JP2006514658A - Inhibitors of phosphatases - Google Patents

Abstract

The present invention relates to compounds that inhibit phosphatases, compositions thereof, and methods of using these compounds and compositions to treat diseases. In one embodiment, the invention is a method of treating or reducing the severity of a disease in a patient, wherein the disease is an autoimmune disease, a proliferative disease, an angiogenic disorder, or Selected from cancer, the method provides a method comprising administering the composition to a patient suffering from these diseases.

Description

(Technical field of the invention)
The present invention relates to compounds that inhibit phosphatases, compositions thereof, and methods of using these compounds and compositions to treat diseases.

(Background of the Invention)
Many biologically important functions are regulated by transfer of phosphate groups. Often, the active or inactive form of a compound is determined by the presence or absence of a phosphate group attached to the compound. Thus, many biological enzymes are involved in regulating this phosphate transfer. For example, the kinase enzyme catalyzes the transfer of a phosphate group from a nucleoside triphosphate to a protein receptor. In contrast, phosphatase enzymes remove phosphate groups from substrates by hydrolysis.

  SHP-2 (src homology 2-containing tyrosine phosphatase) is a 68 kDa phosphatase protein. SHP-2 is also known as SHPTP2, Syp, PTP1D and PTP2C. Lu et al., Molecular Cell (2001) 8,759. This enzyme is expressed in the cytoplasm of all tissues. SHP-2 is an important signaling enzyme, and the biological function of SHP-2 has been widely reviewed. Feng, Exp. Cell Res. (1999) 253, 45; Neel and Tonks, Curr. Opin. Cell Biol. (1997) 9, 193; Tonks, Adv. Pharmacol. (1996) 36, 91. This enzyme is activated through interaction with various ligands (including growth factors), cytokine receptor tyrosine kinases, and adhesion molecules. And this enzyme is recognized as a positive regulator of cell growth, among others. SHP-2 also plays an important function in immune signaling. Huyer and Alexander, Curr. Biol. (1999) 9, R129; Cohen et al., Cell (1995) 80, 237. This SHP-2 enzyme is required for activation of the Ras-MAP kinase cascade, but the detailed role of the SHP-2 enzyme in this pathway is not clear. Van Vactor et al., Curr. Opin. Genet. Dev. (1998) 8, 112. SHP-2 has recently been identified as an intracellular target for Helicobacter pylori. Higashi et al., Science (2002) 295,683. Due to this important role, SHP-2 functions in a variety of biological pathways. The development of inhibitors for this enzyme provides a useful treatment for cancer and other autoimmune diseases.

  The development of new chemical entities that regulate phosphatase enzymes such as SHP-2 is an important advance and may lead to the development of new treatments for diseases in which the phosphatase enzyme plays an important role. The development of phosphatase modulators is an active area of research and has been widely reviewed. Ripka, Annual Rev. Med. Chem. 2000, 35, Chapter 21, and references cited therein.

  More recent work has focused on the development of new heterocyclic groups that can mimic the phosphate moiety (ie, the development of phosphate isosteres). Successful phosphate isosteres are ideally not hydrolyzable and are bioavailable. A successful phosphate mimetic also depends on the form and ionization state of the mimetic. Examples of novel heterocyclic groups designed to mimic the phosphate moiety include the tetronic acid derivatives studied for Cdc25b (Sodeoka et al., J. Med. Chem. (2001) 44 (20), 3216. ), And inhibitors of the azoresin dione class that have been studied against protein tyrosine phosphatase 1B (PTB1B). Malamas et al., J. MoI. Med. Chem. (2000) 43,995. However, the efficacy of these mimetics is still under study.

  There is a greater need to develop potent regulators of phosphatase enzymes and other enzymes involved in regulating phosphate group transfer.

  The present invention provides a compound of formula (I):

に関し、
ここで：
Ａ環は、必要に応じて置換される、アリール環またはヘテロアリール環であり；
Ｒ_ａは、−ＣＯＯＨ、その塩もしくはエステル、またはその生物学的アイソスターであり；
ｎは、１〜３であり；
Ｒ_１は、Ｈ、脂肪族ヒドロキシ、脂肪族アミノ、脂肪族−ＣＯＯＨ、脂肪族−ＣＯＮＨ_２、もしくは脂肪族アリールであり；
Ｒ_２は、脂肪族、脂肪族アリール、脂環式脂肪族、脂肪族ヘテロアリール、または脂肪族複素環であり；
Ｒ^３およびＲ^４は、独立して、Ｒ^１１、Ｒ^１２、Ｒ^１４、またはＲ^１５から選択され；
ここで：
各Ｒ^１１は、独立して、１，２−メチレンジオキシ、１，２−エチレンジオキシ、Ｒ^６または（ＣＨ_２）_ｍ−Ｙから選択され；
ここでｍは、０、１、または２であり；そして
Ｙは、ハロゲン、ＣＮ、ＮＯ_２、ＣＦ_３、ＯＣＦ_３、ＯＨ、ＳＲ^６、Ｓ（Ｏ）Ｒ^６、ＳＯ_２Ｒ^６、ＮＨ_２、ＮＨＲ^６、Ｎ（Ｒ^６）_２、ＮＲ^６Ｒ^８、ＣＯＯＨ、ＣＯＯＲ^６またはＯＲ^６から選択され；
各Ｒ^１２は、独立して、（Ｃ_１〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルキル、（Ｃ_２〜Ｃ_６）の直鎖状もしくは分枝鎖状の、アルケニルもしくはアルキニルから選択され；そして各Ｒ^１２は、２つまでの置換基を必要に応じて含み、ここで：
第１の上記置換基は、存在する場合、Ｒ^１１、Ｒ^１４、およびＲ^１５から選択され、そして
第２の上記置換基は、存在する場合、Ｒ^１１であり；
各Ｒ^１４は、独立して、ＯＲ^１５、ＯＣ（Ｏ）Ｒ^６、ＯＣ（Ｏ）Ｒ^１５、ＯＣ（Ｏ）ＯＲ^６、ＯＣ（Ｏ）ＯＲ^１５、ＯＣ（Ｏ）Ｎ（Ｒ^６）_２、ＯＰ（Ｏ）（ＯＲ^６）_２、ＳＲ^６、ＳＲ^１５、Ｓ（Ｏ）Ｒ^６、Ｓ（Ｏ）Ｒ^１５、ＳＯ_２Ｒ^６、ＳＯ_２Ｒ^１５、ＳＯ_２Ｎ（Ｒ^６）_２、ＳＯ_２ＮＲ^１５Ｒ^６、ＳＯ_３Ｒ^６、Ｃ（Ｏ）Ｒ^１５、Ｃ（Ｏ）ＯＲ^１５、Ｃ（Ｏ）Ｒ^６、Ｃ（Ｏ）ＯＲ^６、ＮＣ（Ｏ）Ｃ（Ｏ）Ｒ^６、ＮＣ（Ｏ）Ｃ（Ｏ）Ｒ^１５、ＮＣ（Ｏ）Ｃ（Ｏ）ＯＲ^６、ＮＣ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ^６）_２、Ｃ（Ｏ）Ｎ（Ｒ^６）_２、Ｃ（Ｏ）Ｎ（ＯＲ^６）Ｒ^６、Ｃ（Ｏ）Ｎ（ＯＲ^６）Ｒ^１５、Ｃ（ＮＯＲ^６）Ｒ^６、Ｃ（ＮＯＲ^６）Ｒ^１５、Ｎ（Ｒ^６）_２、ＮＲ^６Ｃ（Ｏ）Ｒ^１１、ＮＲ^６Ｃ（Ｏ）Ｒ^６、ＮＲ^６Ｃ（Ｏ）Ｒ^１５、ＮＲ^６Ｃ（Ｏ）ＯＲ^６、ＮＲ^６Ｃ（Ｏ）ＯＲ^１５、ＮＲ^６Ｃ（Ｏ）Ｎ（Ｒ^６）_２、ＮＲ^６Ｃ（Ｏ）ＮＲ^１５Ｒ^６、ＮＲ^６ＳＯ_２Ｒ^６、ＮＲ^６ＳＯ_２Ｒ^１５、ＮＲ^６ＳＯ_２Ｎ（Ｒ^６）_２、ＮＲ^６ＳＯ_２ＮＲ^１５Ｒ^６、Ｎ（ＯＲ^６）Ｒ^６、Ｎ（ＯＲ^６）Ｒ^１５、Ｐ（Ｏ）（ＯＲ^６）Ｎ（Ｒ^６）_２、およびＰ（Ｏ）（ＯＲ^６）_２から選択され；
各Ｒ^１５は、脂環式、アリール、複素環、または複素芳香族であり；そして各Ｒ^１５は、３つまでの置換基を必要に応じて含み、この置換基のうちの各々は、存在する場合、Ｒ^１１であり；
各Ｒ^６は、独立して、Ｈ、（Ｃ_１〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルキル、または（Ｃ_２〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルケニルから選択され；そして各Ｒ^６は、Ｒ^７である置換基を必要に応じて含み；
Ｒ^７は、脂環式、アリール、複素環、または複素芳香族であり；そして各Ｒ^７は、Ｈ、（Ｃ_１〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルキル、（Ｃ_２〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルケニル、１，２−メチレンジオキシ、１，２−エチレンジオキシ、または（ＣＨ_２）_Ｐ−Ｚから独立して選択される２つまでの置換基を必要に応じて含み；
ここでｐは、０、１または２であり；そして
Ｚは、ハロゲン、ＣＮ、ＮＯ_２、ＣＦ_３、ＯＣＦ_３、ＯＨ、Ｓ（Ｃ_１〜Ｃ_６）−アルキル、ＳＯ（Ｃ_１〜Ｃ_６）−アルキル、ＳＯ_２（Ｃ_１〜Ｃ_６）−アルキル、ＮＨ_２、ＮＨ（Ｃ_１〜Ｃ_６）−アルキル、Ｎ（（Ｃ_１〜Ｃ_６）−アルキル）_２、Ｎ（（Ｃ_１〜Ｃ_６）−アルキル）Ｒ^８、ＣＯＯＨ、Ｃ（Ｏ）Ｏ（Ｃ_１〜Ｃ_６）−アルキル、またはＯ（Ｃ_１〜Ｃ_６）−アルキルから選択され；そして
Ｒ^８は、アミノ保護基であり；
ただし：
Ｒ^３およびＲ^４は、同時に水素ではなく；
Ｒ^３がＨである場合、Ｒ^４は、クロロでなく；そして
Ｒ^４がＨである場合、Ｒ^３は、−ＳＣＨ_３でも−ＮＨ−Ｃ（Ｏ）ＣＨ_３でもない。

Regarding
here:
Ring A is an optionally substituted aryl or heteroaryl ring;
R _a is —COOH, a salt or ester thereof, or a biological isostere thereof;
n is 1 to 3;
R ₁ is H, aliphatic hydroxy, aliphatic amino, aliphatic-COOH, aliphatic-CONH ₂ , or aliphatic aryl;
R ₂ is aliphatic, aliphatic aryl, alicyclic aliphatic, aliphatic heteroaryl, or aliphatic heterocycle;
R ³ and R ⁴ are independently selected from R ¹¹ , R ¹² , R ¹⁴ , or R ¹⁵ ;
here:
Each R ¹¹ is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R ⁶ or (CH ₂ ) _m —Y;
Wherein m is 0, 1 or 2; and Y is ^{_{halogen, CN, NO 2, CF 3}} , OCF 3, OH, SR 6, S (O) R 6, SO 2 R 6, NH 2 , NHR ⁶ , N (R ⁶ ) ₂ , NR ⁶ R ⁸ , COOH, COOR ⁶ or OR ⁶ ;
Each R ¹² is independently from (C ₁ -C ₆ ) linear or branched alkyl, (C ₂ -C ₆ ) linear or branched, alkenyl or alkynyl. And each R ¹² optionally contains up to two substituents, where:
The first substituent, if present, is selected from R ¹¹ , R ¹⁴ , and R ¹⁵ , and the second substituent, if present, is R ¹¹ ;
Each R ¹⁴ is independently OR ¹⁵ , OC (O) R ⁶ , OC (O) R ¹⁵ , OC (O) OR ⁶ , OC (O) OR ¹⁵ , OC (O) N (R ⁶ ) _2. , OP (O) (OR ⁶ ) ₂ , SR ⁶ , SR ¹⁵ , S (O) R ⁶ , S (O) R ¹⁵ , SO ₂ R ⁶ , SO ₂ R ¹⁵ , SO ₂ N (R ⁶ ) ₂ , ^{_{SO 2 NR 15 R 6, SO}} 3 R 6, C (O) R 15, C (O) OR 15, C (O) R 6, C (O) OR 6, NC (O) C (O) R 6 NC (O) C (O) R ¹⁵ , NC (O) C (O) OR ⁶ , NC (O) C (O) N (R ⁶ ) ₂ , C (O) N (R ⁶ ) ₂ , C (O) N (OR ⁶ ) R ⁶ , C (O) N (OR ⁶ ) R ¹⁵ , C (NOR ⁶ ) R ⁶ , C (NOR ⁶ ) R ¹⁵ , N (R ⁶ ) ₂ , NR ⁶ C ( O) R ¹¹ , NR ⁶ C (O) R ⁶ , NR ⁶ C (O) R ¹⁵ , NR ⁶ C (O) OR ⁶ , NR ⁶ C (O) OR ¹⁵ , NR ⁶ C (O) N (R ⁶ ) ₂ , NR ⁶ C (O) NR ¹⁵ R ⁶ , NR ⁶ SO ₂ R ⁶ , NR ⁶ SO ₂ R ¹⁵ , NR ⁶ SO ₂ N (R ⁶ ) ₂ , NR ⁶ SO ₂ NR ¹⁵ R ⁶ , N (OR ⁶ ) Selected from R ⁶ , N (OR ⁶ ) R ¹⁵ , P (O) (OR ⁶ ) N (R ⁶ ) ₂ , and P (O) (OR ⁶ ) ₂ ;
Each R ¹⁵ is alicyclic, aryl, heterocyclic, or heteroaromatic; and each R ¹⁵ optionally includes up to three substituents, each of which is present R ¹¹ if
Each R ⁶ is independently from H, (C ₁ -C ₆ ) linear or branched alkyl, or (C ₂ -C ₆ ) linear or branched alkenyl. And each R ⁶ optionally includes a substituent that is R ⁷ ;
R ⁷ is alicyclic, aryl, heterocyclic, or heteroaromatic; and each R ⁷ is H, (C ₁ -C ₆ ) linear or branched alkyl, (C ₂ -C ₆₎ linear or branched alkenyl, 1,2-methylenedioxy, up to two selected 1,2-ethylenedioxy, or _{(CH 2)} independently of the P -Z Optionally containing substituents;
Where p is 0, 1 or 2; and Z is halogen, CN, NO ₂ , CF ₃ , OCF ₃ , OH, S (C ₁ -C ₆ ) -alkyl, SO (C ₁ -C ₆ ) -Alkyl, SO ₂ (C ₁ -C ₆ ) -alkyl, NH ₂ , NH (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , N ((C _1- C ₆ ) -alkyl) R ⁸ , COOH, C (O) O (C ₁ -C ₆ ) -alkyl, or O (C ₁ -C ₆ ) -alkyl; and R ⁸ is an amino protecting group Yes;
However:
R ³ and R ⁴ are not simultaneously hydrogen;
When R ³ is H, R ⁴ is not chloro; and when R ⁴ is H, R ³ is neither —SCH ₃ nor —NH—C (O) CH ₃ .

  The invention also relates to compositions thereof and methods of treating diseases using such compounds and compositions.

(Detailed description of the invention)
The present invention relates to a compound of formula (I):

に関し、
ここで：
Ａ環は、必要に応じて置換される、アリール環またはヘテロアリール環であり；
Ｒ_ａは、−ＣＯＯＨであり；
ｎは、０〜４であり；
Ｒ_１は、Ｈ、または必要に応じて置換される、脂肪族ヒドロキシ、脂肪族アミノ、脂肪族−ＣＯＯＨ、脂肪族−ＣＯＮＨ_２、もしくは脂肪族アリールであり；
Ｒ_２は、必要に応じて置換される、脂肪族、脂肪族アリール、脂環式脂肪族、脂肪族ヘテロアリール、または脂肪族複素環であり；
Ｒ^３およびＲ^４は、独立して、Ｒ^１１、Ｒ^１２、Ｒ^１４、またはＲ^１５から選択され；
ここで：
各Ｒ^１１は、独立して、１，２−メチレンジオキシ、１，２−エチレンジオキシ、Ｒ^６または（ＣＨ_２）_ｍ−Ｙから選択され；
ここでｍは、０、１、または２であり；そして
Ｙは、ハロゲン、ＣＮ、ＮＯ_２、ＣＦ_３、ＯＣＦ_３、ＯＨ、ＳＲ^６、Ｓ（Ｏ）Ｒ^６、ＳＯ_２Ｒ^６、ＮＨ_２、ＮＨＲ^６、Ｎ（Ｒ^６）_２、ＮＲ^６Ｒ^８、ＣＯＯＨ、ＣＯＯＲ^６またはＯＲ^６から選択され；
各Ｒ^１２は、独立して、（Ｃ_１〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルキル、（Ｃ_２〜Ｃ_６）の直鎖状もしくは分枝鎖状の、アルケニルまたはアルキニルから選択され；そして各Ｒ^１２は、２つまでの置換基を必要に応じて含み、ここで：
第１の上記置換基は、存在する場合、Ｒ^１１、Ｒ^１４、およびＲ^１５から選択され、そして
第２の上記置換基は、存在する場合、Ｒ^１１であり；
各Ｒ^１４は、独立して、ＯＲ^１５、ＯＣ（Ｏ）Ｒ^６、ＯＣ（Ｏ）Ｒ^１５、ＯＣ（Ｏ）ＯＲ^６、ＯＣ（Ｏ）ＯＲ^１５、ＯＣ（Ｏ）Ｎ（Ｒ^６）_２、ＯＰ（Ｏ）（ＯＲ^６）_２、ＳＲ^６、ＳＲ^１５、Ｓ（Ｏ）Ｒ^６、Ｓ（Ｏ）Ｒ^１５、ＳＯ_２Ｒ^６、ＳＯ_２Ｒ^１５、ＳＯ_２Ｎ（Ｒ^６）_２、ＳＯ_２ＮＲ^１５Ｒ^６、ＳＯ_３Ｒ^６、Ｃ（Ｏ）Ｒ^１５、Ｃ（Ｏ）ＯＲ^１５、Ｃ（Ｏ）Ｒ^６、Ｃ（Ｏ）ＯＲ^６、ＮＣ（Ｏ）Ｃ（Ｏ）Ｒ^６、ＮＣ（Ｏ）Ｃ（Ｏ）Ｒ^１５、ＮＣ（Ｏ）Ｃ（Ｏ）ＯＲ^６、ＮＣ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ^６）_２、Ｃ（Ｏ）Ｎ（Ｒ^６）_２、Ｃ（Ｏ）Ｎ（ＯＲ^６）Ｒ^６、Ｃ（Ｏ）Ｎ（ＯＲ^６）Ｒ^１５、Ｃ（ＮＯＲ^６）Ｒ^６、Ｃ（ＮＯＲ^６）Ｒ^１５、Ｎ（Ｒ^６）_２、ＮＲ^６Ｃ（Ｏ）Ｒ^１１、ＮＲ^６Ｃ（Ｏ）Ｒ^６、ＮＲ^６Ｃ（Ｏ）Ｒ^１５、ＮＲ^６Ｃ（Ｏ）ＯＲ^６、ＮＲ^６Ｃ（Ｏ）ＯＲ^１５、ＮＲ^６Ｃ（Ｏ）Ｎ（Ｒ^６）_２、ＮＲ^６Ｃ（Ｏ）ＮＲ^１５Ｒ^６、ＮＲ^６ＳＯ_２Ｒ^６、ＮＲ^６ＳＯ_２Ｒ^１５、ＮＲ^６ＳＯ_２Ｎ（Ｒ^６）_２、ＮＲ^６ＳＯ_２ＮＲ^１５Ｒ^６、Ｎ（ＯＲ^６）Ｒ^６、Ｎ（ＯＲ^６）Ｒ^１５、Ｐ（Ｏ）（ＯＲ^６）Ｎ（Ｒ^６）_２、およびＰ（Ｏ）（ＯＲ^６）_２から選択され；
各Ｒ^１５は、脂環式、アリール、複素環、または複素芳香族であり；そして各Ｒ^１５は、３つまでの置換基を必要に応じて含み、この置換基のうちの各々は、存在する場合、Ｒ^１１であり；
各Ｒ^６は、独立して、Ｈ、（Ｃ_１〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルキル、または（Ｃ_２〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルケニルから選択され；そして各Ｒ^６は、Ｒ^７である置換基を必要に応じて含み；
Ｒ^７は、脂環式、アリール、複素環、または複素芳香族であり；そして各Ｒ^７は、Ｈ、（Ｃ_１〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルキル、（Ｃ_２〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルケニル、１，２−メチレンジオキシ、１，２−エチレンジオキシ、または（ＣＨ_２）_Ｐ−Ｚから独立して選択される２つまでの置換基を必要に応じて含み；
ここでｐは、０、１または２であり；そして
Ｚは、ハロゲン、ＣＮ、ＮＯ_２、ＣＦ_３、ＯＣＦ_３、ＯＨ、Ｓ（Ｃ_１〜Ｃ_６）−アルキル、ＳＯ（Ｃ_１〜Ｃ_６）−アルキル、ＳＯ_２（Ｃ_１〜Ｃ_６）−アルキル、ＮＨ_２、ＮＨ（Ｃ_１〜Ｃ_６）−アルキル、Ｎ（（Ｃ_１〜Ｃ_６）−アルキル）_２、Ｎ（（Ｃ_１〜Ｃ_６）−アルキル）Ｒ^８、ＣＯＯＨ、Ｃ（Ｏ）Ｏ（Ｃ_１〜Ｃ_６）−アルキル、またはＯ（Ｃ_１〜Ｃ_６）−アルキルから選択され；そして
Ｒ^８は、アミノ保護基であり；
ただし：
Ｒ^３およびＲ^４は、同時に水素ではなく；
Ｒ^３がＨである場合、Ｒ^４は、クロロでなく；そして
Ｒ^４がＨである場合、Ｒ^３は、−ＳＣＨ_３でも−ＮＨ−Ｃ（Ｏ）ＣＨ_３でもない。

Regarding
here:
Ring A is an optionally substituted aryl or heteroaryl ring;
R _a is —COOH;
n is 0-4;
R ₁ is H or optionally substituted aliphatic hydroxy, aliphatic amino, aliphatic —COOH, aliphatic —CONH ₂ , or aliphatic aryl;
R ₂ is an optionally substituted aliphatic, aliphatic aryl, cycloaliphatic, aliphatic heteroaryl, or aliphatic heterocycle;
R ³ and R ⁴ are independently selected from R ¹¹ , R ¹² , R ¹⁴ , or R ¹⁵ ;
here:
Each R ¹¹ is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R ⁶ or (CH ₂ ) _m —Y;
Wherein m is 0, 1 or 2; and Y is ^{_{halogen, CN, NO 2, CF 3}} , OCF 3, OH, SR 6, S (O) R 6, SO 2 R 6, NH 2 , NHR ⁶ , N (R ⁶ ) ₂ , NR ⁶ R ⁸ , COOH, COOR ⁶ or OR ⁶ ;
Each R ¹² is independently from (C ₁ -C ₆ ) linear or branched alkyl, (C ₂ -C ₆ ) linear or branched, alkenyl or alkynyl. And each R ¹² optionally contains up to two substituents, where:
The first substituent, if present, is selected from R ¹¹ , R ¹⁴ , and R ¹⁵ , and the second substituent, if present, is R ¹¹ ;
Each R ¹⁴ is independently OR ¹⁵ , OC (O) R ⁶ , OC (O) R ¹⁵ , OC (O) OR ⁶ , OC (O) OR ¹⁵ , OC (O) N (R ⁶ ) _2. , OP (O) (OR ⁶ ) ₂ , SR ⁶ , SR ¹⁵ , S (O) R ⁶ , S (O) R ¹⁵ , SO ₂ R ⁶ , SO ₂ R ¹⁵ , SO ₂ N (R ⁶ ) ₂ , ^{_{SO 2 NR 15 R 6, SO}} 3 R 6, C (O) R 15, C (O) OR 15, C (O) R 6, C (O) OR 6, NC (O) C (O) R 6 NC (O) C (O) R ¹⁵ , NC (O) C (O) OR ⁶ , NC (O) C (O) N (R ⁶ ) ₂ , C (O) N (R ⁶ ) ₂ , C (O) N (OR ⁶ ) R ⁶ , C (O) N (OR ⁶ ) R ¹⁵ , C (NOR ⁶ ) R ⁶ , C (NOR ⁶ ) R ¹⁵ , N (R ⁶ ) ₂ , NR ⁶ C ( O) R ¹¹ , NR ⁶ C (O) R ⁶ , NR ⁶ C (O) R ¹⁵ , NR ⁶ C (O) OR ⁶ , NR ⁶ C (O) OR ¹⁵ , NR ⁶ C (O) N (R ⁶ ) ₂ , NR ⁶ C (O) NR ¹⁵ R ⁶ , NR ⁶ SO ₂ R ⁶ , NR ⁶ SO ₂ R ¹⁵ , NR ⁶ SO ₂ N (R ⁶ ) ₂ , NR ⁶ SO ₂ NR ¹⁵ R ⁶ , N (OR ⁶ ) Selected from R ⁶ , N (OR ⁶ ) R ¹⁵ , P (O) (OR ⁶ ) N (R ⁶ ) ₂ , and P (O) (OR ⁶ ) ₂ ;
Each R ¹⁵ is alicyclic, aryl, heterocyclic, or heteroaromatic; and each R ¹⁵ optionally includes up to three substituents, each of which is present R ¹¹ if
Each R ⁶ is independently from H, (C ₁ -C ₆ ) linear or branched alkyl, or (C ₂ -C ₆ ) linear or branched alkenyl. And each R ⁶ optionally includes a substituent that is R ⁷ ;
R ⁷ is alicyclic, aryl, heterocyclic, or heteroaromatic; and each R ⁷ is H, (C ₁ -C ₆ ) linear or branched alkyl, (C ₂ -C ₆₎ linear or branched alkenyl, 1,2-methylenedioxy, up to two selected 1,2-ethylenedioxy, or _{(CH 2)} independently of the P -Z Optionally containing substituents;
Where p is 0, 1 or 2; and Z is halogen, CN, NO ₂ , CF ₃ , OCF ₃ , OH, S (C ₁ -C ₆ ) -alkyl, SO (C ₁ -C ₆ ) -Alkyl, SO ₂ (C ₁ -C ₆ ) -alkyl, NH ₂ , NH (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , N ((C _1- C ₆ ) -alkyl) R ⁸ , COOH, C (O) O (C ₁ -C ₆ ) -alkyl, or O (C ₁ -C ₆ ) -alkyl; and R ⁸ is an amino protecting group Yes;
However:
R ³ and R ⁴ are not simultaneously hydrogen;
When R ³ is H, R ⁴ is not chloro; and when R ⁴ is H, R ³ is neither —SCH ₃ nor —NH—C (O) CH ₃ .

  As used herein, the following definitions shall apply unless otherwise indicated.

  The phrase “substituted as necessary” is used interchangeably with the phrase “substituted or unsubstituted”. Unless otherwise indicated, the optionally substituted group may be substituted at each substitutable position of the group, and each substitution is independent of the other substitution.

As used herein, the term “aliphatic” or “aliphatic group” refers to fully saturated (alkyl) or unsaturated (alkenyl or alkynyl), linear or branched. It means a branched, substituted or unsubstituted hydrocarbon chain. Unless otherwise specified, aliphatic groups have 1-12 carbon atoms. Preferably, the aliphatic group has 1 to 6 carbon atoms. Up to _two —CH ₂ — in the aliphatic can be substituted with O, S, or —NR _X —.

  The term “alicyclic” is fully saturated (eg, cycloalkyl) or includes one or more unsaturated units (but this unit is not aromatic) (eg, cycloalkenyl), and By 3-8 membered monocyclic hydrocarbon ring or 8-12 membered bicyclic hydrocarbon ring having a single point of attachment to the rest of the molecule.

Unless otherwise indicated, the term “heteroatom” means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, as well as any tetrasubstituted form of any basic nitrogen. The term “nitrogen” also includes a substitutable nitrogen on a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen is as in (3,4-dihydro-2H-pyrrolyl. N) (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl).

  As used herein, the term “unsaturated” means a double bond or a triple bond. Each such bond constitutes one unsaturated unit.

  The term “aryl” used alone or as part of a larger moiety (as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”) refers to a total of 5-14 rings Monocyclic, bicyclic, and tricyclic ring systems having members, wherein at least one ring in the system is aromatic and each ring in the system is 3-7 Including ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. Phenyl is an example of aryl.

  As used herein, the term “heterocycle”, “heterocycle”, “aliphatic heterocycle”, or “heterocyclic” refers to a total of 5 to 14 Means a non-aromatic, monocyclic, bicyclic, or tricyclic ring system having a ring member, wherein one or more ring members are heteroatoms, wherein the system Each ring in contains 3 to 7 ring members.

  The term “heteroaryl” used alone or as part of a larger moiety (as in “heteroaralkyl” or “heteroarylalkoxy”) refers to monocyclic, bicyclic and tricyclic Wherein at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms. Unless otherwise indicated, such ring systems have a total of 5 to 15 ring members, wherein each ring in the system contains 3 to 7 ring members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

An aryl group (including aralkyl, aralkoxy, aryloxyalkyl and the like) or a heteroaryl group (including heteroaralkyl and heteroarylalkoxy and the like) can include one or more substituents. Suitable substituents on the unsaturated carbon atom of the aryl group, heteroaryl group, aralkyl group, or heteroaralkyl group include the following: halogen, -R ^O , -OR ^O , -SR ^O , 1,2 - methylene - dioxy, 1,2-ethylene - dioxy, phenyl substituted with ^{R O} optionally (Ph), -O substituted with ^{R O} optionally (Ph), optionally ^{R O} in _-CH 2 substituted (Ph), _-CH 2 _CH 2 which is substituted with ^{R O} optionally _{(Ph), - NO 2,} -CN, -N (R O) 2, -NR O C ( _{^{O) R O, -NR O C}} (O) (R O) 2, -NR O CO 2 R O, -NR O NR O C (O) R O, -NR O NR O C (O) N (R _{^{O) 2, -NR O NR O}} CO 2 R O, -C (O) C (O) R O _{^{-C (O) CH 2 C (}} O) R O, -CO 2 R O, -C (O) R O, -C (O) N (R O) 2, -OC (O) N (R O) ₂ , -S (O) ₂ R ^O , -SO ₂ N (R ^O ) ₂ , -S (O) R ^O , -NR ^O SO ₂ N (R ^O ) ₂ , -NR ^O SO ₂ R ^O ,- C (= S) N (R ^O ) ₂ , -C (= NH) -N (R ^O ) ₂ , or-(CH ₂ ) _q NHC (O) R ^O. Where q is 0-2 and each R 2 ^O is independently hydrogen, optionally substituted C1-C6 aliphatic, unsubstituted 5-6 membered heteroaryl or heterocyclic ring, Selected from phenyl, —O (Ph), or —CH ₂ (Ph), or the presence of two R 2 ^O on the same or different substituents taken together can be nitrogen, oxygen, or Forms a 5-8 membered heterocyclic or heteroaryl ring having 1-3 heteroatoms independently selected from sulfur. The optional substituents on the aliphatic group R 2 ^O are selected from: NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halogen, C ₄ aliphatic, OH, _{O (C 1-4 aliphatic), NO 2, CN, CO} 2 H, CO 2 (C 1~4 aliphatic), O (halo _{C 1-4} aliphatic), or Halo C _1-4 aliphatic.

An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on saturated carbons of aliphatic groups or non-aromatic heterocyclic rings include those listed above for unsaturated carbons of aryl groups or heteroaryl groups, and the following substituents: ^{: = O, = S, =} NNHR *, = NH (R *) 2, = NNHC (O) R *, = NNHCO 2 ( alkyl), = NNHSO ₂ (alkyl), or = NR ^* (where each R ^* is independently selected from hydrogen or optionally substituted C _1-6 aliphatic). Optional substituents on the aliphatic group of R ^* are selected _from: NH _2, NH _(C 1~4 aliphatic), _{N (C 1 to 4 aliphatic) 2, halogen, C 1 to 4} Aliphatic, OH, O (C _1-4 aliphatic), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (halo C _1-4 aliphatic), or halo (C _1-4 aliphatic).

Optional substituents on the nitrogen of a non-aromatic heterocyclic ring include the _{^{following: -R +, -N (R +}} ) 2, -C (O) R +, -OR +, -CO 2 _{^{R +, -C (O) C}} (O) R +, -C (O) CH 2 C (O) R +, -SO 2 N (R +) 2, -C (= S) N (R +) ₂ , —C (═NH) —N (R ⁺ ) ₂ , or —NR ⁺ SO ₂ R ⁺ ; where R ⁺ is hydrogen, optionally substituted C _1-6 aliphatic, optionally Optionally substituted phenyl, optionally substituted —O (Ph), optionally substituted —CH ₂ (Ph), optionally substituted —CH ₂ CH ₂ (Ph), Or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, or the presence of two R ⁺ on the same or different substituents is Together, it forms a 5- to 8-membered heteroaryl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on R ⁺ aliphatic group or ^{R +} of the phenyl ring is selected from the _following: NH _2, NH _(C 1~4 aliphatic), _{N (C 1 to 4 aliphatic)} 2, _{halogen, C 1 to 4 aliphatic,} OH, _{O (C 1~4 aliphatic), NO 2, CN, CO} 2 H, CO 2 (C 1~4 aliphatic), O (halo _{C 1 to 4} aliphatic ), Or halo (C _1-4 aliphatic).

  The term “alkylidene chain” refers to a straight or branched chain that can be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule. -Like carbon chain.

  Combinations of substituents or variables are permissible only if such combinations result in stable or chemically feasible compounds. A stable or chemically feasible compound is substantially unmodified when kept at a temperature of 40 ° C. or less without humidity or under other chemically reactive conditions for at least one week. A compound.

It will be apparent to those skilled in the art that certain compounds of the present invention may exist in tautomeric forms. All such tautomeric forms of the compounds are within the scope of the invention. Unless otherwise stated, the structures represented herein are also intended to include all stereoisomeric forms of the structures (ie, the R and S configurations for each asymmetric center). Is done. Accordingly, single stereochemical isomers of the present compounds, as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, the structures represented herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure excluding hydrogen substitution with deuterium or tritium, or carbon substitution with ¹³ C rich carbon or ¹⁴ C rich carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

According to a preferred embodiment, the A ring is an optionally substituted 5- or 6-membered aryl or heteroaryl ring, wherein the heteroaryl ring is independent of O, S, or NR ^+. Containing up to two ring heteroatoms selected by

  According to another preferred embodiment, ring A is phenyl.

According to another preferred embodiment, R ¹ is hydrogen, — (CH ₂ ) _q —X, where q is 1-4, and X is OH, NH ₂ , COOH or CONH ₂ , (C ₁ -C ₆₎ - alkyl or benzyl.

According to another preferred embodiment, R ¹ is hydrogen, hydroxymethyl, methyl, —CH ₂ COOH, —CH ₂ CONH ₂ , aminobutyl, methyl, or isopentyl.

According to another preferred embodiment, R ² is butyl, isobutyl, methoxypropyl, cyclopentyl, cyclohexylmethyl, phenyl, trifluorophenyl, benzyl, fluorobenzyl, methylenedioxybenzyl, pyridylmethyl, furanylmethyl, tetrahydrofuranylmethyl, N- Selected from morpholinylmethyl, thienylmethyl, 2-oxo-pyrrolodinylpropyl, phenylethyl, chlorophenylethyl, methoxyphenylethyl, or dimethoxyphenylethyl.

According to another preferred embodiment, R ² is selected from 2-furanylmethyl or methyl.

According to another preferred embodiment, R ³ and R ⁴ are independently selected from hydrogen, halo, acetamide, allyloxy, thiophenyl, sulfoxyalkyl, or sulfoxyphenyl.

  The term “amino protecting group” refers to a suitable chemical group that can be attached to a nitrogen atom. The term “protected” refers to the case where a designated functional group is attached to a suitable chemical group (protecting group). Examples of suitable amino protecting groups and protecting groups are described below: W. Greene and P.M. G. M.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons (1991); Fieser and M.M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Edited by Packete, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). Examples of suitable amino protecting groups and protecting groups are illustrated by the specific specific compounds used in the present invention.

  According to an alternative embodiment, the present invention provides compounds of formula (II):

の化合物を提供し、
ここで：
Ｘは、−（ＣＨ_２）_ｎ−、または−Ｃ（Ｏ）−であり；
ｎは、１〜３であり；
Ｙは、Ｏ、Ｓ、ＮＨ、またはＮ（Ｃ_１〜Ｃ_６脂肪族）であり；
Ｚは、ＨまたはＣ_１〜Ｃ_６脂肪族であり；
Ｑは、０または１であり；
Ａ、Ｒ^ｘ、Ｒ^ｙ、およびＲ^ｚは、独立して、Ｒ^１１、Ｒ^１２、Ｒ^１４、またはＲ^１５から選択され；
ここで：
各Ｒ^１１は、独立して、１，２−メチレンジオキシ、１，２−エチレンジオキシ、Ｒ^６または（ＣＨ_２）_ｍ−Ｙから選択され；
ここでｍは、０、１、または２であり；そして
Ｙは、ハロゲン、ＣＮ、ＮＯ_２、ＣＦ_３、ＯＣＦ_３、ＯＨ、ＳＲ^６、Ｓ（Ｏ）Ｒ^６、ＳＯ_２Ｒ^６、ＮＨ_２、ＮＨＲ^６、Ｎ（Ｒ^６）_２、ＮＲ^６Ｒ^８、ＣＯＯＨ、ＣＯＯＲ^６またはＯＲ^６から選択され；
各Ｒ^１２は、独立して、（Ｃ_１〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルキル、（Ｃ_２〜Ｃ_６）の直鎖状もしくは分枝鎖状の、アルケニルまたはアルキニルから選択され；そして各Ｒ^１２は、２つまでの置換基を必要に応じて含み、ここで：
第１のこの置換基は、存在する場合、Ｒ^１１、Ｒ^１４、およびＲ^１５から選択され、そして
第２のこの置換基は、存在する場合、Ｒ^１１であり；
各Ｒ^１４は、独立して、ＯＲ^１５、ＯＣ（Ｏ）Ｒ^６、ＯＣ（Ｏ）Ｒ^１５、ＯＣ（Ｏ）ＯＲ^６、ＯＣ（Ｏ）ＯＲ^１５、ＯＣ（Ｏ）Ｎ（Ｒ^６）_２、ＯＰ（Ｏ）（ＯＲ^６）_２、ＳＲ^６、ＳＲ^１５、Ｓ（Ｏ）Ｒ^６、Ｓ（Ｏ）Ｒ^１５、ＳＯ_２Ｒ^６、ＳＯ_２Ｒ^１５、ＳＯ_２Ｎ（Ｒ^６）_２、ＳＯ_２ＮＲ^１５Ｒ^６、ＳＯ_３Ｒ^６、Ｃ（Ｏ）Ｒ^１５、Ｃ（Ｏ）ＯＲ^１５、Ｃ（Ｏ）Ｒ^６、Ｃ（Ｏ）ＯＲ^６、ＮＣ（Ｏ）Ｃ（Ｏ）Ｒ^６、ＮＣ（Ｏ）Ｃ（Ｏ）Ｒ^１５、ＮＣ（Ｏ）Ｃ（Ｏ）ＯＲ^６、ＮＣ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ^６）_２、Ｃ（Ｏ）Ｎ（Ｒ^６）_２、Ｃ（Ｏ）Ｎ（ＯＲ^６）Ｒ^６、Ｃ（Ｏ）Ｎ（ＯＲ^６）Ｒ^１５、Ｃ（ＮＯＲ^６）Ｒ^６、Ｃ（ＮＯＲ^６）Ｒ^１５、Ｎ（Ｒ^６）_２、ＮＲ^６Ｃ（Ｏ）Ｒ^１１、ＮＲ^６Ｃ（Ｏ）Ｒ^６、ＮＲ^６Ｃ（Ｏ）Ｒ^１５、ＮＲ^６Ｃ（Ｏ）ＯＲ^６、ＮＲ^６Ｃ（Ｏ）ＯＲ^１５、ＮＲ^６Ｃ（Ｏ）Ｎ（Ｒ^６）_２、ＮＲ^６Ｃ（Ｏ）ＮＲ^１５Ｒ^６、ＮＲ^６ＳＯ_２Ｒ^６、ＮＲ^６ＳＯ_２Ｒ^１５、ＮＲ^６ＳＯ_２Ｎ（Ｒ^６）_２、ＮＲ^６ＳＯ_２ＮＲ^１５Ｒ^６、Ｎ（ＯＲ^６）Ｒ^６、Ｎ（ＯＲ^６）Ｒ^１５、Ｐ（Ｏ）（ＯＲ^６）Ｎ（Ｒ^６）_２、およびＰ（Ｏ）（ＯＲ^６）_２から選択され；
各Ｒ^１５は、脂環式、アリール、複素環、または複素芳香族であり；そして各Ｒ^１５は、３つまでの置換基を必要に応じて含み、この置換基のうちの各々は、存在する場合、Ｒ^１１であり；
各Ｒ^６は、独立して、Ｈ、（Ｃ_１〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルキル、または（Ｃ_２〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルケニルから選択され；そして各Ｒ^６は、Ｒ^７である置換基を必要に応じて含み；
Ｒ^７は、脂環式、アリール、複素環、または複素芳香族であり；そして各Ｒ^７は、Ｈ、（Ｃ_１〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルキル、（Ｃ_２〜Ｃ_６）の直鎖状もしくは分枝鎖状のアルケニル、１，２−メチレンジオキシ、１，２−エチレンジオキシ、または（ＣＨ_２）_Ｐ−Ｚから独立して選択される２つまでの置換基を必要に応じて含み；
ここでｐは、０、１または２であり；そして
Ｚは、ハロゲン、ＣＮ、ＮＯ_２、ＣＦ_３、ＯＣＦ_３、ＯＨ、Ｓ（Ｃ_１〜Ｃ_６）−アルキル、ＳＯ（Ｃ_１〜Ｃ_６）−アルキル、ＳＯ_２（Ｃ_１〜Ｃ_６）−アルキル、ＮＨ_２、ＮＨ（Ｃ_１〜Ｃ_６）−アルキル、Ｎ（（Ｃ_１〜Ｃ_６）−アルキル）_２、Ｎ（（Ｃ_１〜Ｃ_６）−アルキル）Ｒ^８、ＣＯＯＨ、Ｃ（Ｏ）Ｏ（Ｃ_１〜Ｃ_６）−アルキル、またはＯ（Ｃ_１〜Ｃ_６）−アルキルから選択され；そして
Ｒ^８は、アミノ保護基であるか；
またはＲ^ｘおよびＲ^ｙは、一緒になって、３つまでの置換基を有する、必要に応じて置換される複素環式環を形成する。

A compound of
here:
X is — (CH ₂ ) _n —, or —C (O) —;
n is 1 to 3;
Y is O, S, NH, or N (C ₁ -C ₆ aliphatic);
Z is H or C ₁ -C ₆ aliphatic;
Q is 0 or 1;
A, R ^x , R ^y , and R ^z are independently selected from R ¹¹ , R ¹² , R ¹⁴ , or R ¹⁵ ;
here:
Each R ¹¹ is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R ⁶ or (CH ₂ ) _m —Y;
Wherein m is 0, 1 or 2; and Y is ^{_{halogen, CN, NO 2, CF 3}} , OCF 3, OH, SR 6, S (O) R 6, SO 2 R 6, NH 2 , NHR ⁶ , N (R ⁶ ) ₂ , NR ⁶ R ⁸ , COOH, COOR ⁶ or OR ⁶ ;
Each R ¹² is independently from (C ₁ -C ₆ ) linear or branched alkyl, (C ₂ -C ₆ ) linear or branched, alkenyl or alkynyl. And each R ¹² optionally contains up to two substituents, where:
The first substituent, if present, is selected from R ¹¹ , R ¹⁴ , and R ¹⁵ , and the second this substituent, if present, is R ¹¹ ;
Each R ¹⁴ is independently OR ¹⁵ , OC (O) R ⁶ , OC (O) R ¹⁵ , OC (O) OR ⁶ , OC (O) OR ¹⁵ , OC (O) N (R ⁶ ) _2. , OP (O) (OR ⁶ ) ₂ , SR ⁶ , SR ¹⁵ , S (O) R ⁶ , S (O) R ¹⁵ , SO ₂ R ⁶ , SO ₂ R ¹⁵ , SO ₂ N (R ⁶ ) ₂ , ^{_{SO 2 NR 15 R 6, SO}} 3 R 6, C (O) R 15, C (O) OR 15, C (O) R 6, C (O) OR 6, NC (O) C (O) R 6 NC (O) C (O) R ¹⁵ , NC (O) C (O) OR ⁶ , NC (O) C (O) N (R ⁶ ) ₂ , C (O) N (R ⁶ ) ₂ , C (O) N (OR ⁶ ) R ⁶ , C (O) N (OR ⁶ ) R ¹⁵ , C (NOR ⁶ ) R ⁶ , C (NOR ⁶ ) R ¹⁵ , N (R ⁶ ) ₂ , NR ⁶ C ( O) R ¹¹ , NR ⁶ C (O) R ⁶ , NR ⁶ C (O) R ¹⁵ , NR ⁶ C (O) OR ⁶ , NR ⁶ C (O) OR ¹⁵ , NR ⁶ C (O) N (R ⁶ ) ₂ , NR ⁶ C (O) NR ¹⁵ R ⁶ , NR ⁶ SO ₂ R ⁶ , NR ⁶ SO ₂ R ¹⁵ , NR ⁶ SO ₂ N (R ⁶ ) ₂ , NR ⁶ SO ₂ NR ¹⁵ R ⁶ , N (OR ⁶ ) Selected from R ⁶ , N (OR ⁶ ) R ¹⁵ , P (O) (OR ⁶ ) N (R ⁶ ) ₂ , and P (O) (OR ⁶ ) ₂ ;
Each R ¹⁵ is alicyclic, aryl, heterocyclic, or heteroaromatic; and each R ¹⁵ optionally includes up to three substituents, each of which is present R ¹¹ if
Each R ⁶ is independently from H, (C ₁ -C ₆ ) linear or branched alkyl, or (C ₂ -C ₆ ) linear or branched alkenyl. And each R ⁶ optionally includes a substituent that is R ⁷ ;
R ⁷ is alicyclic, aryl, heterocyclic, or heteroaromatic; and each R ⁷ is H, (C ₁ -C ₆ ) linear or branched alkyl, (C ₂ -C ₆₎ linear or branched alkenyl, 1,2-methylenedioxy, up to two selected 1,2-ethylenedioxy, or _{(CH 2)} independently of the P -Z Optionally containing substituents;
Where p is 0, 1 or 2; and Z is halogen, CN, NO ₂ , CF ₃ , OCF ₃ , OH, S (C ₁ -C ₆ ) -alkyl, SO (C ₁ -C ₆ ) -Alkyl, SO ₂ (C ₁ -C ₆ ) -alkyl, NH ₂ , NH (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , N ((C _1- C ₆ ) -alkyl) R ⁸ , COOH, C (O) O (C ₁ -C ₆ ) -alkyl, or O (C ₁ -C ₆ ) -alkyl; and R ⁸ is an amino protecting group Is there;
Or R ^x and R ^y together form an optionally substituted heterocyclic ring having up to 3 substituents.

  The scope of the invention includes within its scope pharmaceutically acceptable prodrugs of the compounds of the invention. "Pharmaceutically acceptable prodrug" means any pharmaceutically acceptable salt, ester, ester salt, or other derivative of a compound of the present invention, Upon administration to a recipient, it is possible to provide (directly or indirectly) a compound of the invention or an active metabolite or residue thereof. Preferred prodrugs are those that increase the bioavailability of the compounds of the invention when such compounds are administered to a mammal, or the biological compartment of the parent compound compared to the parent species ( For example, delivery to the brain or lymphatic system).

  The compounds of the present invention can be readily prepared using methods known in the art. One such synthetic route is illustrated in Scheme 1 below. One skilled in the art will recognize that this synthetic route can be readily exploited for other embodiments of formula (I).

  (Scheme 1)

式（Ｉ）の化合物の調製は、スキーム１に概略される一般化手順に従って実行される。キナゾリンジオンの調製は、以下の４つの基本的な工程を包含する：ｉ）還元的アルキル化、ｉｉ）樹脂への充填、ｉｉｉ）ペプチド結合、ならびにｉｖ）環化および上記樹脂からの放出。

The preparation of compounds of formula (I) is performed according to the generalized procedure outlined in Scheme 1. The preparation of quinazolinedione involves the following four basic steps: i) reductive alkylation, ii) loading into the resin, iii) peptide bond, and iv) cyclization and release from the resin.

(Step 1: Reductive alkylation of anthranilic acid)
Anthranilic acid and aldehyde (4 eq) were dissolved in DCE in the presence of acetic acid at room temperature. After 15 minutes, sodium triacetoxyborohydride (4 eq) was added and the solution was stirred at room temperature (4-12 hours depending on the aldehyde used). The reaction was quenched with excess 1N NaOH and stirred for 20 minutes. The reaction was extracted several times with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. Purification was performed through silica gel column chromatography using ethyl acetate / hexane.

  Saponification of the anthranilate ester was performed by dissolving the ester in THF / MeOH and treated with 1N lithium hydroxide for 12 hours at room temperature. The reaction was concentrated to 1/3 of the original volume and poured into 10% NaOH. This solution was extracted with ether to remove unreacted material. The aqueous phase was collected and carefully acidified with 1N HCl. In most cases, anthranilic acid was precipitated from the solution and collected by filtration. If no precipitation occurred, the aqueous solution was diluted with brine solution and extracted several times with ethyl acetate. The organic was dried over sodium sulfate, filtered and concentrated to yield the desired anthranilic acid.

(Step 2: Filling resin with substituted anthranilic acid)
Note: The following procedure involves the use of phosgene and should be performed by one skilled in the art in a well-ventilated draft.

（クロロホルメート樹脂の調製）
１０グラムのヒドロキシメチルポリスチレン（１．２ｍｍｏｌ／ｇ充填）を、自重２５０ｍｌペプチドフラスコに入れて秤量した。この樹脂を１００ｍｌの乾燥ＴＨＦで洗浄し、最終的に、さらなる１００ｍｌの乾燥ＴＨＦ中に懸濁させた。この樹脂懸濁液に、トルエン中２５ｍｌ（５．０当量、２．５４Ｍ）のホスゲン溶液を添加した。このフラスコをきつく密封し、オービタルシェーカーで２〜３時間回旋させた。このペプチドフラスコを陽圧下で排液させ、この母液を、濃縮（２０％）水酸化ナトリウム水溶液／メタノール溶液を含むフラスコ中に集めた。

(Preparation of chloroformate resin)
Ten grams of hydroxymethylpolystyrene (1.2 mmol / g charge) was weighed into a self-weight 250 ml peptide flask. The resin was washed with 100 ml dry THF and finally suspended in an additional 100 ml dry THF. To this resin suspension was added 25 ml (5.0 eq, 2.54 M) phosgene solution in toluene. The flask was tightly sealed and rotated on an orbital shaker for 2-3 hours. The peptide flask was drained under positive pressure and the mother liquor was collected in a flask containing concentrated (20%) aqueous sodium hydroxide / methanol solution.

このクロロホルメート樹脂を、２×１００ｍｌ乾燥ＴＨＦ、２×１００ｍｌ乾燥ＤＣＭで連続して洗浄し、陽圧を用いて容器を排液させた。アントラリン酸（３当量）およびＤＩＥＡ（１０当量）を含有する１００ｍｌ ＤＣＭ溶液を、新しく調製したクロロホルメート樹脂に素早く添加し、このフラスコを再密封し、オービタルシェーカーでさらに３．５時間回旋させた。この樹脂を排出させ、何度も洗浄を繰り返した。この樹脂を高真空下で一晩乾燥させた。適切な充填を、重量増加によって決定した。０．７〜０．９ｍｍｏｌ／ｇという代表的な充填は、この方法を使用して慣用的に得ることが可能であった。

The chloroformate resin was washed successively with 2 × 100 ml dry THF, 2 × 100 ml dry DCM and the vessel was drained using positive pressure. A 100 ml DCM solution containing anthralic acid (3 eq) and DIEA (10 eq) was quickly added to the freshly prepared chloroformate resin and the flask was resealed and rotated on an orbital shaker for an additional 3.5 hours. . The resin was discharged and washing was repeated many times. The resin was dried overnight under high vacuum. Appropriate filling was determined by weight gain. A typical packing of 0.7-0.9 mmol / g could be obtained conventionally using this method.

(Step 3: Binding of amino acid to anthraphosphate functionalized resin)
A 1-methyl-2-pyrrolidinone (NMP) solution of HOBT (1M), HBTU (0.5M), amino acid ester (1M) and Hunigs base (2M) were freshly made prior to performing the coupling reaction. The resin was suspended in NMP and a solution of HOBT (5 eq) was added followed by HBTU (5.0 eq). The reaction was sealed and shaken for 15 minutes. The container was opened, the reaction block was placed on a Packard and the remaining reagents were added. After 15 minutes, a solution of amino ester (4 eq) was added followed by diisopropylethylamine (5 eq). The reaction vessel was resealed and shaken at room temperature for 18 hours, after which the resin was washed successively several times.

  (Step 4: Product formation and isolation)

樹脂からの生成物の分割およびキナゾリン−２，４−ジオンの単離を以下のように行った。メタノール中１０％トリエチルアミンの溶液をこの樹脂に添加し、この反応容器を、２０時間６０℃〜６５℃で加熱した。所望の時間後、この反応をわずかに冷却し、この母液を集めた。この樹脂をメタノールで２回洗浄し、この洗浄物を母液と合わせた。ロータリーエバポレーター（ｒｏｔｏｖａｐｏｒａｔｏｒ）を使用してこの溶液を濃縮させ、所望のキナゾリンジオンを得た。

Resolution of the product from the resin and isolation of quinazoline-2,4-dione was performed as follows. A solution of 10% triethylamine in methanol was added to the resin and the reaction vessel was heated at 60-65 ° C. for 20 hours. After the desired time, the reaction was cooled slightly and the mother liquor was collected. The resin was washed twice with methanol and the washed product was combined with the mother liquor. The solution was concentrated using a rotovaptor to give the desired quinazolinedione.

  Subsequent removal of the butyl protecting group was accomplished by adding 1.5 mL of 95: 3: 2 TFA: water: triisopropylsilane to the crude quinazolinedione for 3 hours at room temperature. The TFA solution was removed under reduced pressure and the compound was purified by C18 chromatography.

  The preparation of the compound of formula (II) is depicted in Scheme 2 below:

に概略される一般化手順に従って行う。

Follow the generalized procedure outlined in

  The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins ( Human serum albumin), buffer substances (eg phosphates), glycine, sorbic acid, calcium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (eg protamine sulfate, dihydrogen phosphate) Sodium, potassium hydrogenphosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxyp Pyrene - block polymers, polyethylene glycol and wool fat.

  Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfite, butyrate, citrate, camphoric acid Salt, camphor sulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate (Hemisulfate), heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, palmoate, pectate, persulfate, 3- Enirupuropion, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Preparation of salts in which other acids that are not pharmaceutically acceptable by themselves, such as oxalic acid, are useful as intermediates to obtain the compounds of the present invention, and of other pharmaceutically acceptable acid addition salts Can be used for preparation.

Salts derived from appropriate bases include alkali metal (eg, sodium and potassium), alkaline earth metal (eg, magnesium), ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble products or dispersible products can be obtained by such quaternization.

  The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally mucosally, vaginally, or implanted reservoir. Can be administered via As used herein, the term “parenteral” refers to subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intracapsular, intrahepatic, intralesional, and intracranial. Including injection techniques or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the invention can be an aqueous or oily suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. This sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, 1,3-butanediol In solution. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

  For this purpose any bland fixed oil can be employed including non-volatile, synthetic monoglycerides or synthetic diglycerides. Fatty acids (eg oleic acid) and glyceride derivatives thereof are useful for the preparation of injectables. Similarly, natural pharmaceutically acceptable oils such as olive oil or castor oil are useful for the preparation of injectables, particularly in these polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant (eg, carboxymethylcellulose), or similar dispersing agent. These diluents or dispersants are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants (eg, Tween, Span) and other emulsifiers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms Bioavailability enhancers can also be used for formulation purposes.

  The pharmaceutically acceptable compositions of this invention can be administered orally in any orally acceptable dosage form. This orally acceptable dosage form includes, but is not limited to, capsules, tablets, aqueous suspensions or aqueous solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. A lubricant (eg, magnesium stearate) is also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents can also be added.

  Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. This suppository can be prepared by mixing the agent with a suitable nonirritating excipient. This excipient is solid at room temperature, but is liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

  The pharmaceutically acceptable compositions of the present invention can also be administered locally, particularly when the target of treatment includes a region or organ that is readily acceptable by topical application. These areas or organs include eye diseases, skin diseases, or lower intestinal diseases. Appropriate topical formulations are readily prepared for each of these areas or organs.

  Topical application for the lower intestinal tract can be performed in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches can also be used.

  For topical application, pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to: mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene compounds, polyoxypropylene compounds, emulsifying waxes. And water. Alternatively, the pharmaceutically acceptable composition can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

  For ophthalmic use, pharmaceutically acceptable compositions are isotonic, pH adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. It can be formulated as a micronized suspension in water or, preferably, as a solution in an isotonic, pH adjusted, sterile saline solution. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition can be formulated in an ointment such as petrolatum.

  The pharmaceutically acceptable compositions of this invention can also be administered by nasal aerosol or nasal inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as a solution in saline using the following: benzyl alcohol or other suitable preservative, enhancing bioavailability Absorption enhancers, fluorocarbons, and / or other conventional solubilizers or dispersants.

  Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.

  The amount of the compound of the invention that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular form of administration. Preferably, the composition is formulated such that a dosage of an inhibitor between 0.01 mg / kg body weight / day and 100 mg / kg body weight / day can be administered to a patient receiving these compositions. Should be.

  It should also be understood that the particular medication and treatment regimen for any particular patient will depend on a variety of factors, including: activity of the particular compound used, age, Weight, general health, sex, diet, time of administration, rate of excretion, drug combination, physician judgment, and severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the particular compound in the composition.

  Depending on the particular condition or disease to be treated or prevented, additional therapeutic agents (which are usually administered to treat or prevent this condition) may also be present in the compositions of the invention. . As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as “appropriate for the disease or condition being treated”.

For example, chemotherapeutic agents or other antiproliferative agents can be combined with the compounds of the present invention to treat cancer and proliferative diseases. Examples of known chemotherapeutic agents include, but are not limited to: Gleevec ^™ , adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferon, and platinum derivatives.

  Other examples of agents that can be combined with the compounds of the present invention include, but are not limited to: anti-inflammatory agents (eg, corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide) Immunomodulators and immunosuppressants (eg, cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine); neurotrophic factors (eg, acetylcholine) Stealase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian drugs); treat cardiovascular disease Agents for treating liver diseases (eg, corticosteroids, cholestyramine, interferons, and antivirals) (eg, β-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins) Agents); agents for treating blood disorders (eg, corticosteroids, anti-leukemic agents, and growth factors); agents for treating diabetes (eg, insulin, insulin analogs, alpha glucosidase inhibitors, biguanides, and insulin) Sensitizers); as well as agents for treating immune deficiency disorders (eg, gamma globulin).

  The amount of additional therapeutic agent present in the compositions of this invention is only that amount normally administered in compositions containing this therapeutic agent only as an active agent. Preferably, the amount of additional agent in the compositions disclosed herein is in the range of about 50% to 100% of the amount normally present in compositions containing this agent only as a therapeutically active agent.

  According to another embodiment, the present invention relates to a method of inhibiting SHP-2 phosphatase activity in a biological sample, the method comprising the biological sample and a compound of the invention or a composition containing the compound. The step of contacting.

  As used herein, the term “biological sample” includes, but is not limited to: a cell culture or extract thereof; a biopsy obtained from a mammal or its Extracts; and blood, saliva, urine, stool, semen, tears, or other body fluids or extracts thereof.

  Inhibition of SHP-2 phosphatase activity in a biological sample is useful for a variety of purposes known to those of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

  According to another embodiment, the present invention provides a method for treating or reducing the severity of a disease selected from autoimmune diseases, proliferative diseases, angiogenic disorders, and cancer.

  According to a preferred embodiment, the present invention provides a method for treating or reducing the severity of a SHP-2-mediated disease or condition in a patient, the method comprising: Administering a product.

  As used herein, the term “SHP-2-mediated disease” means any disease or other deleterious condition in which SHP-2 is known to play a role. Such conditions include, but are not limited to, autoimmune diseases, proliferative diseases, angiogenic disorders, and cancer.

  Autoimmune diseases that can be treated or prevented by the compounds of the present invention include, but are not limited to: glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, Autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel Disease, ulcerative colitis, Crohn's disease, psoriasis, or graft-versus-host disease.

  Proliferative diseases that can be treated or prevented by the compounds of the present invention include, but are not limited to: acute myeloid leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, And HTLV-1 mediated tumor formation.

  Angiogenic disorders that can be treated or prevented by the compounds of the present invention include solid tumors, ocular neovascularization, infantile hemangioma.

  Cancers that can be treated or prevented by the compounds of the present invention include, but are not limited to, colon cancer, breast cancer, gastric cancer, and ovarian cancer.

  In another embodiment, the methods of the invention that utilize a composition that does not include an additional therapeutic agent include the additional step of separately administering the additional therapeutic agent to the patient. If these additional therapeutic agents are administered separately, the therapeutic agents can be administered to the patient before, simultaneously with, or after administration of the composition of the invention.

  The compounds of the present invention or pharmaceutical compositions thereof can also be incorporated into compositions to coat implantable medical devices such as prostheses, prosthetic valves, vascular grafts, stents and catheters. For example, vascular stents have been used to overcome restenosis (restenosis of the vessel wall after injury). However, patients using stents or other implantable devices are at risk for thrombus formation or platelet activation. These undesirable effects can be prevented or mitigated by precoating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. General preparations of suitable coatings and coated implantable devices are described in US Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coating is typically a biocompatible polymeric material (eg, hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof). This coating can be further coated with a suitable topcoat (fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or combinations thereof) to provide controlled release characteristics to the composition. Implantable devices coated with the compounds of the invention are another embodiment of the invention.

  In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.

  Example 1: Preparation of 2- (7-acetylamino-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid (Compound 1) )

（４−アセチルアミノ−２−［（フラン−２−イルメチル）−アミノ］−安息香酸）
４−アミノ−２−ニトロ安息香酸（３ｇ）を、２０ｍｌの４：１ ＴＨＦ／ＭｅＯＨ中に懸濁し、０℃に冷却した。ＴＭＳ−ジアゾメタン（５．６ｇ、４９ｍｍｏｌ、３当量、ヘキサン中２Ｍ）を液滴で添加し、この溶液を室温で２時間撹拌した。この反応を１Ｎ酢酸でクエンチし、この有機物を減圧下で除去した。この水相を酢酸エチル中に注ぎ、炭酸水素ナトリウムで中和し、硫酸ナトリウムで乾燥させ、濾過して濃縮し、黄色の油を得た。このエステルを３０％アセトン／ヘキサンを使用して、フラッシュカラムクロマトグラフィーによって精製した。ニトロエステルを明るい黄色の固体として単離した（収率９２％）。

(4-acetylamino-2-[(furan-2-ylmethyl) -amino] -benzoic acid)
4-Amino-2-nitrobenzoic acid (3 g) was suspended in 20 ml of 4: 1 THF / MeOH and cooled to 0 ° C. TMS-diazomethane (5.6 g, 49 mmol, 3 eq, 2M in hexane) was added dropwise and the solution was stirred at room temperature for 2 hours. The reaction was quenched with 1N acetic acid and the organics were removed under reduced pressure. The aqueous phase was poured into ethyl acetate, neutralized with sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to give a yellow oil. The ester was purified by flash column chromatography using 30% acetone / hexane. The nitro ester was isolated as a light yellow solid (92% yield).

  This ester (1.0 g, 5.1 mmol) was dissolved in 20 ml DCM at room temperature. DIEA (0.98 g, 7.6 mmol, 1.5 eq) was added followed by acetyl chloride (0.48 g, 6.1 mmol, 1.2 eq). The reaction was stirred at room temperature for 4 hours. The reaction was poured into 1M HCl, dried over sodium sulfate, filtered and concentrated to give a yellow oil / solid. The crude reaction was taken up in about 20 ml of MeOH and saturated NH 4 Cl was added followed by excess Zn powder. The reaction was stirred at room temperature for 45 minutes, at which time TLC showed complete reduction. The reaction was filtered to remove Zn particulates and extracted with ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the organic phases were combined. Dry over sodium sulfate, filter and concentrate to give a yellow film. The product was taken up in a small amount of acetone and purified using 10% -30% acetone / 2% MeOH / hexane as a gradient. The desired aniline compound was isolated as a light yellow solid (positive APCI, M + 1 = 208.9).

  Reductive amination is performed by dissolving anthranilate (2.3 g, 11 mmol, 1 eq), 2-furylaldehyde (3.2 g, 33 mmol, 3 eq) and 1 ml acetic acid in 50 ml DCE at room temperature. It was. After 15 minutes, sodium triacetoxyborohydride (9.4 g, 44 mmol, 4 eq) was added and the solution was stirred at room temperature for 4 hours. The reaction was quenched by the addition of excess 1N NaOH. After stirring for 20 minutes, the suspension was extracted 3 times with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give a brown oil. The product was isolated by flash column using 10-30% acetic acid / hexane. The desired anilide was obtained as a light yellow solid.

  The ester was taken up in THF, 1N LiOH (1.5 eq) was added and stirred at 60 ° C. for 12 hours. The reaction was cooled, concentrated to remove organics and diluted with water. The solution was washed with ether and the aqueous phase was acidified with 1M HCl. A viscous white precipitate was formed, which was collected by filtration to give the desired compound.

ＭＳ ｍ／ｅ＝２７３．１（ｍ−１）は、Ｃ１４Ｈ１４Ｎ２Ｏ４、Ｍｗ＝２７４．２７に対応する。

MS m / e = 273.1 (m−1) corresponds to C14H14N2O4, Mw = 274.27.

４ｇのヒドロキシメチルＰＳ樹脂（１．２ｍｍｏｌ／ｇ）を、自重１００ｍｌペプチドフラスコ中に配置した。この樹脂を乾燥ＴＨＦで２回洗浄し、そしてこの樹脂を、必要最低量の乾燥ＴＨＦ中に懸濁した。トルエン（２０ｍｌ）中２．５Ｍのホスゲン溶液を、このフラスコに添加し、数時間撹拌させた。この反応を、陽窒素圧を使用して濾過し、そしてこの樹脂を、ＤＣＭで数回洗浄した。ＤＣＭ中４−アセチルアミノ−２−［（フラン−２−イルメチル）−アミノ］−安息香酸（化合物１、３当量）およびＤＩＥＡ（４当量）の溶液を、この樹脂に添加し、３時間撹拌させた。この樹脂を濾過し、ＤＭＦ、ＭｅＯＨおよびＤＣＭで数回洗浄し、減圧下で乾燥させた。この樹脂の充填を、重量増加に基づいて０．９ｍｍｏｌ／ｇと算出した。

4 g of hydroxymethyl PS resin (1.2 mmol / g) was placed in a self-weight 100 ml peptide flask. The resin was washed twice with dry THF and the resin was suspended in the minimum amount of dry THF required. A 2.5M phosgene solution in toluene (20 ml) was added to the flask and allowed to stir for several hours. The reaction was filtered using positive nitrogen pressure and the resin was washed several times with DCM. A solution of 4-acetylamino-2-[(furan-2-ylmethyl) -amino] -benzoic acid (Compound 1, 3 eq) and DIEA (4 eq) in DCM was added to the resin and allowed to stir for 3 hours. It was. The resin was filtered, washed several times with DMF, MeOH and DCM and dried under reduced pressure. The resin loading was calculated as 0.9 mmol / g based on weight gain.

（２−（７−アセチルアミノ−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸（化合物１））
この樹脂（４００ｍｇ）をＮＭＰ中に懸濁し、ＨＢＴＵ（４当量）で処理した。ＨＯＢＴ（４当量）を１５分間添加し、続いて、アスパラギン酸ジｔ−ブチルエステル塩化水素（３当量）を添加し、最後にＤＩＥＡ（４当量）を添加した。この反応を１２時間撹拌し、続いてろ過し、ＮＭＰ、ＤＭＦ、ＭｅＯＨで何度も洗浄した。この樹脂を、８ｍｌの１０％ＴＥＡ／ＭｅＯＨ中に再懸濁させ、６０℃に１８時間加熱した。この母液を収集し、溶液を濃縮させ、乾燥させた。この粗キナゾリンジオンを、２時間、５０％ＴＦＡ／ＤＣＭを使用して脱保護した。この反応を減圧下で濃縮させ、この残留物を少量のＭｅＣＮ中に取り、ＭｅＣＮ／水を使用してＣ１８によって精製した。アセトニロリルとの共沸混合物（ａｚｅｔｒｏｐｅ）から、薄色の泡状の物質を単離した。

(2- (7-acetylamino-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid (Compound 1))
This resin (400 mg) was suspended in NMP and treated with HBTU (4 equivalents). HOBT (4 eq) was added for 15 min, followed by aspartic acid di-t-butyl ester hydrogen chloride (3 eq), and finally DIEA (4 eq). The reaction was stirred for 12 hours, then filtered and washed many times with NMP, DMF, MeOH. The resin was resuspended in 8 ml 10% TEA / MeOH and heated to 60 ° C. for 18 hours. The mother liquor was collected and the solution was concentrated and dried. The crude quinazolinedione was deprotected using 50% TFA / DCM for 2 hours. The reaction was concentrated under reduced pressure and the residue was taken up in a small amount of MeCN and purified by C18 using MeCN / water. A pale foamy material was isolated from an azeotrope with acetonitrile.

ＭＳ ｍ／ｅ＝４１４（ｍ−１）は、Ｃ１９Ｈ１７Ｎ３Ｏ８、Ｍｗ＝４１５．３５に対応する。

MS m / e = 414 (m−1) corresponds to C19H17N3O8, Mw = 415.35.

  Example 2: 2- [6-Chloro-1- (5-methyl-furan-2-ylmethyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] -succinic acid ( Preparation of compound 2))

（５−クロロ−２−（５−メチル−フラン−２−イルメチル）−アミノ］−安息香酸、９１１−７１）
５−クロロ−２−アミノ−メチルアントラニレートの還元的アミノ化を、４時間、ＤＣＥ中５−メチルフルアルデヒドを使用して、化合物１について記載したように行った。この反応後、この生成物を、１０％〜３０％アセトン／ヘキサンを使用して、ＦＣによって単離し、薄い黄色の固体を得た。引き続いて、このエステルをＴＨＦ中に取り、６０℃で１２時間、１Ｎを使用して鹸化させた。この溶液を冷却し、酸性化し、そしてこの生成物を、灰色がかった白色の固体として収集した。

(5-Chloro-2- (5-methyl-furan-2-ylmethyl) -amino] -benzoic acid, 911-71)
Reductive amination of 5-chloro-2-amino-methylanthranilate was performed as described for compound 1 using 5-methylfuraldehyde in DCE for 4 hours. After this reaction, the product was isolated by FC using 10% -30% acetone / hexanes to give a pale yellow solid. Subsequently, the ester was taken up in THF and saponified using 1N at 60 ° C. for 12 hours. The solution was cooled, acidified and the product was collected as an off-white solid.

４．５１ｇのヒドロキシメチルＰＳ樹脂（１．２ｍｍｏｌ／ｇ）を、自重１００ｍｌペプチドフラスコ中（自重＝１１２．８４２６ｇ）に配置した。この樹脂をＴＨＦで２回洗浄し、そしてこの樹脂を、必要最低量のＴＨＦ中に懸濁した。トルエン（２０ｍｌ）中２．５Ｍのホスゲン溶液を、このフラスコに添加し、数時間撹拌させた。反応を、陽圧を使用して濾過し、ＤＣＭで数回洗浄した。ＤＣＭ中アントラニル酸およびＤＩＥＡの溶液を、この反応に添加し、２時間撹拌させた。反応を濾過し、ＤＭＦ、ＭｅＯＨおよびＤＣＭで数回洗浄した。減圧下で乾燥させた。充填を、０．９６ｍｍｏｌ／ｇと算出した。

4.51 g of hydroxymethyl PS resin (1.2 mmol / g) was placed in a self-weight 100 ml peptide flask (self-weight = 11.8426 g). The resin was washed twice with THF and the resin was suspended in the minimum amount of THF required. A 2.5M phosgene solution in toluene (20 ml) was added to the flask and allowed to stir for several hours. The reaction was filtered using positive pressure and washed several times with DCM. A solution of anthranilic acid and DIEA in DCM was added to the reaction and allowed to stir for 2 hours. The reaction was filtered and washed several times with DMF, MeOH and DCM. Dry under reduced pressure. The filling was calculated as 0.96 mmol / g.

（２−［６−クロロ−１−（５−メチル−フラン−２−イルメチル）−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル］−コハク酸（化合物２））
５００ｍｇの樹脂を、Ｑｕｅｓｔ２１０チューブ中に分配した。ＨＯＢＴ（２ｍｌ、ＮＭＰ中１．０Ｍ、４当量）の溶液を添加し、続いて、ＮＭＰ中ＨＢＴＵ（４ｍｌ、０．５Ｍ、４当量）を添加した。この樹脂を１５分間撹拌し、続いて、アミン（４ｍｌ、５当量）とＤＩＥＡ（５当量）とのＮＭＰ溶液を添加した。この反応を１８時間撹拌させた。この樹脂を濾過し、ＤＭＦ、ＭｅＯＨおよびＤＣＭで何度も洗浄し、最後にメタノールで３回洗浄した。この樹脂を８ｍｌの１０％ＴＥＡ／ＭｅＯＨ中に取り、６０℃まで２０時間加熱した。この母液を収集し、濃縮して乾燥させた。保護基を有する化合物を、標準化条件を使用して脱保護し、Ｃ１８および水／アセトニトリル勾配を使用してＦＣによって精製し、灰色がかった白色の泡状の物質を得た。

(2- [6-Chloro-1- (5-methyl-furan-2-ylmethyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] -succinic acid (Compound 2))
500 mg of resin was dispensed into Quest 210 tubes. A solution of HOBT (2 ml, 1.0 M in NMP, 4 eq) was added followed by HBTU in NMP (4 ml, 0.5 M, 4 eq). The resin was stirred for 15 minutes, followed by addition of an NMP solution of amine (4 ml, 5 eq) and DIEA (5 eq). The reaction was allowed to stir for 18 hours. The resin was filtered, washed several times with DMF, MeOH and DCM and finally three times with methanol. The resin was taken up in 8 ml of 10% TEA / MeOH and heated to 60 ° C. for 20 hours. The mother liquor was collected, concentrated and dried. Compounds with protecting groups were deprotected using standardized conditions and purified by FC using a C18 and water / acetonitrile gradient to give an off-white foamy material.

ＭＳ：ｍ／ｅ＝４０５（Ｍ−１）は、Ｃ１８Ｈ１５ＣｌＮ２Ｏ７、Ｍｗ＝４０６．７７に対応する。

MS: m / e = 405 (M−1) corresponds to C18H15ClN2O7, Mw = 406.77.

  Example 3: Preparation of 2- (1-furan-2-ylmethyl-6-methanesulfonyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid (Compound 3) )

（２−［（フラン−２−イルメチル）−アミノ］−５−メチルスルファニル−安息香酸）
２−クロロ−５−（メチルチオ）安息香酸（１５．５ｇ，７６．５ｍｍｏｌ）を、ＤＭＦ（２０ｍＬ）中に溶解した。炭酸カリウム（１０．６ｇ、７６．７ｍｍｏｌ）を添加し、そしてこの溶液を５分間（沸騰が弱まるまで）撹拌させた。次いで、フルフリルアミン（８．８ｍＬ、９９ｍｍｏｌ）を添加し、続いて臭化銅（Ｉ）（１ｇ、７ｍｍｏｌ）を添加した。この反応を、密封チューブ中で一晩１５０℃に加熱し、次いで、（温かいままであるが）１０％ ＮＨ_４ＯＨ（３００ｍＬ）中に注いだ。この混合物を氷ＡｃＯＨでｐＨ４〜５（ｐＨ紙による）に酸性化し、この粗生成物を、濾過によって収集した。次いで、この収集した個体を１Ｎ ＮａＯＨ中に溶解し、不溶な黒色微粒子を、濾過して取り除いた。次いで、この濾液を６Ｎ ＡｃＯＨで酸性化し、この生成物（薄緑色の固体、１１．６４ｇ、５８％）を濾過によって収集し、高減圧下で２日間乾燥させ、残留する水の大部分を除去した。

(2-[(Furan-2-ylmethyl) -amino] -5-methylsulfanyl-benzoic acid)
2-Chloro-5- (methylthio) benzoic acid (15.5 g, 76.5 mmol) was dissolved in DMF (20 mL). Potassium carbonate (10.6 g, 76.7 mmol) was added and the solution was allowed to stir for 5 minutes (until boiling diminished). Furfurylamine (8.8 mL, 99 mmol) was then added followed by copper (I) bromide (1 g, 7 mmol). The reaction was heated to 150 ° C. overnight in a sealed tube and then poured into 10% NH ₄ OH (300 mL) (although still warm). The mixture was acidified with glacial AcOH to pH 4-5 (with pH paper) and the crude product was collected by filtration. The collected individuals were then dissolved in 1N NaOH and insoluble black particulates were removed by filtration. The filtrate was then acidified with 6N AcOH and the product (light green solid, 11.64 g, 58%) was collected by filtration and dried under high vacuum for 2 days to remove most of the remaining water. did.

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_１３Ｈ_１４ＮＯ_３Ｓ（Ｍ＋Ｈ）についての計算値２６４．０７；検出値２６３．９。

Calculated for _{MS (LR-APCI) C 13} H 14 NO 3 S (M + H) 264.07; detection value 263.9.

ヒドロキシメチルポリスチレン（ＨＭ−ＰＳ）樹脂（５．９８８ｇ、１．２９ｍｍｏｌ／ｇ）を、ＴＨＦ中に取り、ホスゲン（トルエン中１５ｍＬ約２．５Ｍの溶液）を添加した。この反応を３時間振とうさせ、次いで、このホスゲン溶液を（注意しながら）排出させ、ＤＣＭで連続的に（４回）洗浄した。次いで、ＤＣＭ中２−［（フラン−２−イルメチル）−アミノ］−５−メチルスルファニル−安息香酸（３．０７ｇ、１．５当量）の溶液を、ＤＩＥＡ（６．６ｍＬ、５当量）と一緒に樹脂に添加し、この反応をさらに３時間振とうさせた。次いで、この樹脂を、ＤＣＭ（３回）、ＭｅＯＨ（３回）、ＤＣＭ（３回）、ＭｅＯＨ（３回）、およびＥｔ_２Ｏ（２回）で連続的にすすぎ、高減圧下で乾燥させた。樹脂の収率＝８．８１１ｇ（重量増加置換＝１．１０ｍｍｏｌ／ｇによって推定された充填）。

Hydroxymethyl polystyrene (HM-PS) resin (5.988 g, 1.29 mmol / g) was taken up in THF and phosgene (15 mL about 2.5 M solution in toluene) was added. The reaction was shaken for 3 hours, then the phosgene solution was drained (carefully) and washed successively with DCM (4 times). Then a solution of 2-[(furan-2-ylmethyl) -amino] -5-methylsulfanyl-benzoic acid (3.07 g, 1.5 eq) in DCM was combined with DIEA (6.6 mL, 5 eq). The reaction was shaken for an additional 3 hours. The resin is then rinsed sequentially with DCM (3 times), MeOH (3 times), DCM (3 times), MeOH (3 times), and Et ₂ O (2 times) and dried under high vacuum. It was. Resin yield = 8.811 g (weight increase substitution = estimated charge by 1.10 mmol / g).

（２−フラン−２−イルメチル−６−メタンスルホニル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸（化合物３））
このＰＳ樹脂を、ＮＭＰ中に取り、ＨＯＢＴ・Ｈ_２Ｏ（ＮＭＰ中４当量）およびＨＢＴＵ（ＮＭＰ中４当量）を添加した。約５分間振とうさせた後、Ｌ−アスパラギン酸□，□−ジ−ｔ−ブチルエステル塩酸塩（ＮＭＰ中４当量）およびＤＩＥＡ（５当量）を、この混合物に添加した。一晩振とうさせた後、この溶液を排液させ、この樹脂をＮＭＰ（２回）、ＤＣＭ（３回）、およびＭｅＯＨ（３回）で連続して洗浄し、高減圧下で乾燥させた。この樹脂を、１０％Ｅｔ_３Ｎ／ＭｅＯＨ溶液中で一晩６０℃に加熱し、樹脂からの化合物の環化的切断に作用した。次いで、この粗生成物をクロマトグラフィーによって精製した（ＳｉＯ_２、２０％ＥｔＯＡｃ／ヘキサンでのＲ_ｆ＝０．２９）。次いで、６−メチルスルファニル−キナゾリン−２，４−ジオンをＣＨＣｌ_３中に取り、氷浴中で冷却させた。次いで、ＭＣＰＢＡ（約７７％、約２当量）を添加し、この反応を、スルホンへの変換についてＴＬＣによってモニタリングした。一旦十分な変換が達成されると、１Ｎ ＮａＯＨを添加し、この相を分離した。この有機相を乾燥させ（ＭｇＳＯ_４）、そしてこのスルホンをクロマトグラフィー（ＳｉＯ_２、６０％ＥｔＯＡｃ／ヘキサンでのＲ_ｆ＝０．３９）によって精製した。６−メタンスルホニル−キナゾリン−２，４−ジオンをＴＦＡ／ＤＣＭ（１：１）で一晩処理し、粗最終生成物を与えた。この粗最終生成物を、逆相Ｃ１８クロマトグラフィーによって精製した。

(2-furan-2-ylmethyl-6-methanesulfonyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid (compound 3))
The PS resin was taken up in NMP and HOBT.H ₂ O (4 equivalents in NMP) and HBTU (4 equivalents in NMP) were added. After shaking for about 5 minutes, L-aspartic acid □, □ -di-t-butyl ester hydrochloride (4 eq in NMP) and DIEA (5 eq) were added to the mixture. After shaking overnight, the solution was drained and the resin was washed successively with NMP (2 times), DCM (3 times), and MeOH (3 times) and dried under high vacuum. . This resin was heated to 60 ° C. overnight in a 10% Et ₃ N / MeOH solution to effect the cyclization of the compound from the resin. The crude product was then purified by chromatography (SiO ₂ , R _f = 0.29 with 20% EtOAc / hexanes). 6-methylsulfanyl-quinazoline-2,4-dione was then taken up in CHCl ₃ and allowed to cool in an ice bath. MCPBA (about 77%, about 2 equivalents) was then added and the reaction was monitored by TLC for conversion to sulfone. Once sufficient conversion was achieved, 1N NaOH was added and the phases were separated. The organic phase was dried (MgSO ₄ ) and the sulfone was purified by chromatography (SiO ₂ , R _f = 0.39 with 60% EtOAc / hexanes). 6-Methanesulfonyl-quinazoline-2,4-dione was treated with TFA / DCM (1: 1) overnight to give the crude final product. The crude final product was purified by reverse phase C18 chromatography.

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_１８Ｈ_１５Ｎ_２Ｏ_９Ｓ（Ｍ−Ｈ）についての計算値４３５．０５；検出値４３５．０。

_{MS (LR-APCI) C 18} H 15 N 2 O 9 Calculated for S (M-H) 435.05; detection value 435.0.

  The following further derivatives were prepared using chemical transformations similar to those described above.

（実施例４：２−（６−ベンゼンスルホニル−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸）

Example 4: 2- (6-Benzenesulfonyl-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２３Ｈ_１７Ｎ_２Ｏ_９Ｓ（Ｍ−Ｈ）についての計算値４９７．０７；検出値４９６．９。

Calculated for _{MS (LR-APCI) C 23} H 17 N 2 O 9 S (M-H) 497.07; detection value 496.9.

（実施例５：２−（７−ベンゾイルアミノ−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸）

Example 5: 2- (7-benzoylamino-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２４Ｈ_１８Ｎ_３Ｏ_８（Ｍ−Ｈ）についての計算値４７６．１１；検出値４７６．０。

Calculated for _{MS (LR-APCI) C 24} H 18 N 3 O 8 (M-H) 476.11; detection value 476.0.

（実施例６：２−（７−ベンゼンスルホニルアミノ−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸）

Example 6: 2- (7-Benzenesulfonylamino-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２３Ｈ_１８Ｎ_３Ｏ_９Ｓ（Ｍ−Ｈ）についての計算値５１２．０８；検出値５１２．１。

Calculated for _{MS (LR-APCI) C 23} H 18 N 3 O 9 S (M-H) 512.08; detection value 512.1.

（実施例７：２−（６−アリルオキシ−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸）

Example 7: 2- (6-Allyloxy-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２０Ｈ_１７Ｎ_２Ｏ_８（Ｍ−Ｈ）についての計算値４１３．１０；検出値４１３．０。

Calculated for _{MS (LR-APCI) C 20} H 17 N 2 O 8 (M-H) 413.10; detection value 413.0.

（実施例８：２−［６−（４−クロロ−ベンゼンスルホニル）−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル］−コハク酸）

Example 8: 2- [6- (4-Chloro-benzenesulfonyl) -1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] -succinic acid )

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２３Ｈ_１６ＣｌＮ_２Ｏ_９Ｓ（Ｍ−Ｈ）についての計算値５３１．０３；検出値５３０．８。

MS _(LR-APCI) calculated for _{C 23 H 16 ClN 2 O 9} S (M-H) 531.03; detection value 530.8.

（実施例９：２−（１−フラン−２−イルメチル−６−メチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸）

Example 9: 2- (1-furan-2-ylmethyl-6-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_１８Ｈ_１５Ｎ_２Ｏ_７（Ｍ−Ｈ）についての計算値３７１．０９；検出値３７１．０。

Calculated for _{MS (LR-APCI) C 18} H 15 N 2 O 7 (M-H) 371.09; detection value 371.0.

（実施例１０：２−（１−フラン−２−イルメチル−２，４−ジオキソ−６−フェニルスルファニル−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸）

Example 10: 2- (1-furan-2-ylmethyl-2,4-dioxo-6-phenylsulfanyl-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２３Ｈ_１７Ｎ_２Ｏ_７Ｓ（Ｍ−Ｈ）についての計算値４６５．０８；検出値４６５．０。

MS _(LR-APCI) calculated for _{C 23 H 17 N 2 O 7} S (M-H) 465.08; detection value 465.0.

（実施例１１：２−［６−（４−クロロ−ベンゼンスルフィニル）−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル］−コハク酸）

Example 11: 2- [6- (4-Chloro-benzenesulfinyl) -1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] -succinic acid )

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２３Ｈ_１６ＣｌＮ_２Ｏ_８Ｓ（Ｍ−Ｈ）についての計算値５１５．０３；検出値５１５．３。

MS _(LR-APCI) calculated for _{C 23 H 16 ClN 2 O 8} S (M-H) 515.03; detection value 515.3.

（実施例１２：２−（６−クロロ−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸）

Example 12: 2- (6-Chloro-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid

ＭＳ（ネガティブＡＰＣＩ）ｍ／ｅ＝３９１（ｍ−１）は、Ｃ１７Ｈ１３ＣｌＮ２Ｏ７（モル重量：３９２．７５）に対応する。

MS (negative APCI) m / e = 391 (m-1) corresponds to C17H13ClN2O7 (molar weight: 392.75).

（実施例１３：２−［１−フラン−２−イルメチル−６−（ナフタレン−２−イルオキシ）−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル］−３−フェニルプロピオン酸）

Example 13: 2- [1-furan-2-ylmethyl-6- (naphthalen-2-yloxy) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] -3-phenylpropi On acid)

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_３２Ｈ_２３Ｎ_２Ｏ_６（Ｍ−Ｈ）についての計算値５３１．１６；検出値５３１．０。

Calculated for _{MS (LR-APCI) C 32} H 23 N 2 O 6 (M-H) 531.16; detection value 531.0.

（実施例１４：２−［６−（ビフェニル−４−イルオキシ）−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル］−コハク酸）

Example 14: 2- [6- (biphenyl-4-yloxy) -1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] -succinic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２９Ｈ_２１Ｎ_２Ｏ_８（Ｍ−Ｈ）についての計算値５２５．１３；検出値５２５．８。

Calculated for _{MS (LR-APCI) C 29} H 21 N 2 O 8 (M-H) 525.13; detection value 525.8.

（実施例１５：２−（１−フラン−２−イルメチル−６−メタンスルフィニル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸）

Example 15: 2- (1-furan-2-ylmethyl-6-methanesulfinyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_１８Ｈ_１５Ｎ_２Ｏ_８Ｓ（Ｍ−Ｈ）についての計算値４１９．０５；検出値４１８．９。

_{MS (LR-APCI) C 18} H 15 N 2 O 8 calculated for S (M-H) 419.05; detection value 418.9.

（実施例１６：（６−アリルオキシ−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−酢酸）

Example 16: (6-Allyloxy-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -acetic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_１８Ｈ_１５Ｎ_２Ｏ_６（Ｍ−Ｈ）についての計算値３５５．０９；検出値３５５．１。

Calculated for _{MS (LR-APCI) C 18} H 15 N 2 O 6 (M-H) 355.09; detection value 355.1.

（実施例１７：２−［６−（ビフェニル−４−イルオキシ）−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル］−３−フェニル−プロピオン酸）

Example 17: 2- [6- (Biphenyl-4-yloxy) -1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] -3-phenyl -Propionic acid)

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_３４Ｈ_２５Ｎ_２Ｏ_６（Ｍ−Ｈ）についての計算値５５７．１７；検出値５５７．０。

Calculated for _{MS (LR-APCI) C 34} H 25 N 2 O 6 (M-H) 557.17; detection value 557.0.

（実施例１８：２−（６−クロロ−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−３−（１Ｈ−インドール−３−イル）−プロピオン酸）

Example 18: 2- (6-Chloro-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -3- (1H-indole-3- Yl) -propionic acid)

ＭＳ（ネガティブＡＰＣＩ）ｍ／ｅ＝４６１．９（ｍ−１）は、Ｃ２４Ｈ１８ＣｌＮ３Ｏ５（モル重量：４６３．８７）に対応する。

MS (negative APCI) m / e = 461.9 (m−1) corresponds to C24H18ClN3O5 (molar weight: 463.87).

（実施例１９：２−［６−（４−クロロ−フェニルスルファニル）−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル］−３−フェニル−プロピオン酸）

Example 19: 2- [6- (4-Chloro-phenylsulfanyl) -1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] -3- Phenyl-propionic acid)

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２８Ｈ_２０ＣｌＮ_２Ｏ_５Ｓ（Ｍ−Ｈ）についての計算値５３１．０８；検出値５３１．０。

_{MS (LR-APCI) C 28} H 20 ClN 2 O 5 calculated for S (M-H) 531.08; detection value 531.0.

（実施例２０：［６−（ビフェニル−４−イルオキシ）−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル］−酢酸）

Example 20: [6- (Biphenyl-4-yloxy) -1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] -acetic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２７Ｈ_１９Ｎ_２Ｏ_６（Ｍ−Ｈ）についての計算値４６７．１２；検出値４６６．９。

Calculated for _{MS (LR-APCI) C 27} H 19 N 2 O 6 (M-H) 467.12; detection value 466.9.

（実施例２１：２−［６−（４−クロロ−フェニルスルファニル）−１−フラン−２−イルメチル−２−，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル］−３−（１Ｈ−インドール−３−イル）−プロピオン酸）

Example 21: 2- [6- (4-Chloro-phenylsulfanyl) -1-furan-2-ylmethyl-2-, 4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] -3 -(1H-indol-3-yl) -propionic acid)

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_３０Ｈ_２１ＣｌＮ_３Ｏ_５Ｓ（Ｍ−Ｈ）についての計算値５７０．０９；検出値５６９．９。

Calculated for _{MS (LR-APCI) C 30} H 21 ClN 3 O 5 S (M-H) 570.09; detection value 569.9.

（実施例２１：２−（６−ベンゼンスルホニルアミノ−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸）

Example 21: 2- (6-Benzenesulfonylamino-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２３Ｈ_１８Ｎ_３Ｏ_９Ｓ（Ｍ−Ｈ）についての計算値５１２．０８；検出値５１２．０。

Calculated for _{MS (LR-APCI) C 23} H 18 N 3 O 9 S (M-H) 512.08; detection value 512.0.

（実施例２２：２−（１−フラン−２−イルメチル−６−メチルスルファニル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−３−（１Ｈ−インドール−３−イル）−プロピオン酸）

Example 22: 2- (1-furan-2-ylmethyl-6-methylsulfanyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -3- (1H-indole-3 -Yl) -propionic acid)

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２５Ｈ_２０Ｎ_３Ｏ_５Ｓ（Ｍ−Ｈ）についての計算値４７４．１１；検出値４７３．９。

Calculated for _{MS (LR-APCI) C 25} H 20 N 3 O 5 S (M-H) 474.11; detection value 473.9.

  (Example 23)

（２−（７−ベンゾイルアミノ−１−フラン−２−イルメチル−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−コハク酸）

(2- (7-Benzoylamino-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -succinic acid)

ＭＳ（ＬＲ−ＡＰＣＩ）Ｃ_２４Ｈ_１８Ｎ_３Ｏ_８（Ｍ−Ｈ）についての計算値４７６．１１；検出値４７６．０。

Calculated for _{MS (LR-APCI) C 24} H 18 N 3 O 8 (M-H) 476.11; detection value 476.0.

  Example 24: 2- [2- (Benzenesulfonylamino-methyl) -1H-indol-6-yloxy] -malonic acid

（工程Ａ：６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール−２−カルボン酸）
６−ヒドロキシ−１Ｈ−インドール−２−カルボン酸（５．４０ｇ、３０．４８ｍｍｏｌ）を、ＴＨＦ（１００ｍｌ）中に溶解し、そしてイミダゾール（１０．３８、１５２．４ｍｍｏｌ）を添加する。この混合物を５分間撹拌し、ＴＢＤＭＳ−Ｃｌ（１３．７８ｇ、９１．４４ｍｍｏｌ）を添加する。この反応を、室温で１時間撹拌する。この混合物を、水（２００ｍｌ）中に濾過する。この固体を、ＴＨＦ（５０ｍｌ）で洗浄する。この濾液を濃縮し、ＴＨＦを除去する。この生成物を、酢酸エチル（１００ｍｌ）で３回抽出する。この有機物を乾燥させ（ＭｇＳＯ_４）、濾過し、そして濃縮して６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール−２−カルボン酸（８．０ｇ、収率９０％）を与える。

(Step A: 6- (tert-butyl-dimethyl-silanyloxy) -1H-indole-2-carboxylic acid)
6-Hydroxy-1H-indole-2-carboxylic acid (5.40 g, 30.48 mmol) is dissolved in THF (100 ml) and imidazole (10.38, 152.4 mmol) is added. The mixture is stirred for 5 minutes and TBDMS-Cl (13.78 g, 91.44 mmol) is added. The reaction is stirred at room temperature for 1 hour. The mixture is filtered into water (200 ml). This solid is washed with THF (50 ml). The filtrate is concentrated to remove THF. The product is extracted 3 times with ethyl acetate (100 ml). The organics are dried (MgSO ₄ ), filtered and concentrated to give 6- (tert-butyl-dimethyl-silanyloxy) -1H-indole-2-carboxylic acid (8.0 g, 90% yield).

（工程Ｂ：［６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール−２−イル］−メタノール）
ＴＨＦ（１０３ｍｌ）中１Ｍ ＬＡＨを、０℃に冷却する。ＴＨＦ（３０ｍｌ）中６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール−２−カルボン酸（６．０ｇ、２０．６０ｍｍｏｌ）の溶液を、ゆっくりと添加する。この反応を、室温で２日間撹拌し、水（１０ｍｌ）、１Ｎ ＮａＯＨ（１０ｍｌ）および水（２０ｍｌ）でクエンチする。この混合物に、ＭｇＳＯ_４を添加する。この混合物を濾過し、酢酸エチル（２００ｍｌ）中１０％メタノールで洗浄する。この濾液を、油にまで濃縮する。この粗生成物をカラムクロマトグラフィー（ヘキサン中２０％酢酸エチル）によって精製し、［６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール−２−イル］−メタノール（２．３０ｇ、収率４０％）を与える。

(Step B: [6- (tert-butyl-dimethyl-silanyloxy) -1H-indol-2-yl] -methanol)
1M LAH in THF (103 ml) is cooled to 0 ° C. A solution of 6- (tert-butyl-dimethyl-silanyloxy) -1H-indole-2-carboxylic acid (6.0 g, 20.60 mmol) in THF (30 ml) is added slowly. The reaction is stirred at room temperature for 2 days and quenched with water (10 ml), 1N NaOH (10 ml) and water (20 ml). To this mixture is added MgSO ₄ . The mixture is filtered and washed with 10% methanol in ethyl acetate (200 ml). The filtrate is concentrated to an oil. The crude product was purified by column chromatography (20% ethyl acetate in hexane) and [6- (tert-butyl-dimethyl-silanyloxy) -1H-indol-2-yl] -methanol (2.30 g, yield). 40%).

（工程Ｃ：２−アジドメチル−６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール）
［６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール−２−イル］−メタノール（２．０ｇ、７．２１ｍｍｏｌ）を、ＤＭＦ（９５０ｍｌ）中に溶解し、０℃に冷却する。ＴＥＡ（２．０１ｍｌ、１４．４２ｍｍｏｌ）およびＭｓＣｌ（０．８３ｇ、７．２１ｍｍｏｌ）を添加する。この混合物を、室温で１時間撹拌する。ＮａＮ_３（２．３４ｇ、３４ｍｍｏｌ）を添加する。この反応を、室温で１時間撹拌し、次いで８０℃で一晩撹拌する。この混合物を、室温まで冷却し、濃縮する。この残留物をカラムクロマトグラフィー（ヘキサン中１０％酢酸エチル）によって精製し、２−アジドメチル６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール（１．４０ｇ、６４％）を与える。

(Step C: 2-azidomethyl-6- (tert-butyl-dimethyl-silanyloxy) -1H-indole)
[6- (tert-Butyl-dimethyl-silanyloxy) -1H-indol-2-yl] -methanol (2.0 g, 7.21 mmol) is dissolved in DMF (950 ml) and cooled to 0 ° C. TEA (2.01 ml, 14.42 mmol) and MsCl (0.83 g, 7.21 mmol) are added. The mixture is stirred at room temperature for 1 hour. NaN ₃ (2.34 g, 34 mmol) is added. The reaction is stirred at room temperature for 1 hour and then at 80 ° C. overnight. The mixture is cooled to room temperature and concentrated. The residue is purified by column chromatography (10% ethyl acetate in hexane) to give 2-azidomethyl 6- (tert-butyl-dimethyl-silanyloxy) -1H-indole (1.40 g, 64%).

（工程Ｄ：［６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール−２−イル］−メチルアミン）
２−アジドメチル−６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール（０．７０ｇ、２．３１ｍｍｏｌ）を、エタノール（１０ｍｌ）中に溶解する。１００ｍｇの１０％Ｐｄ／Ｃを添加する。この混合物を、４０ｐｓｉの水素で一晩水素化し、［６−（ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ）−１Ｈ−インドール−２−イル］−メチルアミンを与える。

(Step D: [6- (tert-butyl-dimethyl-silanyloxy) -1H-indol-2-yl] -methylamine)
2-Azidomethyl-6- (tert-butyl-dimethyl-silanyloxy) -1H-indole (0.70 g, 2.31 mmol) is dissolved in ethanol (10 ml). Add 100 mg of 10% Pd / C. This mixture is hydrogenated with 40 psi of hydrogen overnight to give [6- (tert-butyl-dimethyl-silanyloxy) -1H-indol-2-yl] -methylamine.

(Step E: [6- (tert-Butyl-dimethyl-silanyloxy) -1H-indol-2-ylmethyl] -carbamic acid benzyl ester)
[6- (tert-Butyl-dimethyl-silanyloxy) -1H-indol-2-yl] -methylamine (0.70 g, 1.01 mmol) is dissolved in DCM (10 ml) and cooled to 0 ° C. DIEA (0.35 ml, 2.02 mmol) and Cbz-Cl (0.17 g, 1.01 mmol) are added. The mixture is stirred for 1 hour at room temperature. The reaction mixture was concentrated and the residue was purified by column chromatography (10% ethyl acetate in hexane) to yield [6- (tert-butyl-dimethyl-silanyloxy) -1H-indol-2-ylmethyl]- This gives benzyl carbamic acid ester.

(Step F: (6-Hydroxy-1H-indol-2-ylmethyl) -carbamic acid benzyl ester)
[6- (tert-Butyl-dimethyl-silanyloxy) -1H-indol-2-ylmethyl] -carbamic acid benzyl ester (0.80 g, 1.95 mmol) is dissolved in THF (2 ml). Cool to -78 ° C. Add 1M TBAF solution in THF (3.90 ml). The reaction mixture is concentrated and the residue is purified by column chromatography (30% ethyl acetate in hexane) to give (6-hydroxy-1H-indol-2-ylmethyl) -carbamic acid benzyl ester.

(Step G: 2- (2-Aminomethyl-1H-indol-6-yloxy) -malonic acid diethyl ester)
(6-Hydroxy-1H-indol-2-ylmethyl) -carbamic acid benzyl ester was dissolved in 10 ml acetone and Cs ₂ CO ₃ and diethyl chloromalonate were added. The reaction is stirred overnight. HPLC and TLC showed the reaction was complete. The mixture is diluted with ethyl acetate and filtered through a silica gel plug. The filtrate is concentrated, redissolved in ethanol and hydrogenated with 40 psi hydrogen for 3 hours. The mixture is filtered and washed with ethyl acetate. The filtrate is concentrated to give 2- (2-aminomethyl-1H-indol-6-yloxy) -malonic acid diethyl ester.

(Step H: 2- [2- (Benzenesulfonylamino-methyl) -1H-indol-6-yloxy] -malonic acid diethyl ester)
2- (2-Aminomethyl-1H-indol-6-yloxy) -malonic acid diethyl ester (80 mg, 0.25 mmol) is dissolved in DCM (2 ml). DIEA (87 ml, 0.50 mmol) is added. To this solution is added benzenesulfonyl chloride (44 mg, 0.25 mmol). The reaction is stirred at room temperature for 2 hours. The reaction mixture is concentrated and the residue is purified by column chromatography (30% ethyl acetate in hexane) to give the title compound.

(Step I: 2- [2- (Benzenesulfonylamino-methyl) -1H-indol-6-yloxy] malonic acid)
2- [2- (Benzenesulfonylamino-methyl) -1H-indol-6-yloxy] -diethyl malonate is dissolved in ethanol (3 ml). Add 1M NaOH (2 ml). The mixture is stirred for 1 hour. The mixture was acidified with 1M HCl to pH = 2 and purified by C18 column chromatography (15% acetonitrile in water).

以下の化合物は、上記されるものと類似の化学を使用して調製され得る：
（実施例２４：２−［２−（フェニルメタンスルホニルアミノ−メチル）−１Ｈ−インドール−６−イルオキシ］−マロン酸）

The following compounds can be prepared using chemistry similar to that described above:
Example 24: 2- [2- (Phenylmethanesulfonylamino-methyl) -1H-indol-6-yloxy] -malonic acid

（実施例２５：２−｛２−［（４−アセチルアミノ−ベンゼンスルホニルアミノ）−メチル］−１Ｈ−インドール−６−イルオキシ｝−マロン酸）

Example 25: 2- {2-[(4-Acetylamino-benzenesulfonylamino) -methyl] -1H-indol-6-yloxy} -malonic acid

（実施例２６：２−｛２−［（ビフェニル−４−スルホニルアミノ）−メチル］−１Ｈ−インドール−６−イルオキシ｝−マロン酸）

Example 26: 2- {2-[(biphenyl-4-sulfonylamino) -methyl] -1H-indol-6-yloxy} -malonic acid

（実施例２７：２−（２−｛［（１−アセチル−ピペリジン−４−カルボニル）−アミノ］−メチル｝−１Ｈ−インドール−６−イルオキシ）−マロン酸）

Example 27: 2- (2-{[(1-Acetyl-piperidine-4-carbonyl) -amino] -methyl} -1H-indol-6-yloxy) -malonic acid

（実施例２８：２−［２−（メタンスルホニルアミノ−メチル）−１Ｈ−インドール−６−イルオキシ］−マロン酸）

Example 28: 2- [2- (Methanesulfonylamino-methyl) -1H-indol-6-yloxy] -malonic acid

（実施例２９：２−｛２−［（３，５−ビス−トリフルオロメチル−フェニルメタンスルホニルアミノ）−メチル］−１Ｈ−インドール−６−イルオキシ｝−マロン酸）

Example 29: 2- {2-[(3,5-bis-trifluoromethyl-phenylmethanesulfonylamino) -methyl] -1H-indol-6-yloxy} -malonic acid

（実施例３０：２−｛２−［（３，５−ジクロロ−フェニルメタンスルホニルアミノ）−メチル］−１Ｈ−インドール−６−イルオキシ｝−マロン酸）

Example 30: 2- {2-[(3,5-dichloro-phenylmethanesulfonylamino) -methyl] -1H-indol-6-yloxy} -malonic acid

（実施例３１：２−｛２−［（２，２−ジフェニル−エタンスルホニルアミノ）−メチル］−１Ｈ−インドール−６−イルオキシ｝−マロン酸）

Example 31: 2- {2-[(2,2-diphenyl-ethanesulfonylamino) -methyl] -1H-indol-6-yloxy} -malonic acid

（実施例３２：２−｛２−［（４’−メチル−ビフェニル−４−スルホニルアミノ）−メチル］−１Ｈ−インドール−６−イルオキシ｝−マロン酸）

Example 32: 2- {2-[(4′-methyl-biphenyl-4-sulfonylamino) -methyl] -1H-indol-6-yloxy} -malonic acid

（実施例３３：２−｛２−［（４’−クロロ−ビフェニル−４−スルホニルアミノ）−メチル］−１Ｈ−インドール−６−イルオキシ｝−マロン酸）

Example 33: 2- {2-[(4′-chloro-biphenyl-4-sulfonylamino) -methyl] -1H-indol-6-yloxy} -malonic acid

（実施例３４：２−（２−ベンジルカルバモイル−１Ｈ−インドール−６−イルオキシ）−マロン酸）

Example 34: 2- (2-Benzylcarbamoyl-1H-indol-6-yloxy) -malonic acid

（実施例３５：２−（２−フェネチルカルバモイル−１Ｈ−インドール−６−イルオキシ）−マロン酸）

Example 35: 2- (2-Phenethylcarbamoyl-1H-indol-6-yloxy) -malonic acid

（実施例３６：２−［２−（４−フェニル−ブチルカルバモイル）−１Ｈ−インドール−５−イルオキシ］−マロン酸）

Example 36: 2- [2- (4-Phenyl-butylcarbamoyl) -1H-indol-5-yloxy] -malonic acid

（実施例３７：２−（｛２−［（ベンジル−フェニルメタンスルホニル−アミノ）−メチル］−１Ｈ−インドール−６−イルオキシ｝−マロン酸）

Example 37: 2-({2-[(benzyl-phenylmethanesulfonyl-amino) -methyl] -1H-indol-6-yloxy} -malonic acid)

（実施例３８：２−（２−｛［（４−フェニル−ブチル）−フェニルメタンスルホニル−アミノ］−メチル｝−１Ｈ−インドール−６−イルオキシ）−マロン酸）

Example 38: 2- (2-{[(4-Phenyl-butyl) -phenylmethanesulfonyl-amino] -methyl} -1H-indol-6-yloxy) -malonic acid

２−［２−（フェニルメタンスルホニルアミノ−メチル）−１Ｈ−インドール−６−イルオキシ］−マロン酸ジエチルエステル（２０ｍｇ、０．０４２ｍｍｏｌ）を、ＴＨＦ（１ｍｌ）中に溶解する。Ｐｈ_３Ｐ（１７ｍｇ、０．０６３ｍｍｏｌ）およびＤＩＡＤ（１２８ｍｇ、０．０６３ｍｍｏｌ）を添加する。この混合物を２分間撹拌し、そしてフェンブタノールを添加する。この反応を、一晩撹拌する。この反応混合物を濃縮し、そしてこの残留物をカラムクロマトグラフィー（ヘキサン中１５％酢酸エチル）によって精製し、１４ｍｇのエステルを得る。このエステルをメタノール（２ｍｌ）中に溶解する。１Ｎ ＮａＯＨ水溶液（０．４０ｍｌ）を添加する。この反応を、１時間撹拌し、そして１Ｎ ＨＣｌで酸性化する。この生成物を、Ｃ１８カラム（水中４０％アセトニトリル）によって精製した。

2- [2- (Phenylmethanesulfonylamino-methyl) -1H-indol-6-yloxy] -malonic acid diethyl ester (20 mg, 0.042 mmol) is dissolved in THF (1 ml). Ph ₃ P (17 mg, 0.063 mmol) and DIAD (128 mg, 0.063 mmol) are added. The mixture is stirred for 2 minutes and fenbutanol is added. The reaction is stirred overnight. The reaction mixture is concentrated and the residue is purified by column chromatography (15% ethyl acetate in hexane) to give 14 mg of ester. This ester is dissolved in methanol (2 ml). Add 1N aqueous NaOH (0.40 ml). The reaction is stirred for 1 hour and acidified with 1N HCl. The product was purified by C18 column (40% acetonitrile in water).

（実施例３９：２−［３−アセチル−２−（フェニルメタンスルホニルアミノ−メチル）−１Ｈ−インドール−６−イルオキシ］−マロン酸）

Example 39: 2- [3-Acetyl-2- (phenylmethanesulfonylamino-methyl) -1H-indol-6-yloxy] -malonic acid

（実施例４０：２−［３−ベンゾイル−２−（フェニルメタンスルホニルアミノ−メチル）−１Ｈ−インドール−６−イルオキシ］−マロン酸）

Example 40: 2- [3-Benzoyl-2- (phenylmethanesulfonylamino-methyl) -1H-indol-6-yloxy] -malonic acid

（実施例４１：ＳＨＰ−２アッセイ条件）
ＳＨＰ−２のＮ−末端６Ｈｉｓ−タグ化触媒的ドメイン（２５０〜５２７）を、Ｅ．ｃｏｌｉに発現させ、そしてタンパク質を従来の方法によって精製する。ＳＨＰ−２の活性を、蛍光性二リン酸塩（ＦＤＰ）の脱リン酸化によって生じる蛍光性シグナルを測定することにより、評価した。このアッセイを、９６ウェルポリプロピレンブラックプレートにおいて行う。この最終的なアッセイ容積は、１００μＬであり、そして２５ｍＭ ＮａＯＡｃ、ｐＨ６、０．０２％Ｔｒｉｔｏｎ Ｘ−１００、１０ｍＭ ＤＴＴおよび２ｎＭ ＳＨＰ−２から成る。インヒビターをＤＭＳＯ中に懸濁させ、そして全ての反応（コントロールを含む）を、最終濃度の３％ＤＭＳＯにて行う。反応を、３μＭ ＦＤＰの添加によって開始し、そして周囲温度で２５分間インキュベートする。プレートを、Ｍｏｌｅｃｕｌａｒ Ｄｅｖｉｃｅｓ Ｇｅｍｉｎｉプレートリーダー、Ｅｘ ４８５、Ｅｍ ５３８、Ｃｕｔｏｆｆ ５３０を使用して読み取った。

(Example 41: SHP-2 assay conditions)
The N-terminal 6His-tagged catalytic domain (250-527) of SHP-2 expressed in E. coli and the protein is purified by conventional methods. The activity of SHP-2 was assessed by measuring the fluorescent signal generated by dephosphorylation of fluorescent diphosphate (FDP). This assay is performed in 96 well polypropylene black plates. This final assay volume is 100 μL and consists of 25 mM NaOAc, pH 6, 0.02% Triton X-100, 10 mM DTT and 2 nM SHP-2. Inhibitors are suspended in DMSO and all reactions (including controls) are performed at a final concentration of 3% DMSO. The reaction is initiated by the addition of 3 μM FDP and incubated for 25 minutes at ambient temperature. Plates were read using a Molecular Devices Gemini plate reader, Ex 485, Em 538, Cutoff 530.

Claims (16)

Formula (I):

A compound having
here:
Ring A is an optionally substituted aryl or heteroaryl ring;
R _a is —COOH;
n is 0-4;
R ₁ is H or optionally substituted aliphatic hydroxy, aliphatic amino, aliphatic —COOH, aliphatic —CONH ₂ , or aliphatic aryl;
R ₂ is an optionally substituted aliphatic, aliphatic aryl, cycloaliphatic, aliphatic heteroaryl, or aliphatic heterocycle;
R ³ and R ⁴ are independently selected from R ¹¹ , R ¹² , R ¹⁴ , or R ¹⁵ ;
here:
Each R ¹¹ is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R ⁶ or (CH ₂ ) _m —Y;
Wherein m is 0, 1 or 2; and Y is ^{_{halogen, CN, NO 2, CF 3}} , OCF 3, OH, SR 6, S (O) R 6, SO 2 R 6, NH 2 , NHR ⁶ , N (R ⁶ ) ₂ , NR ⁶ R ⁸ , COOH, COOR ⁶ or OR ⁶ ;
Each R ¹² is independently (C ₁ -C ₆ ) linear or branched alkyl or (C ₂ -C ₆ ) linear or branched alkenyl or alkynyl. And each R ¹² optionally contains up to two substituents, where:
The first substituent, if present, is selected from R ¹¹ , R ¹⁴ , and R ¹⁵ , and the second substituent, if present, is R ¹¹ ;
Each R ¹⁴ is independently OR ¹⁵ , OC (O) R ⁶ , OC (O) R ¹⁵ , OC (O) OR ⁶ , OC (O) OR ¹⁵ , OC (O) N (R ⁶ ) _2. , OP (O) (OR ⁶ ) ₂ , SR ⁶ , SR ¹⁵ , S (O) R ⁶ , S (O) R ¹⁵ , SO ₂ R ⁶ , SO ₂ R ¹⁵ , SO ₂ N (R ⁶ ) ₂ , ^{_{SO 2 NR 15 R 6, SO}} 3 R 6, C (O) R 15, C (O) OR 15, C (O) R 6, C (O) OR 6, NC (O) C (O) R 6 NC (O) C (O) R ¹⁵ , NC (O) C (O) OR ⁶ , NC (O) C (O) N (R ⁶ ) ₂ , C (O) N (R ⁶ ) ₂ , C (O) N (OR ⁶ ) R ⁶ , C (O) N (OR ⁶ ) R ¹⁵ , C (NOR ⁶ ) R ⁶ , C (NOR ⁶ ) R ¹⁵ , N (R ⁶ ) ₂ , NR ⁶ C ( O) R ¹¹ , NR ⁶ C (O) R ⁶ , NR ⁶ C (O) R ¹⁵ , NR ⁶ C (O) OR ⁶ , NR ⁶ C (O) OR ¹⁵ , NR ⁶ C (O) N (R ⁶ ) ₂ , NR ⁶ C (O) NR ¹⁵ R ⁶ , NR ⁶ SO ₂ R ⁶ , NR ⁶ SO ₂ R ¹⁵ , NR ⁶ SO ₂ N (R ⁶ ) ₂ , NR ⁶ SO ₂ NR ¹⁵ R ⁶ , N (OR ⁶ ) Selected from R ⁶ , N (OR ⁶ ) R ¹⁵ , P (O) (OR ⁶ ) N (R ⁶ ) ₂ , and P (O) (OR ⁶ ) ₂ ;
Each R ¹⁵ is alicyclic, aryl, heterocyclic, or heteroaromatic; and each R ¹⁵ optionally includes up to three substituents, each of which is present R ¹¹ if
Each R ⁶ is independently from H, (C ₁ -C ₆ ) linear or branched alkyl, or (C ₂ -C ₆ ) linear or branched alkenyl. And each R ⁶ optionally includes a substituent that is R ⁷ ;
R ⁷ is alicyclic, aryl, heterocyclic, or heteroaromatic; and each R ⁷ is H, (C ₁ -C ₆ ) linear or branched alkyl, (C ₂ -C ₆₎ linear or branched alkenyl, 1,2-methylenedioxy, up to two selected 1,2-ethylenedioxy, or _{(CH 2)} independently of the P -Z Optionally containing substituents;
Where p is 0, 1 or 2; and Z is halogen, CN, NO ₂ , CF ₃ , OCF ₃ , OH, S (C ₁ -C ₆ ) -alkyl, SO (C ₁ -C ₆ ) -Alkyl, SO ₂ (C ₁ -C ₆ ) -alkyl, NH ₂ , NH (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , N ((C _1- C ₆ ) -alkyl) R ⁸ , COOH, C (O) O (C ₁ -C ₆ ) -alkyl, or O (C ₁ -C ₆ ) -alkyl; and R ⁸ is an amino protecting group Yes;
However:
R ³ and R ⁴ are not simultaneously hydrogen;
When R ³ is H, R ⁴ is not chloro; and when R ⁴ is H, R ³ is neither —SCH ₃ nor —NH—C (O) CH ₃ ,
Compound. A ring is an optionally substituted 5- or 6-membered aryl or heteroaryl ring, wherein the heteroaryl ring is independently selected from O, S, or NH 2. A compound according to claim 1 comprising up to ring heteroatoms. The compound according to claim 2, wherein the A ring is phenyl. R ₁ is hydrogen, — (CH ₂ ) _q —X, where q is 1-4, and X is OH, NH ₂ , COOH or CONH ₂ , (C ₁ -C ₆ ) — The compound according to claim 1, which is alkyl or benzyl. R ₁ is hydrogen, hydroxymethyl, _{methyl, -CH 2 COOH, -CH 2 CONH} 2, an amino-butyl, methyl or isopentyl, A compound according to claim 4. R ₂ is butyl, isobutyl, methoxypropyl, cyclopentyl, cyclohexylmethyl, phenyl, trifluorophenyl, benzyl, fluorobenzyl, methylenedioxybenzyl, pyridylmethyl, furanylmethyl, tetrahydrofuranylmethyl, N-morpholinylmethyl, thienylmethyl 2. A compound according to claim 1, selected from: 2-oxo-pyrrolodinylpropyl, phenylethyl, chlorophenylethyl, methoxyphenylethyl, or dimethoxyphenylethyl. R ₂ is selected from 2-furanylmethyl or methyl, and according to another preferred embodiment, R ³ and R ⁴ are independently from hydrogen, halo, acetamide, allyloxy, thiophenyl, sulfoxyalkyl, or sulfoxyphenyl 7. A compound according to claim 6 which is selected. Formula (II):

A compound of
here:
X is — (CH ₂ ) _n —, or —C (O) —;
n is 1 to 3;
Y is O, S, NH, or N (C ₁ -C ₆ aliphatic);
Z is H or C ₁ -C ₆ aliphatic;
Q is 0 or 1;
A, R ^x , R ^y , and R ^z are independently selected from R ¹¹ , R ¹² , R ¹⁴ , or R ¹⁵ ;
here:
Each R ¹¹ is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R ⁶ or (CH ₂ ) _m —Y;
Wherein m is 0, 1 or 2; and Y is ^{_{halogen, CN, NO 2, CF 3}} , OCF 3, OH, SR 6, S (O) R 6, SO 2 R 6, NH 2 , NHR ⁶ , N (R ⁶ ) ₂ , NR ⁶ R ⁸ , COOH, COOR ⁶ or OR ⁶ ;
Each R ¹² is independently from (C ₁ -C ₆ ) linear or branched alkyl, (C ₂ -C ₆ ) linear or branched, alkenyl or alkynyl. And each R ¹² optionally contains up to two substituents, where:
The first substituent, if present, is selected from R ¹¹ , R ¹⁴ , and R ¹⁵ , and the second substituent, if present, is R ¹¹ ;
Each R ¹⁴ is independently OR ¹⁵ , OC (O) R ⁶ , OC (O) R ¹⁵ , OC (O) OR ⁶ , OC (O) OR ¹⁵ , OC (O) N (R ⁶ ) _2. , OP (O) (OR ⁶ ) ₂ , SR ⁶ , SR ¹⁵ , S (O) R ⁶ , S (O) R ¹⁵ , SO ₂ R ⁶ , SO ₂ R ¹⁵ , SO ₂ N (R ⁶ ) ₂ , ^{_{SO 2 NR 15 R 6, SO}} 3 R 6, C (O) R 15, C (O) OR 15, C (O) R 6, C (O) OR 6, NC (O) C (O) R 6 NC (O) C (O) R ¹⁵ , NC (O) C (O) OR ⁶ , NC (O) C (O) N (R ⁶ ) ₂ , C (O) N (R ⁶ ) ₂ , C (O) N (OR ⁶ ) R ⁶ , C (O) N (OR ⁶ ) R ¹⁵ , C (NOR ⁶ ) R ⁶ , C (NOR ⁶ ) R ¹⁵ , N (R ⁶ ) ₂ , NR ⁶ C ( O) R ¹¹ , NR ⁶ C (O) R ⁶ , NR ⁶ C (O) R ¹⁵ , NR ⁶ C (O) OR ⁶ , NR ⁶ C (O) OR ¹⁵ , NR ⁶ C (O) N (R ⁶ ) ₂ , NR ⁶ C (O) NR ¹⁵ R ⁶ , NR ⁶ SO ₂ R ⁶ , NR ⁶ SO ₂ R ¹⁵ , NR ⁶ SO ₂ N (R ⁶ ) ₂ , NR ⁶ SO ₂ NR ¹⁵ R ⁶ , N (OR ⁶ ) Selected from R ⁶ , N (OR ⁶ ) R ¹⁵ , P (O) (OR ⁶ ) N (R ⁶ ) ₂ , and P (O) (OR ⁶ ) ₂ ;
Each R ¹⁵ is alicyclic, aryl, heterocyclic, or heteroaromatic; and each R ¹⁵ optionally includes up to three substituents, each of which is present R ¹¹ if
Each R ⁶ is independently from H, (C ₁ -C ₆ ) linear or branched alkyl, or (C ₂ -C ₆ ) linear or branched alkenyl. And each R ⁶ optionally includes a substituent that is R ⁷ ;
R ⁷ is alicyclic, aryl, heterocyclic, or heteroaromatic; and each R ⁷ is H, (C ₁ -C ₆ ) linear or branched alkyl, (C ₂ -C ₆₎ linear or branched alkenyl, 1,2-methylenedioxy, up to two selected 1,2-ethylenedioxy, or _{(CH 2)} independently of the P -Z Optionally containing substituents;
Where p is 0, 1 or 2; and Z is halogen, CN, NO ₂ , CF ₃ , OCF ₃ , OH, S (C ₁ -C ₆ ) -alkyl, SO (C ₁ -C ₆ ) -Alkyl, SO ₂ (C ₁ -C ₆ ) -alkyl, NH ₂ , NH (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , N ((C _1- C ₆ ) -alkyl) R ⁸ , COOH, C (O) O (C ₁ -C ₆ ) -alkyl, or O (C ₁ -C ₆ ) -alkyl; and R ⁸ is an amino protecting group Is there;
Or R ^x and R ^y together form an optionally substituted heterocyclic ring having up to 3 substituents,
Compound. 9. A pharmaceutical composition comprising a compound according to any one of claims 1-8 and a pharmaceutically acceptable adjuvant or carrier. A method of treating or reducing the severity of a disease in a patient, wherein the disease is selected from an autoimmune disease, a proliferative disease, an angiogenic disorder, or a cancer, the method claiming A method comprising administering the composition according to item 9 to the patient. A method of treating or reducing the severity of a SHP-2-mediated disease or condition in a patient comprising administering to the patient the composition of claim 9. ,Method. The autoimmune disease is glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia Thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, or graft-versus-host disease 11. The method of claim 10, wherein: 11. The method of claim 10, wherein the proliferative disease is selected from acute myeloid leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, or HTLV-1-mediated tumor formation. 11. The method of claim 10, wherein the angiogenic disorder is selected from solid tumors, ocular neovascularization, or infantile hemangiomas. 11. The method of claim 10, wherein the cancer is selected from colon cancer, breast cancer, gastric cancer, or ovarian cancer. 9. An implantable medical device coated with a compound according to any one of claims 1-8, wherein the device is selected from a prosthesis, a prosthetic valve, a vascular graft, a stent or a catheter. .