 3.0 Hz, 1H), 7.41 (d, J = 5.2 Hz, 1H), 6.88 (s, 1H), 4.21-4.31 (m, 1H), 2.82-3.01 (m, 2H), 1.72-1.78 (m, 1H), 1.51-1.71 (m, 5H), 1.42-1.48 (m, 2H) ), 1.12-1.14 (m, 3H), 0.88-1.11 (m, 2H).

Example 102

3-[(2-aminoethyl) oxy] -N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H- Preparation of pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide 1,1-dimethylethyl (2-hydroxyethyl) carbamate (0.048 g, 0.3 mmol) was used instead of methanol. , 1-Dimethylethyl (2-amino-3-phenylpropyl) carbamate instead of 2-{(2S) -2-amino-3- [2- (trifluoromethyl) phenyl] propyl} -1H-isoindole- 1,3 (2H) -dione (0.105 g, 0.3 mmol)) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -2- (trifluoromethyl) -L Phenylalanine, except using] was prepared according to Preparation Example 7, according to the method of Example 77, the title compound was obtained as a yellow solid: LC-MS (ES) m / z = 583 (M + H) +; 1 H NMR (CD ₃ OD, 400 MHz) δ 8.39 (m, 1H), 7.74 (m, 1H), 7.60 (m, 3H), 7.45 (m, 2H), 6.74 (m, 1H), 4.73 (m, 1H), 4.41 (m, 2H), 3.39 (m, 3H) and 3.22 (m, 3H).

Example 103

3-[(2-aminoethyl) oxy] -N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2, 3-b] Preparation of pyridin-4-yl) -2 -furancarboxamide 1,1-dimethylethyl instead of (2-amino-3-phenylpropyl) carbamate 2-{(2S) -2-amino-3- [2- (Trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (0.105 g, 0.3 mmol) [N-{[(1,1-dimethylethyl) oxy] The title compound was obtained as a yellow solid according to the method of Example 88 except using carbonyl} -2- (trifluoromethyl) -L-phenylalanine, prepared according to Preparation Example 7]: L C-MS (ES) m / z = 504 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.38 (brs, 1H), 7.84 (m, 1H), 7.72 (m, 3H), 7.57 (m, 2H), 7.45 (m, 1H), 7.13 (m, 1H), 4.75 (m, 1H), 4.63 (m, 2H), 3. 45 (m, 3H) and 3.26 (m, 3H).

Example 104

ジオキサン／Ｈ_２Ｏ（５：１、３．８ｍＬ）中の１，１−ジメチルエチル （２−｛［（４，５−ジブロモ−２−チエニル）カルボニル］アミノ｝−３−フェニルプロピル）カルバメート（２００ｍｇ、０．３８５ｍｍｏｌ）［実施例７６で調製した］の溶液に、Ｋ_２ＣＯ_３（２１３ｍｇ、１．５４ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（２２ｍｇ、１９．３μｍｏｌ）、および３−フラニルボロン酸（４３ｍｇ、０．３８５ｍｍｏｌ）を加えた。反応混合物をシールしたチューブで３時間８０℃で加熱した。反応溶液をＨ_２Ｏ（１００ｍＬ）に注ぎ、ＤＣＭで抽出した。有機層を乾燥し（Ｎａ_２ＳＯ_４）、減圧下で濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５０６。 Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide a) 1,1-dimethylethyl (2-{[(4,5-dibromo-2-thienyl) carbonyl] amino} -3-phenylpropyl) carbamate

1,1-Dimethylethyl (2-{[(4,5-dibromo-2-thienyl) carbonyl] amino} -3-phenylpropyl) carbamate in dioxane / H ₂ O (5: 1, 3.8 mL) 200 mg, 0.385 mmol) [prepared in Example 76] to a solution of K ₂ CO ₃ (213 mg, 1.54 mmol), tetrakistriphenylphosphine Pd (0) (22 mg, 19.3 μmol), and 3-furanylboron Acid (43 mg, 0.385 mmol) was added. The reaction mixture was heated at 80 ° C. for 3 hours in a sealed tube. The reaction solution was poured into H ₂ O (100 mL) and extracted with DCM. The organic layer was dried (Na ₂ SO ₄ ), concentrated under reduced pressure and used directly: LC-MS (ES) m / z = 506.

ジオキサン／Ｈ_２Ｏ（５：１、３．８ｍＬ）中の１，１−ジメチルエチル （２−｛［（４，５−ジブロモ−２−チエニル）カルボニル］アミノ｝−３−フェニルプロピル）カルバメート（１９５ｍｇ、０．３８５ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（２１３ｍｇ、１．５４ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（２２ｍｇ、１９．３μｍｏｌ）、および１−（フェニルスルホニル）−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１４８ｍｇ、０．３８５ｍｍｏｌ）を加えた。反応混合物を、シールしたチューブで１２時間８０℃で加熱した。反応溶液をＨ_２Ｏ（１００ｍＬ）に注ぎ、ＤＣＭで抽出した。有機層を乾燥し（Ｎａ_２ＳＯ_４）、減圧下で濃縮し、シリカゲル（ＤＣＭ中１％ＭｅＯＨ）で精製して、標題化合物（２５０ｍｇ、９５％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６８３。 b) 1,1-dimethylethyl {2-[({5- (3-furanyl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2 -Thienyl} carbonyl) amino] -3-phenylpropyl} carbamate

1,1-Dimethylethyl (2-{[(4,5-dibromo-2-thienyl) carbonyl] amino} -3-phenylpropyl) carbamate in dioxane / H ₂ O (5: 1, 3.8 mL) To a solution of 195 mg, 0.385 mmol), K ₂ CO ₃ (213 mg, 1.54 mmol), tetrakistriphenylphosphine Pd (0) (22 mg, 19.3 μmol), and 1- (phenylsulfonyl) -3- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (148 mg, 0.385 mmol) was added. The reaction mixture was heated at 80 ° C. for 12 hours in a sealed tube. The reaction solution was poured into H ₂ O (100 mL) and extracted with DCM. The organic layer was dried (Na ₂ SO ₄ ), concentrated under reduced pressure and purified on silica gel (1% MeOH in DCM) to give the title compound (250 mg, 95%) as a yellow solid: LC-MS ( ES) m / z = 683.

c) N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide i) 1,1-dimethylethyl {2-[({5- (3-furanyl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3] in THF (2 mL) and MeOH (2 mL) To a solution of -b] pyridin-3-yl] -2-thienyl} carbonyl) amino] -3-phenylpropyl} carbamate (250 mg, 0.366 mmol) was added 6N NaOH (4 mL). After 1 hour at 25 ° C., the reaction mixture was neutralized with 1M HCl and extracted with DCM. The DCM solution was dried over Na ₂ SO ₄ , concentrated under reduced pressure and used directly: LC-MS (ES) m / z = 543 (M + H) ⁺ .
ii) Boc-amine (crude material from above) was dissolved in TFA / MeOH (1: 2, 3 mL) and stirred at room temperature for 30 minutes. The solution was then concentrated azeotropically with toluene and neutralized with a silica plug (4% MeOH in DCM (1% NH ₄ OH)), followed by further reverse phase chromatography to give the title compound (16 mg 10% -2 steps) was obtained as a TFA salt: LC-MS (ES) m / z 443 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400 MHz) δ 8.58 (d, J = 8.6 Hz, 1H), 8.28 (dd, J = 1.3, 4.6 Hz, 1H), 8.06 (bs, 2H), 7.98 (s, 1H), 7.80 (s, 1H), 7 .71 (d, J = 6.6 Hz, 1H), 7.66 (s, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.26-7.33 (m, 3H) , 7.19-7.22 (m, 1H), 7.04-7.11 (m, 1H), 6.36 ( , 1H), 4.38-4.44 (m, 1H), 2.98-3.00 (m, 2H), 2.89-2.91 (m, 2H).

Example 105

ＬＤＡの溶液を、ｎＢｕＬｉ（１ｍＬ、ヘキサン中２．５Ｍ）を、ＴＨＦ（５．２ｍＬ）中のジイソプロピルアミン（０．３９９ｍＬ、２．８６ｍｍｏｌ）に−７８℃で加えることにより調製した。これに、ＴＨＦ（２．６ｍＬ）中の３−ヨウド−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（１ｇ、２．６ｍｍｏｌ）の溶液を滴下した。１時間後、ＴＨＦ（２．６ｍＬ）中のＭｅＩ（０．１７８ｍＬ、２．８６ｍｍｏｌ）を滴下した。２５℃で１２時間加温し、溶液をＨ_２Ｏ／ＤＣＭ間で分配した。水相をさらにＤＣＭで数回抽出し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮した。残渣をＭｅＯＨでトリチュレートし、固体を濾過し、乾燥し、直接用いた（４５０ｍｇ、４３％）：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ３９９（Ｍ＋Ｈ）^＋。 3-Amino-N- [5- (3-furanyl) -4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenylmethyl) Preparation of Propanamide a) 3-Iodo-2-methyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine

A solution of LDA was prepared by adding nBuLi (1 mL, 2.5 M in hexane) to diisopropylamine (0.399 mL, 2.86 mmol) in THF (5.2 mL) at −78 ° C. To this was added dropwise a solution of 3-iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (1 g, 2.6 mmol) in THF (2.6 mL). After 1 hour, MeI (0.178 mL, 2.86 mmol) in THF (2.6 mL) was added dropwise. Warm at 25 ° C. for 12 h and partition the solution between H ₂ O / DCM. The aqueous phase was further extracted several times with DCM and the combined organic fractions were dried over Na ₂ SO ₄ and concentrated. The residue was triturated with MeOH and the solid was filtered, dried and used directly (450 mg, 43%): LC-MS (ES) m / z 399 (M + H) ⁺ .

ＤＭＦ（６ｍＬ）中の３−ヨウド−２−メチル−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（４５０ｍｇ、１．１３ｍｍｏｌ）、ビス−ピナコレートジボラン（５７４ｍｇ、２．２６ｍｍｏｌ）、酢酸カリウム（３３３ｍｇ、３．３９ｍｍｏｌ）およびＰｄ（ｄｐｐｆ）Ｃｌ_２−複合体とジクロロメタン（８１ｍｇ、０．１０２ｍｍｏｌ）の溶液を、シールしたチューブで１２時間９０℃で撹拌した。溶液を氷を加えて冷却し、６ＮのＮａＯＨでｐＨ１２〜１４に塩基性化した。水相をＤＣＭで抽出し、ついで、６ＮのＨＣｌで約ｐＨ１に酸性化した。水相をＤＣＭで数回抽出し、合したフラクションを乾燥し（Ｎａ_２ＳＯ_４）、濃縮して、標題化合物を褐色固体として得、これをさらに精製することなく用いた；ＬＣＭＳ（ｍ／ｅ）３９９（ボロン酸エステルＭ＋Ｈ）^＋、３１７（ボロン酸Ｍ＋Ｈ）^＋。 b) 2-Methyl-1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] Pyridine

3-iodo-2-methyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (450 mg, 1.13 mmol), bis-pinacolate diborane (574 mg, 2.DM in DMF (6 mL). 26 mmol), potassium acetate (333 mg, 3.39 mmol) and a solution of Pd (dppf) Cl ₂ -complex and dichloromethane (81 mg, 0.102 mmol) were stirred in a sealed tube for 12 hours at 90 ° C. The solution was cooled with ice and basified to pH 12-14 with 6N NaOH. The aqueous phase was extracted with DCM and then acidified to about pH 1 with 6N HCl. The aqueous phase was extracted several times with DCM and the combined fractions were dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a brown solid that was used without further purification; LCMS (m / e ) 399 (boronic acid ester M + H) ⁺ , 317 (boronic acid M + H) ⁺ .

c) 3-Amino-N- [5- (3-furanyl) -4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenyl) Methyl) propanamide of 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine Instead 2-methyl-1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] The title compound was obtained as a tan solid according to Example 49 except using pyridine (440 mg, 1.28 mmol): LC-MS (ES) m / z 457 (M + H) ⁺ ; ¹ H NMR (d6-DMSO, 400MHz) δ8.2 (Dd, J = 1.3, 5.3 Hz, 1H), 7.97 (bs, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 9. 4 Hz, 1H), 7.30-7.35 (m, 4H), 7.24-7.28 (m, 2H), 7.08-7.11 (m, 1H), 6.69 (s, 1H), 6.11 (s, 1H), 3.04-3.16 (m, 3H), 2.50-2.88 (m, 2H), 2.21 (s, 3H).

Example 106

Preparation of 3-amino-2- (phenylmethyl) -N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide 3-({[(1, 1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid instead of 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- (phenylmethyl) propanoic acid (0 The title compound was obtained as a brown solid according to the method of Example 21 except using .37 g, 1.3 mmol): LC-MS (ES) m / z = 377 (M + H) ⁺ ; ¹ H NMR (d _4- MeOH, 400 MHz) δ 8.38 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 1.4 Hz, 1H), 7.75 (d, J = 3.5 Hz, 1H) , 7.36 (d, J = 1.7 z, 1H), 7.31-7.20 (m, 5H), 7.15 (d, J = 3.5 Hz, 1H), 3.41-3.25 (m, 2H), 3.19- 3.09 (m, 1H) and 2.00 (dd, J = 7.0, 13.7 Hz, 1H).

Example 107

ｎＢｕＬｉ（ヘキサン中２．５Ｍ、５．５２ｍｌ）を、ＴＨＦ（２０ｍＬ）中のテトラブロモチオフェン（５．０ｇ、１２．５ｍｍｏｌ）に−７８℃で滴下し、得られた溶液を３０分間撹拌した。固体ＣＯ_２（５ｇ、１１３ｍｍｏｌ）を、上記溶液に加えた。得られた懸濁液を１時間０℃に加温した。混合物を水に注ぎ、ｐＨをＫＯＨで１０に調節し、ＥｔＯＡｃで抽出した。水層をＨＣｌでｐＨ１に調節し、ＣＨ_２Ｃｌ_２（３×３０ｍＬ）で抽出した。回収した有機層を濃縮して、所望の酸（２．３ｇ、５０％）を灰白色固体として得た。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３６６（Ｍ＋Ｈ）^＋ Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -3,4-dibromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 3,4,5-tribromo-2-thiophenecarboxylic acid

nBuLi (2.5 M in hexane, 5.52 ml) was added dropwise at −78 ° C. to tetrabromothiophene (5.0 g, 12.5 mmol) in THF (20 mL) and the resulting solution was stirred for 30 minutes. Solid CO ₂ (5 g, 113 mmol) was added to the above solution. The resulting suspension was warmed to 0 ° C. for 1 hour. The mixture was poured into water, the pH was adjusted to 10 with KOH and extracted with EtOAc. The aqueous layer was adjusted to pH 1 with HCl and extracted with CH ₂ Cl ₂ (3 × 30 mL). The collected organic layer was concentrated to give the desired acid (2.3 g, 50%) as an off-white solid. LC-MS (ES) m / z = 366 (M + H) ⁺

ジオキサン（５ｍＬ）およびＨ_２Ｏ（１ｍＬ）中の３，４，５−トリブロモ−２−チオフェンカルボン酸（０．３６ｇ、１．０ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（０．４ｇ、３．０ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．０５７ｇ、０．０５ｍｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．３８ｇ、１．０ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で４時間７０℃に加熱した。反応溶液を減圧下で濃縮し、水（５ｍＬ）で希釈した。懸濁液をＥｔＯＡｃ（５ｍＬ×３）で洗浄し、水層をｐＨ２に酸性化して、ＣＨ_２Ｃｌ_２（５ｍＬ×３）で抽出した。回収した有機層を乾燥し（Ｎａ_２ＳＯ_４）、濃縮して、灰白色固体（５５０ｍｇ）を得、これをさらに精製することなく次の工程に直接用いた。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５４３（Ｍ＋Ｈ）^＋ b) 3,4-Dibromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylic acid

To a solution of 3,4,5-tribromo-2-thiophenecarboxylic acid (0.36 g, 1.0 mmol) in dioxane (5 mL) and H ₂ O (1 mL) was added K ₂ CO ₃ (0.4 g, 3. 0 mmol), tetrakistriphenylphosphine Pd (0) (0.057 g, 0.05 mmol), and 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) -1H-pyrrolo [2,3-b] pyridine (0.38 g, 1.0 mmol) was added. The reaction mixture was heated to 70 ° C. for 4 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and diluted with water (5 mL). The suspension was washed with EtOAc (5 mL × 3) and the aqueous layer was acidified to pH 2 and extracted with CH ₂ Cl ₂ (5 mL × 3). The collected organic layer was dried (Na ₂ SO ₄ ) and concentrated to give an off-white solid (550 mg) that was used directly in the next step without further purification. LC-MS (ES) m / z = 543 (M + H) ⁺

ＤＣＭ（１０ｍＬ）中の３，４−ジブロモ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸（０．５４ｇ、１．０ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（０．７ｇ、１．５ｍｍｏｌ）およびＨｕｎｉｇ塩基（３ｍＬ、１７．０ｍｍｏｌ）を加えた。１５分後、１，１−ジメチルエチル （２−アミノ−３−フェニルプロピル）カルバメートをＤＣＭ（２ｍＬ）中の反応混合物に加え、室温で１２時間撹拌した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、１０〜２０％）で精製して、標題化合物（２６０ｍｇ、３３％、２工程）を黄色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝７７５（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl {2-[({3,4-dibromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl } Carbonyl) amino] -3-phenylpropyl} carbamate

3,4-Dibromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylic acid (0.54 g, 1 in DCM (10 mL) To a solution of PyBrop (0.7 g, 1.5 mmol) and Hunig base (3 mL, 17.0 mmol). After 15 minutes, 1,1-dimethylethyl (2-amino-3-phenylpropyl) carbamate was added to the reaction mixture in DCM (2 mL) and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 10-20%) to give the title compound (260 mg, 33%, 2 steps) as a yellow foam: LC-MS (ES) m / z = 775 (M + H) ⁺ .

ＭｅＯＨ（１０ｍＬ）中の１，１−ジメチルエチル ｛２−［（｛３，４−ジブロモ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］−３−フェニルプロピル｝カルバメート（０．２６０ｇ、０．３４ｍｍｏｌ）の溶液に、６ＮのＮａＯＨ（２．０ｍＬ）を加えた。５５℃で０．５時間後、溶媒を除去し、反応混合物をＤＣＭで抽出した。ＤＣＭ溶液をＮａ_２ＳＯ_４で乾燥し、減圧下で濃縮し、シリカゲル［ＣＨＣｌ_３：（ＣＨＣｌ_３／ＭｅＯＨ／ＮＨ_４ＯＨ、９０：１０：１）＝２０％］で精製して、黄褐色固体を得た（１６０ｍｇ、７５％）。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６３５（Ｍ＋Ｈ）^＋
上記からの固体物質をＭｅＯＨ（２ｍＬ）中に溶解し、この溶液に、ジオキサン（２．５ｍＬ）中の４ＭのＨＣｌを加えた。室温で１２時間後、反応溶液を減圧下で濃縮して、標題化合物を黄色固体として得た（８０ｍｇ、７０％）：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５３５（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ，４００ＭＨｚ）δ８．５６（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ），８．３３（ｄ，Ｊ＝９．０，１Ｈ，ＮＨ），７．８５（ｄ，Ｊ＝３．７Ｈｚ，１Ｈ），７．８１（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ），７．３８−７．２５（ｍ，５Ｈ），６．９４（ｄ，Ｊ＝３．７Ｈｚ，１Ｈ），４．６６（ｍ，１Ｈ），３．３０−３．２３（ｍ，２Ｈ），および３．１５−３．０２（ｍ，２Ｈ）。 d) N- [2-amino-1- (phenylmethyl) ethyl] -3,4-dibromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

1,1-Dimethylethyl {2-[({3,4-Dibromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] in MeOH (10 mL) To a solution of 2-thienyl} carbonyl) amino] -3-phenylpropyl} carbamate (0.260 g, 0.34 mmol) was added 6N NaOH (2.0 mL). After 0.5 h at 55 ° C., the solvent was removed and the reaction mixture was extracted with DCM. The DCM solution was dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified on silica gel [CHCl ₃ : (CHCl ₃ / MeOH / NH ₄ OH, 90: 10: 1) = 20%] to give a tan solid (160 mg, 75%) was obtained. LC-MS (ES) m / z = 635 (M + H) ⁺
The solid material from above was dissolved in MeOH (2 mL) and to this solution was added 4M HCl in dioxane (2.5 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound as a yellow solid (80 mg, 70%): LC-MS (ES) m / z = 535 (M + H) ⁺ ; ¹ H NMR (D ₄ -MeOH, 400 MHz) δ 8.56 (d, J = 6.6 Hz, 1H), 8.33 (d, J = 9.0, 1H, NH), 7.85 (d, J = 3. 7 Hz, 1H), 7.81 (d, J = 6.6 Hz, 1H), 7.38-7.25 (m, 5H), 6.94 (d, J = 3.7 Hz, 1H), 4. 66 (m, 1H), 3.30-3.23 (m, 2H), and 3.15-3.02 (m, 2H).

４−ブロモ−３−｛［（トリフルオロメチル）スルホニル］オキシ｝−２−チオフェンカルボン酸メチル

ＣＨ_２Ｃｌ_２（５ｍＬ）およびピリジン（１ｍＬ）中の４−ブロモ−３−｛［（トリフルオロメチル）スルホニル］オキシ｝−２−チオフェンカルボン酸メチル（０．９４８ｇ、４．０ｍｍｏｌ）の溶液に、０℃で、Ｔｆ_２Ｏ（１．０ｍＬ、６．０ｍｍｏｌ）を加えた。混合物を１時間撹拌し、氷水（１０ｍＬ）に注ぎ、ＣＨ_２Ｃｌ_２（５ｍＬ×３）で抽出した。回収した有機層を乾燥し（Ｎａ_２ＳＯ_４）、濃縮して、赤色油を得、これをさらに精製することなく次の工程に直接用いた。 Example 108
Of N- [2-amino-1- (phenylmethyl) ethyl] -3- (4-methylphenyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation

4-Bromo-3-{[(trifluoromethyl) sulfonyl] oxy} -2-thiophenecarboxylate methyl

To a solution of methyl 4-bromo-3-{[(trifluoromethyl) sulfonyl] oxy} -2-thiophenecarboxylate (0.948 g, 4.0 mmol) in CH ₂ Cl ₂ (5 mL) and pyridine (1 mL). At 0 ° C., Tf ₂ O (1.0 mL, 6.0 mmol) was added. The mixture was stirred for 1 hour, poured into ice water (10 mL) and extracted with CH ₂ Cl ₂ (5 mL × 3). The collected organic layer was dried (Na ₂ SO ₄ ) and concentrated to give a red oil that was used directly in the next step without further purification.

ジオキサン（５ｍＬ）中の４−ブロモ−３−｛［（トリフルオロメチル）スルホニル］オキシ｝−２−チオフェンカルボン酸メチル（０．２６ｇ、０．７１ｍｍｏｌ）の溶液に、Ｋ_３ＰＯ_４（０．４５１ｇ、２．３ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．０２０ｇ、０．０１７ｍｍｏｌ）、および（４−メチルフェニル）ボロン酸（０．１２ｇ、０．８５ｍｍｏｌ）を加えた。反応混合物をシールしたチューブで２０時間８５℃で加熱した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、５：１）で精製して、標題化合物（１８７ｍｇ、８５％）を褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３１２（Ｍ＋Ｈ）^＋。 b) methyl 4-bromo-3- (4-methylphenyl) -2-thiophenecarboxylate

To a solution of methyl 4-bromo-3-{[(trifluoromethyl) sulfonyl] oxy} -2-thiophenecarboxylate (0.26 g, 0.71 mmol) in dioxane (5 mL) was added K ₃ PO ₄ (. 451 g, 2.3 mmol), tetrakistriphenylphosphine Pd (0) (0.020 g, 0.017 mmol), and (4-methylphenyl) boronic acid (0.12 g, 0.85 mmol) were added. The reaction mixture was heated at 85 ° C. in a sealed tube for 20 hours. The reaction solution was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 5: 1) to give the title compound (187 mg, 85%) as a brown solid: LC-MS (ES) m / z = 312 (M + H) ⁺ .

ＴＨＦ／Ｈ_２Ｏ（９／１、Ｖ／Ｖ、５ｍＬ）中の４−ブロモ−３−（４−メチルフェニル）−２−チオフェンカルボン酸（１７０ｍｇ、０．５５ｍｍｏｌ）の溶液に、ＫＯＨ（１５０ｍｇ、２．６７ｍｍｏｌ）を加え、得られた混合物を２０時間５５℃で加熱した。ＴＨＦを除去した後、水層を、６ＮのＨＣｌでｐＨ２に酸性化し、ＣＨ_２Ｃｌ_２（５ｍＬ×３）で抽出した。有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮して、粗酸を得、これを次の工程に直接用いた。 c) 1,1-Dimethylethyl [2-({[4-Bromo-3- (4-methylphenyl) -2-thienyl] carbonyl} amino) -3-phenylpropyl] carbamate

To a solution of 4-bromo-3- (4-methylphenyl) -2-thiophenecarboxylic acid (170 mg, 0.55 mmol) in THF / H ₂ O (9/1, V / V, 5 mL) was added KOH (150 mg 2.67 mmol) was added and the resulting mixture was heated at 55 ° C. for 20 hours. After removal of THF, the aqueous layer was acidified to pH 2 with 6N HCl and extracted with CH ₂ Cl ₂ (5 mL × 3). The organic fraction was dried over Na ₂ SO ₄ and concentrated to give the crude acid, which was used directly in the next step.

To a solution of 4-bromo-3- (4-methylphenyl) -2-thiophenecarboxylic acid in DCM (10 mL) was added PyBrop (0.256 g, 0.55 mmol) and Hunig base (1 mL, 6.3 mmol). It was. After 15 minutes, 1,1-dimethylethyl (2-amino-3-phenylpropyl) carbamate was added to the reaction mixture in DCM (2 mL) and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 30%) to give the title compound (100 mg, 37%, 2 steps) as a yellow foam: LC-MS (ES) m / z = 502 (M + H) ⁺ .

ジオキサン（２ｍＬ）およびＨ_２Ｏ（０．４ｍＬ）中の１，１−ジメチルエチル ［２−（｛［４−ブロモ−３−（４−メチルフェニル）−２−チエニル］カルボニル｝アミノ）−３−フェニルプロピル］カルバメート（０．１０ｇ、０．２ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（０．０８５ｇ、０．６ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．０１２ｇ、０．０１ｍｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．０９２ｇ、０．２４ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で４時間７０℃に加熱した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、３：１）で精製して、標題化合物（０．０８ｇ、５７％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝７０７（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl {2-[({3- (4-methylphenyl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl]- 2-thienyl} carbonyl) amino] -3-phenylpropyl} carbamate

1,1-Dimethylethyl [2-({[4-Bromo-3- (4-methylphenyl) -2-thienyl] carbonyl} amino) -3 in dioxane (2 mL) and H ₂ O (0.4 mL) In a solution of -phenylpropyl] carbamate (0.10 g, 0.2 mmol), K ₂ CO ₃ (0.085 g, 0.6 mmol), tetrakistriphenylphosphine Pd (0) (0.012 g, 0.01 mmol), And 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (0.092 g) 0.24 mmol) was added. The reaction mixture was heated to 70 ° C. for 4 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 3: 1) to give the title compound (0.08 g, 57%) as a white solid: LC-MS (ES) m / z = 707 (M + H) ^<+> .

ＭｅＯＨ（３ｍＬ）中の１，１−ジメチルエチル ｛２−［（｛３−（４−メチルフェニル）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］−３−フェニルプロピル｝カルバメート（０．０８ｇ、０．１１ｍｍｏｌ）の溶液に、６ＮのＮａＯＨ（３．０ｍＬ）を加えた。５５℃で０．５時間後、溶媒を除去し、反応混合物をＤＣＭで抽出して、固体を得た（６０ｍｇ、９３％）。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５６７（Ｍ＋Ｈ）^＋
上記からの固体物質をＭｅＯＨ（２ｍＬ）中に溶解し、この溶液に、ジオキサン（２．５ｍＬ）中の４ＭのＨＣｌを加えた。室温で１２時間後、反応溶液を減圧下で濃縮して、標題化合物を黄色固体として得た（５０．４ｍｇ、１００％）：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４６７（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ、４００ＭＨｚ）δ８．２０−８．１８（ｍ，２Ｈ），７．６９（ｄ，Ｊ＝４．０Ｈｚ，１Ｈ），７．３５−７．２６（ｍ，３Ｈ），７．１４−７．１１（ｍ，５Ｈ），７．０１（ｓ，１Ｈ），７．００（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），６．９７（ｄ，Ｊ＝７．１Ｈｚ，１Ｈ０，６．７７（ｄ，Ｊ＝３．６Ｈｚ，１Ｈ），４．３９（ｍ，１Ｈ），３．０８（ｄｄ，Ｊ＝４．５，１２．７Ｈｚ，１Ｈ），２．９８（ｄｄ，Ｊ＝９．６，１３．３Ｈｚ，１Ｈ），２．７８（ｄｄ，Ｊ＝６．２，１４．０Ｈｚ，１Ｈ），２．６４（ｄｄ，Ｊ＝９．０，１３．９Ｈｚ，１Ｈ），および２．３２（ｓ，３Ｈ）。 e) N- [2-amino-1- (phenylmethyl) ethyl] -3- (4-methylphenyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophene Carboxamide

1,1-dimethylethyl {2-[({3- (4-methylphenyl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-4 in MeOH (3 mL) To a solution of -yl] -2-thienyl} carbonyl) amino] -3-phenylpropyl} carbamate (0.08 g, 0.11 mmol) was added 6N NaOH (3.0 mL). After 0.5 h at 55 ° C., the solvent was removed and the reaction mixture was extracted with DCM to give a solid (60 mg, 93%). LC-MS (ES) m / z = 567 (M + H) ⁺
The solid material from above was dissolved in MeOH (2 mL) and to this solution was added 4M HCl in dioxane (2.5 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound as a yellow solid (50.4 mg, 100%): LC-MS (ES) m / z = 467 (M + H) ⁺ ; ¹ 1 H NMR (d ₄ -MeOH, 400 MHz) δ 8.20-8.18 (m, 2H), 7.69 (d, J = 4.0 Hz, 1H), 7.35-7.26 (m, 3H) , 7.14-7.11 (m, 5H), 7.01 (s, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 7.1 Hz, 1H0, 6.77 (d, J = 3.6 Hz, 1H), 4.39 (m, 1H), 3.08 (dd, J = 4.5, 12.7 Hz, 1H), 2.98 (dd , J = 9.6, 13.3 Hz, 1H), 2.78 (dd, J = 6.2, 14.0 Hz, 1H), 2.64 (dd, J = 9.0). 13.9 Hz, IH), and 2.32 (s, 3H).

ａ）４−ブロモ−３−（メチルオキシ）−２−チオフェンカルボン酸メチル

ＤＭＦ（２０ｍＬ）中のＮａＨ（鉱油中６０％、２４２ｍｇ、６．０５ｍｍｏｌ）の懸濁液に、ＤＭＦ（５ｍＬ）中の４−ブロモ−３−ヒドロキシ−２−チオフェンカルボン酸メチル（１．１５ｇ、４．８５ｍｍｏｌ）を滴下した。得られた懸濁液を３０分間撹拌した。上記した混合物に、ＭｅＩ（１．７ｇ、９．７ｍｍｏｌ）を入れた。３０分後、混合物を水に注ぎ、ジエチルエーテル（１０ｍＬ×３）で抽出した。有機フラクションを乾燥し、減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、１０％）により精製して、標題化合物（１．２ｇ、９５％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝２５２（Ｍ＋Ｈ）^＋。 Example 109
Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -3- (methyloxy) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

a) Methyl 4-bromo-3- (methyloxy) -2-thiophenecarboxylate

To a suspension of NaH (60% in mineral oil, 242 mg, 6.05 mmol) in DMF (20 mL) was added methyl 4-bromo-3-hydroxy-2-thiophenecarboxylate (1.15 g, DMF (5 mL). 4.85 mmol) was added dropwise. The resulting suspension was stirred for 30 minutes. To the above mixture was added MeI (1.7 g, 9.7 mmol). After 30 minutes, the mixture was poured into water and extracted with diethyl ether (10 mL × 3). The organic fraction was dried, concentrated under reduced pressure and purified by silica gel (hexane / EtOAc, 10%) to give the title compound (1.2 g, 95%) as a white solid: LC-MS (ES) m / Z = 252 (M + H) ⁺ .

ＴＨＦ（５ｍＬ）中の４−ブロモ−３−（メチルオキシ）−２−チオフェンカルボン酸メチル（５００ｍｇ、２．０ｍｍｏｌ）の溶液に、ＫＯＨ（８Ｎ、５ｍＬ、４０ｍｍｏｌ）を加え、得られた混合物を５時間５５℃で加熱した。ＴＨを除去した後、水層を６ＮのＨＣｌでｐＨ２に酸性化し、ＣＨ_２Ｃｌ_２（５ｍＬ×３）で抽出した。有機フラクションを乾燥Ｎａ_２ＳＯ_４し、濃縮して、粗固体を得、これを次の工程に直接用いた。 b) 1,1-dimethylethyl {2-[({3- (methyloxy) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2- Thienyl} carbonyl) amino] -3-phenylpropyl} carbamate

To a solution of methyl 4-bromo-3- (methyloxy) -2-thiophenecarboxylate (500 mg, 2.0 mmol) in THF (5 mL) was added KOH (8N, 5 mL, 40 mmol) and the resulting mixture was Heated at 55 ° C. for 5 hours. After removing TH, the aqueous layer was acidified with 6N HCl to pH 2 and extracted with CH ₂ Cl ₂ (5 mL × 3). The organic fraction was dried Na ₂ SO ₄ and concentrated to give a crude solid that was used directly in the next step.

To a solution of the above acid (213 mg, 0.9 mmol) in DCM (5 mL) was added PyBrop (0.42 g, 0.9 mmol) and Hunig base (2 mL, 12.6 mmol). After 15 minutes, 1,1-dimethylethyl (2-amino-3-phenylpropyl) carbamate (150 mg, 0.6 mmol) was added into the reaction mixture and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel (hexane / EtOAc, 10-20%) to give the title compound (250 mg, 59%) as a yellow foam: LC-MS (ES) m / z = 470 (M + H) ^<+> .

ジオキサン（１０ｍＬ）およびＨ_２Ｏ（２ｍＬ）中の１，１−ジメチルエチル ｛２−［（｛３−（メチルオキシ）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］−３−フェニルプロピル｝カルバメート（０．２８０ｇ、０．６２ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（０．３４ｇ、２．４ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．０４０ｇ、０．０３４ｍｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．２３６ｇ、０．６２ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で７０℃で２時間加熱した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、３：１）で精製して、標題化合物（０．２０ｇ、５７％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６４７（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl {2-[({3- (methyloxy) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2- Thienyl} carbonyl) amino] -3-phenylpropyl} carbamate

1,1-dimethylethyl {2-[({3- (methyloxy) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-] in dioxane (10 mL) and H ₂ O (2 mL) b] Pyridin-4-yl] -2-thienyl} carbonyl) amino] -3-phenylpropyl} carbamate (0.280 g, 0.62 mmol) was added to a solution of K ₂ CO ₃ (0.34 g, 2.4 mmol). , Tetrakistriphenylphosphine Pd (0) (0.040 g, 0.034 mmol), and 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) -1H-pyrrolo [2,3-b] pyridine (0.236 g, 0.62 mmol) was added. The reaction mixture was heated in a sealed tube at 70 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 3: 1) to give the title compound (0.20 g, 57%) as a white solid: LC-MS (ES) m / z = 647 (M + H) ^<+> .

ＭｅＯＨ（３ｍＬ）中の１，１−ジメチルエチル ｛２−［（｛３−（メチルオキシ）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］−３−フェニルプロピル｝カルバメート（０．１７ｇ、０．２６ｍｍｏｌ）の溶液に、６ＮのＮａＯＨ（３．０ｍＬ）を加えた。５５℃で０．５時間後、溶媒を除去し、反応混合物をＤＣＭで抽出して、純粋な固体を得た。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５０７（Ｍ＋Ｈ）^＋ d) N- [2-amino-1- (phenylmethyl) ethyl] -3- (methyloxy) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

1,1-Dimethylethyl {2-[({3- (Methyloxy) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] in MeOH (3 mL) To a solution of] -2-thienyl} carbonyl) amino] -3-phenylpropyl} carbamate (0.17 g, 0.26 mmol) was added 6N NaOH (3.0 mL). After 0.5 h at 55 ° C., the solvent was removed and the reaction mixture was extracted with DCM to give a pure solid. LC-MS (ES) m / z = 507 (M + H) ⁺

The solid material from above was dissolved in MeOH (2 mL) and to this solution was added 4M HCl in dioxane (2.5 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound as a yellow solid (55.0 mg, 100%): LC-MS (ES) m / z = 407 (M + H) ⁺ ; ¹ 1 H NMR (d ₄ -MeOH, 400 MHz) δ 8.48 (d, J = 6.0 Hz, 1H), 8.22 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7 .78 (d, J = 3.7 Hz, 1H), 7.72 (d, J = 5.8 Hz, 1H), 7.35 (m, 5H), 6.97 (d, 3.7 Hz, 1H) 4.36 (d, J = 3.7 Hz, 1H), 4.67 (m, 1H), 3.36 (s, 3H), 3.30 (m, 2H), 3.14 (dd, J = 5.3, 14.3 Hz, 1 H) and 3.07 (dd, J = 9.3, 14.6 Hz, 1 H).

３−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−２−フェニルプロパン酸の代わりに３−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−２−（フェニルメチル）プロパン酸（０．４７ｇ、１．６ｍｍｏｌ）を用いること以外は、実施例２７に従って、標題化合物を黄色固体として得た。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４５６（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ、４００ＭＨｚ）δ８．４５（ｂｒｓ，１Ｈ），７．９３（ｄ，Ｊ＝６．４Ｈｚ，１Ｈ），７．８０（ｄ，Ｊ＝３．６Ｈｚ，１Ｈ），７．３５−７．２４（ｍ，６Ｈ），７．１１（ｄ，Ｊ＝３．６Ｈｚ，１Ｈ），６．９１（ｓ，１Ｈ），３．４１−３．２２（ｍ，２Ｈ），および３．００（ｄｄ，Ｊ＝７．５，１３．３Ｈｚ，１Ｈ） Example 110
Preparation of 3-amino-N- [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -2- (phenylmethyl) propanamide

3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-phenylpropanoic acid instead of 3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- The title compound was obtained as a yellow solid according to Example 27 except that (phenylmethyl) propanoic acid (0.47 g, 1.6 mmol) was used. LC-MS (ES) m / z = 456 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.45 (brs, 1H), 7.93 (d, J = 6.4 Hz, 1H) , 7.80 (d, J = 3.6 Hz, 1H), 7.35-7.24 (m, 6H), 7.11 (d, J = 3.6 Hz, 1H), 6.91 (s, 1H), 3.41-3.22 (m, 2H), and 3.00 (dd, J = 7.5, 13.3 Hz, 1H)

Example 111
Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -2-thiophenecarboxamide

３−アミノ−４−ピラゾールカルボキサミド（４．０ｇ、２２．８ｍｍｏｌ）およびホルムアルデヒド（１５ｍＬ）の硫酸塩を、１８０〜１９０℃で４５分間加熱した。反応混合物を室温に冷却した後、水（３０ｍＬ）に注ぎ、濾過して、標題化合物（２．８ｇ、８８％）を白色固体として得た。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝１３７（Ｍ＋Ｈ）^＋ a) 1,5-Dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one

3-Amino-4-pyrazolecarboxamide (4.0 g, 22.8 mmol) and formaldehyde (15 mL) sulfate were heated at 180-190 ° C. for 45 minutes. The reaction mixture was cooled to room temperature and then poured into water (30 mL) and filtered to give the title compound (2.8 g, 88%) as a white solid. LC-MS (ES) m / z = 137 (M + H) ⁺

ＰＯＣｌ_３（４０ｍＬ）中の１，５−ジヒドロ−４Ｈ−ピラゾロ［３，４−ｄ］ピリミジン−４−オン（２．０ｇ、１４．８ｍｍｏｌ）の溶液に、Ｎ，Ｎ−ジメチルアニリン（５ｍＬ）を加えた。混合物を１２５℃で１時間加熱した。ＰＯＣｌ_３のほとんどを減圧蒸留により除去した。残渣を氷水に撹拌しながら注ぎ、ジエチルエーテル（２０ｍＬ×３）で抽出した。有機フラクションを乾燥し、濃縮して、標題化合物（１．５ｇ、６７％）を白色固体として得た。 b) 4-Chloro-1H-pyrazolo [3,4-d] pyrimidine

To a solution of 1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one (2.0 g, 14.8 mmol) in POCl ₃ (40 mL), N, N-dimethylaniline (5 mL). Was added. The mixture was heated at 125 ° C. for 1 hour. Most of POCl ₃ was removed by vacuum distillation. The residue was poured into ice water with stirring and extracted with diethyl ether (20 mL × 3). The organic fraction was dried and concentrated to give the title compound (1.5 g, 67%) as a white solid.

ＣＨ_３ＣＮ（２ｍＬ）中の４−クロロ−１Ｈ−ピラゾロ［３，４−ｄ］ピリミジン（０．５ｇ、３．２ｍｍｏｌ）の溶液に、Ｂｏｃ_２Ｏ（０．８４ｇ、３．８ｍｍｏｌ）およびＤＭＡＰ（約２ｍｇ）を加えた。混合物を室温で１０分間撹拌し、減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、３：１）により精製して、標題化合物（０．７４ｇ、９０％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝２５５（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-1-carboxylate

To a solution of 4-chloro-1H-pyrazolo [3,4-d] pyrimidine (0.5 g, 3.2 mmol) in CH ₃ CN (2 mL) was added Boc ₂ O (0.84 g, 3.8 mmol) and DMAP. (About 2 mg) was added. The mixture was stirred at room temperature for 10 minutes, concentrated under reduced pressure, and purified by silica gel (hexane / EtOAc, 3: 1) to give the title compound (0.74 g, 90%) as a white solid: LC-MS (ES) m / z = 255 (M + H) ⁺ .

ｉ−ＰｒＭｇＣｌ（エーテル中２．０Ｍ、１．３ｍＬ）を、ＴＨＦ（５ｍＬ）中の２，２’−オキシビス（Ｎ，Ｎ−ジメチルエタンアミン）（０．４７ｍＬ）に１５℃で加えた。反応混合物を室温に加温し、１０分間撹拌した。上記の懸濁液に、ＴＨＦ（２ｍＬ）の５−ブロモ−２−チオフェンカルボン酸メチル（５６３ｍｇ、２．５５ｍｍｏｌ）を加えた。混合物を０℃に冷却し、ＴＨＦ（１ｍＬ）中の４−クロロ−１Ｈ−ピラゾロ［３，４−ｄ］ピリミジン−１−カルボン酸１，１−ジメチルエチル（２１５ｍｇ、０．８５ｍｍｏｌ）を加えた。室温で３０分間撹拌した後、反応混合物をＮＨ_４Ｃｌ（飽和水溶液）でクエンチし、ＣＨ_２Ｃｌ_２（５ｍＬ×３）で抽出した。回収した有機層を乾燥し（Ｎａ_２ＳＯ_４）、濃縮し、残渣をシリカゲル（ヘキサン／ＥｔＯＡｃ、３：１）で精製して、標題化合物（０．１６ｇ、７４％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝２６１（Ｍ＋Ｈ）^＋。 d) methyl 5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -2-thiophenecarboxylate

i-PrMgCl (2.0 M in ether, 1.3 mL) was added to 2,2′-oxybis (N, N-dimethylethanamine) (0.47 mL) in THF (5 mL) at 15 ° C. The reaction mixture was warmed to room temperature and stirred for 10 minutes. To the above suspension was added methyl 5-bromo-2-thiophenecarboxylate (563 mg, 2.55 mmol) in THF (2 mL). The mixture was cooled to 0 ° C. and 1,1-dimethylethyl 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-1-carboxylate (215 mg, 0.85 mmol) in THF (1 mL) was added. . After stirring at room temperature for 30 minutes, the reaction mixture was quenched with NH ₄ Cl (saturated aqueous solution) and extracted with CH ₂ Cl ₂ (5 mL × 3). The collected organic layers were dried (Na ₂ SO ₄ ), concentrated, and the residue was purified on silica gel (hexane / EtOAc, 3: 1) to give the title compound (0.16 g, 74%) as a white solid. : LC-MS (ES) m / z = 261 (M + H) ⁺ .

ＴＨＦ（５ｍＬ）中の５−（１Ｈ−ピラゾロ［３，４−ｄ］ピリミジン−４−イル）−２−チオフェンカルボン酸メチル（５０ｍｇ、０．１９ｍｍｏｌ）の溶液に、ＫＯＨ（５３ｍｇ、０．９５ｍｍｏｌ）を加え、得られた混合物を１２時間６０℃で加熱した。減圧下でＴＨＦを除去した後、水層を６ＮのＨＣｌでｐＨ２に酸性化し、ＣＨ_２Ｃｌ_２（５ｍＬ×３）で抽出した。有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮して、粗酸を得、これを次の工程に直接用いた。
ＤＣＭ（２ｍＬ）およびＴＨＦ（２ｍＬ）中の上記酸に、ＰｙＢｒｏｐ（０．１３２ｇ、０．２８ｍｍｏｌ）およびＨｕｎｉｇ塩基（０．２ｍＬ、１．２６ｍｍｏｌ）を加えた。１５分後、１，１−ジメチルエチル （２−アミノ−３−フェニルプロピル）カルバメート（７１ｍｇ、０．２８ｍｍｏｌ）を、反応混合物に加え、室温で１２時間撹拌した。反応溶液を減圧下で濃縮し、逆相ＨＰＬＣ（Ｃ１８カラム：Ｈ_２Ｏ／ＣＨ_３ＣＮ勾配）により精製して、標題化合物をＴＦＡ塩として得た。遊離塩基（２１ｍｇ、２３％、２工程）を、上記ＴＦＡ塩とＮＨ_４ＯＨで処理し、ついで、ＣＨ_２Ｃｌ_２で抽出することにより得た。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４７９（Ｍ＋Ｈ）^＋ e) 1,1-dimethylethyl [3-phenyl-2-({[5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -2-thienyl] carbonyl} amino) propyl] carbamate

To a solution of methyl 5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -2-thiophenecarboxylate (50 mg, 0.19 mmol) in THF (5 mL) was added KOH (53 mg, 0.95 mmol). ) And the resulting mixture was heated at 60 ° C. for 12 hours. After removing THF under reduced pressure, the aqueous layer was acidified with 6N HCl to pH 2 and extracted with CH ₂ Cl ₂ (5 mL × 3). The organic fraction was dried over Na ₂ SO ₄ and concentrated to give the crude acid, which was used directly in the next step.
To the above acid in DCM (2 mL) and THF (2 mL) was added PyBrop (0.132 g, 0.28 mmol) and Hunig base (0.2 mL, 1.26 mmol). After 15 minutes, 1,1-dimethylethyl (2-amino-3-phenylpropyl) carbamate (71 mg, 0.28 mmol) was added to the reaction mixture and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and purified by reverse phase HPLC (C18 column: H ₂ O / CH ₃ CN gradient) to give the title compound as a TFA salt. The free base (21 mg, 23%, 2 steps) was obtained by treating with the above TFA salt and NH ₄ OH followed by extraction with CH ₂ Cl ₂ . LC-MS (ES) m / z = 479 (M + H) ⁺

１，１−ジメチルエチル ［３−フェニル−２−（｛［５−（１Ｈ−ピラゾロ［３，４−ｄ］ピリミジン−４−イル）−２−チエニル］カルボニル｝アミノ）プロピル］カルバメート（２１ｍｇ、０．０４３ｍｍｏｌ）をＭｅＯＨ（２ｍＬ）中に溶解し、この溶液に、ジオキサン（１ｍＬ）中の４ＭのＨＣｌを加えた。室温で１２時間後、反応溶液を減圧下で濃縮して、標題化合物を黄色固体として得た（１０．０ｍｇ、６３％）：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３７９（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ，４００ＭＨｚ）δ８．９２（ｓ，１Ｈ），８．６９（ｓ，１Ｈ），８．２７（ｄ，Ｊ＝４．２Ｈｚ，１Ｈ），７．８３（ｄ，Ｊ＝４．２Ｈｚ，１Ｈ），７．３７−７．２２（ｍ，５Ｈ），４．５７（ｍ，１Ｈ），３．２８−３．１２（ｍ，２Ｈ），および３．１２−２．９４（ｍ，２Ｈ）。 f) N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -2-thiophenecarboxamide

1,1-dimethylethyl [3-phenyl-2-({[5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -2-thienyl] carbonyl} amino) propyl] carbamate (21 mg, 0.043 mmol) was dissolved in MeOH (2 mL) and to this solution was added 4M HCl in dioxane (1 mL). After 12 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the title compound as a yellow solid (10.0 mg, 63%): LC-MS (ES) m / z = 379 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.92 (s, 1H), 8.69 (s, 1H), 8.27 (d, J = 4.2 Hz, 1H), 7.83 (d, J = 4.2 Hz, 1H), 7.37-7.22 (m, 5H), 4.57 (m, 1H), 3.28-3.12 (m, 2H), and 3.12-2. 94 (m, 2H).

ａ）２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−１−（フェニルメチル）エチル（４，５−ジブロモ−２−チエニル）カルバメート

トルエン（１０ｍＬ）中の４，５−ジブロモチオフェンカルボン酸（０．８５ｇ、３．０ｍｍｏｌ）の混合物に、ＤＰＰＡ（１．０ｍＬ．４．５ｍｍｏｌ）およびトリエチルアミン（１．８ｍＬ、２７ｍｍｏｌ）を加えた。混合物をＮ_２雰囲気下１０分で８５に加熱し、１，１−ジメチルエチル （２−ヒドロキシ−３−フェニルプロピル）カルバメート（１．５ｇ、６．０ｍｍｏｌ）を一度に加えた。混合物を１０時間加熱還流した。これを室温に冷却した後、反応混合物を減圧下で濃縮した。フラッシュクロマトグラフィー（シリカゲル、ヘキサン／ＥｔＯＡｃ、３：１））により精製して、標題化合物（５１６ｍｇ、３２％）を白色固体として得た。ＬＣＭＳ（ＥＳ）ｍ／ｚ５３５（Ｍ＋Ｈ）^＋ Example 112
Preparation of 2-amino-1- (phenylmethyl) ethyl [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbamate

a) 2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -1- (phenylmethyl) ethyl (4,5-dibromo-2-thienyl) carbamate

To a mixture of 4,5-dibromothiophenecarboxylic acid (0.85 g, 3.0 mmol) in toluene (10 mL) was added DPPA (1.0 mL.4.5 mmol) and triethylamine (1.8 mL, 27 mmol). The mixture was heated to 85 under N ₂ atmosphere in 10 minutes and 1,1-dimethylethyl (2-hydroxy-3-phenylpropyl) carbamate (1.5 g, 6.0 mmol) was added in one portion. The mixture was heated to reflux for 10 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexane / EtOAc, 3: 1)) gave the title compound (516 mg, 32%) as a white solid. LCMS (ES) m / z 535 (M + H) ⁺

ジオキサン（１５ｍＬ）およびＨ_２Ｏ（３ｍＬ）中の２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−１−（フェニルメチル）エチル（４，５−ジブロモ−２−チエニル）カルバメート（０．１８ｇ、０．３３ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（０．１３８ｇ、１．０ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．０１８ｇ、０．０１５ｍｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．１２３ｇ、０．３２ｍｍｏｌ）を加えた。反応混合物をシールしたチューブ中で１０時間７０℃で加熱した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、２：１〜１：１）に注いで、標題化合物（１１０ｍｇ、４６％）を褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝７１２（Ｍ＋Ｈ）^＋。 b) 2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -1- (phenylmethyl) ethyl {4-bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b] pyridin-4-yl] -2-thienyl} carbamate

2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -1- (phenylmethyl) ethyl (4,5-dibromo-2-thienyl) in dioxane (15 mL) and H ₂ O (3 mL) ) A solution of carbamate (0.18 g, 0.33 mmol) was added to K ₂ CO ₃ (0.138 g, 1.0 mmol), tetrakistriphenylphosphine Pd (0) (0.018 g, 0.015 mmol), and 1- (Phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (0.123 g,. 32 mmol) was added. The reaction mixture was heated at 70 ° C. in a sealed tube for 10 hours. The reaction solution was concentrated under reduced pressure and poured onto silica gel (hexane / EtOAc, 2: 1 to 1: 1) to give the title compound (110 mg, 46%) as a brown solid: LC-MS (ES) m / z = 712 (M + H) ⁺ .

ＭｅＯＨ（３ｍＬ）中の１，１−ジメチルエチル ｛２−［（｛３−（４−メチルフェニル）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］−３−フェニルプロピル｝カルバメート（０．０６ｇ、０．０９ｍｍｏｌ）に、６ＮのＮａＯＨ（１．０ｍＬ）を加えた。５５℃で０．５時間後、溶媒を除去し、反応混合物をＤＣＭで抽出し、濃縮して、粗生成物を得た。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５７１（Ｍ＋Ｈ）^＋
上記からの固体物質をＣＨ_２Ｃｌ_２（２ｍＬ）に溶解し、この溶液にＴＦＡ（０．５ｍＬ）を加えた。１０分後、反応溶液を濃縮し、逆相ＨＰＬＣ（Ｃ１８カラム：Ｈ_２Ｏ／ＣＨ_３ＣＮ勾配）により精製して、標題化合物を黄色固体として得た（３０ｍｇ、５１％）：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４７１（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ，４００ＭＨｚ）δ８．３９（ｂｄ，Ｊ＝５．９Ｈｚ，１Ｈ），７．８４（ｄ，Ｊ＝５．８Ｈｚ，１Ｈ），７．７３（ｄ，Ｊ＝３．８Ｈｚ，１Ｈ），７．３７−７．２６（ｍ，５Ｈ），７．０３（ｄ，Ｊ＝３．４Ｈｚ，１Ｈ），６．８０（ｓ，１Ｈ），５．３３（ｍ，１Ｈ），３．３１−３．１６（ｍ，２Ｈ）および３．１３−３．０２（ｍ，２Ｈ）。 c) 2-Amino-1- (phenylmethyl) ethyl [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbamate

1,1-dimethylethyl {2-[({3- (4-methylphenyl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-4 in MeOH (3 mL) To -yl] -2-thienyl} carbonyl) amino] -3-phenylpropyl} carbamate (0.06 g, 0.09 mmol) was added 6N NaOH (1.0 mL). After 0.5 h at 55 ° C., the solvent was removed and the reaction mixture was extracted with DCM and concentrated to give the crude product. LC-MS (ES) m / z = 571 (M + H) ⁺
The solid material from above was dissolved in CH ₂ Cl ₂ (2 mL) and TFA (0.5 mL) was added to this solution. After 10 minutes, the reaction solution was concentrated and purified by reverse phase HPLC (C18 column: H ₂ O / CH ₃ CN gradient) to give the title compound as a yellow solid (30 mg, 51%): LC-MS ( ^{ES) m / z = 471 (} M + H) +; 1 H NMR (d 4 -MeOH, 400MHz) δ8.39 (bd, J = 5.9Hz, 1H), 7.84 (d, J = 5.8Hz, 1H), 7.73 (d, J = 3.8 Hz, 1H), 7.37-7.26 (m, 5H), 7.03 (d, J = 3.4 Hz, 1H), 6.80 ( s, 1H), 5.33 (m, 1H), 3.31-3.16 (m, 2H) and 3.13-3.02 (m, 2H).

ａ）４−ブロモ−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−カルボン酸

ｎＢｕＬｉ（ヘキサン中２．５Ｍ、０．８６ｍＬ）を、ＴＨＦ（５ｍＬ）中の４−ブロモ−３−ヨウド−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．５０ｇ、２．１６ｍｍｏｌ）の溶液に、−７８℃で滴下し、得られた溶液を１０分間撹拌した。ドライアイス（２ｇ、４５ｍｍｏｌ）を上記溶液に加えた。得られた懸濁液を１時間にわたって０℃に加温した。混合物を水に注ぎ、ｐＨを１０にＫＯＨで調節し、ＥｔＯＡｃで抽出した。水層をｐＨ２にＨＣｌで調節し、ＣＨ_２Ｃｌ_２（１０ｍＬ×３）で抽出した。合した有機層を濃縮して、所望の酸（０．３ｇ、７３％）を灰白色固体として得た。ＭＳ（ＥＳ）ｍ／ｚ＝３８２（Ｍ＋Ｈ）^＋ Example 113
4- [5-({[2-Amino-1- (phenylmethyl) ethyl] amino} carbonyl) -2-thienyl] -N- (2-furanylmethyl) -1H-pyrrolo [2,3-b] pyridine- Preparation of 3-carboxamide

a) 4-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid

nBuLi (2.5 M in hexane, 0.86 mL) was added 4-bromo-3-iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.50 g) in THF (5 mL). , 2.16 mmol) at −78 ° C., and the resulting solution was stirred for 10 minutes. Dry ice (2 g, 45 mmol) was added to the above solution. The resulting suspension was warmed to 0 ° C. over 1 hour. The mixture was poured into water, the pH was adjusted to 10 with KOH and extracted with EtOAc. The aqueous layer was adjusted to pH 2 with HCl and extracted with CH ₂ Cl ₂ (10 mL × 3). The combined organic layers were concentrated to give the desired acid (0.3 g, 73%) as an off-white solid. MS (ES) m / z = 382 (M + H) ⁺

ＤＣＭ（５ｍＬ）中の４−ブロモ−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−カルボン酸（２５０ｍｇ、０．６６ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（０．３１ｇ、０．６６ｍｍｏｌ）およびＨｕｎｉｇ塩基（０．２２ｍＬ、１．２６ｍｍｏｌ）を加えた。１５分後、１−（２−フラニル）メタンアミン（０．２ｍＬ、１．９ｍｍｏｌ）を、反応混合物に加え、２時間室温で撹拌した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、４０％）で精製して、標題化合物（２７０ｍｇ、９０％）を白色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４６１（Ｍ＋Ｈ）^＋。 b) 4-Bromo-N- (2-furanylmethyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-3-carboxamide

To a solution of 4-bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid (250 mg, 0.66 mmol) in DCM (5 mL) was added PyBrop (0.31 g, 0.66 mmol) and Hunig base (0.22 mL, 1.26 mmol) were added. After 15 minutes, 1- (2-furanyl) methanamine (0.2 mL, 1.9 mmol) was added to the reaction mixture and stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 40%) to give the title compound (270 mg, 90%) as a white foam: LC-MS (ES) m / z = 461. (M + H) ⁺ .

ＤＣＭ（１０ｍＬ）中の５−ブロモ−２−チオフェンカルボン酸（７００ｍｇ、３．３８ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（１．８１ｇ、３．８９ｍｍｏｌ）およびＨｕｎｉｇ塩基（２．２ｍＬ、１２．６ｍｍｏｌ）を加えた。１５分後、１，１−ジメチルエチル （２−アミノ−３−フェニルプロピル）カルバメート（７００ｍｇ、２．７８ｍｍｏｌ）を反応混合物に加え、室温で２時間撹拌した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、４０％）で精製して、標題化合物（１．１２ｇ、９２％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４４０（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl (2-{[(5-bromo-2-thienyl) carbonyl] amino} -3-phenylpropyl) carbamate

To a solution of 5-bromo-2-thiophenecarboxylic acid (700 mg, 3.38 mmol) in DCM (10 mL) was added PyBrop (1.81 g, 3.89 mmol) and Hunig base (2.2 mL, 12.6 mmol). It was. After 15 minutes, 1,1-dimethylethyl (2-amino-3-phenylpropyl) carbamate (700 mg, 2.78 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 40%) to give the title compound (1.12 g, 92%) as a white solid: LC-MS (ES) m / z = 440 (M + H) ⁺ .

ＤＭＦ（１０ｍＬ）中の１，１−ジメチルエチル （２−｛［（５−ブロモ−２−チエニル）カルボニル］アミノ｝−３−フェニルプロピル）カルバメート（１．１ｇ、２．５ｍｍｏｌ）の溶液に、ＫＯＡｃ（０．７４ｇ、５．５ｍｍｏｌ）、ビス（ピナコレート）ジボラン（０．７６ｇ、３．０ｍｍｏｌ）およびＰｄ（ｄｐｐｆ）Ｃｌ_２（０．１０ｇ、０．１３ｍｍｏｌ）を加えた。反応物を、シールしたチューブ中で１２時間８０℃で加熱した。反応溶液を減圧下で濃縮して固体を得、次の反応に直接用いた。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４０５（Ｍ＋Ｈ）^＋ d) [5-({[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -1- (phenylmethyl) ethyl] amino} carbonyl) -2-thienyl] boronic acid

To a solution of 1,1-dimethylethyl (2-{[(5-bromo-2-thienyl) carbonyl] amino} -3-phenylpropyl) carbamate (1.1 g, 2.5 mmol) in DMF (10 mL), KOAc (0.74 g, 5.5 mmol), bis (pinacolato) diborane (0.76 g, 3.0 mmol) and Pd (dppf) Cl ₂ (0.10 g, 0.13 mmol) were added. The reaction was heated at 80 ° C. for 12 hours in a sealed tube. The reaction solution was concentrated under reduced pressure to give a solid that was used directly in the next reaction. LC-MS (ES) m / z = 405 (M + H) ⁺

ジオキサン（５ｍＬ）およびＨ_２Ｏ（１ｍＬ）中の［５−（｛［２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−１−（フェニルメチル）エチル］アミノ｝カルボニル）−２−チエニル］ボロン酸（０．１４ｇ、０．３５ｍｍｏｌ）の混合物に、４−ブロモ−Ｎ−（２−フラニルメチル）−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−カルボキサミド（０．１ｇ、０．２２ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（１３ｍｇ、０．０１１ｍｍｏｌ）およびＫ_２ＣＯ_３（０．０９ｇ、０．６５ｍｍｏｌ）を加えた。Ｎ_２雰囲気下７０℃で１２時間撹拌し、反応溶液を減圧下で濃縮し、シリカ（ヘキサン／ＥｔＯＡｃ、４０〜５０％）により精製して、標題化合物（０．１５６ｇ、９７％）を明黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝７４０（Ｍ＋Ｈ）^＋。 e) 1,1-dimethylethyl {2-[({5- [3-{[(2-furanylmethyl) amino] carbonyl} -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine- 4-yl] -2-thienyl} carbonyl) amino] -3-phenylpropyl} carbamate

[5-({[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -1- (phenylmethyl) ethyl] amino} carbonyl in dioxane (5 mL) and H ₂ O (1 mL) ) -2-thienyl] boronic acid (0.14 g, 0.35 mmol) was added to 4-bromo-N- (2-furanylmethyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]. Pyridine-3-carboxamide (0.1 g, 0.22 mmol), Pd (PPh ₃ ) ₄ (13 mg, 0.011 mmol) and K ₂ CO ₃ (0.09 g, 0.65 mmol) were added. Stir at 70 ° C. under N ₂ atmosphere for 12 hours, concentrate the reaction solution under reduced pressure and purify on silica (hexane / EtOAc, 40-50%) to give the title compound (0.156 g, 97%) as light yellow Obtained as a solid: LC-MS (ES) m / z = 740 (M + H) ⁺ .

ＭｅＯＨ（３ｍＬ）中の１，１−ジメチルエチル ｛２−［（｛５−［３−｛［（２−フラニルメチル）アミノ］カルボニル｝−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］−３−フェニルプロピル｝カルバメート（０．１６ｇ、０．２６ｍｍｏｌ）の溶液に、６ＮのＮａＯＨ（２．０ｍＬ）を加えた。室温で０．５時間後、溶媒を除去し、反応混合物をＤＣＭで抽出し、濃縮して、粗生成物を得た。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６００（Ｍ＋Ｈ）^＋
上記からの固体物質をＣＨ_２Ｃｌ_２（２ｍＬ）中に溶解し、この溶液にＴＦＡ（２ｍＬ）を加えた。１０分後、反応溶液を濃縮し、逆相ＨＰＬＣ（Ｃ１８カラム：Ｈ_２Ｏ／ＣＨ_３ＣＮ勾配）に付して、標題化合物を黄色固体として得た（８０ｍｇ、５１％）：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５００（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ，４００ＭＨｚ）δ８．３７（ｂｒｓ，１Ｈ），７．７０（ｂｒｓ，２Ｈ），７．５０（ｄ，Ｊ＝４．９Ｈｚ，１Ｈ），７．４８（ｍ，１Ｈ），７．３２−７．２９（ｍ，５Ｈ），７．２６−７．２０（ｍ，１Ｈ０，６．４０（ｄｄ，Ｊ＝１．９，３．２Ｈｚ，１Ｈ），６．３７（ｄｄ，Ｊ＝０．７，３．３Ｈｚ，１Ｈ），４．５０−４．６７（ｍ，３Ｈ），３．２９−３．１７（ｍ，２Ｈ），および３．０７−２．９８（ｍ，２Ｈ）。 f) 4- [5-({[2-Amino-1- (phenylmethyl) ethyl] amino} carbonyl) -2-thienyl] -N- (2-furanylmethyl) -1H-pyrrolo [2,3-b] Pyridine-3-carboxamide

1,1-dimethylethyl {2-[({5- [3-{[(2-furanylmethyl) amino] carbonyl} -1- (phenylsulfonyl) -1H-pyrrolo [2,3-] in MeOH (3 mL) b] To a solution of pyridin-4-yl] -2-thienyl} carbonyl) amino] -3-phenylpropyl} carbamate (0.16 g, 0.26 mmol) was added 6N NaOH (2.0 mL). After 0.5 h at room temperature, the solvent was removed and the reaction mixture was extracted with DCM and concentrated to give the crude product. LC-MS (ES) m / z = 600 (M + H) ⁺
The solid material from above was dissolved in CH ₂ Cl ₂ (2 mL) and TFA (2 mL) was added to this solution. After 10 minutes, the reaction solution was concentrated and subjected to reverse phase HPLC (C18 column: H ₂ O / CH ₃ CN gradient) to give the title compound as a yellow solid (80 mg, 51%): LC-MS ( ES) m / z = 500 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.37 (brs, 1H), 7.70 (brs, 2H), 7.50 (d, J = 4) .9 Hz, 1H), 7.48 (m, 1H), 7.32-7.29 (m, 5H), 7.26-7.20 (m, 1H0, 6.40 (dd, J = 1. 9, 3.2 Hz, 1H), 6.37 (dd, J = 0.7, 3.3 Hz, 1H), 4.50-4.67 (m, 3H), 3.29-3.17 (m) , 2H), and 3.07-2.98 (m, 2H).

ａ）４−ブロモ−２−（３−フラニル）−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン

ＤＭＦ（２ｍＬ）およびトリエチルアミン（１ｍＬ）中の４−ブロモ−２−ヨウド−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（２２０ｍｇ、０．４８ｍｍｏｌ）および３−フラニルボロン酸（５７ｍｇ、０．５０ｍｍｏｌ）の混合物に、ＣｕＩ（１０ｍｇ、０．０５ｍｍｏｌ）、およびＰｄ（ＰＰｈ_３）_２Ｃｌ_２（１７ｍｇ、０．０２４ｍｍｏｌ）を加えた。Ｎ_２雰囲気下室温で４時間撹拌し、反応溶液を減圧下で濃縮し、シリカ（ＣＨＣｌ_３／ＭｅＯＨ、９５：５）で精製して、標題化合物（０．１５６ｇ、８３％）を明黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４０４（Ｍ＋Ｈ）^＋。 Example 114
Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- [2- (3-furanyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxamide

a) 4-Bromo-2- (3-furanyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine

4-Bromo-2-iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (220 mg, 0.48 mmol) and 3-furanylboronic acid in DMF (2 mL) and triethylamine (1 mL) ( To a mixture of 57 mg, 0.50 mmol) was added CuI (10 mg, 0.05 mmol) and Pd (PPh ₃ ) ₂ Cl ₂ (17 mg, 0.024 mmol). Stir at room temperature for 4 hours under N ₂ atmosphere and concentrate the reaction solution under reduced pressure and purify on silica (CHCl ₃ / MeOH, 95: 5) to give the title compound (0.156 g, 83%) as a light yellow solid Obtained as: LC-MS (ES) m / z = 404 (M + H) ^<+> .

ジオキサン（５ｍＬ）およびＨ_２Ｏ（１ｍＬ）中の［５−（｛［２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−１−（フェニルメチル）エチル］アミノ｝カルボニル）−２−チエニル］ボロン酸（０．１６ｇ、０．４０ｍｍｏｌ）の混合物に、４−ブロモ−２−（３−フラニル）−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．０８ｇ、０．２ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（１２ｍｇ、０．０１１ｍｍｏｌ）およびＫ_２ＣＯ_３（０．０８ｇ、０．６ｍｍｏｌ）を加えた。Ｎ_２雰囲気下１２時間７０℃で加熱し、反応溶液を減圧下で濃縮し、シリカ（Ｈｅｘ／ＥｔＯＡｃ、３０〜４０％）により精製して、標題化合物（０．０５５ｇ、４１％）を明黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６８３（Ｍ＋Ｈ）^＋。 b) 1,1-dimethylethyl {2-[({5- [2- (3-furanyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2 -Thienyl} carbonyl) amino] -3-phenylpropyl} carbamate

[5-({[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -1- (phenylmethyl) ethyl] amino} carbonyl in dioxane (5 mL) and H ₂ O (1 mL) ) -2-thienyl] boronic acid (0.16 g, 0.40 mmol) was added to 4-bromo-2- (3-furanyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]. Pyridine (0.08 g, 0.2 mmol), Pd (PPh ₃ ) ₄ (12 mg, 0.011 mmol) and K ₂ CO ₃ (0.08 g, 0.6 mmol) were added. Heat at 70 ° C. under N ₂ atmosphere for 12 hours, concentrate the reaction solution under reduced pressure and purify on silica (Hex / EtOAc, 30-40%) to give the title compound (0.055 g, 41%) as light yellow Obtained as a solid: LC-MS (ES) m / z = 683 (M + H) ⁺ .

ＭｅＯＨ（２ｍＬ）中の１，１−ジメチルエチル ｛２−［（｛５−［２−（３−フラニル）−１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）アミノ］−３−フェニルプロピル｝カルバメート（０．０４２ｇ、０．０６ｍｍｏｌ）の溶液に、６ＮのＮａＯＨ（２．０ｍＬ）を加えた。室温で０．５時間後、溶媒を除去し、反応混合物をＤＣＭで抽出し、Ｎａ_２ＳＯ_４で乾燥し、濃縮して、粗生成物を得、これを次の工程に直接用いた。
上記からの固体物質をＣＨ_２Ｃｌ_２（２ｍＬ）に溶解し、この溶液にＴＦＡ（２ｍＬ）を加えた。１０分後、反応溶液を濃縮し、逆相ＨＰＬＣ（Ｃ１８カラム：Ｈ_２Ｏ／ＣＨ_３ＣＮ勾配）により精製して、標題化合物を黄色固体として得た（１３ｍｇ、３１％）：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４４３（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ、４００ＭＨｚ）δ８．２１（ｂｒｓ，１Ｈ），７．９４（ｄ，Ｊ＝４．１Ｈｚ，１Ｈ），７．８４（ｄ，Ｊ＝３．９Ｈｚ，１Ｈ），７．７０（ｄｄ，Ｊ＝１．７，１．７Ｈｚ，１Ｈ），７．６５（ｄ，Ｊ＝５．９Ｈｚ，１Ｈ），７．３４−７．３３（ｍ，５Ｈ），７．２８−７．２２（ｍ，２Ｈ），７．０３（ｄｄ，Ｊ＝２．０，０．８Ｈｚ，１Ｈ），４．５９（ｍ，１Ｈ），３．２８−３．１４（ｍ，２Ｈ）および３．０６−２．９９（ｍ，２Ｈ）。 c) N- [2-amino-1- (phenylmethyl) ethyl] -5- [2- (3-furanyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxamide

1,1-dimethylethyl in MeOH (2 mL) {2-[({5- [2- (3-furanyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-4- To a solution of yl] -2-thienyl} carbonyl) amino] -3-phenylpropyl} carbamate (0.042 g, 0.06 mmol) was added 6N NaOH (2.0 mL). After 0.5 h at room temperature, the solvent was removed and the reaction mixture was extracted with DCM, dried over Na ₂ SO ₄ and concentrated to give the crude product, which was used directly in the next step.
The solid material from above was dissolved in CH ₂ Cl ₂ (2 mL) and TFA (2 mL) was added to this solution. After 10 minutes, the reaction solution was concentrated and purified by reverse phase HPLC (C18 column: H ₂ O / CH ₃ CN gradient) to give the title compound as a yellow solid (13 mg, 31%): LC-MS ( ES) m / z = 443 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.21 (brs, 1 H), 7.94 (d, J = 4.1 Hz, 1 H), 7.84 (D, J = 3.9 Hz, 1H), 7.70 (dd, J = 1.7, 1.7 Hz, 1H), 7.65 (d, J = 5.9 Hz, 1H), 7.34− 7.33 (m, 5H), 7.28-7.22 (m, 2H), 7.03 (dd, J = 2.0, 0.8 Hz, 1H), 4.59 (m, 1H), 3.28-3.14 (m, 2H) and 3.06-2.99 (m, 2H).

ａ）１，１−ジメチルエチル （２−オキソ−３−フェニルプロピル）カルバメート

ＤＣＭ（８０ｍＬ）中の塩化オキサリル（１．６ｍＬ、１８ｍｍｏｌ）の溶液に、−７８℃で、ＤＭＳＯ（２．０ｍＬ、２８ｍｍｏｌ）を加え、２０分間撹拌した。上記懸濁液に、ＤＣＭ（３ｍＬ）中の１，１−ジメチルエチル （２−ヒドロキシ−３−フェニルプロピル）カルバメート（３．０ｇ、１２ｍｍｏｌ）を加えた。混合物を−７８℃で２時間撹拌した後、トリエチルアミン（２０ｍＬ）を加えた。得られた懸濁液を１時間にわたって０℃に加温した。混合物を−７８℃に再び冷却し、５０ｍＬの飽和ＮＨ_４Ｃｌでクエンチした。混合物をＤＣＭで抽出し、合した有機相を乾燥し（Ｎａ_２ＳＯ_４）、減圧下で濃縮した。残渣をシリカゲル（ヘキサン／ＥｔＯＡｃ、２０％）により精製して、標題化合物（２．２ｇ、７０％）を無色油として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝２５０（Ｍ＋Ｈ）^＋。 Example 115
Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-N-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

a) 1,1-dimethylethyl (2-oxo-3-phenylpropyl) carbamate

To a solution of oxalyl chloride (1.6 mL, 18 mmol) in DCM (80 mL) at −78 ° C. was added DMSO (2.0 mL, 28 mmol) and stirred for 20 minutes. To the above suspension was added 1,1-dimethylethyl (2-hydroxy-3-phenylpropyl) carbamate (3.0 g, 12 mmol) in DCM (3 mL). The mixture was stirred at −78 ° C. for 2 hours before triethylamine (20 mL) was added. The resulting suspension was warmed to 0 ° C. over 1 hour. The mixture was cooled again to −78 ° C. and quenched with 50 mL of saturated NH ₄ Cl. The mixture was extracted with DCM and the combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel (hexane / EtOAc, 20%) to give the title compound (2.2 g, 70%) as a colorless oil: LC-MS (ES) m / z = 250 (M + H) ⁺ .

ＥｔＯＨ（１０ｍＬ）および水（２０ｍＬ）中の１，１−ジメチルエチル （２−オキソ−３−フェニルプロピル）カルバメート（２．０ｇ、８ｍｍｏｌ）、ヒドロキシ塩化アンモニウム（１．６５ｇ、２４ｍｍｏｌ）の混合物に、ＮａＯＡｃ（２．６４ｇ、３２ｍｍｏｌ）を加えた。３０分間撹拌した後、混合物を濃縮して、粗１，１−ジメチルエチル ［（２Ｅ）−２−（ヒドロキシイミノ）−３−フェニルプロピル］カルバメートを得た。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝２６５（Ｍ＋Ｈ）^＋ b) 1,1-dimethylethyl [2- (hydroxyamino) -3-phenylpropyl] carbamate

To a mixture of 1,1-dimethylethyl (2-oxo-3-phenylpropyl) carbamate (2.0 g, 8 mmol), hydroxyammonium chloride (1.65 g, 24 mmol) in EtOH (10 mL) and water (20 mL), NaOAc (2.64 g, 32 mmol) was added. After stirring for 30 minutes, the mixture was concentrated to give crude 1,1-dimethylethyl [(2E) -2- (hydroxyimino) -3-phenylpropyl] carbamate. LC-MS (ES) m / z = 265 (M + H) ⁺

To a solution of the above compound (˜8 mmol) in THF (20 mL) and AcOH (5 mL) was added NaBH ₃ CN (1.5 g, 24 mmol). The mixture was stirred for 2 h and quenched with 10 mL saturated NH ₄ Cl. The mixture was neutralized with DCM and the combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel (hexane / EtOAc, 10%) to give the title compound (1.6 g, 74%) as a clear oil: LC-MS (ES) m / z = 267 (M + H) ⁺ .

ＤＣＭ（１０ｍＬ）中の４，５−ジブロモ−２−チオフェンカルボン酸（１．０ｇ、３．２５ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（１．５ｇ、３．２５ｍｍｏｌ）およびＨｕｎｉｇ塩基（１ｍＬ、６．３ｍｍｏｌ）を加えた。１５分後、１，１−ジメチルエチル ［２−（ヒドロキシアミノ）−３−フェニルプロピル］カルバメート（３５０ｍｇ、１．３１ｍｍｏｌ）を、ＤＣＭ（２ｍＬ）中の反応混合物に加え、室温で２時間撹拌した。反応溶液を濃縮して、粗１，１−ジメチルエチル ［２−（［（４，５−ジブロモ−２−チエニル）カルボニル］｛［（４，５−ジブロモ−２−チエニル）カルボニル］オキシ｝アミノ）−３−フェニルプロピル］カルバメートを得た。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝８０３（Ｍ＋Ｈ）^＋ c) 1,1-dimethylethyl {2-[[(4,5-dibromo-2-thienyl) carbonyl] (hydroxy) amino] -3-phenylpropyl} carbamate

To a solution of 4,5-dibromo-2-thiophenecarboxylic acid (1.0 g, 3.25 mmol) in DCM (10 mL) was added PyBrop (1.5 g, 3.25 mmol) and Hunig base (1 mL, 6.3 mmol). Was added. After 15 minutes, 1,1-dimethylethyl [2- (hydroxyamino) -3-phenylpropyl] carbamate (350 mg, 1.31 mmol) was added to the reaction mixture in DCM (2 mL) and stirred at room temperature for 2 hours. . The reaction solution was concentrated to give crude 1,1-dimethylethyl [2-([(4,5-dibromo-2-thienyl) carbonyl] {[(4,5-dibromo-2-thienyl) carbonyl] oxy} amino. ) -3-Phenylpropyl] carbamate was obtained. LC-MS (ES) m / z = 803 (M + H) ⁺

1,1-dimethylethyl [2-([(4,5-dibromo-2-thienyl) carbonyl] {[(4,5-dibromo-2-thienyl) carbonyl] oxy} amino)-in MeOH (5 mL)- to a solution of 3-phenylpropyl] _{carbamate, K 2 CO 3 (1.0g,} 7.3mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 30%) to give the title compound (350 mg, 50%, 2 steps) as a yellow solid: LC-MS (ES) m / z = 535 (M + H) ⁺ .

ジオキサン（５ｍＬ）およびＨ_２Ｏ（１ｍＬ）中の１，１−ジメチルエチル ｛２−［［（４，５−ジブロモ−２−チエニル）カルボニル］（ヒドロキシ）アミノ］−３−フェニルプロピル｝カルバメート（０．３０ｇ、０．５６ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（０．２３ｇ、１．６７ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．０３２ｇ、０．０２８ｍｍｏｌ）、および［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］ボロン酸（０．２０４ｇ、０．６２ｍｍｏｌ）を加えた。反応混合物をシールしたチューブで２時間７０℃に加熱した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、３：１）で精製して、標題化合物（０．２９ｇ、７２％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝７１２（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl {2-[({4-bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbonyl ) (Hydroxy) amino] -3-phenylpropyl} carbamate

1,1-dimethylethyl {2-[[(4,5-dibromo-2-thienyl) carbonyl] (hydroxy) amino] -3-phenylpropyl} carbamate (1 mL in dioxane (5 mL) and H ₂ O (1 mL) 0.30 g, 0.56 mmol) to a solution of K ₂ CO ₃ (0.23 g, 1.67 mmol), tetrakistriphenylphosphine Pd (0) (0.032 g, 0.028 mmol), and [1- (phenyl Sulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] boronic acid (0.204 g, 0.62 mmol) was added. The reaction mixture was heated to 70 ° C. for 2 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 3: 1) to give the title compound (0.29 g, 72%) as a yellow solid: LC-MS (ES) m / z = 712 (M + H) ^<+> .

ＭｅＯＨ（３ｍＬ）中の１，１−ジメチルエチル ｛２−［（｛４−ブロモ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チエニル｝カルボニル）（ヒドロキシ）アミノ］−３−フェニルプロピル｝カルバメート（０．１２ｇ、０．１７ｍｍｏｌ）の溶液に、６ＮのＮａＯＨ（２．０ｍＬ）を加えた。室温で０．５時間後、溶媒を除去し、反応混合物をＤＣＭで抽出し、Ｎａ_２ＳＯ_４で乾燥し、濃縮して、粗生成物を得、これを次の工程に直接用いた。 e) N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-N-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

1,1-dimethylethyl {2-[({4-bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2 in MeOH (3 mL) To a solution of -thienyl} carbonyl) (hydroxy) amino] -3-phenylpropyl} carbamate (0.12 g, 0.17 mmol) was added 6N NaOH (2.0 mL). After 0.5 h at room temperature, the solvent was removed and the reaction mixture was extracted with DCM, dried over Na ₂ SO ₄ and concentrated to give the crude product, which was used directly in the next step.

The solid material from above was dissolved in CH ₂ Cl ₂ (2 mL) and TFA (2 mL) was added to this solution. After 10 minutes, the reaction solution was concentrated and purified by reverse phase HPLC (C18 column: H ₂ O / CH ₃ CN gradient) to give the title compound as a yellow solid (61 mg, 51%) 10: 1 isomer mixture. Obtained as: LC-MS (ES) m / z = 472 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz), main isomer: δ 8.40 (brs, 1H), 7.94 (s , 1H), 7.65 (d, 2.9 Hz, 1H), 7.53 (d, J = 6.4 Hz, 1H), 7.35-7.21 (m, 6H), 6.77 (d , J = 2.9 Hz, 1H), 5.16 (m, 1H), 3.39 (dd, J = 11.3, 13.4 Hz, 1H), 3.180-3.11 (m, 2H) , And 2.97 (dd, J = 6.3, 14.0 Hz, 1H).

４，５−ジブロモ−２−チオフェンカルボン酸の代わりに４−ブロモ−２−チオフェンカルボン酸（０．２３ｇ、１．１２ｍｍｏｌ）を用いること以外は、実施例１１５に従って、標題化合物を褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３９３（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ，４００ＭＨｚ）δ８．８５（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），８．４５（ｂｒｓ，１Ｈ），８．２４（ｓ，１Ｈ），８．０３（ｄ，Ｊ＝１．５Ｈｚ，１Ｈ），７．９６−７．９２（ｍ，１Ｈ），７．６０−７．５６（ｍ，１Ｈ），７．３６−７．３２（ｍ，２Ｈ），７．２９−７．２５（ｍ，２Ｈ），７．２２−７．１８（ｍ，１Ｈ），５．１９（ｍ，１Ｈ），３．４０（ｄｄ，Ｊ＝１０．８，１３．５Ｈｚ，１Ｈ），３．１９−３．１３（ｍ，２Ｈ），および２．９６（ｄｄ，Ｊ＝７．０，１３．９，１Ｈ）。 Example 116
Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -N-hydroxy-4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

The title compound was obtained as a brown solid according to Example 115 except that 4-bromo-2-thiophenecarboxylic acid (0.23 g, 1.12 mmol) was used instead of 4,5-dibromo-2-thiophenecarboxylic acid. : LC-MS (ES) m / z = 393 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.85 (d, J = 8.6 Hz, 1 H), 8.45 (brs, 1H), 8.24 (s, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.96-7.92 (m, 1H), 7.60-7.56 (m, 1H), 7.36-7.32 (m, 2H), 7.29-7.25 (m, 2H), 7.22-7.18 (m, 1H), 5.19 (m, 1H) 3.40 (dd, J = 10.8, 13.5 Hz, 1H), 3.19-3.13 ( , 2H), and 2.96 (dd, J = 7.0,13.9,1H).

４，５−ジブロモ−２−チオフェンカルボン酸の代わりに４−ブロモ−２−チオフェンカルボン酸（０．２３ｇ、１．１２ｍｍｏｌ）を、１−（フェニルスルホニル）−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジンの代わりに１−（フェニルスルホニル）−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．２ｇ、０．５２ｍｍｏｌ）を用いること以外は、実施例１１５に従って、標題化合物を褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３９３（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ，４００ＭＨｚ）δ８．８４（ｂｒｄ，Ｊ＝７．３Ｈｚ，１Ｈ），８．４５（ｂｒｄ，Ｊ＝３．０Ｈｚ，１Ｈ），８．２４（ｓ，１Ｈ），８．０４（ｄ，７．５，１Ｈ），７．９６−７．９３（ｍ，１Ｈ），７．６０−７．５６（ｍ，１Ｈ），７．３５−７．１８（ｍ，５Ｈ），５．２０（ｍ，１Ｈ），３．４０（ｄｄ，Ｊ＝１１．０，１４．０Ｈｚ，１Ｈ），３．１９−３．１３（ｍ，２Ｈ），および２．９６（ｄｄ，Ｊ＝７．０，１３．５Ｈｚ，１Ｈ）。 Example 117
Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -N-hydroxy-3- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide

Instead of 4,5-dibromo-2-thiophenecarboxylic acid, 4-bromo-2-thiophenecarboxylic acid (0.23 g, 1.12 mmol) was replaced with 1- (phenylsulfonyl) -3- (4,4,5,5). Instead of 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine, 1- (phenylsulfonyl) -3- (4,4,5,5- The title compound was prepared according to Example 115 except that tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (0.2 g, 0.52 mmol) was used. Obtained as a brown solid: LC-MS (ES) m / z = 393 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.84 (brd, J = 7.3 Hz, 1H), 8. 45 (b d, J = 3.0 Hz, 1H), 8.24 (s, 1H), 8.04 (d, 7.5, 1H), 7.96-7.93 (m, 1H), 7.60- 7.56 (m, 1H), 7.35-7.18 (m, 5H), 5.20 (m, 1H), 3.40 (dd, J = 11.0, 14.0 Hz, 1H), 3.19-3.13 (m, 2H), and 2.96 (dd, J = 7.0, 13.5 Hz, 1H).

１，１−ジメチルエチル ［２−（ヒドロキシアミノ）−３−フェニルプロピル］カルバメートの代わりに１，１−ジメチルエチル （３−フェニル−２−｛［（フェニルメチル）オキシ］アミノ｝プロピル）カルバメート（０．１５ｇ、０．４２ｍｍｏｌ）を用いること以外は、実施例１１６に従って、標題化合物を褐色固体として得た。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４８３（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ，４００ＭＨｚ）δ８．５４（ｄ，Ｊ＝１．５Ｈｚ，１Ｈ），８．３９（ｄ，Ｊ＝５．６Ｈｚ，１Ｈ），８．２５（ｄ，Ｊ＝１．５Ｈｚ，１Ｈ），７．７０（ｄ，Ｊ＝３．８Ｈｚ，１Ｈ），７．５３（ｄ，Ｊ＝６．０Ｈｚ，１Ｈ），７．４０−７．３６（ｍ，５Ｈ），７．３４−７．１６（ｍ，５Ｈ），６．９３（ｄ，Ｊ＝３．５Ｈｚ，１Ｈ），４．９５（ｓ，２Ｈ），４．８８（ｍ，１Ｈ），３．６０（ｄｄ，Ｊ＝９．２，１２．８Ｈｚ，１Ｈ），３．４３−３．３５（ｍ，２Ｈ），および３．１５（ｄｄ，Ｊ＝６．０，１４．０Ｈｚ，１Ｈ） Example 118
N- [2-amino-1- (phenylmethyl) ethyl] -N-[(phenylmethyl) oxy] -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation of

1,1-dimethylethyl (3-phenyl-2-{[(phenylmethyl) oxy] amino} propyl) carbamate instead of 1,1-dimethylethyl [2- (hydroxyamino) -3-phenylpropyl] carbamate ( 0.15 g, 0.42 mmol) was used according to Example 116 to give the title compound as a brown solid. LC-MS (ES) m / z = 483 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.54 (d, J = 1.5 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.25 (d, J = 1.5 Hz, 1H), 7.70 (d, J = 3.8 Hz, 1H), 7.53 (d, J = 6.0 Hz, 1H) ), 7.40-7.36 (m, 5H), 7.34-7.16 (m, 5H), 6.93 (d, J = 3.5 Hz, 1H), 4.95 (s, 2H) ), 4.88 (m, 1H), 3.60 (dd, J = 9.2, 12.8 Hz, 1H), 3.43-3.35 (m, 2H), and 3.15 (dd, J = 6.0, 14.0 Hz, 1H)

ａ）５−ブロモ−２−チオフェンカルボアルデヒドオキシム（異性体ＡおよびＢ）

ＥｔＯＨ（１０ｍＬ）および水（２０ｍＬ）中の５−ブロモ−２−チオフェンカルボアルデヒド（３．８２ｇ、２０ｍｍｏｌ）、ヒドロキシル塩化アンモニウム（４．１４ｇ、６０ｍｍｏｌ）の混合物に、ＮａＯＡｃ（６．５ｇ、８０ｍｍｏｌ）を加えた。３０分間撹拌した後、混合物を濃縮し、フラッシュクロマトグラフィー（シリカゲル、ヘキサン／ＥｔＯＡｃ、１：１）を用いて精製して、分離可能な異性体Ａ（１．２ｇ、３０％）および異性体Ｂ（２．４１ｇ、６０％）をそれぞれ黄褐色固体として得た。相対的な幾何学は不明であるが、記載のように決定する。ＬＣＭＳ（ＥＳ）ｍ／ｚ２０７（Ｍ＋Ｈ）^＋ Example 119
Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -N′-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboximidamide

a) 5-Bromo-2-thiophenecarbaldehyde oxime (isomers A and B)

To a mixture of 5-bromo-2-thiophenecarbaldehyde (3.82 g, 20 mmol), hydroxylammonium chloride (4.14 g, 60 mmol) in EtOH (10 mL) and water (20 mL) was added NaOAc (6.5 g, 80 mmol). Was added. After stirring for 30 minutes, the mixture was concentrated and purified using flash chromatography (silica gel, hexane / EtOAc, 1: 1) to give separable isomer A (1.2 g, 30%) and isomer B. (2.41 g, 60%) were each obtained as a tan solid. The relative geometry is unknown but is determined as described. LCMS (ES) m / z 207 (M + H) ⁺

ＤＭＦ（５ｍＬ）中の異性体Ｂ（７３０ｍｇ、３．５４ｍｍｏｌ）の溶液に、室温で、Ｎ−クロロスクシンアミド（４７８ｍｇ、３．６ｍｍｏｌ）を加えた。得られた混合物を３０分間７０℃で加熱し、室温に冷却した。上記混合物に、１，１−ジメチルエチル （２−アミノ−３−フェニルプロピル）カルバメート（１．１５ｇ、４．６ｍｍｏｌ）を加えた。３０分間撹拌した後、混合物を濃縮し、フラッシュクロマトグラフィー（シリカゲル、ヘキサン／ＥｔＯＡｃ、２：１）を用いて精製して、標題化合物（３００ｍｇ、２０％、２工程）を黄褐色固体として得た。ＬＣＭＳ（ＥＳ）ｍ／ｚ４５５（Ｍ＋Ｈ）^＋ b) 1,1-dimethylethyl (2-{[(5-bromo-2-thienyl) (hydroxyamino) methylidene] amino} -3-phenylpropyl) carbamate (from isomer B)

To a solution of isomer B (730 mg, 3.54 mmol) in DMF (5 mL) was added N-chlorosuccinamide (478 mg, 3.6 mmol) at room temperature. The resulting mixture was heated at 70 ° C. for 30 minutes and cooled to room temperature. To the above mixture was added 1,1-dimethylethyl (2-amino-3-phenylpropyl) carbamate (1.15 g, 4.6 mmol). After stirring for 30 minutes, the mixture was concentrated and purified using flash chromatography (silica gel, hexane / EtOAc, 2: 1) to give the title compound (300 mg, 20%, 2 steps) as a tan solid. . LCMS (ES) m / z 455 (M + H) ⁺

ジオキサン（１０ｍＬ）およびＨ_２Ｏ（２ｍＬ）中の１，１−ジメチルエチル （２−｛［（５−ブロモ−２−チエニル）（ヒドロキシアミノ）メチリデン］アミノ｝−３−フェニルプロピル）カルバメート（異性体Ｂから）（０．３ｇ、０．６６ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（０．２７ｇ、１．９５ｍｍｏｌ）、テトラキストリフェニルホスフィンＰｄ（０）（０．０７５ｇ、０．０６ｍｍｏｌ）、および１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．２６ｇ、０．６８ｍｍｏｌ）を加えた。反応混合物をシールしたチューブで２時間７０℃に加熱した。反応溶液を減圧下で濃縮し、シリカゲル（ヘキサン／ＥｔＯＡｃ、２：１〜１：１）で精製して、標題化合物（３４０ｍｇ、８２％）を褐色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝６３２（Ｍ＋Ｈ）^＋。 c) N- [2- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) -1- (phenylmethyl) ethyl] -N′-hydroxy-5- [1- ( Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboximidamide (from isomer B)

1,1-Dimethylethyl (2-{[(5-bromo-2-thienyl) (hydroxyamino) methylidene] amino} -3-phenylpropyl) carbamate (isomerism) in dioxane (10 mL) and H ₂ O (2 mL) (From Form B) (0.3 g, 0.66 mmol) in a solution of K ₂ CO ₃ (0.27 g, 1.95 mmol), tetrakistriphenylphosphine Pd (0) (0.075 g, 0.06 mmol), and 1- (phenylsulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (0.26 g, 0.68 mmol) was added. The reaction mixture was heated to 70 ° C. for 2 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and purified on silica gel (hexane / EtOAc, 2: 1 to 1: 1) to give the title compound (340 mg, 82%) as a brown solid: LC-MS (ES) m / Z = 632 (M + H) ⁺ .

ＭｅＯＨ（２ｍＬ）中のＮ−［２−（１，３−ジオキソ−１，３−ジヒドロ−２Ｈ−イソインドール−２−イル）−１−（フェニルメチル）エチル］−Ｎ’−ヒドロキシ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボキシイミダミド（異性体Ｂから）（０．０７７ｇ、０．１２ｍｍｏｌ）の溶液に、６ＮのＮａＯＨ（１．０ｍＬ）を加えた。室温で０．５時間後、溶媒を除去し、反応混合物をＤＣＭで抽出し、濃縮して、粗生成物を得、これを次の工程に直接用いた。
上記からの固体物質をＣＨ_２Ｃｌ_２（２ｍＬ）中に溶解し、この溶液にＴＦＡ（１ｍＬ）を加えた。３０分後、反応溶液を濃縮し、逆相ＨＰＬＣ（Ｃ１８カラム：Ｈ_２Ｏ／ＣＨ_３ＣＮ勾配）で精製して、標題化合物を黄色固体として得た（２６ｍｇ、３５％、２工程）：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３９２（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ，４００ＭＨｚ）δ８．３４（ｄ，Ｊ＝５．８Ｈｚ，１Ｈ），７．８４（ｄ，Ｊ＝３．８Ｈｚ，１Ｈ），７．７１（ｄ，Ｊ＝３．５Ｈｚ，１Ｈ），７．６０（ｄ，Ｊ＝５．６Ｈｚ，１Ｈ），７．３１−７．３０（ｍ，３Ｈ），７．２０−７．１８（ｍ，２Ｈ），７．０７−７．０４（ｍ，２Ｈ），４．１２（ｍ，１Ｈ），３．２５−３．２４（ｍ，２Ｈ），および２．９６−２．８２（ｍ，２Ｈ）。 d) N- [2-amino-1- (phenylmethyl) ethyl] -N′-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboximidamide

N- [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1- (phenylmethyl) ethyl] -N′-hydroxy-5 in MeOH (2 mL) To a solution of [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboximidamide (from isomer B) (0.077 g, 0.12 mmol), 6N NaOH (1.0 mL) was added. After 0.5 h at room temperature, the solvent was removed and the reaction mixture was extracted with DCM and concentrated to give the crude product, which was used directly in the next step.
The solid material from above was dissolved in CH ₂ Cl ₂ (2 mL) and TFA (1 mL) was added to this solution. After 30 min, the reaction solution was concentrated and purified by reverse phase HPLC (C18 column: H ₂ O / CH ₃ CN gradient) to give the title compound as a yellow solid (26 mg, 35%, 2 steps): LC -MS (ES) m / z = 392 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.34 (d, J = 5.8 Hz, 1H), 7.84 (d, J = 3 .8 Hz, 1H), 7.71 (d, J = 3.5 Hz, 1H), 7.60 (d, J = 5.6 Hz, 1H), 7.31-7.30 (m, 3H), 7 20-7.18 (m, 2H), 7.07-7.04 (m, 2H), 4.12 (m, 1H), 3.25-3.24 (m, 2H), and 2. 96-2.82 (m, 2H).

異性体Ｂの代わりに５−ブロモ−２−チオフェンカルボアルデヒドオキシム異性体Ａ（０．７３ｇ、０．５４ｍｍｏｌ）を用いること以外は、実施例１１９の方法に従って標題化合物を調製した。ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３９２（Ｍ＋Ｈ）^＋；^１Ｈ ＮＭＲ（ｄ_４−ＭｅＯＨ，４００ＭＨｚ）δ８．３４（ｄ，Ｊ＝５．８Ｈｚ，１Ｈ），７．８４（ｄ，Ｊ＝３．８Ｈｚ，１Ｈ），７．７１（ｄ，Ｊ＝３．５Ｈｚ，１Ｈ），７．６０（ｄ，Ｊ＝５．６Ｈｚ，１Ｈ），７．３１−７．３０（ｍ，３Ｈ），７．２０−７．１８（ｍ，２Ｈ），７．０７−７．０４（ｍ，２Ｈ），４．１２（ｍ，１Ｈ），３．２５−３．２４（ｍ，２Ｈ），および２．９６−２．８２（ｍ，２Ｈ） Example 120
N- [2-amino-1- (phenylmethyl) ethyl] -N′-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboximidamide (from oxime Preparation of isomer A)

The title compound was prepared according to the method of Example 119 except that 5-bromo-2-thiophenecarbaldehyde oxime isomer A (0.73 g, 0.54 mmol) was used in place of isomer B. LC-MS (ES) m / z = 392 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.34 (d, J = 5.8 Hz, 1H), 7.84 (d, J = 3.8 Hz, 1H), 7.71 (d, J = 3.5 Hz, 1H), 7.60 (d, J = 5.6 Hz, 1H), 7.31-7.30 (m, 3H), 7.20-7.18 (m, 2H), 7.07-7.04 (m, 2H), 4.12 (m, 1H), 3.25-3.24 (m, 2H), and 2 96-2.82 (m, 2H)

ａ）［４−（メチルオキシ）フェニル］メチル ４，５−ジブロモ−２−チオフェンカルボキシレート

４，５−ジブロモ−２−チオフェンカルボン酸（５．０ｇ、１７．４ｍｍｏｌ）およびＤＣＣ（４．３８ｇ、２２．５ｍｍｏｌ）の混合物に、［４−（メチルオキシ）フェニル］メタノール（２．８６ｍＬ、２２．５ｍｍｏｌ）を滴下した。室温でＮ_２雰囲気下で１２時間撹拌し後、反応溶液を減圧下で濃縮し、シリカ（ヘキサン／ＥｔＯＡｃ、５：９５）で洗浄して、標題化合物（６．８ｇ、９６％）を白色固体として得た。 Example 121
Preparation of 3-amino-2- (phenylmethyl) -N- [5- (3-pyridinyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide

a) [4- (Methyloxy) phenyl] methyl 4,5-dibromo-2-thiophenecarboxylate

To a mixture of 4,5-dibromo-2-thiophenecarboxylic acid (5.0 g, 17.4 mmol) and DCC (4.38 g, 22.5 mmol) was added [4- (methyloxy) phenyl] methanol (2.86 mL, 22.5 mmol) was added dropwise. After stirring at room temperature under N ₂ atmosphere for 12 hours, the reaction solution was concentrated under reduced pressure and washed with silica (hexane / EtOAc, 5:95) to give the title compound (6.8 g, 96%) as a white solid Got as.

ジオキサン（５ｍＬ）およびＨ_２Ｏ（１ｍＬ）中の［４−（メチルオキシ）フェニル］メチル ４，５−ジブロモ−２−チオフェンカルボキシレート（０．５ｇ、１．２ｍｍｏｌ）の溶液に、３−ピリジニルボロン酸（０．２４ｇ、１．９ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（１３０ｍｇ、０．１１ｍｍｏｌ）およびＫ_２ＣＯ_３（０．５４ｇ、３．９ｍｍｏｌ）を加えた。Ｎ_２雰囲気下７０℃で１０時間加熱した後、反応溶液を減圧下で濃縮し、シリカ（ヘキサン／ＥｔＯＡｃ、４０：６０）で精製して、標題化合物（０．４０３ｇ、８１％）を白色泡沫体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４０５（Ｍ＋Ｈ）^＋。 b) [4- (Methyloxy) phenyl] methyl 4-bromo-5- (3-pyridinyl) -2-thiophenecarboxylate

To a solution of [4- (methyloxy) phenyl] methyl 4,5-dibromo-2-thiophenecarboxylate (0.5 g, 1.2 mmol) in dioxane (5 mL) and H ₂ O (1 mL) was added 3-pyridinylboron. Acid (0.24 g, 1.9 mmol), Pd (PPh ₃ ) ₄ (130 mg, 0.11 mmol) and K ₂ CO ₃ (0.54 g, 3.9 mmol) were added. After heating at 70 ° C. for 10 hours under N ₂ atmosphere, the reaction solution was concentrated under reduced pressure and purified on silica (hexane / EtOAc, 40:60) to give the title compound (0.403 g, 81%) as a white foam. Obtained as a body: LC-MS (ES) m / z = 405 (M + H) ^<+> .

ジオキサン（１０ｍＬ）およびＨ_２Ｏ（２ｍＬ）中の［４−（メチルオキシ）フェニル］メチル ４−ブロモ−５−（３−ピリジニル）−２−チオフェンカルボキシレート（０．５ｇ、１．２ｍｍｏｌ）の溶液に、１−（フェニルスルホニル）−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．６８ｇ、１．７６ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（１３０ｍｇ、０．１１ｍｍｏｌ）およびＫ_２ＣＯ_３（０．５０ｇ、３．６ｍｍｏｌ）を加えた。Ｎ_２雰囲気下で１０時間７０℃で加熱した後、反応溶液を減圧下で濃縮し、シリカ（ヘキサン／ＥｔＯＡｃ、１：２）で精製して、標題化合物（０．５２ｇ、７２％）を明黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５８２（Ｍ＋Ｈ）^＋。 c) [4- (Methyloxy) phenyl] methyl 4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -5- (3-pyridinyl) -2-thiophene Carboxylate

Of [4- (Methyloxy) phenyl] methyl 4-bromo-5- (3-pyridinyl) -2-thiophenecarboxylate (0.5 g, 1.2 mmol) in dioxane (10 mL) and H ₂ O (2 mL). To the solution was added 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (0 .68 g, 1.76 mmol), Pd (PPh ₃ ) ₄ (130 mg, 0.11 mmol) and K ₂ CO ₃ (0.50 g, 3.6 mmol) were added. After heating at 70 ° C. for 10 hours under N ₂ atmosphere, the reaction solution was concentrated under reduced pressure and purified on silica (hexane / EtOAc, 1: 2) to give the title compound (0.52 g, 72%). Obtained as a yellow solid: LC-MS (ES) m / z = 582 (M + H) ⁺ .

ＣＨ_２Ｃｌ_２（１５ｍＬ）中の［４−（メチルオキシ）フェニル］メチル ４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−５−（３−ピリジニル）−２−チオフェンカルボキシレート（１．２ｇ、２．１ｍｍｏｌ）の溶液に、ＴＦＡ（２ｍＬ）を加えた。室温で１時間撹拌した後、反応溶液を減圧下で濃縮して、４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−５−（３−ピリジニル）−２−チオフェンカルボン酸を赤色固体として得、これを次の工程に直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４６３（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl [4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -5- (3-pyridinyl) -2-thienyl] carbamate

[4- (Methyloxy) phenyl] methyl 4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -5- (3) in CH ₂ Cl ₂ (15 mL) To a solution of -pyridinyl) -2-thiophenecarboxylate (1.2 g, 2.1 mmol) was added TFA (2 mL). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to give 4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -5- (3- Pyridinyl) -2-thiophenecarboxylic acid was obtained as a red solid and used directly in the next step: LC-MS (ES) m / z = 463 (M + H) ⁺ .

To a mixture of the above acids in t-BuOH (15 mL) was added DPPA (2.5 mmol, 0.55 mL) and triethylamine (14.4 mmol, 2.0 mL). The mixture was heated to 85 ° C. for 10 hours under N ₂ atmosphere. After cooling to room temperature, the reaction was concentrated under reduced pressure. Flash chromatography (silica gel, hexane / EtOAc, 4: 1) gave the title compound (0.69 g, 63%) as a yellow foam. LCMS (ES) m / z 533 (M + H) ⁺

ＣＨ_２Ｃｌ_２（５ｍＬ）中の１，１−ジメチルエチル ［４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−５−（３−ピリジニル）−２−チエニル］カルバメート（０．３ｇ、０．５６ｍｍｏｌ）の溶液に、ＴＦＡ（２ｍＬ）を加えた。１時間室温で撹拌した後、反応溶液を減圧下で濃縮して、［４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−５−（３−ピリジニル）−２−チエニル］アミンを赤色固体として得、これを次の工程に直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４３３（Ｍ＋Ｈ）^＋。 e) 1,1-dimethylethyl [(4Z, 6Z) -4-ethenyl-2-({[4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -5- (3-pyridinyl) -2-thienyl] amino} carbonyl) -4,6-octadien-1-yl] carbamate

CH ₂ Cl ₂ (5 mL) solution of 1,1-dimethylethyl [4- [1- (phenylsulfonyl)-1H-pyrrolo [2,3-b] pyridin-3-yl] -5- (3-pyridinyl) To a solution of -2-thienyl] carbamate (0.3 g, 0.56 mmol) was added TFA (2 mL). After stirring for 1 hour at room temperature, the reaction solution was concentrated under reduced pressure to give [4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -5- (3 -Pyridinyl) -2-thienyl] amine was obtained as a red solid which was used directly in the next step: LC-MS (ES) m / z = 433 (M + H) ⁺ .

The above amine TFA salt (0.5 mmol) was dissolved in DCM (5 mL) and to this solution was added PyBrop (0.417 g, 0.89 mmol), (iPr) ₂ NEt (1.74 mL, 10.0 mmol) and 3 -({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2- (phenylmethyl) propanoic acid (0.25 g, 0.89 mmol) was added. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure and purified on silica (hexane / EtOAc, 1: 2) to give the title compound (0.19 g, 49%, 2 steps) as an off-white solid. LC: MS (ES) m / z = 694 (M + H) ⁺ .

ＭｅＯＨ（５ｍＬ）中の１，１−ジメチルエチル ［（４Ｚ，６Ｚ）−４−エテニル−２−（｛［４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−５−（３−ピリジニル）−２−チエニル］アミノ｝カルボニル）−４，６−オクタジエン−１−イル］カルバメート（０．１７０ｇ、０．２５ｍｍｏｌ）の溶液に、６ＮのＮａＯＨ（２．０ｍＬ）を加えた。室温で０．５時間後、溶媒を除去し、反応混合物をＤＣＭで抽出し、濃縮して、粗生成物を得、これを次の工程に直接用いた。 f) 3-Amino-2- (phenylmethyl) -N- [5- (3-pyridinyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide

1,1-dimethylethyl in MeOH (5 mL) [(4Z, 6Z) -4-ethenyl-2-({[4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine- To a solution of 3-yl] -5- (3-pyridinyl) -2-thienyl] amino} carbonyl) -4,6-octadien-1-yl] carbamate (0.170 g, 0.25 mmol) was added 6N NaOH ( 2.0 mL) was added. After 0.5 h at room temperature, the solvent was removed and the reaction mixture was extracted with DCM and concentrated to give the crude product, which was used directly in the next step.

The solid material from above was dissolved in CH ₂ Cl ₂ (2 mL) and TFA (1 mL) was added to this solution. After 10 minutes, the reaction solution was concentrated and purified by reverse phase HPLC (C18 column: H ₂ O / CH ₃ CN gradient) to give the title compound as a yellow solid (55 mg, 33%, 2 steps): LC -MS (ES) m / z = 454 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.65 (brs, 1H), 8.57 (brs, 1H), 8.36-8. 34 (m, 2H), 7.94 (d, J = 7.8 Hz, 1H), 7.81 (m, 1H), 7.62 (s, 1H), 7.34-7.23 (m, 6H), 6.91 (s, 1H), 3.39 (dd, J = 8.6, 12.9 Hz, 1H), 3.23 (m, 1H), 3.18-3.11 (m, 2H), and 3.00 (dd, J = 6.8, 13.4 Hz, 1H).

ａ）［４−（メチルオキシ）フェニル］メチル ４−ブロモ−５−（１，３−オキサゾール−２−イル）−２−チオフェンカルボキシレート

ジオキサン（１５ｍＬ）中の［４−（メチルオキシ）フェニル］メチル ４，５−ジブロモ−２−チオフェンカルボキシレート（１．２ｇ、０．３ｍｍｏｌ）の溶液に、２−（トリブチルスタナニル）−１，３−オキサゾール（１．４ｇ、３．９ｍｍｏｌ）、およびＰｄ（ＰＰｈ_３）_４（２７７ｍｇ、０．２４ｍｍｏｌ）を加えた。Ｎ_２雰囲気下１００℃で７２時間加熱し、反応溶液を減圧下で濃縮し、シリカ（ヘキサン／ＥｔＯＡｃ、２：１）により精製して、標題化合物（０．３５ｇ、３０％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝３９５（Ｍ＋Ｈ）^＋。 Example 122
3-Amino-N- [5- (1,3-oxazol-2-yl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenyl Preparation of methyl) propanamide

a) [4- (Methyloxy) phenyl] methyl 4-bromo-5- (1,3-oxazol-2-yl) -2-thiophenecarboxylate

To a solution of [4- (methyloxy) phenyl] methyl 4,5-dibromo-2-thiophenecarboxylate (1.2 g, 0.3 mmol) in dioxane (15 mL) was added 2- (tributylstannanyl) -1, 3-Oxazole (1.4 g, 3.9 mmol), and Pd (PPh ₃ ) ₄ (277 mg, 0.24 mmol) were added. Heat at 100 ° C. under N ₂ atmosphere for 72 hours, concentrate the reaction solution under reduced pressure and purify on silica (hexane / EtOAc, 2: 1) to give the title compound (0.35 g, 30%) as a white solid. Obtained: LC-MS (ES) m / z = 395 (M + H) ⁺ .

ジオキサン（１０ｍＬ）およびＨ_２Ｏ（２ｍＬ）中の［４−（メチルオキシ）フェニル］メチル ４−ブロモ−５−（１，３−オキサゾール−２−イル）−２−チオフェンカルボキシレート（０．３５ｇ、０．８９ｍｍｏｌ）の溶液に、１−（フェニルスルホニル）−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．４ｇ、１．０４ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（１１５ｍｇ、０．１ｍｍｏｌ）およびＫ_２ＣＯ_３（１．２４ｇ、７．２ｍｍｏｌ）を加えた。Ｎ_２雰囲気下で１０時間７０℃に加熱し、反応溶液を減圧下で濃縮し、シリカ（ヘキサン／ＥｔＯＡｃ、１：２）で精製して、標題化合物（０．４２ｇ、８４％）を明黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝５７２（Ｍ＋Ｈ）^＋。 b) [4- (Methyloxy) phenyl] methyl 5- (1,3-oxazol-2-yl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-3- Yl] -2-thiophenecarboxylate

[4- (Methyloxy) phenyl] methyl 4-bromo-5- (1,3-oxazol-2-yl) -2-thiophenecarboxylate (0.35 g) in dioxane (10 mL) and H ₂ O (2 mL) , 0.89 mmol) was added to 1- (phenylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3 -b] pyridine (0.4g, _1.04mmol), was added _{Pd (PPh 3) 4 (115mg} , 0.1mmol) and _{K 2 CO 3 (1.24g, 7.2mmol} ). Heat to 70 ° C. for 10 hours under N ₂ atmosphere and concentrate the reaction solution under reduced pressure and purify on silica (hexane / EtOAc, 1: 2) to give the title compound (0.42 g, 84%) as light yellow Obtained as a solid: LC-MS (ES) m / z = 572 (M + H) ⁺ .

ＣＨ_２Ｃｌ_２（１０ｍＬ）中の［４−（メチルオキシ）フェニル］メチル ５−（１，３−オキサゾール−２−イル）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−２−チオフェンカルボキシレート（０．５５ｇ、０．９６ｍｍｏｌ）の溶液に、ＴＦＡ（２ｍＬ）を加えた。室温で１時間撹拌した後、反応溶液を減圧下で濃縮して、５−（１，３−オキサゾール−２−イル）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−２−チオフェンカルボン酸を赤色固体として得、これを次の工程に直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４５２（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl {5- (1,3-oxazol-2-yl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl]- 2-thienyl} carbamate

[4- (Methyloxy) phenyl] methyl 5- (1,3-oxazol-2-yl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3] in CH ₂ Cl ₂ (10 mL) -B] To a solution of pyridin-3-yl] -2-thiophenecarboxylate (0.55 g, 0.96 mmol) was added TFA (2 mL). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to give 5- (1,3-oxazol-2-yl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3- b] Pyridin-3-yl] -2-thiophenecarboxylic acid was obtained as a red solid and used directly in the next step: LC-MS (ES) m / z = 452 (M + H) ⁺ .

To a mixture of the above acids in t-BuOH (10 mL) was added DPPA (1.16 mmol, 0.25 mL) and triethylamine (14.4 mmol, 2.0 mL). The mixture was heated at 85 ° C. for 10 hours under N ₂ atmosphere. After cooling to room temperature, the reaction was concentrated under reduced pressure. Flash chromatography (silica gel, hexane / EtOAc, 4: 1) gave the title compound (0.33 g, 65%, 2 steps) as a yellow foam. LCMS (ES) m / z 523 (M + H) ⁺

ＣＨ_２Ｃｌ_２（５ｍＬ）中の１，１−ジメチルエチル ｛（４Ｚ，６Ｚ）−４−エテニル−２−［（｛５−（１，３−オキサゾール−２−イル）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−２−チエニル｝アミノ）カルボニル］−４，６−オクタジエン−１−イル｝カルバメート（０．１５ｇ、０．２８ｍｍｏｌ）の溶液に、ＴＦＡ（２ｍＬ）を加えた。室温で１時間撹拌した後、反応溶液を減圧下で濃縮して、５−（１，３−オキサゾール−２−イル）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−２−チオフェンアミンを赤色固体として得、これを次の工程に直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ＝４２３（Ｍ＋Ｈ）^＋。 d) 1,1-dimethylethyl {(4Z, 6Z) -4-ethenyl-2-[({5- (1,3-oxazol-2-yl) -4- [1- (phenylsulfonyl) -1H- Pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} amino) carbonyl] -4,6-octadien-1-yl} carbamate

1,1-dimethylethyl in CH ₂ Cl ₂ (5 mL) {(4Z, 6Z) -4-ethenyl-2-[({5- (1,3-oxazol-2-yl) -4- [1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} amino) carbonyl] -4,6-octadien-1-yl} carbamate (0.15 g, 0.28 mmol) ) Was added TFA (2 mL). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to give 5- (1,3-oxazol-2-yl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3- b] Pyridin-3-yl] -2-thiophenamine was obtained as a red solid, which was used directly in the next step: LC-MS (ES) m / z = 423 (M + H) ⁺ .

The amine TFA salt (0.28 mmol) was dissolved in DCM (5 mL) and this solution was added to PyBrop (0.260 g, 0.56 mmol), (iPr) ₂ NEt (5 mL, 28 mmol) and 3-({[( 1,1-Dimethylethyl) oxy] carbonyl} amino) -2- (phenylmethyl) propanoic acid (0.16 g, 0.56 mmol) was added. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure and purified on silica (hexane / EtOAc, 1: 2) to give the title compound (0.078 g, 40%, 2 steps) as an off-white solid. : LC-MS (ES) m / z = 684 (M + H) ⁺ .

ＭｅＯＨ（２ｍＬ）中の１，１−ジメチルエチル ｛（４Ｚ，６Ｚ）−４−エテニル−２−［（｛５−（１，３−オキサゾール−２−イル）−４−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−イル］−２−チエニル｝アミノ）カルボニル］−４，６−オクタジエン−１−イル｝カルバメート（０．０６５ｇ、０．０９５ｍｍｏｌ）の溶液に、６ＮのＮａＯＨ（１．０ｍＬ）を加えた。室温で０．５時間後、溶媒を除去し、反応混合物をＤＣＭで抽出し、濃縮して、粗生成物を得、これを次の工程に直接用いた。 f) 3-Amino-N- [5- (1,3-oxazol-2-yl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (Phenylmethyl) propanamide

1,1-dimethylethyl {(4Z, 6Z) -4-ethenyl-2-[({5- (1,3-oxazol-2-yl) -4- [1- (phenylsulfonyl) in MeOH (2 mL) ) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thienyl} amino) carbonyl] -4,6-octadien-1-yl} carbamate (0.065 g, 0.095 mmol) To this was added 6N NaOH (1.0 mL). After 0.5 h at room temperature, the solvent was removed and the reaction mixture was extracted with DCM and concentrated to give the crude product, which was used directly in the next step.

The solid material from above was dissolved in CH ₂ Cl ₂ (2 mL) and to this solution was added TFA (1 mL). After 10 minutes, the reaction solution was concentrated and subjected to reverse phase HPLC (C18 column: H ₂ O / CH ₃ CN gradient) to give the title compound as a yellow solid (32 mg, 51%, 2 steps): LC -MS (ES) m / z = 444 (M + H) ⁺ ; ¹ H NMR (d ₄ -MeOH, 400 MHz) δ 8.44 (brs, J = 5.0 Hz, 1H), 8.26 (dd, J = 1) 0.0, 7.8 Hz, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.48 (m, 1H), 7.35-7.23 (m, 5H), 7.15 (s, 1H), 6.87 (s, 1H), 3.39 (dd, J = 8.3, 12.6 Hz, 1H), 3.25-3.09 (m, 3H) and 2.98 (dd, J = 6.6, 12.9 Hz, 1H).

Example 123

Preparation of N- {2-amino-1- [2- (methyloxy) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1 -1,1-dimethylethyl {2-amino-2- [2- (methyloxy) phenyl] ethyl} carbamate (40 mg, 0.25 mmol) instead of dimethylethyl (3-amino-3-phenylpropyl) carbamate [ The title compound was obtained as a yellow solid according to Example 15 except that 2- (methyloxy) benzaldehyde was prepared according to Preparation 9]: LC-MS (ES) m / z 393 (M + H) ⁺ ; ¹ H NMR (400 MHz, d4-MeOH) δ ppm 3.40-3.44 (m, 2H) 3.97 (s, 3H) 5.75 (dd, J = 8 .34, 6.06 Hz, 1H) 6.93 (d, J = 3.54 Hz, 1H) 7.04 (t, J = 7.58 Hz, 1H) 7.11 (d, J = 7.83 Hz, 1H) ) 7.37-7.44 (m, 3H) 7.55 (d, J = 3.54 Hz, 1H) 7.79 (d, J = 3.79 Hz, 1H) 7.93 (d, J = 4) .04 Hz, 1H) 8.26 (d, J = 5.31 Hz, 1H).

Example 124

Preparation of N- {2-amino-1- [3- (methyloxy) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1 -1,1-dimethylethyl {2-amino-2- [3- (methyloxy) phenyl] ethyl} carbamate (84 mg, 0.32 mmol) instead of dimethylethyl (3-amino-3-phenylpropyl) carbamate [ The title compound was obtained as a yellow solid according to Example 15 except using 3- (methyloxy) benzaldehyde prepared according to Preparation 9]: LC-MS (ES) m / z 393 (M + H) ⁺ ; ¹ H NMR (400 MHz, d4-MeOH) δ ppm 3.16-3.18 (m, 2H) 3.83 (s, 3H) 5.20 (dd, J = 7. 96, 6.19 Hz, 1H) 6.87-6.91 (m, 1H) 6.93 (d, J = 3.54 Hz, 1H) 7.01-7.04 (m, 2H) 7.32 ( t, J = 8.21 Hz, 1H) 7.42 (d, J = 0.05 Hz, 1H) 7.54 (d, J = 3.79 Hz, 1H) 7.77 (d, J = 4.04 Hz, 1H) 7.93 (d, J = 4.04 Hz, 1H) 8.24 (d, J = 0.05 Hz, 1H).

Example 125

Preparation of N- {2-amino-1- [4- (methyloxy) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1 -1,1-dimethylethyl {2-amino-2- [4- (methyloxy) phenyl] ethyl} carbamate (84 mg, 0.32 mmol) instead of dimethylethyl (3-amino-3-phenylpropyl) carbamate [ The title compound was obtained as a yellow solid according to Example 15 except that 4- (methyloxy) benzaldehyde was prepared according to Preparation 9]: LC-MS (ES) m / z 393 (M + H) ⁺ ; ¹ H NMR (400 MHz, d4-MeOH) δ ppm 3.38-3.48 (m, 2H) 3.82 (s, 3H) 5.39 (dd, J = 9 .47, 5.43 Hz, 1H) 6.93 (d, J = 3.54 Hz, 1H) 6.98-7.02 (m, 2H) 7.40-7.44 (m, 3H) 7.55 (D, J = 3.54 Hz, 1H) 7.77 (d, J = 4.04 Hz, 1H) 7.90 (d, J = 4.04 Hz, 1H) 8.25 (d, J = 0.05 Hz , 1H).

Example 126

Of N- {2-amino-1- [2- (methyloxy) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate instead of 1,1-dimethylethyl {2-amino-2- [2- (methyloxy) phenyl] ethyl} carbamate (200 mg, 0 .43 mmol) [prepared from 2- (methyloxy) benzaldehyde according to Preparative Example 9] in place of 5-bromo-2-thiophenecarboxylic acid, 4,5-dibromo-2-thiophenecarboxylic acid (2.07 g, The title compound was obtained as a yellow solid according to Example 15 except using 5.4 mmol): LC-MS (ES) m / z 472 ( ^{+ H) +; 1 H NMR} (400MHz, d4-MeOH) δppm 3.24-3.41 (m, 2H) 3.79-3.83 (m, 3H) 5.31 (dd, J = 9.35 , 5.56 Hz, 1H) 6.62 (d, J = 3.79 Hz, 1H) 6.96-7.01 (m, 2H) 7.35 (d, J = 0.05 Hz, 1H) 7.37 -7.42 (m, 2H) 7.52 (d, J = 3.54 Hz, 1H) 7.94 (s, 1H) 8.30 (d, J = 5.05 Hz, 1H).

Example 127

Of N- {2-amino-1- [3- (methyloxy) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate instead of 1,1-dimethylethyl {2-amino-2- [3- (methyloxy) phenyl] ethyl} carbamate (159 mg, 0 .60 mmol) [prepared from 3- (methyloxy) benzaldehyde according to Preparative Example 9] in place of 5-bromo-2-thiophenecarboxylic acid, 4,5-dibromo-2-thiophenecarboxylic acid (2.07 g, The title compound was obtained as a yellow solid according to Example 15 except using 5.4 mmol): LC-MS (ES) m / z 472 ( ^{+ H) +; 1 H NMR} (400MHz, d4-MeOH) δppm 3.07-3.14 (m, 2H) 3.83 (s, 3H) 5.13 (dd, J = 7.83,6.32Hz , 1H) 6.62 (d, J = 3.54 Hz, 1H) 6.86-6.91 (m, 1H) 6.99-7.03 (m, 2H) 7.29-7.37 (m , 2H) 7.51 (d, J = 3.54 Hz, 1H) 7.97 (s, 1H) 8.30 (d, J = 0.05 Hz, 1H).

Example 128

Of N- {2-amino-1- [4- (methyloxy) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate instead of 1,1-dimethylethyl {2-amino-2- [4- (methyloxy) phenyl] ethyl} carbamate (118 mg, 0 .44 mmol) [prepared from 4- (methyloxy) benzaldehyde according to Preparative Example 9] in place of 5-bromo-2-thiophenecarboxylic acid, 4,5-dibromo-2-thiophenecarboxylic acid (2.07 g, The title compound was obtained as a yellow solid according to Example 15 except using 5.4 mmol): LC-MS (ES) m / z 472 ( ^{+ H) +; 1 H NMR} (400MHz, d4-MeOH) δppm 3.39-3.44 (m, 2H) 3.96 (s, 3H) 5.74 (t, J = 7.07Hz, 1H) 6 .66 (d, J = 3.54 Hz, 1H) 7.01-7.06 (m, 1H) 7.09 (d, J = 7.58 Hz, 1H) 7.35-7.43 (m, 4H) ) 7.55 (d, J = 3.54 Hz, 1H) 7.9 (s, 1H) 8.34 (s, 1H).

Example 129

N-{(1R) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 Preparation of thiophenecarboxamide 2-[(2R) -2-amino-3 instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione According to the method of Example 43, except that-(4-fluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (0.45 g, 1.3 mmol) was used, the title compound was light yellow. Obtained as a solid: LC-MS (ES) m / z 473 (M + H) ⁺ ; ¹ H NMR (400 MHz, d4-MeOH) δ ppm 2.99 (td, J = 14.08, 8.21 Hz, 2H) 18-3 29 (m, 2H) 4.55 (td, J = 6.19, 3.54 Hz, 1H) 6.75 (d, J = 3.54 Hz, 1H) 7.01-7.09 (m, 2H) 7.28-7.36 (m, 2H) 7.54 (d, J = 5.56 Hz, 1H) 7.65 (d, J = 3.79 Hz, 1H) 7.83 (s, 1H) 39 (d, J = 5.31 Hz, 1H).

Example 130

N-{(1S) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 Preparation of thiophenecarboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-[(2S) -2-amino-3 -(4-Fluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (0.25 g, 0.7 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl}- The title compound was obtained as a light yellow solid according to the method of Example 43 except using 4-fluoro-L-phenylalanine prepared according to Preparation 7]: LC-MS (ES) m / z 474 (M + H ^{+; 1 H NMR (400MHz,} d4-MeOH) δppm 2.99 (td, J = 13.89,8.08Hz, 2H) 3.12-3.23 (m, 2H) 4.50 (ddd, J = 6.00, 3.28, 3.09 Hz, 1H) 6.60 (t, J = 3.54 Hz, 1H) 7.03-7.09 (m, 2H) 7.33 (td, J = 5 .94, 2.02 Hz, 3H) 7.41-7.46 (m, 1H) 7.52 (d, J = 3.79 Hz, 1H) 7.83-7.88 (m, 1H) 8.28 −8.32 (m, 1H).

Example 131

Preparation of N- [1- (aminomethyl) -3-phenylpropyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1- 1,1-dimethylethyl (2-amino-4-phenylbutyl) carbamate (222 mg, 0.84 mmol) [2- (2-phenylethyl) oxirane instead of dimethylethyl (3-amino-3-phenylpropyl) carbamate Prepared according to Preparation Example 10] except that 4,5-dibromo-2-thiophenecarboxylic acid (2.07 g, 5.4 mmol) was used instead of 5-bromo-2-thiophenecarboxylic acid. The title compound was obtained as a yellow solid according to Example 15: LC-MS (ES) m / z 470 (M + H) ⁺ ; ¹ H NMR (400M Hz d4-MeOH) δ ppm 1.97-2.09 (m, J = 8.91, 8.56, 8.56, 5.56 Hz, 2H) 2.73-2.84 (m, 2H) 08 (dd, J = 13.01, 9.73 Hz, 1H) 3.15-3.24 (m, 1H) 4.32 (ddd, J = 9.35, 5.05, 4.80 Hz, 1H) 6.64 (d, J = 3.54 Hz, 1H) 7.15-7.21 (m, 1H) 7.22-7.30 (m, 4H) 7.37 (d, J = 0.05 Hz, 1H) 7.54 (d, J = 3.54 Hz, 1H) 7.85 (s, 1H) 8.32 (s, 1H).

Example 132

N-((1S) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) Preparation of 2-thiophenecarboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-{(2S) -2- Amino-3- [4- (methyloxy) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (476 mg, 1.37 mmol) [1,1-dimethylethyl ((1S) -2- The title compound was obtained as a yellow solid according to Example 43, except using hydroxy-1-{[4- (methyloxy) phenyl] methyl} ethyl) carbamate, prepared according to Preparation 11]: L C-MS (ES) m / z 486 (M + H) ⁺ ; ¹ H NMR (400 MHz, d4-MeOH) δ ppm 2.95 (d, J = 7.33 Hz, 2H) 3.13-3.25 (m, 2H 3.75 (s, 3H) 4.50 (d, J = 5.81 Hz, 1H) 6.57-6.61 (m, 1H) 6.85-6.90 (m, 2H) 7.21 −7.26 (m, 2H) 7.32 (t, J = 4.55 Hz, 1H) 7.51 (t, J = 3.16 Hz, 1H) 7.83 to 7.88 (m, 1H) 8 .26-8.31 (m, 1H).

Example 133

N-((1R) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) Preparation of 2-thiophenecarboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-{(2R) -2- Amino-3- [4- (methyloxy) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (368 mg, 1.06 mmol) [N-{[(1,1-dimethylethyl) oxy ] The title compound was obtained as a yellow solid according to Example 43, except using carbonyl} -O-methyl-D-tyrosine according to Preparative Example 11: LC-MS (ES) m / z 486 ( M + ^{) +; 1 H NMR (400MHz} , d4-MeOH) δppm 2.93 (d, J = 7.83Hz, 2H) 3.03-3.19 (m, 2H) 3.77 (s, 3H) 4. 45 (td, J = 6.69, 3.54 Hz, 1H) 6.60 (t, J = 2.91 Hz, 1H) 6.87-6.91 (m, 2H) 7.20-7.24 ( m, 2H) 7.33-7.36 (m, 1H) 7.50-7.54 (m, 1H) 7.80 (s, 1H) 8.28-8.32 (m, 1H).

Example 134

Of N-{(1S) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-[(2S) -2-amino-3- (4- Fluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (612 mg, 1.83 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -4-fluoro-L- Prepared from phenylalanine according to Preparative Example 11] instead of 4,5-dibromo-2-thiophenecarboxylic acid with 5-bromo-2-thiophenecarboxylic acid (5.39 g, 14.0 mmol). Except that there, according to Example 43, the title compound was obtained as a yellow ^{solid: LC-MS (ES) m} / z495 (M + H) +; 1 H NMR (400MHz, d4-MeOH) δppm 2.81-3. 00 (m, 4H) 4.30 (ddd, J = 7.96, 5.18, 2.53 Hz, 1H) 6.91 (d, J = 3.54 Hz, 1H) 6.98-7.04 ( m, 2H) 7.30 (dd, J = 8.46, 5.43 Hz, 2H) 7.39 (d, J = 5.31 Hz, 1H) 7.52 (d, J = 3.79 Hz, 1H) 7.71 (d, J = 4.04 Hz, 1H) 7.77 (d, J = 4.04 Hz, 1H) 8.23 (d, J = 0.05 Hz, 1H).

Example 135

N-((1R) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Preparation of thiophene carboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-{(2R) -2-amino-3- [4- (Methyloxy) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (405 mg, 1.17 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl}- Prepared from O-methyl-D-tyrosine according to Preparative Example 11] in place of 4,5-dibromo-2-thiophenecarboxylic acid, 5-bromo-2-thiophenecarboxylic acid (5.39 g, 14.0 mmo). ) But using, according to Example 43 to give the title compound as a yellow ^{solid: LC-MS (ES) m} / z407 (M + H) +; 1 H NMR (400MHz, DMSO-d 6) δppm 2.64 -2.68 (m, 2H) 2.73-2.89 (m, 2H) 3.70 (s, 3H) 3.99 (s, 1H) 6.83 (d, J = 6.32 Hz, 2H 6.84 (s, 1H) 7.17 (d, J = 8.59 Hz, 2H) 7.37 (d, J = 0.05 Hz, 1H) 7.63 (d, J = 3.54 Hz, 1H) ) 7.80 (d, J = 4.04 Hz, 1H) 7.89 (d, J = 4.04 Hz, 1H) 8.26 (d, J = 0.05 Hz, 1H) 11.92 (s, 1H) ).

Example 136

N-((1S) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Preparation of thiophene carboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-{(2S) -2-amino-3- [4- (Methyloxy) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (0.57 g, 1.64 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl } -O-methyl-L-tyrosine was prepared according to Preparative Example 11] in the place of 4,5-dibromo-2-thiophenecarboxylic acid instead of 5-bromo-2-thiophenecarboxylic acid (5.39 g, 14. 0mmo ) But using, according to Example 43, the title compound was obtained as a yellow ^{solid: LC-MS (ES) m} / z407 (M + H) +; 1 H NMR (400MHz, d4-MeOH) δppm 2.80- 2.90 (m, 4H) 3.73 (s, 3H) 4.23-4.31 (m, 1H) 6.81-6.86 (m, 2H) 6.89 (d, J = 3. 54 Hz, 1H) 7.17-7.22 (m, 2H) 7.35-7.38 (m, 1H) 7.51 (t, J = 2.91 Hz, 1H) 7.69 (t, J = 3.28 Hz, 1H) 7.76 (d, J = 4.04 Hz, 1H) 8.21 (d, J = 0.05 Hz, 1H).

Example 137

Of N-{(1R) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation 2-[(2R) -2-amino-3- (4-) instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione Fluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (624 mg, 1.86 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -4-fluoro-D- Prepared from phenylalanine according to Preparative Example 11] instead of 4,5-dibromo-2-thiophenecarboxylic acid with 5-bromo-2-thiophenecarboxylic acid (5.39 g, 14.0 mmol). Except that there, according to Example 43, the title compound was obtained as a yellow ^{solid: LC-MS (ES) m} / z395 (M + H) +; 1 H NMR (400MHz, d4-MeOH) δppm 2.75-3. 00 (m, 4H) 4.29 (ddd, J = 7.96, 5.18, 2.27 Hz, 1H) 6.91 (d, J = 3.54 Hz, 1H) 7.01 (ddd, J = 8.91, 6.63, 2.15 Hz, 2H) 7.27-7.33 (m, 2H) 7.39 (d, J = 5.31 Hz, 1H) 7.52 (d, J = 3. 54 Hz, 1H) 7.71 (d, J = 4.04 Hz, 1H) 7.77 (d, J = 3.79 Hz, 1H) 8.23 (d, J = 0.05 Hz, 1H).

Example 138

N-((1S) -2-amino-1-{[4- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-thiophenecarboxamide preparation 2-[(2S) -2 instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione -Amino-3- [4- (trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (1.63 mg, 4.24 mmol) [N-{[(1,1- The title compound was obtained as a yellow solid according to Example 43 except using [Dimethylethyl) oxy] carbonyl} -4- (trifluoromethyl) -L-phenylalanine according to Preparative Example 11. ^{LC-MS (ES) m /} z524 (M + H) +; 1 H NMR (400MHz, d4-MeOH) δppm 2.82-3.13 (m, 4H) 4.32-4.40 (m, 1H) 6 .61 (d, J = 3.54 Hz, 1H) 7.34 (d, J = 0.05 Hz, 1H) 7.47-7.54 (m, 3H) 7.61 (d, J = 8.08 Hz) , 2H) 7.79 (s, 1H) 8.30 (d, J = 5.05 Hz, 1H).

Example 139

N-((1S) -2-amino-1-{[4- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 Preparation of thiophenecarboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-{(2S) -2-amino-3 -[4- (Trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (1.56 mg, 4.05 mmol) [N-{[(1,1-dimethylethyl) oxy Prepared according to Preparation 11 from carbonyl} -4- (trifluoromethyl) -L-phenylalanine] in place of 4,5-dibromo-2-thiophenecarboxylic acid Carboxylic acid (5.39 g, 14.0 mmol) except using, according to Example 43, the title compound was obtained as a yellow solid: LC-MS (ES) m / z445 (M + H) +; 1 H NMR (400MHz , D4-MeOH) δ ppm 2.87-3.13 (m, 4H) 4.39 (ddd, J = 8.08, 5.05, 2.78 Hz, 1H) 6.92 (t, J = 3. 16 Hz, 1H) 7.40 (d, J = 0.05 Hz, 1H) 7.50 (d, J = 8.08 Hz, 2H) 7.54 (t, J = 2.91 Hz, 1H) 7.60 ( d, J = 8.08 Hz, 2H) 7.72-7.75 (m, 1H) 7.76-7.79 (m, 1H) 8.23-8.26 (m, 1H).

Example 140

ジオキサン（１２０ｍＬ）およびＨ_２Ｏ（２８ｍＬ）中の４，５−ジブロモ−３−ヒドロキシ−２−チオフェンカルボン酸メチル（４．４３ｇ、１４．０ｍｍｏｌ）、１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（５．３７ｇ、１４．０ｍｍｏｌ）［調製例２で調製した］、Ｐｄ（ＰＰｈ_３）_４（８０８ｍｇ、０．７０ｍｍｏｌ）およびＫ_２ＣＯ_３（７．７ｇ、５５．９ｍｍｏｌ）をシールしたチューブに合した。７０℃で１２時間後、反応物をＨ_２Ｏ／ＣＨＣｌ_３間で分配した。水相をＣＨＣｌ_３で数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）により精製して、標題化合物（５ｇ、７２％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ４９４（Ｍ＋Ｈ）^＋。 Preparation of 3-[(2-aminoethyl) oxy] -N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 4-Bromo Methyl 3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate

Dioxane (120 mL) and _H 2 O (28 mL) solution of 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (4.43 g, 14.0 mmol), 1-(phenylsulfonyl) -4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (5.37 g, 14.0 mmol) [prepared in Preparation Example 2. ], Pd (PPh ₃ ) ₄ (808 mg, 0.70 mmol) and K ₂ CO ₃ (7.7 g, 55.9 mmol) were combined in a sealed tube. After 12 hours at 70 ° C., the reaction was partitioned between H ₂ O / CHCl ₃ . The aqueous phase was washed several times with CHCl ₃ and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexanes) to give the title compound (5 g, 72 %) Was obtained as a yellow solid: LC-MS (ES) m / z 494 (M + H) ⁺ .

ＴＨＦ（５０ｍＬ）中の４−ブロモ−３−ヒドロキシ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（５ｇ、１０．１３ｍｍｏｌ）、１，１−ジメチルエチル （２−ヒドロキシエチル）カルバメート（１．６ｍＬ、１０．３４ｍｍｏｌ）、ＰＰｈ_３（３．２ｇ、１２．２０ｍｍｏｌ）の溶液に、２５℃で、ＤＥＡＤ（１．６ｍＬ、８．３１ｍｍｏｌ）を加えた。３０分後、反応を濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）により精製して、標題化合物（５．０ｇ、９５％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ６３７（Ｍ＋Ｈ）^＋。 b) 4-Bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b] Methyl pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4-bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate in THF (50 mL) (5 g, 10.13 mmol), 1,1-dimethylethyl (2-hydroxyethyl) carbamate (1.6 mL, 10.34 mmol), PPh ₃ (3.2 g, 12.20 mmol) at 25 ° C. at 25 ° C. .6 mL, 8.31 mmol) was added. After 30 minutes, the reaction was concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexanes) to give the title compound (5.0 g, 95%) as a yellow solid: LC-MS (ES) m / Z637 (M + H) ⁺ .

ＭｅＯＨ（３０ｍＬ）中の４−ブロモ−３−｛［２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）エチル］オキシ｝−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（１．２ｇ、１．８９ｍｍｏｌ）の溶液を、２０ｗｔ％Ｐｄ（ＯＨ）_２（５２５ｍｇ）と、Ｐａｒｒシェーカーに３０ｐｓｉのＨ_２雰囲気下で１２時間置いた。反応物を濾過して触媒を除去し、濃縮して、白色固体を得（０．７１ｇ、１．２７ｍｍｏｌ）、これをさらに精製することなく用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ５５８（Ｍ＋Ｈ）^＋。 c) 3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] Pyridin-4-yl] -2-thiophenecarboxylate methyl

4-Bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [1- (phenylsulfonyl) -1H- in MeOH (30 mL). A solution of methyl pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate (1.2 g, 1.89 mmol) was added to 20 wt% Pd (OH) ₂ (525 mg) and 30 psi on a Parr shaker. For 12 hours under H ₂ atmosphere. The reaction was filtered to remove the catalyst and concentrated to give a white solid (0.71 g, 1.27 mmol) which was used without further purification: LC-MS (ES) m / z 558 (M + H ) ⁺ .

ｉ）６ＮのＮａＯＨ（３ｍＬ）およびＴＨＦ（６ｍＬ）中の３−｛［２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）エチル］オキシ｝−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（２．５ｇ、３．９３ｍｍｏｌ）の溶液を、シールしたチューブにて８０℃で撹拌した。４時間後、溶液を、ｐＨ５に２．５ＮのＨＣｌを用いて調節し、ついで、ＣＨＣｌ_３で数回抽出した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ４８３（Ｍ＋Ｈ）。 d) 1,1-dimethylethyl (2-{[2-{[(phenylmethyl) amino] carbonyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thienyl] Oxy} ethyl) carbamate

i) 3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [1- (phenyl) in 6N NaOH (3 mL) and THF (6 mL) A solution of sulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate (2.5 g, 3.93 mmol) was stirred at 80 ° C. in a sealed tube. After 4 hours, the solution was adjusted to pH 5 with 2.5 N HCl and then extracted several times with CHCl ₃ . The combined organic fractions were dried over _Na 2 SO _4, concentrated and used directly: LC-MS (ES) m / z483 (M + H).

ii) Crude acid in CHCl ₃ (15 mL), 3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- (1H-pyrrolo [2,3 -B] A solution of pyridin-4-yl) -2-thiophenecarboxylic acid (132 mg, 0.328 mmol), 1-phenylmethanamine (50 μL, 0.46 mmol), diisopropylethylamine (290 μL, 1.66 mmol) was added to PyBrop. (180 mg, 0.386 mmol) was added in one portion. After 12 hours, the reaction was concentrated and purified by column chromatography (silica, 5% MeOHCHCl ₃ (0.5% NH ₄ OH)) to give the title compound (110 mg, 68%) as a white solid: LC-MS (ES) m / z 493 (M + H) ^<+> .

e) 3-[(2-Aminoethyl) oxy] -N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide CHCl ₃ (15 mL) And 1,1-dimethylethyl (2-{[2-{[(phenylmethyl) amino] carbonyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) in MeOH (3 mL)) A solution of -3-thienyl] oxy} ethyl) carbamate (110 mg, 0.223 mmol) was added 4M HCl in dioxane (3 mL) and stirred at 25 ° C. overnight. The solution was concentrated and dry loaded onto a silica plug (5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) to give the free base of the title compound.

The free base as a solution in MeOH was then treated with HCl in Et ₂ O to give the title compound as the HCl salt: LC-MS (ES) m / z 393 (M + H) ⁺ ; ¹ H NMR (400 MHz , DMSO-d ₆ ) δ ppm 3.00 (t, J = 5.31 Hz, 2H) 4.35 (t, J = 5.31 Hz, 2H) 4.54 (d, J = 6.06 Hz, 2H) 6 .88 (d, J = 3.54 Hz, 1H) 7.23-7.29 (m, 1H) 7.30-7.37 (m, 4H) 7.42 (m, 1H) 7.64 (m , 1H) 7.78 (s, 1H) 8.28 (m, 1H) 8.43 (t, J = 6.06 Hz, 1H) 11.96 (s, 1H).

Example 141

Preparation of 3-[(2-aminoethyl) oxy] -N- (3-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1-phenyl The title compound was obtained as a yellow solid according to Example 140, except that 2-phenylethanamine (90 μL, 0.72 mmol) was used instead of methanamine: LC-MS (ES) m / z 407 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.81-1.89 (m, 2H) 2.61-2.69 (m, 2H) 2.96 (t, J = 5.31 Hz, 2H) 3.25-3.40 (M, 2H) 4.30 (t, J = 5.31 Hz, 2H) 6.87 (d, J = 3.54 Hz, 1H) 7.19 (t, J = 7) .20Hz, 1H) 7.22- .26 (m, 2H) 7.30 (t, J = 7.45 Hz, 2H) 7.42 (d, J = 0.05 Hz, 1H) 7.64 (d, J = 3.54 Hz, 1H) 7 .77 (s, 1H) 8.04 (t, J = 5.68 Hz, 1H) 8.28 (d, J = 0.05 Hz, 1H) 11.95 (s, 1H).

Example 142

Preparation of 3-[(2-aminoethyl) oxy] -N- (2-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1-phenyl The title compound was obtained as a yellow solid according to Example 140 except that (3-phenylpropyl) amine (90 μL, 0.63 mmol) was used instead of methanamine: LC-MS (ES) m / z 421 (M + H ) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.82-2.90 (m, 4H) 3.53-3.61 (m, 2H) 4.23 (t, J = 5.56 Hz) , 2H) 6.87 (d, J = 3.54 Hz, 1H) 7.21-7.26 (m, 1H) 7.26-7.36 (m, 4H) 7.40 (t, J = 4 .29 Hz, 1H) 7.64 (d, = 3.54 Hz, 1H) 7.75 (s, 1H) 7.96 (t, J = 5.81 Hz, 1H) 8.27 (d, J = 5.05 Hz, 1H) 11.95 (s, 1H) ).

Example 143

N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 Preparation of furancarboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-{(2S) -2-amino-3 -[3- (Trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (424 mg, 1.1 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl } -3- (trifluoromethyl) -L-phenylalanine was prepared according to Preparation 11] in place of 4,5-dibromo-2-thiophenecarboxylic acid ( .5G, but using 6.5 mmol), according to Example 43, the title compound was obtained as a yellow ^{solid: LC-MS (ES) m} / z428 (M + H) +; 1 H NMR (400MHz, d4-MeOH ) Δ ppm 2.85-2.95 (m, 2H) 2.98 (dd, J = 13.77, 8.97 Hz, 1H) 3.06-3.14 (m, 1H) 4.33-4. 42 (m, 1H) 6.93 (d, J = 3.54 Hz, 1H) 7.25 (s, 2H) 7.44-7.52 (m, 3H) 7.57 (d, J = 6. 82 Hz, 1H) 7.62-7.67 (m, 2H) 8.26 (d, J = 0.05 Hz, 1H).

Example 144

N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-furancarboxamide Preparation of 2-{(2S) -2 instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione -Amino-3- [3- (trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (510 mg, 1.3 mmol) [N-{[(1,1-dimethylethyl ) Oxy] carbonyl} -3- (trifluoromethyl) -L-phenylalanine was prepared according to Preparation 11] in place of 4,5-dibromo-2-thiophenecarboxylic acid. Run carboxylic acid (2.5 g, 6.6 mmol) except using, according to Example 43, the title compound was obtained as a yellow solid: LC-MS (ES) m / z507 (M + H) +; 1 H NMR ( 400 MHz, d4-MeOH) δ ppm 3.06-3.16 (m, 2H) 3.28 (d, J = 7.07 Hz, 2H) 4.62 (dd, J = 8.97, 6.44 Hz, 1H 6.90 (d, J = 3.54 Hz, 1H) 7.33 (s, 1H) 7.37-7.43 (m, 1H) 7.46-7.54 (m, 2H) 7.55 −7.60 (m, 1H) 7.63 (s, 1H) 7.74 (d, J = 0.05 Hz, 1H) 7.81-7.87 (m, 1H) 8.26 (d, J = 5.05 Hz, 1H).

Example 145

ジオキサン（１２０ｍＬ）およびＨ_２Ｏ（２８ｍＬ）中の４，５−ジブロモ−３−ヒドロキシ−２−チオフェンカルボン酸メチル（４．４３ｇ、１４．０ｍｍｏｌ）、１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（５．３７ｇ、１４．０ｍｍｏｌ）［調製例２で調製した］、Ｐｄ（ＰＰｈ_３）_４（８０８ｍｇ、０．７０ｍｍｏｌ）およびＫ_２ＣＯ_３（７．７ｇ、５５．９ｍｍｏｌ）を、シールしたチューブで合した。７０℃で１２時間後、反応物をＨ_２Ｏ／ＣＨＣｌ_３間で分配した。水相をＣＨＣｌ_３で数回抽出し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）により精製して、標題化合物（５ｇ、７２％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ４９４（Ｍ＋Ｈ）^＋。 Preparation of 3-[(2-aminoethyl) oxy] -4-bromo-N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a ) Methyl 4-bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (4.43 g, 14.0 mmol), 1- (phenylsulfonyl) -4- (4) in dioxane (120 mL) and H ₂ O (28 mL). , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (5.37 g, 14.0 mmol) [prepared in Preparation Example 2. ], Pd (PPh ₃ ) ₄ (808 mg, 0.70 mmol) and K ₂ CO ₃ (7.7 g, 55.9 mmol) were combined in a sealed tube. After 12 hours at 70 ° C., the reaction was partitioned between H ₂ O / CHCl ₃ . The aqueous phase was extracted several times with CHCl ₃ and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexane) to give the title compound (5 g, 72 %) Was obtained as a yellow solid: LC-MS (ES) m / z 494 (M + H) ⁺ .

ＴＨＦ（５０ｍＬ）中の４−ブロモ−３−ヒドロキシ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（５ｇ、１０．１３ｍｍｏｌ）、１，１−ジメチルエチル （２−ヒドロキシエチル）カルバメート（１．６ｍＬ、１０．３４ｍｍｏｌ）、ＰＰｈ_３（３．２ｇ、１２．２０ｍｍｏｌ）の溶液に、２５℃で、ＤＥＡＤ（１．６ｍＬ、８．３１ｍｍｏｌ）を一度に加えた。３０分後、反応物を濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）により精製して、標題化合物（５．０ｇ、９５％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ６３７（Ｍ＋Ｈ）^＋。 b) 4-Bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b] Methyl pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4-bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate in THF (50 mL) (5 g, 10.13 mmol), 1,1-dimethylethyl (2-hydroxyethyl) carbamate (1.6 mL, 10.34 mmol), PPh ₃ (3.2 g, 12.20 mmol) in a solution of DEAD (1 .6 mL, 8.31 mmol) was added in one portion. After 30 minutes, the reaction was concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexanes) to give the title compound (5.0 g, 95%) as a yellow solid: LC-MS (ES) m / z 637 (M + H) ⁺ .

ｉ）６ＮのＮａＯＨ（３ｍＬ）およびＴＨＦ（６ｍＬ）中の４−ブロモ−３−｛［２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）エチル］オキシ｝−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（２．５ｇ、３．９３ｍｍｏｌ）の溶液を、シールしたチューブ中、８０℃で撹拌した。４時間後、溶液を、２．５ＮのＨＣｌを用いてｐＨ５に酸性化し、ついで、ＣＨＣｌ_３で数回抽出した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ４８３（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl (2-{[4-bromo-2-{[(phenylmethyl) amino] carbonyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl)- 3-thienyl] oxy} ethyl) carbamate

i) 4-Bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [6] in 6N NaOH (3 mL) and THF (6 mL). A solution of methyl 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate (2.5 g, 3.93 mmol) was placed in a sealed tube at 80 ° C. Stir with. After 4 hours, the solution was acidified to pH 5 using 2.5N HCl and then extracted several times with CHCl ₃ . The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z 483 (M + H) ⁺ .

ii) Crude acid in CHCl ₃ (15 mL), 4-bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- (1H-pyrrolo Of [2,3-b] pyridin-4-yl) -2-thiophenecarboxylic acid (132 mg, 0.328 mmol), 1-phenylmethanamine (50 μL, 0.46 mmol), diisopropylethylamine (290 μL, 1.66 mmol) To the solution was added PyBrop (180 mg, 0.386 mmol) in one portion. After 12 hours, the reaction was concentrated and purified by column chromatography (silica, 5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) to afford the title compound (110 mg, 68%) as a white solid. Obtained: LC-MS (ES) m / z 493 (M + H) ⁺ .

d) 3-[(2-Aminoethyl) oxy] -4-bromo-N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide CHCl 1,1-dimethylethyl (2-{[4-bromo-2-{[(phenylmethyl) amino] carbonyl} -5- (1H-pyrrolo [2,3-]) in ₃ (15 mL) and MeOH (3 mL). b] A solution of pyridin-4-yl) -3-thienyl] oxy} ethyl) carbamate (110 mg, 0.223 mmol) was added to 4M HCl in dioxane (3 mL) and stirred at 25 ° C. overnight. The solution was concentrated and dry loaded onto a silica plug (5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) to give the free base of the title compound.

The free base as a solution in MeOH was treated with 2M HCl in excess Et ₂ O to give the title compound as the HCl salt: LC-MS (ES) m / z 472 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.95 (t, J = 4.93 Hz, 2H) 4.26 (t, J = 4.93 Hz, 2H) 4.50 (d, J = 5.05 Hz, 2H) 6.55 (d, J = 3.54 Hz, 1H) 7.23-7.35 (m, 5H) 7.63 (d, J = 3.28 Hz, 1H) 8.33 (d, J = 4) .80 Hz, 1H) 9.96 (s, 1H) 11.99 (s, 1H).

Example 146

Of 3-[(2-aminoethyl) oxy] -4-bromo-N- (3-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation 1- The title compound was obtained as a yellow solid according to Example 145 except that (3-phenylpropyl) amine (130 μL, 0.91 mmol) was used instead of phenylmethanamine: LC-MS (ES) m / Z500 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.82-1.92 (m, 2H) 2.61-2.67 (m, 2H) 2.96 (t, J = 4.80 Hz, 2H) 3.30-3.37 (m, 2H) 4.23 (t, J = 4.80 Hz, 2H) 6.55 (d, J = 3.28 Hz, 1H) 7.16 -7.21 (m, 1H 7.23-7.31 (m, 4H) 7.62 (d, J = 1.52 Hz, 1H) 8.31-8.35 (m, 1H) 9.38-9.32 (m, 1H) 11.99 (s, 1H).

Example 147

Of 3-[(2-aminoethyl) oxy] -4-bromo-N- (2-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation 1- The title compound (2-phenylethyl) amine (100 μL, 0.80 mmol) was obtained as a yellow solid according to Example 145 except using instead of 1-phenylmethanamine: LC-MS (ES) m / H 486 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.84-2.91 (m, 4H) 3.49-3.57 (m, 2H) 4.15 (t, J = 4.93 Hz, 2H) 6.55 (d, J = 3.28 Hz, 1H) 7.21-7.35 (m, 5H) 7.63 (d, J = 3.28 Hz, 1H) 8.31 -8.35 (m, 1H) 9 40 (t, J = 5.56Hz, 1H) 11.99 (s, 1H).

Example 148

Preparation of N- {2-amino-1- [3- (trifluoromethyl) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1, 1,1-dimethylethyl {2-amino-2- [3- (trifluoromethyl) phenyl] ethyl} carbamate (0.52 g, 1) instead of 1-dimethylethyl (3-amino-3-phenylpropyl) carbamate .7 mmol) The title compound was obtained as a yellow solid according to Example 15 except using [prepared from 3- (trifluoromethyl) benzaldehyde according to Preparation 9]: LC-MS (ES) m / z 431 ^{(M + H) +; 1} H NMR (400MHz, DMSO-d 6) δppm 2.91-3.02 (m, 2H) 5.05 (s, 1H) 6 85 (d, J = 3.54 Hz, 1H) 7.39 (d, J = 0.05 Hz, 1H) 7.57-7.65 (m, 3H) 7.70 (d, J = 7.07 Hz, 1H) 7.75 (s, 1H) 7.86 (d, J = 4.04 Hz, 1H) 8.07 (d, J = 4.04 Hz, 1H) 8.27 (d, J = 5.05 Hz, 1H) 8.97 (s, 1H) 11.94 (s, 1H).

Example 149

N- {2-amino-1- [3- (trifluoromethyl) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation of 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate 1,1-dimethylethyl {2-amino-2- [3- (trifluoromethyl) phenyl] ethyl} carbamate (0 .45 g, 1.5 mmol) [prepared from 3- (trifluoromethyl) benzaldehyde according to Preparative Example 9] in place of 5-bromo-2-thiophenecarboxylic acid, 4,5-dibromo-2-thiophenecarboxylic acid The title compound was obtained as a yellow solid according to Example 15 except that (3.41 g, 11.9 mmol) was used: LC-MS (E ^{) M / z510 (M + H} ) +; 1 H NMR (400MHz, d4-MeOH) δppm 3.07-3.11 (m, 2H) 5.19 (dd, J = 8.08,6.06Hz, 1H) 6.61 (d, J = 3.54 Hz, 1H) 7.35 (d, J = 0.05 Hz, 1H) 7.51 (d, J = 3.54 Hz, 1H) 7.58-7.64 ( m, 2H) 7.70 (d, J = 7.07 Hz, 1H) 7.76 (s, 1H) 7.98 (s, 1H) 8.29 (d, J = 0.05 Hz, 1H).

Example 150

ｉ）ＣＨＣｌ_３（２５ｍＬ）中のベンゾイルクロライド（５．９ｇ、４２．２ｍｍｏｌ）の溶液を、ＣＨＣｌ_３（１０５ｍＬ）中の１，１−ジメチルエチル ［（１Ｓ）−２−ヒドロキシ−１−（フェニルメチル）エチル］カルバメート（５．３ｇ、２１．０ｍｍｏｌ）およびＥｔ_３Ｎ（８．８ｍＬ、６３．１ｍｍｏｌ）の溶液に加え、室温にて一晩撹拌した。反応をＭｅＯＨでクエンチし、溶媒を蒸発させ、残った油を、シリカ（１：３ＥｔＯＡｃ／ヘキサン）に乾燥充填して、透明油（７．５ｇ、定量）を得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ３５５（Ｍ＋Ｈ）^＋。
ｉｉ）（２Ｓ）−２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）−３−フェニルプロピルベンゾエートを、ＣＨＣｌ_３（７５ｍＬ）およびＭｅＯＨ（１０ｍＬ）中に入れ、ジオキサン（２９ｍＬ）中の４ＭのＨＣｌを加え、反応物を一晩撹拌した。溶媒を蒸発させて、標題化合物（２．４７ｇ、４６％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ２５５（Ｍ＋Ｈ）^＋。 Preparation of 4-bromo-N-[(1S) -2-hydroxy-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) (2S) -2-Amino-3-phenylpropylbenzoate

i) A solution of benzoyl chloride (5.9 g, 42.2 mmol) in CHCl ₃ (25 mL) was added to 1,1-dimethylethyl [(1S) -2-hydroxy-1- (phenyl] in CHCl ₃ (105 mL). Methyl) ethyl] carbamate (5.3 g, 21.0 mmol) and Et ₃ N (8.8 mL, 63.1 mmol) were added and stirred at room temperature overnight. The reaction was quenched with MeOH, the solvent was evaporated and the remaining oil was dry loaded onto silica (1: 3 EtOAc / hexane) to give a clear oil (7.5 g, quantitative): LC-MS (ES) m / z 355 (M + H) ⁺ .
ii) (2S) -2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -3-phenylpropylbenzoate was placed in CHCl ₃ (75 mL) and MeOH (10 mL) and dioxane (29 mL 4M HCl in) was added and the reaction was stirred overnight. The solvent was evaporated to give the title compound (2.47 g, 46%) as a white solid: LC-MS (ES) m / z 255 (M + H) ⁺ .

ＣＨＣｌ_３（１５ｍＬ）中の粗酸、４−ブロモ−３−｛［２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）エチル］オキシ｝−５−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）−２−チオフェンカルボン酸（９０５ｍｇ、１．９５ｍｍｏｌ）［調製例２で調製した］、（２Ｓ）−２−アミノ−３−フェニルプロピルベンゾエート（５４５ｍｇ、２．１３ｍｍｏｌ）、ジイソプロピルエチルアミン（１．３ｍＬ、７．４６ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（１．２ｇ、２．５７ｍｍｏｌ）を一度に加えた。１２時間後、反応物を濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）により精製して、標題化合物（５９３ｍｇ、４３％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ７０１（Ｍ＋Ｈ）^＋。 b) (2S) -2-[({4-Bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thienyl} carbonyl) amino] -3-Phenylpropylbenzoate

Crude acid, 4-bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- (1H-pyrrolo [2], in CHCl ₃ (15 mL). , 3-b] pyridin-4-yl) -2-thiophenecarboxylic acid (905 mg, 1.95 mmol) [prepared in Preparation Example 2], (2S) -2-amino-3-phenylpropylbenzoate (545 mg, 2 PyBrop (1.2 g, 2.57 mmol) was added in one portion to a solution of .13 mmol), diisopropylethylamine (1.3 mL, 7.46 mmol). After 12 hours, the reaction was concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexanes) to give the title compound (593 mg, 43%) as a white solid: LC-MS (ES) m / z701 (M + H) ⁺ .

c) 4-Bromo-N-[(1S) -2-hydroxy-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide (2S) -2-[({4-Bromo-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] in THF (10 mL) and MeOH (2 mL) To a solution of 2-thienyl} carbonyl) amino] -3-phenylpropylbenzoate was added 6N NaOH (1 mL) and the mixture was stirred overnight at room temperature. The reaction mixture is slightly acidified with 2.5N HCl, the solvent is evaporated, the mixture is dry loaded onto a silica plug (5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) and the title compound Of free base was obtained (35 mg, 10%).

The free base as a solution in MeOH was then treated with excess 2M HCl in Et ₂ O to give the title compound as the HCl salt: LC-MS (ES) m / z 457 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.79 (dd, J = 13.64, 9.09 Hz, 1H) 2.96 (dd, J = 13.64, 5.05 Hz, 1H) 3.48 ( ddd, J = 19.83, 10.61, 5.94 Hz, 2H) 4.13 (dt, J = 14.66, 5.40 Hz, 1H) 4.92 (s, 1H) 6.51 (d, J = 3.28 Hz, 1H) 7.15-7.23 (m, 1H) 7.26-7.30 (m, 5H) 7.59-7.63 (m, 1H) 8.04 (s, 1H) 8.33 (d, J = 4.80 Hz, 1H) 11.98 (s, 1H).

Example 151

N - Preparation of [(1S) -2-hydroxy-1- (phenylmethyl) ethyl]-5-(1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 4,5 The title compound was obtained as a yellow solid according to Example 154 except that 5-bromo-2-thiophenecarboxylic acid (3.16 g, 15.3 mmol) was used instead of dibromo-2-thiophenecarboxylic acid: LC-MS (ES) m / z 378 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.81 (dd, J = 13.77, 9.22 Hz, 1H) 2.97 (dd, J = 13 .77, 5.18 Hz, 1H) 3.43-3.55 (m, 2H) 4.14 (dd, J = 8.59, 3.54 Hz, 1H) 4.90 (t, J = 5.68 Hz) , 1H) 6 .84 (dd, J = 3.54, 1.77 Hz, 1H) 7.17 (td, J = 5.56, 2.78 Hz, 1H) 7.24-7.30 (m, 4H) 7.37 (D, J = 5.05 Hz, 1H) 7.61-7.64 (m, 1H) 7.80 (d, J = 4.04 Hz, 1H) 7.90 (d, J = 4.04 Hz, 1H) ) 8.26 (d, J = 5.05 Hz, 1H) 8.34-8.39 (m, 1H) 11.92 (s, 1H).

Example 152

Preparation of N- {2-amino-1- [2- (trifluoromethyl) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1, 1,1-dimethylethyl {2-amino-2- [2- (trifluoromethyl) phenyl] ethyl} carbamate (0.31 g, 1) instead of 1-dimethylethyl (3-amino-3-phenylpropyl) carbamate 0.0 mmol) The title compound was obtained as a yellow solid according to Example 15 except using [prepared from 2- (trifluoromethyl) benzaldehyde according to Preparation 9]: LC-MS (ES) m / z 431 (M + H) ⁺ ; ¹ H NMR (400 MHz, d4-MeOH) δ ppm 3.06-3.08 (m, 2H) 5.53-5.61 (m, 1H) 6.92 (d, J = 3.54 Hz, 1H) 7.40 (d, J = 5.30 Hz, 1H) 7.49 (t, J = 7.71 Hz, 1H) 7.52 (d, J = 3.79 Hz, 1H) 7.67 (t, J = 7.58 Hz, 1H) 7.73-7.78 (m, 3H) 7.95 (d, J = 4.04 Hz, 1H) 23 (d, J = 0.05 Hz, 1H).

Example 153

N- {2-amino-1- [2- (trifluoromethyl) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation of 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate 1,1-dimethylethyl {2-amino-2- [2- (trifluoromethyl) phenyl] ethyl} carbamate (0 .37 g, 1.2 mmol) [prepared from 2- (trifluoromethyl) benzaldehyde according to Preparative Example 9] to 4,5-dibromo-2-thiophenecarboxylic acid instead of 5-bromo-2-thiophenecarboxylic acid The title compound was obtained as a yellow solid according to Example 15 except that (7.25 g, 18.9 mmol) was used: LC-MS (E ^{) M / z510 (M + H} ) +; 1 H NMR (400MHz, d4-MeOH) δppm 3.04 (d, J = 6.82Hz, 2H) 5.53 (t, J = 6.82Hz, 1H) 6. 58 (d, J = 3.54 Hz, 1H) 7.31 (d, J = 0.05 Hz, 1H) 7.43-7.50 (m, 2H) 7.64 (t, J = 7.71 Hz, 1H) 7.73 (d, J = 8.34 Hz, 2H) 7.99 (s, 1H) 8.27 (d, J = 0.05 Hz, 1H).

Example 154

ジオキサン（１２０ｍＬ）およびＨ_２Ｏ（２８ｍＬ）中の４，５−ジブロモ−３−ヒドロキシ−２−チオフェンカルボン酸メチル（４．４３ｇ、１４．０ｍｍｏｌ）、１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（５．３７ｇ、１４．０ｍｍｏｌ）［調製例２で調製した］、Ｐｄ（ＰＰｈ_３）_４（８０８ｍｇ、０．７０ｍｍｏｌ）およびＫ_２ＣＯ_３（７．７ｇ、５５．９ｍｍｏｌ）を、シールしたチューブで合した。７０℃で１２時間後、反応物をＨ_２Ｏ／ＣＨＣｌ_３間で分配した。水相をＣＨＣｌ_３で数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）により精製して、標題化合物（５ｇ、７２％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ４９４（Ｍ＋Ｈ）^＋。 3-[(2-aminoethyl) oxy] -N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H- Preparation of pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide a) 4-Bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] Methyl pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (4.43 g, 14.0 mmol), 1- (phenylsulfonyl) -4- (4) in dioxane (120 mL) and H ₂ O (28 mL). , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (5.37 g, 14.0 mmol) [prepared in Preparation Example 2. ], Pd (PPh ₃ ) ₄ (808 mg, 0.70 mmol) and K ₂ CO ₃ (7.7 g, 55.9 mmol) were combined in a sealed tube. After 12 hours at 70 ° C., the reaction was partitioned between H ₂ O / CHCl ₃ . The aqueous phase was washed several times with CHCl ₃ and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexanes) to give the title compound (5 g, 72 %) Was obtained as a yellow solid: LC-MS (ES) m / z 494 (M + H) ⁺ .

ＴＨＦ（５０ｍＬ）中の４−ブロモ−３−ヒドロキシ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（５ｇ、１０．１３ｍｍｏｌ）、１，１−ジメチルエチル （２−ヒドロキシエチル）カルバメート（１．６ｍＬ、１０．３４ｍｍｏｌ）、ＰＰｈ_３（３．２ｇ、１２．２０ｍｍｏｌ）の溶液に、２５℃で、ＤＥＡＤ（１．６ｍＬ、８．３１ｍｍｏｌ）を一度で加えた。３０分後、反応物を濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）により精製して、標題化合物（５．０ｇ、９５％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ６３７（Ｍ＋Ｈ）^＋。 b) 4-Bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b] Methyl pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4-bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate in THF (50 mL) (5 g, 10.13 mmol), 1,1-dimethylethyl (2-hydroxyethyl) carbamate (1.6 mL, 10.34 mmol), PPh ₃ (3.2 g, 12.20 mmol) in a solution of DEAD (1 .6 mL, 8.31 mmol) was added in one portion. After 30 minutes, the reaction was concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexanes) to give the title compound (5.0 g, 95%) as a yellow solid: LC-MS (ES) m / z 637 (M + H) ⁺ .

ｉ）６ＮのＮａＯＨ（３ｍＬ）およびＴＨＦ（６ｍＬ）中の４−ブロモ−３−｛［２−（｛［（１，１−ジメチルエチル）オキシ］カルボニル｝アミノ）エチル］オキシ｝−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（２．５ｇ、３．９３ｍｍｏｌ）の溶液を、シールしたチューブ中、８０℃で撹拌した。４時間後、溶液を２．５ＮのＨＣｌを用いてｐＨ５に酸性化し、ついで、ＣＨＣｌ_３で数回抽出した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ４８３（Ｍ＋Ｈ）^＋。 c) 1,1-dimethylethyl (2-{[2-{[((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) amino] carbonyl} -4- Bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thienyl] oxy} ethyl) carbamate

i) 4-Bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- [6] in 6N NaOH (3 mL) and THF (6 mL). A solution of methyl 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate (2.5 g, 3.93 mmol) was placed in a sealed tube at 80 ° C. Stir with. After 4 hours, the solution was acidified to pH 5 with 2.5N HCl and then extracted several times with CHCl ₃ . The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z 483 (M + H) ⁺ .

ii) Crude acid in CHCl ₃ (20 mL), 4-bromo-3-{[2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] oxy} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxylic acid (280 mg, 0.450 mmol), 2-{(2S) -2-amino-3- [3- (trifluoromethyl) phenyl] Propyl} -1H-isoindole-1,3 (2H) -dione (227 mg, 0.59 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -3- (trifluoromethyl) -L -Prepared from phenylalanine according to Preparative Example 11] to a solution of diisopropylethylamine (0.5 mL, 2.87 mmol) in PyBrop (289 mg, 0.62 mmol). It was added at once. After 12 hours, the reaction was concentrated and purified by column chromatography (silica, 5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) to afford the title compound (0.36 g, quantitative) as a white solid. Obtained: LC-MS (ES) m / z 813 (M + H) ⁺ .

iii) 1,1-dimethylethyl (2-{[2-{[((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl]) in THF (10 mL) and MeOH (5 mL) Methyl} ethyl) amino] carbonyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thienyl] oxy} ethyl) carbamate in a solution of hydrazine (150 μL, 4.8 mmol) was added and the mixture was stirred overnight at room temperature. The solution was concentrated and dry packed into a silica plug (5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) to give a white solid (84 mg, 0.123 mmol): LC-MS (ES) m / z683 (M + H) ⁺ .

d) 3-[(2-Aminoethyl) oxy] -N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- ( 1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1-dimethylethyl (2-{[2-{[(()) in CHCl ₃ (15 mL) and MeOH (3 mL) 1S) -2-Amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) amino] carbonyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- To a solution of (yl) -3-thienyl] oxy} ethyl) carbamate (84 mg, 0.123 mmol) was added 4M HCl in dioxane (1.2 mL) and stirred at 25 ° C. overnight. The solution was concentrated and dry packed in a silica plug (5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) to give the free base of the title compound (56 mg, 78%).

The free base as a solution in MeOH was then treated with excess 2M HCl in Et ₂ O to give the title compound as the HCl salt: LC-MS (ES) m / z 583 (M + H) ⁺ ; ¹ H NMR (400 MHz, d4-MeOH) δ ppm 2.91 (d, J = 6.06 Hz, 2H) 3.01-3.12 (m, 4H) 4.19 (ddd, J = 13.26, 9.85) , 4.42 Hz, 2H) 4.35 (dd, J = 8.08, 6.32 Hz, 1H) 6.60 (d, J = 3.79 Hz, 1H) 7.29 (d, J = 5.05 Hz) , 1H) 7.48-7.55 (m, 3H) 7.56-7.61 (m, 1H) 7.64 (s, 1H) 8.29 (d, J = 0.05 Hz, 1H).

Example 155

ジオキサン（１２０ｍＬ）およびＨ_２Ｏ（２８ｍＬ）中の４，５−ジブロモ−３−ヒドロキシ−２−チオフェンカルボキシレート（４．４３ｇ、１４．０ｍｍｏｌ）、１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（５．３７ｇ、１４．０ｍｍｏｌ）［調製例２で調製した］、Ｐｄ（ＰＰｈ_３）_４（８０８ｍｇ、０．７０ｍｍｏｌ）およびＫ_２ＣＯ_３（７．７ｇ、５５．９ｍｍｏｌ）をシールしたチューブで合した。７０℃で１２時間後、反応物をＨ_２Ｏ／ＣＨＣｌ_３間で分配した。水相をＣＨＣｌ_３で数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）で精製して、標題化合物（５ｇ、７２％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ４９４（Ｍ＋Ｈ）^＋。 N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3 -B] Preparation of pyridin-4-yl) -2-thiophenecarboxamide a) 4-Bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-4- Yl] -2-thiophenecarboxylate methyl

Dioxane (120 mL) and _H 2 O (28 mL) solution of 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (4.43 g, 14.0 mmol), 1-(phenylsulfonyl) -4- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (5.37 g, 14.0 mmol) [prepared in Preparation Example 2] , Pd (PPh ₃ ) ₄ (808 mg, 0.70 mmol) and K ₂ CO ₃ (7.7 g, 55.9 mmol) were combined in a sealed tube. After 12 hours at 70 ° C., the reaction was partitioned between H ₂ O / CHCl ₃ . The aqueous phase was washed several times with CHCl ₃ and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexane) to give the title compound (5 g, 72 %) Was obtained as a yellow solid: LC-MS (ES) m / z 494 (M + H) ⁺ .

ＴＨＦ（６０ｍＬ）中の４−ブロモ−３−ヒドロキシ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（２．２ｇ、４．４８ｍｍｏｌ）、ＭｅＯＨ（１ｍＬ、２５ｍｍｏｌ）、ＰＰｈ_３（１．４ｇ、５．４ｍｍｏｌ）の溶液に、２５℃で、ＤＥＡＤ（８３５μＬ、５．３０ｍｍｏｌ）を一度に加えた。３０分後、反応物を濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）により精製して、標題化合物（１．６ｇ、７１％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ５０８（Ｍ＋Ｈ）^＋。 b) Methyl 4-bromo-3- (methyloxy) -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4-bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate in THF (60 mL) (2. To a solution of 2 g, 4.48 mmol), MeOH (1 mL, 25 mmol), PPh ₃ (1.4 g, 5.4 mmol) at 25 ° C. was added DEAD (835 μL, 5.30 mmol) in one portion. After 30 minutes, the reaction was concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexanes) to give the title compound (1.6 g, 71%) as a white solid: LC-MS (ES) m / z 508 (M + H) ⁺ .

ｉ）６ＮのＮａＯＨ（１ｍＬ）およびＴＨＦ（１０ｍＬ）中の４−ブロモ−３−（メチルオキシ）−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（６１１ｍｇ、１．２ｍｍｏｌ）の溶液を、シールしたチューブ中８０℃で撹拌した。４時間後、溶液を２．５ＮのＨＣｌを用いてｐＨ５に酸性化し、ついで、ＣＨＣｌ_３で数回抽出した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ３５４（Ｍ＋Ｈ）^＋。
ｉｉ）ＣＨＣｌ_３（１５ｍＬ）中の粗酸、４−ブロモ−３−（メチルオキシ）−５−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）−２−チオフェンカルボン酸（０．３４ｇ、０．９６３ｍｍｏｌ）、２−｛（２Ｓ）−２−アミノ−３−［３−（トリフルオロメチル）フェニル］プロピル｝−１Ｈ−イソインドール−１，３（２Ｈ）−ジオン（３８０ｍｇ、０．９９ｍｍｏｌ）［Ｎ−｛［（１，１−ジメチルエチル）オキシ］カルボニル｝−３−（トリフルオロメチル）−Ｌ−フェニルアラニンから、調製例１１に従って調製した］、ジイソプロピルエチルアミン（０．８８ｍＬ、５．０５ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（５４９ｍｇ、１．１８ｍｍｏｌ）を一度に加えた。１２時間後、反応物を濃縮し、カラムクロマトグラフィー（シリカ、ＣＨＣｌ_３中５％ＭｅＯＨ（０．５％ＮＨ_４ＯＨ））により精製して、標題化合物（１１０ｍｇ、０．１６ｍｍｏｌ）を黄色油として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ６８４（Ｍ＋Ｈ）^＋。 c) N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2 , 3-b] pyridin-4-yl) -2-thiophenecarboxamide

i) 4-Bromo-3- (methyloxy) -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-4-in in 6N NaOH (1 mL) and THF (10 mL) A solution of methyl yl] -2-thiophenecarboxylate (611 mg, 1.2 mmol) was stirred at 80 ° C. in a sealed tube. After 4 hours, the solution was acidified to pH 5 with 2.5N HCl and then extracted several times with CHCl ₃ . The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z 354 (M + H) ⁺ .
ii) Crude acid in CHCl ₃ (15 mL), 4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxylic acid (0 .34 g, 0.963 mmol), 2-{(2S) -2-amino-3- [3- (trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (380 mg, 0.99 mmol) [prepared according to Preparation 11 from N-{[(1,1-dimethylethyl) oxy] carbonyl} -3- (trifluoromethyl) -L-phenylalanine], diisopropylethylamine (0.88 mL, PyBrop (549 mg, 1.18 mmol) was added in one portion to the 5.05 mmol) solution. After 12 hours, the reaction was concentrated and purified by column chromatography (silica, 5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) to afford the title compound (110 mg, 0.16 mmol) as a yellow oil. Obtained: LC-MS (ES) m / z 684 (M + H) ⁺ .

d) N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2 , 3-b] pyridin-4-yl) -2-thiophenecarboxamide 4-bromo-N-((1S) -2- (1,3-dioxo-1,3 in THF (10 mL) and MeOH (2 mL). -Dihydro-2H-isoindol-2-yl) -1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -3- (methyloxy) -5- (1H-pyrrolo [2,3-b To a solution of pyridin-4-yl) -2-thiophenecarboxamide was added hydrazine (50 μL, 1.6 mmol) and the mixture was stirred overnight at room temperature. The solution was concentrated and dry packed into a silica plug (5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) to give a white solid (19 mg, 21%): LC-MS (ES) m / z 554 (M + H) ⁺ .

The free base as a solution in MeOH was then treated with excess 2M HCl in Et ₂ O to give the title compound as the HCl salt: LC-MS (ES) m / z 472 (M + H) ⁺ ; ¹ H NMR (400 MHz, d4-MeOH) δ ppm 2.93 (br.s, 2H) 2.99-3.08 (m, 1H) 3.10-3.19 (m, 1H) 3.91 (s, 3H ) 4.39 (td, J = 5.87, 3.16 Hz, 1H) 6.59 (d, J = 3.54 Hz, 1H) 7.29 (d, J = 0.05 Hz, 1H) 7.49 −7.56 (m, 3H) 7.60 (d, J = 6.57 Hz, 1H) 7.65 (s, 1H) 8.29 (d, J = 0.05 Hz, 1H).

Example 156

ジオキサン（１２０ｍＬ）およびＨ_２Ｏ（２８ｍＬ）中の４，５−ジブロモ−３−ヒドロキシ−２−チオフェンカルボン酸メチル（４．４３ｇ、１４．０ｍｍｏｌ）、１−（フェニルスルホニル）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（５．３７ｇ、１４．０ｍｍｏｌ）［調製例２で調製した］、Ｐｄ（ＰＰｈ_３）_４（８０８ｍｇ、０．７０ｍｍｏｌ）およびＫ_２ＣＯ_３（７．７ｇ、５５．９ｍｍｏｌ）をシールしたチューブで合した。７０℃で１２時間後、反応物をＨ_２Ｏ／ＣＨＣｌ_３間で分配した。水相をＣＨＣｌ_３で数回洗浄し、合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）により精製して、標題化合物（５ｇ、７２％）を黄色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ４９４（Ｍ＋Ｈ）^＋。 N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridine Preparation of -4-yl) -2-thiophenecarboxamide a) 4-Bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2 -Methyl thiophenecarboxylate

Dioxane (120 mL) and _H 2 O (28 mL) solution of 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (4.43 g, 14.0 mmol), 1-(phenylsulfonyl) -4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (5.37 g, 14.0 mmol) [prepared in Preparation Example 2. ], Pd (PPh ₃ ) ₄ (808 mg, 0.70 mmol) and K ₂ CO ₃ (7.7 g, 55.9 mmol) were combined in a sealed tube. After 12 hours at 70 ° C., the reaction was partitioned between H ₂ O / CHCl ₃ . The aqueous phase was washed several times with CHCl ₃ and the combined organic fractions were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexanes) to give the title compound (5 g, 72 %) Was obtained as a yellow solid: LC-MS (ES) m / z 494 (M + H) ⁺ .

ＴＨＦ（６０ｍＬ）中の４−ブロモ−３−ヒドロキシ−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（２．２ｇ、４．４８ｍｍｏｌ）、ＭｅＯＨ（１ｍＬ、２５ｍｍｏｌ）、ＰＰｈ_３（１．４ｇ、５．４ｍｍｏｌ）の溶液に、２５℃で、ＤＥＡＤ（８３５μＬ、５．３０ｍｍｏｌ）を一度に加えた。３０分後、反応物を濃縮し、カラムクロマトグラフィー（シリカ、１：３ＥｔＯＡｃ／ヘキサン）により精製して、標題化合物（１．６ｇ、７１％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ５０８（Ｍ＋Ｈ）^＋。 b) Methyl 4-bromo-3- (methyloxy) -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4-bromo-3-hydroxy-5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate in THF (60 mL) (2. To a solution of 2 g, 4.48 mmol), MeOH (1 mL, 25 mmol), PPh ₃ (1.4 g, 5.4 mmol) at 25 ° C. was added DEAD (835 μL, 5.30 mmol) in one portion. After 30 minutes, the reaction was concentrated and purified by column chromatography (silica, 1: 3 EtOAc / hexanes) to give the title compound (1.6 g, 71%) as a white solid: LC-MS (ES) m / z 508 (M + H) ⁺ .

ＭｅＯＨ（２０ｍＬ）中の４−ブロモ−３−（メチルオキシ）−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（１ｇ、１．９７ｍｍｏｌ）の溶液を、２０ｗｔ％Ｐｄ（ＯＨ）_２（５２５ｍｇ）と一緒に、Ｐａｒｒシェーカーに３０ｐｓｉのＨ_２雰囲気下で１２時間置いた。反応物を濾過して、触媒を除去し、濃縮して、白色固体を得（０．４１ｇ、０．９６ｍｍｏｌ）、さらに精製することなく次に用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ４２９（Ｍ＋Ｈ）^＋。 c) Methyl 3- (methyloxy) -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate

Methyl 4-bromo-3- (methyloxy) -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxylate in MeOH (20 mL) A solution of (1 g, 1.97 mmol) was placed on a Parr shaker with 20 wt% Pd (OH) ₂ (525 mg) under 30 psi H ₂ atmosphere for 12 hours. The reaction was filtered to remove the catalyst and concentrated to give a white solid (0.41 g, 0.96 mmol) that was then used without further purification: LC-MS (ES) m / z 429 ( M + H) ⁺ .

ｉ）６ＮのＮａＯＨ（２ｍＬ）およびＴＨＦ（２０ｍＬ）中の３−（メチルオキシ）−５−［１−（フェニルスルホニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル］−２−チオフェンカルボン酸メチル（０．４１ｇ、０．９６ｍｍｏｌ）の溶液を、シールしたチューブで８０℃で撹拌した。４時間後、溶液を、２．５ＮのＨＣｌを用いてｐＨ５に酸性化し、ＣＨＣｌ_３で数回抽出した。合した有機フラクションをＮａ_２ＳＯ_４で乾燥し、濃縮し、直接用いた：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ２７５（Ｍ＋Ｈ）^＋。
ｉｉ）ＣＨＣｌ_３（１５ｍＬ）中の粗酸、３−（メチルオキシ）−５−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）−２−チオフェンカルボン酸（２６２ｍｇ、０．９６ｍｍｏｌ）、２−｛（２Ｓ）−２−アミノ−３−［３−（トリフルオロメチル）フェニル］プロピル｝−１Ｈ−イソインドール−１，３（２Ｈ）−ジオン（４２０ｍｇ、１．１ｍｍｏｌ）［Ｎ−｛［（１，１−ジメチルエチル）オキシ］カルボニル｝−３−（トリフルオロメチル）−Ｌ−フェニルアラニンから、調製例１１に従って調製した］、ジイソプロピルエチルアミン（１．７ｍＬ、９．７６ｍｍｏｌ）の溶液に、ＰｙＢｒｏｐ（７００ｍｇ、１．５ｍｍｏｌ）を一度に加えた。１２時間後、反応物を濃縮し、カラムクロマトグラフィー（シリカ、ＣＨＣｌ_３中５％ＭｅＯＨ（０．５％ＮＨ_４ＯＨ））により精製して、標題化合物（１１０ｍｇ、６８％）を白色固体として得た：ＬＣ−ＭＳ（ＥＳ）ｍ／ｚ６０５（Ｍ＋Ｈ）^＋。 d) N-((1S) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1-{[3- (trifluoromethyl) phenyl] methyl} ethyl ) -3- (Methyloxy) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide

i) 3- (Methyloxy) -5- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2 in 6N NaOH (2 mL) and THF (20 mL) A solution of methyl thiophenecarboxylate (0.41 g, 0.96 mmol) was stirred at 80 ° C. in a sealed tube. After 4 hours, the solution was acidified to pH 5 using 2.5N HCl and extracted several times with CHCl ₃ . The combined organic fractions were dried over Na ₂ SO ₄ , concentrated and used directly: LC-MS (ES) m / z 275 (M + H) ⁺ .
ii) Crude acid in CHCl ₃ (15 mL), 3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxylic acid (262 mg, 0.96 mmol) ), 2-{(2S) -2-amino-3- [3- (trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (420 mg, 1.1 mmol) [N -Prepared according to Preparation Example 11 from {[(1,1-dimethylethyl) oxy] carbonyl} -3- (trifluoromethyl) -L-phenylalanine], a solution of diisopropylethylamine (1.7 mL, 9.76 mmol) To this was added PyBrop (700 mg, 1.5 mmol) in one portion. After 12 hours, the reaction was concentrated and purified by column chromatography (silica, 5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) to give the title compound (110 mg, 68%) as a white solid. : LC-MS (ES) m / z 605 (M + H) ⁺ .

e) 3-[(2-Aminoethyl) oxy] -N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide THF (10 mL) and N-((1S) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1-{[3- (trifluoromethyl) phenyl in MeOH (2 mL) ] Methyl} ethyl) -3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide in solution with hydrazine (360 μL, 11.5 mmol). In addition, the mixture was stirred overnight at room temperature. The solution was concentrated and dry packed into a silica plug (5% MeOH in CHCl ₃ (0.5% NH ₄ OH)) to give a white solid (50 mg, 8%): LC-MS (ES) m / z 475 (M + H) ⁺ .

The free base as a solution in MeOH was then treated with excess HCl to give the title compound as the HCl salt: LC-MS (ES) m / z 475 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO— d ₆ ) δ ppm 3.02-3.13 (m, 4H) 4.10 (s, 3H) 4.47 (m, 1H) 6.86 (dd, J = 3.66, 1.89 Hz, 1H) 7.43 (d, J = 0.05 Hz, 1H) 7.53 (d, J = 8.59 Hz, 1H) 7.55-7.61 (m, 2H) 7.65 (dd, J = 6. 06, 3.03 Hz, 2H) 7.77 (s, 1H) 7.92 (br.s, 2H) 8.28-8.38 (m, 1H) 12.03 (s, 1H).

Example 157

Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 4,5-dibromo-2- 4-Bromo-2-thiophenecarboxylic acid (0.62 g, 3.0 mmol) instead of thiophenecarboxylic acid and 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate instead of 1,1- The title compound was prepared according to the method described in Example 15 except that dimethylethyl (2-amino-3-phenylpropyl) carbamate (0.75 g, 3.0 mmol) [prepared in Example 76] was used. as a ^{solid: LC-MS (ES) m} / z = 377 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.47 (s, 1H), 8 43 (m, 1H), 8.3 (m, 1H), 7.74 (m, 1H), 7.67 (m, 1H), 7.33 (m, 4H), 7.23 (m, 1H) ), 7.14 (m, 1H), 4.6 (m, 1H), 3.21 (m, 2H), and 3.04 (m, 2H).

Example 158

Preparation of N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 4,5-dibromo-2- 5-Bromo-2-thiophenecarboxylic acid (0.62 g, 3.0 mmol) instead of thiophenecarboxylic acid and 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate The title compound was converted to a yellow solid according to the method described in Example 15 except that dimethylethyl (2-amino-3-phenylpropyl) carbamate (0.75 g, 3.0 mmol) [prepared in Example 76] was used. ^{and-obtained: LC-MS (ES) m} / z = 377 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.38 (brs, 1H), .92 (m, 1H), 7.82 (m, 1H), 7.69 (m, 2H), 7.33 (m, 4H), 7.25 (m, 1H), 7.12 (m, 1H), 4.59 (m, 1H), 3.25 (m, 1H), 3.17 (m, 1H) and 3.03 (m, 2H).

Example 159

Preparation of N-[(2S) -2-amino-3-phenylpropyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 4,5-dibromo-2 5-Bromo-2-thiophenecarboxylic acid (0.05 g, 0.25 mmol) instead of thiophenecarboxylic acid, 1,1 instead of 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate -Dimethylethyl [(1S) -2-amino-1- (phenylmethyl) ethyl] carbamate (0.06 g, 0.25 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -L- The title compound was obtained as a yellow solid according to the method described in Example 15 except that was prepared from phenylalanine according to Example 7: LC- ^{S (ES) m / z =} 377 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.36 (brs, 1H), 7.92 (m, 1H), 7.84 (m, 1H) , 7.69 (m, 1H), 7.65 (m, 1H), 7.38 (m, 5H), 7.11 (m, 1H), 3.73 (m, 1H), 3.64 ( m, 2H) and 3.04 (m, 2H).

Example 160

Preparation of N-[(2R) -2-amino-3-phenylpropyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1 -1,1-dimethylethyl [(1R) -2-amino-1- (phenylmethyl) ethyl] carbamate (0.063 g, 0.25 mmol) instead of dimethylethyl (3-amino-3-phenylpropyl) carbamate The title compound was prepared as a yellow solid according to the method described in Example 15 except using [N-{[(1,1-dimethylethyl) oxy] carbonyl} -D-phenylalanine prepared according to Example 7]. ^{and-obtained: LC-MS (ES) m} / z = 456 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.38 (m, 1H), 7. 0 (m, 1H), 7.61 (m, 1H), 7.47 (m, 6H), 6.7 (m, 1H), 3.73 (m, 1H), 3.62 (m, 2H) ) And 3.03 (m, 2H).

Example 161

Preparation of N-[(2S) -2-amino-3-phenylpropyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 1,1 -1,1-dimethylethyl [(1S) -2-amino-1- (phenylmethyl) ethyl] carbamate (0.063 g, 0.25 mmol) instead of dimethylethyl (3-amino-3-phenylpropyl) carbamate The title compound was prepared as a yellow solid according to the method described in Example 15 except using [N-{[(1,1-dimethylethyl) oxy] carbonyl} -L-phenylalanine prepared according to Example 7]. ^{and-obtained: LC-MS (ES) m} / z = 456 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.39 (s, 1H), 7. 0 (m, 1H), 7.63 (m, 1H), 7.5 (m, 1H), 7.41 (m, 5H), 6.72 (m, 1H), 3.77 (m, 1H) ), 3.47 (m, 2H) and 3.03 (m, 2H).

Example 162

Preparation of N-[(2R) -2-amino-3-phenylpropyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 4,5-dibromo-2 5-Bromo-2-thiophenecarboxylic acid (0.052 g, 0.25 mmol) instead of thiophenecarboxylic acid, 1,1 instead of 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate -Dimethylethyl [(1R) -2-amino-1- (phenylmethyl) ethyl] carbamate (0.063 g, 0.25 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -D- The title compound was obtained as a yellow solid according to the method described in Example 15 except that was prepared from phenylalanine according to Example 7: L ^{-MS (ES) m / z =} 377 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.36 (brs, 1H), 7.12 (m, 1H), 7.84 (m, 1H ), 7.67 (m, 2H), 7.38 (m, 5H), 7.11 (m, 1H), 3.74 (m, 1H), 3.66 (m, 2H) and 3.03 (M, 2H).

Example 163

Preparation of N- (3-amino-1-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 4,5-dibromo-2-thiophenecarboxylic acid 5-bromo-2-thiophenecarboxylic acid (0.052 g, 0.25 mmol) instead of 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate instead of 1,1-dimethylethyl ( 3-amino-3-phenylpropyl) carbamate (0.063 g, 0.25 mmol) [prepared from Preparation 6 according to Example 7], using the title compound according to the method described in Example 15. as a yellow ^{solid: LC-MS (ES) m} / z = 377 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.64 m, 1H), 8.4 (brs, 1H), 7.96 (m, 1H), 7.84 (s, 1H), 7.49 (m, 6H), 7.34 (m, 1H), 5.25 (m, 1H), 3.12 (m, 1H), 3.0 (m, 1H) and 2.35 (m, 2H).

Example 164

Preparation of N- [2-amino-1- (4-fluorophenyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 1, 1,1-dimethylethyl [2-amino-2- (4-fluorophenyl) ethyl] carbamate (0.064 g, 0.25 mmol) instead of 1-dimethylethyl (3-amino-3-phenylpropyl) carbamate [ The title compound was obtained as a yellow solid according to the method described in Example 15 except using 4-fluorobenzaldehyde prepared according to Preparative Example 9]: LC-MS (ES) m / z = 460 (M + H _{^{) +; 1 H NMR (CD}} 3 OD, 400MHz) δ8.34 (brs, 1H), 7.94 (m, 1H), 7.53 (m, 3H), 7. (M, 1H), 7.21 (m, 2H), 7.64 (m, 1H), 5.45 (m, 1H) and 3.48 (m, 2H).

Example 165

Preparation of N- [2-amino-1- (4-fluorophenyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 4,5-dibromo- Instead of 2-thiophenecarboxylic acid, 5-bromo-2-thiophenecarboxylic acid (0.052 g, 0.25 mmol) was used instead of 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate. 1-dimethylethyl [2-amino-2- (4-fluorophenyl) ethyl] carbamate (0.064 g, 0.25 mmol) carried out except using 4-fluorobenzaldehyde, prepared according to Preparation Example 9 according to the method described in example 15, the title compound was obtained as a yellow solid: LC-MS (ES) m / z = 381 (M + H) +; 1 _{NMR (CD 3 OD, 400MHz)} δ8.3 (m, 1H), 7.95 (m, 2H), 7.68 (m, 2H), 7.54 (m, 2H), 7.15 (m, 3H), 5.49 (m, 1H) and 3.5 (m, 2H).

Example 166

Preparation of N- [2-amino-1- (2-fluorophenyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 4,5-dibromo- Instead of 2-thiophenecarboxylic acid, 5-bromo-2-thiophenecarboxylic acid (0.052 g, 0.25 mmol) was used instead of 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate. 1-dimethylethyl [2-amino-2- (2-fluorophenyl) ethyl] carbamate (0.064 g, 0.25 mmol) carried out except using 2-fluorobenzaldehyde, prepared according to Preparation Example 9 according to the method described in example 15, the title compound was obtained as a yellow solid: LC-MS (ES) m / z = 381 (M + H) +; 1 _{NMR (CD 3 OD, 400MHz)} δ8.36 (m, 1H), 7.97 (m, 2H), 7.69 (m, 2H), 7.58 (m, 1H), 7.46 (m, 1H), 7.26 (m, 2H), 7.12 (m, 1H), 5.78 (m, 1H) and 3.51 (m, 2H).

Example 167

Preparation of N- [2-amino-1- (2-fluorophenyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 1, 1,1-dimethylethyl [2-amino-2- (2-fluorophenyl) ethyl] carbamate (0.064 g, 0.25 mmol) instead of 1-dimethylethyl (3-amino-3-phenylpropyl) carbamate [ The title compound was obtained as a yellow solid according to the method described in Example 15, except using 2-fluorobenzaldehyde prepared according to Preparation 9]: LC-MS (ES) m / z = 460 (M + H _{^{) +; 1 H NMR (CD}} 3 OD, 400MHz) δ8.36 (m, 1H), 7.99 (s, 1H), 7.56 (m, 2H), 7.45 m, 2H), 7.26 (m, 2H), 6.68 (m, 1H), 5.74 (m, 1H) and 3.5 (m, 2H).

Example 168

Preparation of N- [2-amino-1- (3-fluorophenyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 1, 1,1-dimethylethyl [2-amino-2- (3-fluorophenyl) ethyl] carbamate (0.064 g, 0.25 mmol) instead of 1-dimethylethyl (3-amino-3-phenylpropyl) carbamate [ The title compound was obtained as a brown solid according to the method described in Example 15, except using 3-fluorobenzaldehyde prepared according to Preparation 9]: LC-MS (ES) m / z = 460 (M + H _{^{) +; 1 H NMR (CD}} 3 OD, 400MHz) δ8.38 (m, 1H), 7.98 (m, 1H), 7.63 (m, 1H), 7.51 m, 2H), 7.3 (m, 2H), 7.14 (m, 1H), 6.75 (m, 1H), 5.48 (m, 1H) and 3.49 (m, 2H).

Example 169

Preparation of N- [2-amino-1- (3-fluorophenyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide 4,5-dibromo- Instead of 2-thiophenecarboxylic acid, 5-bromo-2-thiophenecarboxylic acid (0.052 g, 0.25 mmol) was used instead of 1,1-dimethylethyl (3-amino-3-phenylpropyl) carbamate. Example 15 except that 1-dimethylethyl [2-amino-3-fluorophenyl) ethyl] carbamate (0.064 g, 0.25 mmol) [prepared from 3-fluorobenzaldehyde according to Preparation 9] was used. The title compound was obtained as a yellow solid according to the described method: LC-MS (ES) m / z = 381 (M + H) ⁺ ; ¹ H NM R (CD ₃ OD, 400 MHz) δ 8.37 (m, 1H), 7.99 (m, 2H), 7.72 (m, 2H), 7.48 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1), 7.14 (m, 2), 5.51 m, 1H) and 3.51 (m, 2H).

Example 170

N-[(2R) -2-amino-3- (3-fluorophenyl) propyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-[(2R) -2-amino-3- (3 -Fluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (0.075 g, 0.25 mmol)) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -3- The title compound was obtained as a brown solid according to the method of Example 43 except that was prepared from fluoro-D-phenylalanine according to Example 7]: LC-MS (ES) m / z = 474 (M + H) ⁺ : ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.41 (m, 1H), 7.85 (m, 1H), 7.67 (m, 1H), 7.52 (m, 1H), 7. 44 (m, 1H), 7.19 (m, 2H), 7.09 (m, 1H), 6.75 (m, 1H), 3.78 (m, 1H), 3.66 (m, 2H) ) And 3.08 (m, 2H).

Example 171

N-{(1R) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 Preparation of thiophenecarboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-[(2S) -2-amino-3 -(2-Fluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (0.075 g, 0.25 mmol)) [N-{[(1,1-dimethylethyl) oxy] carbonyl} The title compound was obtained as a yellow solid according to the method of Example 43, except using 2-fluoro-D-phenylalanine prepared according to Preparation Example 7: LC-MS (ES) m / z = 474 ( _{^{+ H) +; 1 H NMR}} (CD 3 OD, 400MHz) δ8.36 (m, 1H), 7.8 (m, 1H), 7.61 (m, 1H), 7.49 (m, 1H), 7.32 (m, 2H), 7.14 (m, 2H), 6.7 (m, 1H), 4.61 (m, 1H), 3.27 (m, 1H), 3.16 (m , 2H) and 3.03 (m, 1H).

Example 172

N-{(1R) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 Preparation of thiophene carboxamide 2-[(2S) -2-amino-3 instead of 2-[(2R) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione -(3-Fluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (0.075 g, 0.25 mmol)) [N-{[(1,1-dimethylethyl) oxy] carbonyl} The title compound was obtained as a yellow solid according to the method of Example 43 except that it was prepared according to Preparation Example 7 from -3-fluoro-D-phenylalanine]: LC-MS (ES) m / z = 474 ( _{^{+ H) +; 1 H NMR}} (CD 3 OD, 400MHz) δ8.4 (m, 1H), 7.8 (m, 1H), 7.65 (m, 1H), 7.52 (m, 1H), 7.37 (m, 1H), 7.13 (m, 2H), 7.0 (m, 1H), 6.74 (m, 1H), 4.6 (m, 1H), 3.26 (m , 1H), 3.15 (m, 1H) and 3.01 (m, 2H).

Example 173

Of N-{(1R) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation Instead of 4,5-dibromo-2-thiophenecarboxylic acid, 5-bromo-2-thiophenecarboxylic acid (0.052 g, 0.25 mmol) was replaced with 2-[(2S) -2-amino-3-phenylpropyl. ] Instead of 1H-isoindole-1,3 (2H) -dione 2-[(2S) -2-amino-3- (3-fluorophenyl) propyl] -1H-isoindole-1,3 (2H ) -Dione (0.075 g, 0.25 mmol)) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -3-fluoro-D-phenylalanine prepared according to Preparation Example 7. According the method of Example 43 but using the title compound as a yellow ^{solid: LC-MS (ES) m} / z = 395 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8. 33 (m, 1H), 7.88 (m, 1H), 7.81 (m, 1H), 7.67 (m, 1H), 7.61 (m, 1H), 7.34 (m, 1H) ), 7.11 (m, 3H), 6.99 (m, 1H), 4.59 (m, 1H), 3.27 (m, 1H), 3.17 (m, 1H) and 3.02 (M, 2H).

Example 174

N-{(1S) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 Preparation of thiophenecarboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-[(2S) -2-amino-3 -(3-Fluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (0.075 g, 0.25 mmol)) [N-{[(1,1-dimethylethyl) oxy] carbonyl} The title compound was obtained as a yellow solid according to the method of Example 43 except that the compound was prepared according to Preparation 7 from -3-fluoro-L-phenylalanine]: LC-MS (ES) m / z = 474 ( _{^{+ H) +; 1 H NMR}} (CD 3 OD, 400MHz) δ8.36 (m, 1H), 7.79 (m, 1H), 7.6 (m, 1H), 7.46 (m, 1H), 7.35 (m, 1H), 7.11 (m, 2H), 7.0 (m, 1H), 6.68 (m, 1H), 4.57 (m, 1H), 3.26 (m , 1H), 3.15 (m, 1H) and 3.02 (m, 2H).

Example 175

Of N-{(1S) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation Instead of 4,5-dibromo-2-thiophenecarboxylic acid, 5-bromo-2-thiophenecarboxylic acid (0.052 g, 0.25 mmol) was replaced with 2-[(2S) -2-amino-3-phenylpropyl. ] Instead of 1H-isoindole-1,3 (2H) -dione 2-[(2S) -2-amino-3- (3-fluorophenyl) propyl] -1H-isoindole-1,3 (2H ) -Dione (0.075 g, 0.25 mmol)) prepared from N-{[(1,1-dimethylethyl) oxy] carbonyl} -3-fluoro-L-phenylalanine according to Preparation Example 7. According the method of Example 43 but using the title compound as a yellow ^{solid: LC-MS (ES) m} / z = 395 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8. 35 (m, 1H), 7.92 (m, 1H), 7.82 (m, 1H), 7.68 (m, 2H), 7.33 (m, 1H), 7.12 (m, 3H) ), 6.99 (m, 1H), 4.58 (m, 1H), 3.27 (m, 1H), 3.18 (m, 1H) and 3.03 (m, 2H).

Example 176

Of N-{(1S) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation Instead of 4,5-dibromo-2-thiophenecarboxylic acid, 5-bromo-2-thiophenecarboxylic acid (0.052 g, 0.25 mmol) was replaced with 2-[(2S) -2-amino-3-phenylpropyl. ] Instead of 1H-isoindole-1,3 (2H) -dione 2-[(2S) -2-amino-3- (2-fluorophenyl) propyl] -1H-isoindole-1,3 (2H ) -Dione (0.075 g, 0.25 mmol)) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -2-fluoro-L-phenylalanine prepared according to Preparation Example 7. According the method of Example 43 but using the title compound as a yellow ^{solid: LC-MS (ES) m} / z = 395 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8. 37 (m, 1H), 7.96 (m, 1H), 7.84 (m, 1H), 7.72 (m, 2H), 7.36 (m, 1H), 7.3 (m, 1H) ), 7.11 (m, 3H), 4.63 (m, 1H), 3.21 (m, 3H) and 3.03 (m, 1H).

Example 177

N-{(1R) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 Preparation of thiophenecarboxamide 2-[(2R) -2-amino-3 instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione -(2-Fluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (0.075 g, 0.25 mmol)) [N-{[(1,1-dimethylethyl) oxy] carbonyl} The title compound was obtained as a yellow solid according to the method of Example 43, except using 2-fluoro-D-phenylalanine prepared according to Preparation Example 7: LC-MS (ES) m / z = 474 ( _{^{+ H) +; 1 H NMR}} (CD 3 OD, 400MHz) δ8.38 (m, 1H), 7.81 (m, 1H), 7.64 (m, 1H), 7.51 (m, 1H), 7.32 (m, 2H), 7.13 (m, 2H), 6.72 (m, 1H), 4.61 (m, 1H), 3.28 (m, 1H), 3.21 (m , 1H), 3.13 (m, 1H) and 3.02 (m, 1H).

Example 178

Of N-{(1R) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation Instead of 4,5-dibromo-2-thiophenecarboxylic acid, 5-bromo-2-thiophenecarboxylic acid (0.052 g, 0.25 mmol) was replaced with 2-[(2S) -2-amino-3-phenylpropyl. ] Instead of 1H-isoindole-1,3 (2H) -dione 2-[(2R) -2-amino-3- (2-fluorophenyl) propyl] -1H-isoindole-1,3 (2H ) -Dione (0.075 g, 0.25 mmol)) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -2-fluoro-D-phenylalanine prepared according to Preparation Example 7. According the method of Example 43 but using the title compound as a yellow ^{solid: LC-MS (ES) m} / z = 395 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8. 35 (m, 1H), 7.91 (m, 1H), 7.82 (m, 1H), 7.66 (m, 2H), 7.33 (m, 2H), 7.12 (m, 3H) ), 4.63 (m, 1H), 3.28 (m, 1H), 3.17 (m, 2H) and 3.03 (m, 1H).

Example 179

N- [2-amino-1- (phenylmethyl) ethyl] -3-[(3-aminopropyl) oxy] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) Preparation of 2-thiophenecarboxamide The title compound was prepared according to the method of Example 77 except for using 1,1-dimethylethyl (3-hydroxypropyl) carbamate (0.088 g, 0.5 mmol) instead of methanol. Obtained as a yellow solid: LC-MS (ES) m / z = 529 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.42 (m, 1H), 7.65 (m, 1H), 7.51 (m, 1H), 7.35 (m, 4H), 7.27 (m, 1H), 6.76 (m, 1H), 4.67 (m, 1H), 4.01 (m , 1H), 3.93 (m, 1H), 3.29 (m, 2H), 3.20 (m, 2H), 3.08 (m, 2H) and 2.09 (m, 2H).

Example 180

N- {2-amino-1-[(2,6-difluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophene Preparation of carboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2- [2-amino-3- (2,6- Difluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (0.126 g, 0.4 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -2,6- difluoromethoxy phenylalanine, except using] was prepared according to preparation example 7, according to the method of example 43, the title compound was obtained as a yellow solid: LC-MS (ES) m / z = 492 (M + H) + _{^{1 H NMR (CD 3 OD,}} 400MHz) δ8.37 (m, 1H), 7.80 (m, 1H), 7.62 (m, 1H), 7.47 (m, 1H), 7.34 ( m, 1H), 7.01 (m, 2H), 6.68 (m, 1H), 4.62 (m, 1H), 3.30 (m, 1H), 3.25 (m, 1H) and 3.10 (m, 2H).

Example 181

N-{(1S) -2-amino-1-[(3,5-difluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) Preparation of 2-thiophenecarboxamide 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2- [2-amino-3- ( 3,5-difluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione (0.126 g, 0.4 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl}- The title compound was obtained as a yellow solid according to the method of Example 43, except using 3,5-difluoro-L-phenylalanine according to Preparation Example 7]: LC-MS (ES) m / z = 49 _{^{(M + H) +; 1}} H NMR (CD 3 OD, 400MHz) δ8.37 (m, 1H), 7.83 (m, 1H), 7.62 (m, 2H), 6.96 (m, 2H) , 6.82 (m, 2H), 4.58 (m, 1H), 3.27 (m, 1H), 3.18 (m, 1H), 3.05 (m, 1H) and 2.98 ( m, 1H).

Example 182

Preparation 4 of N- {2-amino-1-[(3,5-difluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide , 5-Dibromo-2-thiophenecarboxylic acid instead of 5-bromo-2-thiophenecarboxylic acid (0.082 g, 0.4 mmol), 2-[(2S) -2-amino-3-phenylpropyl]- Instead of 1H-isoindole-1,3 (2H) -dione, 2- [2-amino-3- (3,5-difluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione ( 0.126 g, 0.4 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -2,6-difluorophenylalanine prepared according to Preparation Example 7] Outside, according to the method of Example 43, the title compound was obtained as a yellow ^{solid: LC-MS (ES) m} / z = 413 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.35 (m , 1H), 7.92 (m, 1H), 7.82 (m, 1H), 7.67 (m, 2H), 7.11 (m, 1H), 6.97 (m, 2H), 6 .85 (m, 1H), 4.59 (m, 1H), 3.27 (m, 1H), 3.18 (m, 1H), 3.08 (m, 1H) and 2.99 (m, 1H).

Example 183

N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 Preparation of thiophenecarboxamide 5-bromo-2-thiophenecarboxylic acid (0.102 g, 0.5 mmol) instead of 4,5-dibromo-2-thiophenecarboxylic acid was replaced with 2-[(2S) -2-amino- 2-{(2S) -2-amino-3- [3- (trifluoromethyl) phenyl] propyl} -1H- instead of 3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione Isoindole-1,3 (2H) -dione (0.174 g, 0.5 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -3- (trifluoromethyl) -L-phenyla Except for using the Nin, the] was prepared according to Preparation Example 7, according to the method of Example 43, the title compound was obtained as a yellow solid: LC-MS (ES) m / z = 445 (M + H) +; 1 H NMR (CD ₃ OD, 400 MHz) δ 8.43 (m, 1H), 8.05 (m, 1H), 7.95 (m, 1H), 7.87 (m, 1H), 7.82 (m, 1H), 7.68 (m, 1H), 7.62 (m, 1H), 7.53 (m, 2H), 7.27 (m, 1H), 4.61 (m, 1H), 3. 27 (m, 2H) and 3.14 (m, 2H).

Example 184

N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-thiophenecarboxamide preparation 2-[(2S) -2 instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione -Amino-3- [3- (trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (0.174 g, 0.5 mmol) [N-{[(1,1- The title compound was obtained as a yellow solid according to the method of Example 43 except using [Dimethylethyl) oxy] carbonyl} -3- (trifluoromethyl) -L-phenylalanine prepared in accordance with Preparation 7. ^{: LC-MS (ES) m} / z = 524 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.53 (m, 1H), 7.93 (m, 1H), 7.82 (m , 2H), 7.66 (m, 1H), 7.62 (m, 1H), 7.55 (m, 2H), 6.95 (m, 1H), 4.58 (m, 1H) and 3 .17 (m, 4H).

Example 185

N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-thiophenecarboxamide preparation 2-[(2S) -2 instead of 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione -Amino-3- [2- (trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (0.174 g, 0.5 mmol) [N-{[(1,1- [Dimethylethyl) oxy] carbonyl} -2- (trifluoromethyl) -L-phenylalanine was used according to the method of Example 43 except that the title compound was obtained as a yellow solid. ^{: LC-MS (ES) m} / z = 524 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.57 (m, 1H), 8.07 (m, 1H), 7.89 (m , 2H), 7.73 (m, 1H), 7.59 (m, 2H), 7.45 (m, 1H), 7.0 (m, 1H), 4.69 (m, 1H), 3 .27 (m, 3H) and 3.18 (m, 1H).

Example 186

N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 Preparation of thiophenecarboxamide 5-bromo-2-thiophenecarboxylic acid (0.102 g, 0.5 mmol) instead of 4,5-dibromo-2-thiophenecarboxylic acid was replaced with 2-[(2S) -2-amino- 2-{(2S) -2-amino-3- [2- (trifluoromethyl) phenyl] propyl} -1H- instead of 3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione Isoindole-1,3 (2H) -dione (0.174 g, 0.5 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -2- (trifluoromethyl) -L-phenyla Except for using the Nin, the] was prepared according to Preparation Example 7, according to the method of Example 43, the title compound was obtained as a yellow solid: LC-MS (ES) m / z = 445 (M + H) +; 1 H NMR (CD ₃ OD, 400 MHz) δ 8.46 (m, 1H), 8.09 (m, 2H), 7.89 (m, 1H), 7.83 (m, 1H), 7.72 (m, 1H), 7.63 (m, 1H), 7.54 (m, 1H), 7.44 (m, 1H), 7.27 (m, 1H), 4.72 (m, 1H) and 3. 21 (m, 4H).

Example 187

Preparation 4 of N- {2-amino-1-[(2,6-difluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide , 5-Dibromo-2-thiophenecarboxylic acid instead of 5-bromo-2-thiophenecarboxylic acid (0.08 g, 0.4 mmol), 2-[(2S) -2-amino-3-phenylpropyl]- Instead of 1H-isoindole-1,3 (2H) -dione, 2- [2-amino-3- (2,6-difluorophenyl) propyl] -1H-isoindole-1,3 (2H) -dione ( 0.126 g, 0.4 mmol) [prepared according to Preparation Example 7 from N-{[(1,1-dimethylethyl) oxy] carbonyl} -2,6-difluorophenylalanine] According to the method of Example 43 to give the title compound as a yellow ^{solid: LC-MS (ES) m} / z = 413 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.36 (m, 1H), 7.92 (m, 1H), 7.82 (m, 1H), 7.68 (m, 2H), 7.31 (m, 1H), 7.11 (m, 1H), 6. 98 (m, 2H), 4.66 (m, 1H), 3.26 (m, 2H) and 3.12 (m, 2H).

Example 188

Of N-[(1S) -2-amino-1- (4-pyridinylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide Preparation 2-[(2S) -2-amino-3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione instead of 2-[(2S) -2-amino-3- (4- Pyridinyl) propyl] -1H-isoindole-1,3 (2H) -dione (0.086 g, 0.3 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -3- (4- The title compound was obtained as a yellow solid according to the method of Example 43 except that was prepared according to Preparative Example 7 from pyridinyl) -L-alanine: LC-MS (ES) m / z = 457 (M + H ) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.80 (m, 2H), 8.39 (m, 1H), 8.04 (m, 2H), 7.85 (m, 1H), 7.66 (m, 1H), 7.52 (m, 1H), 6.66 (m, 1H), 4.79 (m, 1H), 3.41 (m, 2H) and 3.29 (m, 2H).

Example 189

Preparation of N-[(1S) -2-amino-1- (4-pyridinylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide 4,5 -Instead of dibromo-2-thiophenecarboxylic acid, 5-bromo-2-thiophenecarboxylic acid (0.062 g, 0.3 mmol) was replaced with 2-[(2S) -2-amino-3-phenylpropyl] -1H- 2-[(2S) -2-amino-3- (4-pyridinyl) propyl] -1H-isoindole-1,3 (2H) -dione (0) instead of isoindole-1,3 (2H) -dione 0.086 g, 0.3 mmol) except using [N-{[(1,1-dimethylethyl) oxy] carbonyl} -3- (4-pyridinyl) -L-alanine according to Preparation Example 7]. According to the method of Example 43, the title compound was obtained as a yellow ^{solid: LC-MS (ES) m} / z = 378 (M + H) +; 1 H NMR (CD 3 OD, 400MHz) δ8.80 (m, 2H) , 8.4 (m, 1H), 8.11 (m, 2H), 7.94 (m, 1H), 7.89 (m, 1H), 7.72 (m, 2H), 7.19 ( m, 1H), 4.82 (m, 1H) and 3.42 (m, 4H).

Example 190

N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Preparation of furancarboxamide Instead of 4,5-dibromo-2-thiophenecarboxylic acid, 5-bromo-2-thiophenecarboxylic acid (0.062 g, 0.3 mmol) was replaced with 2-[(2S) -2-amino- 2-{(2S) -2-amino-3- [2- (trifluoromethyl) phenyl] propyl} -1H- instead of 3-phenylpropyl] -1H-isoindole-1,3 (2H) -dione Isoindole-1,3 (2H) -dione (0.104 g, 0.3 mmol) [N-{[(1,1-dimethylethyl) oxy] carbonyl} -2- (trifluoromethyl) -L-phenylalani From except using] was prepared according to Preparation Example 7, according to the method of Example 43, the title compound was obtained as a yellow solid: LC-MS (ES) m / z = 378 (M + H) +; 1 H NMR (CD ₃ OD, 400 MHz) δ 8.50 (d, J = 4 Hz, 1H), 8.24 (d, J = 8 Hz, 1H), 7.84 (d, J = 4 Hz, 1H), 7.78 ( d, J = 4 Hz, 1H), 7.71 (d, J = 8 Hz, 1H), 7.64 (d, J = 8 Hz, 1H), 7.53 (m, 2H), 7.42 (m, 2H), 4.77 (m, 1H), 3.42 (m, 1H) and 3.27 (m, 3H).

Example 191

N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3 -B] Preparation of pyridin-4-yl) -2 -furancarboxamide 1,1-dimethylethyl instead of (2-amino-3-phenylpropyl) carbamate 2-{(2S) -2-amino-3- [ 2- (Trifluoromethyl) phenyl] propyl} -1H-isoindole-1,3 (2H) -dione (0.105 g, 0.3 mmol)) [N-{[(1,1-dimethylethyl) oxy] The title compound was obtained as a yellow solid according to the method of Example 77 except using carbonyl} -2- (trifluoromethyl) -L-phenylalanine, prepared according to Preparation 7]: L C-MS (ES) m / z = 554 (M + H) ⁺ ; ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.34 (m, 1H), 7.88 (m, 1H), 7.76 (m, 1H), 7.60 (m, 2H), 7.48 (m, 1H), 7.38 (m, 1H), 6.66 (m, 1H), 4.78 (m, 1H), 3. 96 (m, 3H), 3.39 (m, 1H) and 3.27 (m, 3H).

Example 192-Capsule Composition An oral dosage form for administering a compound of the invention is prepared by filling a standard two piece hard gelatin capsule with the ingredients in the amounts shown in Table I below.

Example 193-Injectable Parenteral Composition An injectable form for administering a compound of the invention is 1.5% by weight of 4-bromo-N- [2- (methylamino) -1-phenylethyl]. Prepared by stirring 5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide (the compound of Example 10) in 10% by volume propylene glycol in water. .

Example 194-Tablet Composition Sucrose , calcium sulfate dihydrate and Akt inhibitor shown in Table II below are mixed and granulated with the indicated amounts with a 10% gelatin solution. The wet granules are screened, dried, mixed with starch, talc and stearic acid, screened and compressed.

  While preferred embodiments of the invention have been described above, the invention is not limited to the precise instructions disclosed herein and is entitled to all modifications within the scope of the claims. Should be interpreted as possessing

Claims (40)

Formula (I):

[Where:
V is selected from the group consisting of CH and N;
Z is selected from the group consisting of CR ⁷ and N, wherein R ⁷ is selected from hydrogen, —CO ₂ R ²⁰ and C _1-3 alkyl, wherein R ²⁰ is hydrogen and C _1- Selected from ₃ alkyls;
W, X and Y are selected from the group consisting of CR ⁵ , CR ¹⁰ and N, wherein R ⁵ is hydrogen, C _1-3 alkyl, aryl, heteroaryl, —CO ₂ R ⁸ , —CN and -COR ⁸ and R ¹⁰ is selected from the formula (X):

(Where:
R ¹ and R ²⁸ are independently selected from hydrogen, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C _1-3 alkyl, —NR ¹⁴ R ¹⁵ , cyano and —OR ³⁰ ;
L ¹ is —NR ⁶ CO—, —CONR ⁶ —, —NR ⁶ SO ₂ —, —SO ₂ NR ⁶ —, —NR ⁶ CH ₂ —, —CH ₂ NR ⁶ —, —CH═CH—, — Selected from CF═CH— and —CH═CF—
R ² is hydrogen, — (CH ₂ ) _m -aryl, — (CH ₂ ) _m —C _3-7 cycloalkyl, C _1-3 alkyl, substituted — (CH ₂ ) _m -aryl, substituted — (CH ₂ ) Selected from _m- C _3-7 cycloalkyl and substituted C _1-3 alkyl, wherein m is 0-4;
R ²⁵ is hydrogen or R ²⁵ together with R ³ or R ⁴ forms a 4-7 membered carbocyclic ring which may contain one additional heteroatom,
R ³ and R ⁴ are independently selected from hydrogen and C _1-5 alkyl, or R ³ and R ⁴ together with the nitrogen to which they are attached, 1 or 2 Forms a 4-6 membered carbocycle which may contain further heteroatoms, or R ³ or R ⁴ together with R ²⁵ may contain one further heteroatom Forming a good 4-7 membered carbocyclic ring,
Q is, - _{(CH 2) p} aryl _{(CH 2) p} -, substituted - _{(CH 2) p} aryl _{(CH 2) p} - and - _{(CH 2) n} - is selected from, where, p is 0 4 and n is 0 to 4 and when n is other than 0, the — (CH ₂ ) _n — group may be substituted by oxo,
Wherein R ⁶ is selected from the group consisting of hydrogen and C _1-3 alkyl;
R ³⁰ is selected from the group consisting of hydrogen, — (CH ₂ ) _q NR ²⁶ R ²⁷ and C _1-3 alkyl, wherein q is 0-4, R ²⁶ and R ²⁷ are hydrogen and C Selected from _1-5 alkyl, or R ²⁶ and R ²⁷ together with the nitrogen to which they are attached may contain 1 or 2 additional heteroatoms 4-6 members Form a carbocycle of
R ¹⁴ and R ¹⁵ are independently selected from hydrogen and C _1-3 alkyl)
A substituent represented by;
Wherein R ⁸ is selected from hydrogen and C _1-3 alkyl:
Where one of W, X and Y is CR ¹⁰ ; up to three of V, W, X, Y and Z are N]
A compound represented by   A pharmaceutically acceptable salt, hydrate, solvate or prodrug of the compound of formula (I) according to claim 1. Formula (Ia):

[Where:
Z is CR ⁷ wherein R ⁷ is selected from hydrogen and —CO ₂ R ²⁰ , wherein R ²⁰ is selected from hydrogen and C _1-3 alkyl;
W, X and Y are selected from the group consisting of CR ⁵ , CR ¹⁰ and N, wherein R ⁵ is hydrogen, C _1-3 alkyl, aryl, heteroaryl, —CO ₂ R ⁸ , —CN and -COR ⁸ and R ¹⁰ is selected from the formula (X):

(Where:
R ¹ is selected from hydrogen, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C _1-3 alkyl, —NR ¹⁴ R ¹⁵ , cyano and —OR ⁶ ;
L ¹ is —NR ⁶ CO—, —CONR ⁶ —, —NR ⁶ SO ₂ —, —SO ₂ NR ⁶ —, —NR ⁶ CH ₂ —, —CH ₂ NR ⁶ —, —CH═CH—, — Selected from CF═CH— and —CH═CF—
R ² is hydrogen, — (CH ₂ ) _m -aryl, — (CH ₂ ) _m —C _3-7 cycloalkyl, C _1-3 alkyl, substituted — (CH ₂ ) _m -aryl, substituted — (CH ₂ ) Selected from _m- C _3-7 cycloalkyl and substituted C _1-3 alkyl, wherein m is 0-4;
R ²⁵ is hydrogen or R ²⁵ together with R ³ or R ⁴ forms a 4-7 membered carbocycle;
R ³ and R ⁴ are independently selected from hydrogen and C _1-5 alkyl, or R ³ and R ⁴ together with the nitrogen to which they are attached, 1 or 2 Forming a 4-6 membered carbocycle which may contain additional heteroatoms, or R ³ or R ⁴ together with R ²⁵ form a 4-7 membered carbocycle;
Q is, - _{(CH 2) p} aryl _{(CH 2) p} -, substituted - _{(CH 2) p} aryl _{(CH 2) p} - and - _{(CH 2) n} - is selected from, where, p is 0 4 and n is 0 to 4 and when n is other than 0, the — (CH ₂ ) _n — unit may be substituted by oxo,
Wherein R ⁶ is selected from the group consisting of hydrogen and C _1-3 alkyl;
R ³⁰ is selected from the group consisting of hydrogen, — (CH ₂ ) _q NR ²⁶ R ²⁷ and C _1-3 alkyl, wherein q is 0-4, R ²⁶ and R ²⁷ are hydrogen and C Selected from _1-5 alkyl, or R ²⁶ and R ²⁷ together with the nitrogen to which they are attached may contain 1 or 2 additional heteroatoms 4-6 members Form a carbocycle of
R ¹⁴ and R ¹⁵ are independently selected from hydrogen and C _1-3 alkyl)
A substituent represented by
Wherein R ⁸ is selected from hydrogen and C _1-3 alkyl:
Where one of W, X and Y is CR ¹⁰ ; up to three of W, X, Y and Z are N]
The compound of Claim 1 shown by these.   A pharmaceutically acceptable salt, hydrate, solvate or prodrug of the compound of formula (Ia) according to claim 3. Z is CR ⁷ , wherein R ⁷ is selected from hydrogen and —CO ₂ R ²⁰ , wherein R ²⁰ is selected from hydrogen and C _1-3 alkyl;
W, X and Y are selected from the group consisting of CR ⁵ and CR ¹⁰ , wherein R ⁵ is hydrogen and R ¹⁰ is of formula (X):

(Where:
R ¹ is selected from hydrogen, halogen, aryl, heteroaryl and cyano;
L ¹ is selected from —NR ⁶ CO— and —CONR ⁶ —,
R ² is selected from hydrogen, — (CH ₂ ) _m -aryl, substituted — (CH ₂ ) _m -aryl, where m is 0-4;
R ²⁵ is hydrogen, or R ²⁵ together with R ³ or R ⁴ forms a 4-7 membered carbocycle;
R ³ and R ⁴ are independently selected from hydrogen and C _1-5 alkyl, or R ³ and R ⁴ together with the nitrogen to which they are attached, 1 or 2 Forming a 4-6 membered carbocycle which may contain additional heteroatoms, or R ³ or R ⁴ together with R ²⁵ form a 4-7 membered carbocycle;
Q is, - _{(CH 2) p} aryl _{(CH 2) p} - and - _{(CH 2) n} - is selected from, where, p is 0 to 4, n is 0 to 4, n is 0 If other than, - _{(CH 2) n} - group may be substituted)
A substituent represented by
Wherein R ⁶ is selected from the group consisting of hydrogen and C _1-3 alkyl:
Where one of W, X and Y is CR ¹⁰ ;
4. A compound according to claim 3.   A pharmaceutically acceptable salt, hydrate, solvate or prodrug of the compound of formula (Ia) according to claim 5. 3-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide;
3-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide;
4-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] butanamide;
4-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] butanamide;
3-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide;
4-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide;
N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
4-bromo-N- [2- (methylamino) -1-phenylethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- (3-amino-1-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (3-amino-1-phenylpropyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (3-amino-1-phenylpropyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (3-amino-1-phenylpropyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (4-amino-1-phenylbutyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (4-amino-1-phenylbutyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
3-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide;
4-amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide;
N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] phenylalaninamide;
2-Amino-2-phenyl-N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] acetamide;
N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] phenylalaninamide;
3-amino-2- (phenylmethyl) -N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide;
3-amino-N- [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -2-phenylpropanamide;
3-amino-2-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thienyl] propanamide;
4- [5-({[2- (dimethylamino) -1-phenylethyl] amino} carbonyl) -2-thienyl] -1H-pyrrolo [2,3-b] pyridine-2-carboxylate;
N- [2- (dimethylamino) -1-phenylethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
4-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -4-piperidinecarboxamide;
N-{[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbonyl} tyrosine amide;
N- [2- (4-morpholinyl) -1-phenylethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-phenyl-2- (1-pyrrolidinyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(2-aminophenyl) methyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(3-aminophenyl) methyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-aminoethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -4- (3-pyridinyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -4- (1H-pyrazol-4-yl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -4-ethenyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -4-cyclopropyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
3-amino-N- [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylpropanamide;
N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-phenyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
3-amino-N- [5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenylmethyl) propanamide;
3-amino-2- (phenylmethyl) -N- [4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-furancarboxamide;
3-amino-N- [5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylpropanamide;
N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide;
N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide;
N-[(1R) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide;
N-[(1S) -2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide;
N-[(1S) -2-amino-1-phenylethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(1R) -2-amino-1-phenylethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-furancarboxamide;
N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-furancarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-furancarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-furancarboxamide;
(2-amino-1-phenylethyl) {[5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] methyl} amine;
N- (2-amino-1-phenylethyl) -4-phenyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -4-methyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-2-phenylethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-2-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
(3-amino-2-phenylpropyl) [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] amine;
3-amino-3-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide;
4-amino-3-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide;
N- (2-amino-1-phenylethyl) -4-bromo-5- (3-phenyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
4-amino-4-phenyl-N- [5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] butanamide;
4-bromo-N- [2- (methylamino) -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophene Carboxamide;
3-[(2-Aminoethyl) oxy] -N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -4-chloro-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-aminoethyl) -4-bromo-N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-aminoethyl) -4-bromo-N-phenyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-3-fluoro-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
4-Bromo-N- [2-[(1-methylethyl) amino] -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Thiophene carboxamide;
4-bromo-N- [2- (ethylamino) -1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
3-{[2-amino-1- (phenylmethyl) ethyl] oxy} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-N-methyl-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (6-amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
3-[(2-Aminoethyl) oxy] -N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Thiophene carboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-amino-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {4- [5-({[2-amino-1- (phenylmethyl) ethyl] amino} carbonyl) -2-thienyl] -1H-pyrrolo [2,3-b] pyridin-3-yl}- 3-furancarboxamide;
3-amino-N- [4- (2-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylpropanamide;
N- (2-amino-1-phenylethyl) -4- [2- (3-furanyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2-thiophenecarboxamide;
4-amino-N- [5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2-phenylbutanamide;
3-amino-2- (phenylmethyl) -N- [5-phenyl-4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-chloro-1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thiophenecarboxamide;
N- (2-amino-1-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -3-thiophenecarboxamide;
N-[(1S) -2-amino-1- (cyclohexylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(1S) -2-amino-1- (cyclohexylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (3-furanyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
3-Amino-N- [5- (3-furanyl) -4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenylmethyl) Propanamide;
3-amino-2- (phenylmethyl) -N- [4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] propanamide;
N- [2-amino-1- (phenylmethyl) ethyl] -3,4-dibromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -3- (4-methylphenyl) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -3- (methyloxy) -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
3-amino-N- [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] -2- (phenylmethyl) propanamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -2-thiophenecarboxamide;
2-amino-1- (phenylmethyl) ethyl [4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thienyl] carbamate;
4- [5-({[2-Amino-1- (phenylmethyl) ethyl] amino} carbonyl) -2-thienyl] -N- (2-furanylmethyl) -1H-pyrrolo [2,3-b] pyridine- 3-carboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- [2- (3-furanyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -4-bromo-N-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide N- [2-amino-1- (phenylmethyl) ethyl] -N-hydroxy-4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -N-hydroxy-3- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -N-[(phenylmethyl) oxy] -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide ;
N- [2-amino-1- (phenylmethyl) ethyl] -N′-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboximidamide;
N- [2-amino-1- (phenylmethyl) ethyl] -N′-hydroxy-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboximidamide;
3-amino-2- (phenylmethyl) -N- [5- (3-pyridinyl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] propanamide;
3-Amino-N- [5- (1,3-oxazol-2-yl) -4- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thienyl] -2- (phenyl Methyl) propanamide;
N- {2-amino-1- [2- (methyloxy) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {2-amino-1- [3- (methyloxy) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {2-amino-1- [4- (methyloxy) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {2-amino-1- [2- (methyloxy) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {2-amino-1- [3- (methyloxy) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {2-amino-1- [4- (methyloxy) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-{(1R) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
N-{(1S) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophenecarboxamide N- [1- (aminomethyl) -3-phenylpropyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-((1S) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) -2-thiophenecarboxamide;
N-((1R) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) -2-thiophenecarboxamide;
N-{(1S) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-((1R) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Thiophene carboxamide;
N-((1S) -2-amino-1-{[4- (methyloxy) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2- Thiophene carboxamide;
N-{(1R) -2-amino-1-[(4-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-((1S) -2-amino-1-{[4- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-thiophenecarboxamide;
N-((1S) -2-amino-1-{[4- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
3-[(2-aminoethyl) oxy] -N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
3-[(2-aminoethyl) oxy] -N- (3-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
3-[(2-aminoethyl) oxy] -N- (2-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Furan carboxamide;
N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-furancarboxamide;
3-[(2-aminoethyl) oxy] -4-bromo-N- (phenylmethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
3-[(2-aminoethyl) oxy] -4-bromo-N- (3-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
3-[(2-aminoethyl) oxy] -4-bromo-N- (2-phenylethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {2-amino-1- [3- (trifluoromethyl) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {2-amino-1- [3- (trifluoromethyl) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide ;
4-bromo-N-[(1S) -2-hydroxy-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide ;
N-[(1S) -2-hydroxy-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {2-amino-1- [2- (trifluoromethyl) phenyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {2-amino-1- [2- (trifluoromethyl) phenyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide ;
3-[(2-aminoethyl) oxy] -N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H- Pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3 -B] pyridin-4-yl) -2-thiophenecarboxamide;
N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -3- (methyloxy) -5- (1H-pyrrolo [2,3-b] pyridine -4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -4- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(2S) -2-amino-3-phenylpropyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(2R) -2-amino-3-phenylpropyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(2S) -2-amino-3-phenylpropyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(2R) -2-amino-3-phenylpropyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- (3-amino-1-phenylpropyl) -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (4-fluorophenyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (4-fluorophenyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (2-fluorophenyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (2-fluorophenyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (3-fluorophenyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (3-fluorophenyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2-thiophenecarboxamide;
N-[(2R) -2-amino-3- (3-fluorophenyl) propyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide N-{(1R) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
N-{(1R) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
N-{(1R) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-{(1S) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
N-{(1S) -2-amino-1-[(3-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-{(1S) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-{(1R) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
N-{(1R) -2-amino-1-[(2-fluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- [2-amino-1- (phenylmethyl) ethyl] -3-[(3-aminopropyl) oxy] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl ) -2-thiophenecarboxamide;
N- {2-amino-1-[(2,6-difluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophene Carboxamide;
N-{(1S) -2-amino-1-[(3,5-difluorophenyl) methyl] ethyl} -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N- {2-amino-1-[(3,5-difluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
N-((1S) -2-amino-1-{[3- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-thiophenecarboxamide;
N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-thiophenecarboxamide;
N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Thiophene carboxamide;
N- {2-amino-1-[(2,6-difluorophenyl) methyl] ethyl} -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(1S) -2-amino-1- (4-pyridinylmethyl) ethyl] -4-bromo-5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-[(1S) -2-amino-1- (4-pyridinylmethyl) ethyl] -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-thiophenecarboxamide;
N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2 -Furan carboxamide;
N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H-pyrrolo [2,3-b] pyridine-4- Yl) -2-furancarboxamide;
N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-3- (methyloxy) -5- (1H-pyrrolo [2,3 -B] pyridin-4-yl) -2-furancarboxamide;
3-[(2-Aminoethyl) oxy] -N-((1S) -2-amino-1-{[2- (trifluoromethyl) phenyl] methyl} ethyl) -4-bromo-5- (1H- Pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide; and 3-[(2-aminoethyl) oxy] -N-((1S) -2-amino-1-{[2- (Trifluoromethyl) phenyl] methyl} ethyl) -5- (1H-pyrrolo [2,3-b] pyridin-4-yl) -2-furancarboxamide,
The compound of claim 1 selected from.   A pharmaceutically acceptable salt, hydrate, solvate or prodrug of the compound of claim 7.   A pharmaceutical composition comprising a compound according to claim 1 and / or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and a pharmaceutically acceptable carrier.   A medicament comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula (I) according to claim 1 and / or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. A method for producing a composition comprising a compound of formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof together with a pharmaceutically acceptable carrier or diluent. A method comprising:   A method of treating or reducing the severity of a disease or condition selected from cancer and arthritis in a mammal in need of treatment or alleviation, wherein said mammal is in a therapeutically effective amount. Administering a compound of formula I and / or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.   The method according to claim 11, wherein the mammal is a human.   A method of treating or reducing the severity of a disease or condition selected from cancer and arthritis in a mammal in need of treatment or alleviation, wherein the mammal is in a therapeutically effective amount. Administering a compound of formula I and / or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.   14. The method of claim 13, wherein the mammal is a human.   Brain tumor (glioma), glioblastoma, Bannayan-Zonana syndrome, Corden's disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer 12. The method of claim 11, wherein the method is selected from pancreatic cancer, prostate cancer, sarcoma and thyroid cancer.   Brain tumor (glioma), glioblastoma, Bannayan-Zonana syndrome, Corden's disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer 14. The method of claim 13, selected from pancreatic cancer, prostate cancer, sarcoma and thyroid cancer.   A compound of formula (I) according to claim 1 and / or a pharmaceutically acceptable thereof in the manufacture of a medicament used to treat or reduce the severity of a disease or condition selected from cancer and arthritis Use of salts, hydrates, solvates or prodrugs.   A method of inhibiting Akt activity in a mammal in need of inhibition, wherein the mammal has a therapeutically effective amount of a compound of formula I according to claim 1 and / or a pharmaceutically acceptable salt thereof. Administering a salt, hydrate, solvate or prodrug.   The method of claim 18, wherein the mammal is a human. A method of treating cancer in a mammal in need of treatment, comprising a therapeutically effective amount of a) a compound of formula I and / or a pharmaceutically acceptable salt, hydrate thereof according to claim 1 Solvates or prodrugs; and b) at least one antitumor agent,
Administering.   At least one anti-tumor agent is essentially an anti-microtubule agent, a platinum coordination complex, an alkylating agent, an antibiotic, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone and an h hormone analog; 20. The method of claim 19, wherein the method is selected from the group consisting of: a signal transduction pathway inhibitor; a non-receptor tyrosine kinase angiogenesis inhibitor; an immunotherapeutic agent; a proapoptotic agent; and a cell cycle signaling inhibitor.   21. The method of claim 20, wherein the at least one anti-tumor agent is an anti-microtubule agent selected from diterpenoids and vinca alkaloids.   21. The method of claim 20, wherein the at least one antitumor agent is a diterpenoid.   21. The method of claim 20, wherein the at least one antitumor agent is a vinca alkaloid.   21. The method of claim 20, wherein the at least one antitumor agent is a platinum coordination complex.   21. The method of claim 20, wherein the at least one anti-tumor agent is paclitaxel, carboplatin or vinorelbine tartrate.   21. The method of claim 20, wherein the at least one antitumor agent is paclitaxel.   21. The method of claim 20, wherein the at least one anti-tumor agent is carboplatin.   21. The method of claim 20, wherein the at least one antitumor agent is vinorelbine tartrate.   21. The method of claim 20, wherein the at least one anti-tumor agent is a signal transduction pathway inhibitor.   31. The signal transduction pathway inhibitor is an inhibitor of a growth factor receptor kinase selected from the group consisting of VEGFR2, TIE2, PDGFR, BTK, IGFR-1, TrkA, TrkB, TrkC, and c-fms. The method described.   31. The method of claim 30, wherein the signaling pathway inhibitor is a serine / threonine kinase inhibitor selected from rafk, akt, and PKC-zeta.   31. The method of claim 30, wherein the signaling pathway inhibitor is a serine / threonine kinase inhibitor selected from the src family of kinases.   34. The method of claim 33, wherein the signal transduction pathway inhibitor is an inhibitor of c-src.   31. The method of claim 30, wherein the signal transduction pathway inhibitor is an Ras oncogene inhibitor selected from an inhibitor of farnesyl transferase and geranylgeranyl transferase.   31. The method of claim 30, wherein the signal transduction pathway inhibitor is a serine / threonine kinase inhibitor selected from the group consisting of PI3K.   20. The method of claim 19, wherein the at least one antitumor agent is a cell cycle signaling inhibitor.   38. The method of claim 37, wherein the cell cycle signaling inhibitor is selected from inhibitors of CDK2, CDK4 and CDK6.   20. A pharmaceutical combination according to claim 19 for use in therapy.   20. Use of the pharmaceutical combination according to claim 19 in the manufacture of a medicament useful for the treatment of cancer.