JP2010527999A - Prinones and 1H-imidazopyridinones as PKC-θ inhibitors - Google Patents

Abstract

A group of chemicals of prinones and IH-imidazopyridinones useful as PKCθ inhibitors and methods of their use are disclosed. This group of substances is represented by Formula I. A typical example is II.

Description

  The present invention relates to a group of chemical substances of prinones and 1H-imidazopyridinones useful as PKCθ inhibitors.

Serine / threonine kinases, members of the protein kinase C (PKC) family, play a critical role in the regulation of cell differentiation and growth of various cell types. Ten mammalian members of the PKC family have been identified and have been named α, β, γ, δ, ε, ζ, η, θ, μ, and λ. The predicted structure of PKCθ shows the highest degree of homology with members of a new Ca ²⁺ -independent PKC subfamily, including PKCδ, ε and η. PKCθ is related to the highest degree to PKCδ.

  PKCθ is mainly expressed in lymphoid tissues and skeletal muscle. PKCθ has been shown to be essential for T cell receptor (TCR) -mediated T cell activation but not during TCR-dependent thymocyte development. PKCθ translocates to the site of cell contact between antigen-specific T cells and antigen-presenting cells (APCs), where it localizes together with the TCR in the core of T cell activation. Other PKC isoforms are not. PKCθ selectively activated the FasL promoter-reporter gene and up-regulated cell surface expression of mRNA or endogenous FasL, but not the α, ε or ζ isozymes. On the other hand, PKCθ and PKCε helped T cell survival by protecting cells from Fas-induced apoptosis, and this protective effect was mediated by promoting p90Rsk-dependent phosphorylation of BAD. Thus, PKCθ appears to play a dual regulatory role in T cell apoptosis.

  This essential role in selective expression of PKCθ in T cells and activation of mature T cells is due to disorders or diseases in which PKCθ inhibitors are mediated by T lymphocytes, such as autoimmune diseases such as rheumatoid arthritis and lupus erythematosus And has proved useful for the treatment or prevention of inflammatory diseases such as asthma and inflammatory bowel disease.

  PKCθ has been identified as a drug target for immunosuppression in transplantation and autoimmune diseases (Isakov et al. (2002) Annual Review of Immunology, 20, 761-794). PCT International Publication No. 2004/043386 identifies PKCθ as a target for the treatment of transplant rejection and multiple sclerosis. PKCθ is an inflammatory bowel disease (The Journal of Pharmacology and Experimental Therapeutics (2005), 313 (3), 962-982), asthma (International Publication No. 2005062918) and lupus (CurrentTurgDretDrgentDrugetDrG Allergy (2005), Volume 4 (3), 295-298) also plays a role.

  In addition, PKCθ is highly expressed in stromal tumors of the gastrointestinal tract (Bray, P. et al. (2004), Clinical Cancer Research, 10, 12, 1 part), and PKCθ is a treatment for gastrointestinal cancer. (Wiedmann, M. et al., (2005), Current Cancer Drug Targets, Vol. 5 (No. 3), p. 171). Thus, small molecule PKCθ inhibitors may be useful for the treatment of gastrointestinal cancer.

  Experiments performed in PKCθ knockout mice led to the conclusion that inactivation of PKCθ prevents defects in fat-induced insulin signaling and transport of glucose in skeletal muscle (Kim J. et al., 2004). The J. of Clinical Investigation 114 (6), 823). This data suggests that PKCθ is a promising therapeutic target for the treatment of type 2 diabetes, and therefore small molecule PKCθ inhibitors may be useful for treating such diseases.

  Thus, PKCθ inhibitors are useful in the treatment of diseases mediated by T cells, including autoimmune diseases such as rheumatoid arthritis, lupus erythematosus and multiple sclerosis and inflammatory diseases such as asthma and inflammatory bowel disease. is there. In addition, PKCθ inhibitors are useful in the treatment of transplant rejection, gastrointestinal cancer and diabetes.

International Publication No. 2004/043386 International Publication No. 2005062918

Isakov et al. (2002), Annual Review of Immunology, 20, 761-794. The Journal of Pharmacology and Experimental Therapeutics (2005), 313 (3), 962-982 Current Drug Targets: Inflammation & Allergy (2005), Volume 4 (No. 3), pages 295-298 Bray, P.M. (2004), Clinical Cancer Research, 10, 12, 1 part Wiedmann, M .; (2005), Current Cancer Drug Targets, Vol. 5 (No. 3), p. 171 Kim J. et al. Et al., 2004, The J. et al. of Clinical Investigation 114 (6), 823

(Summary of the Invention)
In one aspect, the present invention provides:

［式中、
Ｑは、ＮおよびＣＨから選択され、
Ｒ^１は、窒素結合ヘテロシクリル、置換された窒素結合ヘテロシクリルおよび

[Where:
Q is selected from N and CH;
R ¹ is a nitrogen-bonded heterocyclyl, substituted nitrogen-bonded heterocyclyl and

（式中、
ｎは、２から６の整数であり、
Ｒ^２１は、それぞれの出現において個別に、−Ｈ、Ｃ_１−Ｃ_４アルキルおよび−ＯＨから選択され、
Ｒ^２２は、それぞれの出現において個別に、−Ｈ、Ｃ_１−Ｃ_４アルキルおよびＲ^２４への結合から選択され、
Ｒ^２３は、−Ｈ、Ｃ_１−Ｃ_４アルキルおよびＲ^２４への結合から選択され、
Ｒ^２４は、−Ｈ、Ｃ_１−Ｃ_４アルキルから選択され、またはＲ^２２またはＲ^２３のどちらかと一緒になって、Ｃ_１−Ｃ_４アルキルで場合によって置換された５−７員の含窒素ヘテロ環を形成している。）
から選択され、
Ｒ^２は、アリール、置換されたアリール、アリールアルキル、置換されたアリールアルキル、ヘテロアリール、置換されたヘテロアリール、ヘテロアリールアルキルおよび置換されたヘテロアリールアルキルから選択される。］式Ｉの化合物に関する。

(Where
n is an integer from 2 to 6,
R ²¹ is independently selected at each occurrence from —H, C ₁ -C ₄ alkyl and —OH;
R ²² is independently selected at each occurrence from —H, C ₁ -C ₄ alkyl and a bond to R ²⁴ ;
R ²³ is selected from —H, C ₁ -C ₄ alkyl and a bond to R ²⁴ ;
R ²⁴ is selected from —H, C ₁ -C ₄ alkyl, or together with either R ²² or R ²³ , optionally substituted with a C ₁ -C ₄ alkyl, 5-7 membered nitrogen-containing Heterocycle is formed. )
Selected from
R ² is selected from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl. ] Relates to compounds of formula I;

  In another aspect, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I or a salt thereof.

  In another aspect, the present invention relates to autoimmune diseases such as rheumatoid arthritis, lupus erythematosus and multiple sclerosis, inflammatory diseases such as asthma and inflammatory bowel disease, transplant rejection, gastrointestinal cancer and diabetes. It relates to a method for treating cell mediated diseases. This method comprises administering a therapeutically effective amount of a compound of formula I or a salt thereof.

  In its broadest sense, the present invention

［式中、
Ｑは、ＮおよびＣＨから選択され、
Ｒ^１は、窒素結合ヘテロシクリル、置換された窒素結合ヘテロシクリルおよび

[Where:
Q is selected from N and CH;
R ¹ is a nitrogen-bonded heterocyclyl, substituted nitrogen-bonded heterocyclyl and

（式中、
ｎは、２から６の整数であり、
Ｒ^２１は、それぞれの出現において個別に、−Ｈ、Ｃ_１−Ｃ_４アルキルおよび−ＯＨから選択され、
Ｒ^２２は、それぞれの出現において個別に、−Ｈ、Ｃ_１−Ｃ_４アルキルおよびＲ^２４への結合から選択され、
Ｒ^２３は、−Ｈ、Ｃ_１−Ｃ_４アルキルおよびＲ^２４への結合から選択され、
Ｒ^２４は、−Ｈ、Ｃ_１−Ｃ_４アルキルから選択され、またはＲ^２２もしくはＲ^２３のどちらかと一緒になって、Ｃ_１−Ｃ_４アルキルで場合によって置換された５−７員の含窒素ヘテロ環を形成している。）
から選択され、
Ｒ^２は、アリール、置換されたアリール、アリールアルキル、置換されたアリールアルキル、ヘテロアリール、置換されたヘテロアリール、ヘテロアリールアルキルおよび置換されたヘテロアリールアルキルから選択される。］式Ｉの化合物またはこの塩に関する。

(Where
n is an integer from 2 to 6,
R ²¹ is independently selected at each occurrence from —H, C ₁ -C ₄ alkyl and —OH;
R ²² is independently selected at each occurrence from —H, C ₁ -C ₄ alkyl and a bond to R ²⁴ ;
R ²³ is selected from —H, C ₁ -C ₄ alkyl and a bond to R ²⁴ ;
R ²⁴ is selected from —H, C ₁ -C ₄ alkyl, or, together with either R ²² or R ²³ , a 5-7 membered nitrogen-containing optionally substituted with C ₁ -C ₄ alkyl Heterocycle is formed. )
Selected from
R ² is selected from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl. ] Relates to compounds of formula I or salts thereof.

In the description of R ^{1, R 1} is

であるとき、用語「Ｒ^２１は、それぞれの出現において個別に、−Ｈ、Ｃ_１−Ｃ_４アルキルおよび−ＯＨから選択される」および「Ｒ^２２は、それぞれの出現において個別に、−Ｈ、Ｃ_１−Ｃ_４アルキルから選択される」は、ｎが３である場合は、例えばＲ^１は

The term “R ²¹ is independently selected at each occurrence from —H, C ₁ -C ₄ alkyl and —OH” and “R ²² is independently at each occurrence, —H, “C ₁ -C ₄ alkyl” is selected when “n” is 3, for example R ¹ is

であってよく、ここで、Ｒ^２１のそれぞれの出現およびＲ^２２のそれぞれの出現が前記された可能性の中から選択され、例えば

Where each occurrence of R ²¹ and each occurrence of R ²² is selected from the possibilities described above, eg

などであり得ることを意味することが意図されている。

It is intended to mean that it can be.

Further, when the definition of R ¹ states that R ²² can be a bond to R ²⁴ , for example, when n is 3, R ¹ is

であり得る。同様に、Ｒ^１の定義において、Ｒ^２３はＲ^２４への結合であり得ると記載されている場合には、Ｒ^１は、

It can be. Similarly, if the definition of R ¹ states that R ²³ can be a bond to R ²⁴ , then R ¹ is

であり得る。

It can be.

The following structure is an example of a compound in which R ²⁴ in the compound together with either R ²² or R ²³ forms a 5-7 membered nitrogen-containing heterocycle.

In one embodiment, R ¹ is

から選択され、式中、Ｒ^２は、アミノ（Ｃ_１−Ｃ_６）アルキル、（Ｃ_１−Ｃ_６）アルキルアミノ（Ｃ_１−Ｃ_６）アルキルおよびジ［（Ｃ_１−Ｃ_６）アルキル］アミノ（Ｃ_１−Ｃ_６）アルキルから選択される。

In which R ² is amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl and di [(C ₁ -C ₆ ) alkyl] Selected from amino (C ₁ -C ₆ ) alkyl.

In another embodiment, R ¹ is

である。

It is.

In another embodiment, R ²² is independently selected at each occurrence from —H and C ₁ -C ₄ alkyl, wherein R ²⁴ together with R ²³ is C ₁ -C ₄ alkyl. Forms a 5-7 membered nitrogen-containing heterocycle substituted by

In another embodiment, R ²² is independently selected at each occurrence from —H, and C ₁ -C ₄ alkyl, R ²³ is selected from —H, C ₁ -C ₄ alkyl, and R ²⁴ is it is -H or _C 1 -C ₄ alkyl.

In another embodiment, R ²² is independently selected at each occurrence from H, C ₁ -C ₄ alkyl and a bond to R ²⁴ , R ²³ is selected from H, C ₁ -C ₄ alkyl, R ²⁴ together with one occurrence of R ²² forms a 5-7 membered nitrogen-containing heterocycle optionally substituted with C ₁ -C ₄ alkyl.

In another embodiment, R ² is

から選択され、
式中、
Ｒ^１０、Ｒ^１１およびＲ^１２は、独立に、−Ｈ、ハロゲン、−ＯＣＨ_３、−ＯＣＦ_３、−ＣＦ_３、Ｃ_１−Ｃ_４アルキルおよびフェニルから選択され、
Ｌは、Ｃ_０−Ｃ_１０アルキルである。

Selected from
Where
R ¹⁰ , R ¹¹ and R ¹² are independently selected from —H, halogen, —OCH ₃ , —OCF ₃ , —CF ₃ , C ₁ -C ₄ alkyl and phenyl;
L is C ₀ -C ₁₀ alkyl.

In another embodiment, R ² is

から選択され、
式中、
Ｒ^１０、Ｒ^１１およびＲ^１２は、独立に、−Ｈ、ハロゲン、−ＯＣＨ_３、−ＯＣＦ_３、−ＣＦ_３およびＣ_１−Ｃ_４アルキルから選択され、
Ｒ^１５およびＲ^１６は、独立に、−ＨおよびＣ_１−Ｃ_４アルキルから選択される。

Selected from
Where
R ¹⁰ , R ¹¹ and R ¹² are independently selected from —H, halogen, —OCH ₃ , —OCF ₃ , —CF ₃ and C ₁ -C ₄ alkyl;
R ¹⁵ and R ¹⁶ are independently selected from —H and C ₁ -C ₄ alkyl.

  In a narrower embodiment, the present invention provides:

［式中、
Ｑは、ＮおよびＣＨから選択され、
Ｒ^１は、

[Where:
Q is selected from N and CH;
R ¹ is

から選択され、
（式中、
Ｒ^４は、

Selected from
(Where
R ⁴ is

および−Ｍ−ＮＲ^７Ｒ^８から選択される
（式中、
Ｒ^５、Ｒ^６およびＲ^９は、独立に、−Ｈ、Ｃ_１−Ｃ_４アルキル、−ＯＨ、−ＯＣＨ、ハロゲンおよびアミノアルキルから選択され、
Ｒ^７およびＲ^８は、独立に、−Ｈ、Ｃ_１−Ｃ_４アルキルおよびアミノアルキルから選択され、
Ｌ^１は、−ＯＨで場合によって置換されたＣ_０−Ｃ_１０アルキル、ただし−ＯＨはＮにも結合されている炭素原子には結合されることができないという条件が付き、
Ｍは、−ＯＨで場合によって置換されたＣ_２−Ｃ_１０アルキルであり、ただし−ＯＨはＮにも結合されている炭素原子には結合されることができない。））
Ｒ^２は、

And -M-NR < ⁷ > R < ⁸ > (wherein
R ⁵ , R ⁶ and R ⁹ are independently selected from —H, C ₁ -C ₄ alkyl, —OH, —OCH, halogen and aminoalkyl;
R ⁷ and R ⁸ are independently selected from —H, C ₁ -C ₄ alkyl and aminoalkyl;
L ¹ is C ₀ -C ₁₀ alkyl optionally substituted with —OH, provided that —OH cannot be bonded to a carbon atom that is also bonded to N;
M is a C ₂ -C ₁₀ alkyl optionally substituted with -OH, however -OH can not at a carbon atom that is bonded to N is bonded. ))
R ² is

から選択される
（式中、
Ｒ^１０、Ｒ^１１およびＲ^１２は、独立に、−Ｈ、ハロゲン、−ＯＣＨ_３、−ＯＣＦ_３、−ＣＦ_３、Ｃ_１−Ｃ_４アルキルおよびフェニルから選択され、
Ｌは、Ｃ_０−Ｃ_１０アルキルである。）］式Ｉの化合物またはこの塩に関する。

Selected from (where
R ¹⁰ , R ¹¹ and R ¹² are independently selected from —H, halogen, —OCH ₃ , —OCF ₃ , —CF ₃ , C ₁ -C ₄ alkyl and phenyl;
L is C ₀ -C ₁₀ alkyl. )] Relates to compounds of formula I or salts thereof.

In another embodiment,
R ⁴ is

から選択される
（式中、
Ｒ^５、Ｒ^６およびＲ^９は、独立に、−Ｈ、Ｃ_１−Ｃ_４アルキル、−ＯＨ、−ＯＣＨ_３、ハロゲンおよびアミノアルキルから選択され、
Ｒ^７およびＲ^８は、独立に、−Ｈ、Ｃ_１−Ｃ_４アルキル、およびアミノアルキルから選択され、
Ｒ^１３およびＲ^１４は、独立に、−Ｈ、−ＯＨおよびＣ_１−Ｃ_４アルキルから選択され、ただし−ＯＨはＮにも結合されている炭素原子には結合されることができない。）。

Selected from (where
R ⁵ , R ⁶ and R ⁹ are independently selected from —H, C ₁ -C ₄ alkyl, —OH, —OCH ₃ , halogen and aminoalkyl;
R ⁷ and R ⁸ are independently selected from —H, C ₁ -C ₄ alkyl, and aminoalkyl;
R ¹³ and R ¹⁴ are independently selected from —H, —OH and C ₁ -C ₄ alkyl, provided that —OH cannot be bound to a carbon atom that is also bound to N. ).

In another embodiment,
R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from —H and C ₁ -C ₄ alkyl;
R ⁹ is —R ¹⁷ —NR ⁷ R ⁸ (wherein
R ¹⁷ is C ₁ -C ₄ alkyl. ).

In another embodiment,
R ⁴ is

から選択される
（式中、Ｒ^７およびＲ^８は、独立に、−Ｈおよび−ＣＨ_３から選択され、
Ｒ^１８は、−Ｈおよび−ＯＨから選択される。）。

Wherein R ⁷ and R ⁸ are independently selected from —H and —CH ₃ ,
R ¹⁸ is selected from —H and —OH. ).

In another embodiment,
R ² is

から選択される
（式中、
Ｒ^１０、Ｒ^１１およびＲ^１２は、独立に、−Ｈ、ハロゲン、−ＯＣＨ_３、−ＯＣＦ_３、−ＣＦ_３およびＣ_１−Ｃ_４アルキルから選択され、
Ｒ^１５およびＲ^１６は、独立に、−ＨおよびＣ_１−Ｃ_４アルキルから選択される。）。

Selected from (where
R ¹⁰ , R ¹¹ and R ¹² are independently selected from —H, halogen, —OCH ₃ , —OCF ₃ , —CF ₃ and C ₁ -C ₄ alkyl;
R ¹⁵ and R ¹⁶ are independently selected from —H and C ₁ -C ₄ alkyl. ).

  In yet another embodiment, the present invention provides:

［式中、
Ｑは、ＮおよびＣＨから選択され、
Ｒ^１は、

[Where:
Q is selected from N and CH;
R ¹ is

から選択され、
（式中、
Ｒ^４は、

Selected from
(Where
R ⁴ is

から選択される
（式中、
Ｒ^５、Ｒ^６およびＲ^９は、独立に、−Ｈ、Ｃ_１−Ｃ_４アルキル、−ＯＨ、−ＯＣＨ_３、ハロゲンおよびアミノアルキルから選択され、
Ｒ^７およびＲ^８は、独立に、−Ｈ、Ｃ_１−Ｃ_４アルキルおよびアミノアルキルから選択され、
Ｒ^１３およびＲ^１４は、独立に、−Ｈ、−ＯＨおよびＣ_１−Ｃ_４アルキルから選択され、ただし−ＯＨはＮにも結合されている炭素原子には結合されることができない。））
Ｒ^２は、

Selected from (where
R ⁵ , R ⁶ and R ⁹ are independently selected from —H, C ₁ -C ₄ alkyl, —OH, —OCH ₃ , halogen and aminoalkyl;
R ⁷ and R ⁸ are independently selected from —H, C ₁ -C ₄ alkyl and aminoalkyl;
R ¹³ and R ¹⁴ are independently selected from —H, —OH and C ₁ -C ₄ alkyl, provided that —OH cannot be bound to a carbon atom that is also bound to N. ))
R ² is

から選択される
（式中、
Ｒ^１０、Ｒ^１１およびＲ^１２は、独立に、−Ｈ、ハロゲン、−ＯＣＨ_３、−ＯＣＦ_３、−ＣＦ_３およびＣ_１−Ｃ_４アルキルから選択され、
Ｒ^１５およびＲ^１６は、独立に、−ＨおよびＣ_１−Ｃ_４アルキルから選択される。）］式Ｉの化合物またはこの塩に関する。

Selected from (where
R ¹⁰ , R ¹¹ and R ¹² are independently selected from —H, halogen, —OCH ₃ , —OCF ₃ , —CF ₃ and C ₁ -C ₄ alkyl;
R ¹⁵ and R ¹⁶ are independently selected from —H and C ₁ -C ₄ alkyl. )] Relates to compounds of formula I or salts thereof.

In another embodiment, R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from —H and C ₁ -C ₄ alkyl;
R ⁹ is —R ¹⁷ —NR ⁷ R ⁸ (wherein
R ¹⁷ is C ₁ -C ₄ alkyl. ).

In another embodiment,
R ⁴ is

から選択される
（式中、
Ｒ^７およびＲ^８は、独立に、−Ｈおよび−ＣＨ_３から選択され、
Ｒ^１８は、−Ｈおよび−ＯＨから選択される。）。

Selected from (where
R ⁷ and R ⁸ are independently selected from —H and —CH ₃ ;
R ¹⁸ is selected from —H and —OH. ).

  In another embodiment, Q is N. In yet another embodiment, Q is CH.

  In one embodiment, the invention is directed to a method of treating a T cell mediated disorder comprising administering a therapeutically effective amount of a compound of formula I or a salt thereof. The T cell mediated disease can be, for example, an autoimmune disease or an inflammatory disease. The autoimmune disease can be, for example, rheumatoid arthritis or lupus erythematosus. The inflammatory disease can be, for example, asthma or inflammatory bowel disease.

  In another embodiment, the present invention is directed to a method of treating cancer, such as gastrointestinal cancer, comprising administering a therapeutically effective amount of a compound of formula I or a salt thereof.

  In yet another embodiment, the present invention is directed to a method of treating diabetes comprising administering a therapeutically effective amount of a compound of formula I or a salt thereof.

Definitions Throughout this specification the terms and substituents retain their definitions.

Alkyl and alkene are intended to include linear, branched or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to an alkyl group of 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like. Preferred alkyl groups are those of C ₂₀ or less. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.

(C ₁ -C _n ) hydrocarbons include hydrogen and alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and combinations thereof containing only 1 to n carbons. Examples include vinyl, allyl, cyclopropyl, propargyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Saturated (C ₁ to C _n ) hydrocarbons have the same meaning as (C ₁ to C _n ) alkyl or (C ₁ to C _n ) alkanes used herein. Whenever C _0-n alkyl, (C ₀ to C _n ) alkyl or (C ₀ to C _n ) alkane is mentioned, it is a direct bond when the carbon number is zero.

  Alkoxy or alkoxyl refers to straight chain, branched chain, cyclic structure groups of 1 to 8 carbon atoms and combinations thereof bonded to the parent structure by oxygen. Examples are methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower alkoxy refers to a group containing 1 to 4 carbons.

  Fluoroalkyl refers to an alkyl residue in which one or more hydrogens are replaced by fluorine. This includes perfluoroalkyl in which all hydrogen has been replaced by fluorine. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl and pentafluoroethyl.

  Oxaalkyl refers to an alkyl residue in which one or more carbons (and the hydrogens associated with them) are replaced by oxygen. Examples are methoxypropoxy, 3,6,9-trioxadecyl and the like. The term oxaalkyl means as understood in the art [Naming and Indexing of Chemical Substitutes for Chemical Abstracts, American Chemical Society, ¶ 196, restricted by ¶ 127. No reference], that is, a compound in which oxygen is bonded to an adjacent atom through a single bond (forming an ether bond), and a double bond as found in a carbonyl group. It doesn't mean oxygen. Similarly, thiaalkyl and azaalkyl refer to an alkyl residue in which one or more carbons are replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

  Acyl refers to linear, branched, cyclic, saturated, unsaturated, and aromatic groups of 1 to 8 carbon atoms and combinations thereof connected to the parent structure by a carbonyl function. It is. As long as the point of attachment to the parent remains carbonyl, one or more carbons of the acyl residue may be replaced by nitrogen, oxygen or sulfur. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl refers to a group containing 1 to 4 carbons.

  Aryl and heteroaryl are 5- or 6-membered aromatic or heteroaromatic rings containing 0-3 heteroatoms selected from O, N or S, 0 selected from O, N or S A 9- or 10-membered bicyclic aromatic or heteroaromatic ring system containing 3 heteroatoms, or 0-3 heteroatoms selected from O, N or S By 13 or 14 membered tricyclic aromatic ring system or heteroaromatic ring system is meant. When referring to aryl as a substituent as generally understood, it is meant that the point of attachment is the ring carbon (or ring carbon or heteroaryl heteroatom) of the aryl group. For the purposes of the present invention, aryl and heteroaryl are systems in which at least one ring therein is not necessarily all, but is completely aromatic. Thus, aromatic 6 to 14 membered carbocycles include, for example, benzene, naphthalene, indane, tetralin, benzocycloheptane and fluorene, and 5 to 10 membered aromatic heterocycles include, for example, imidazole, pyridine, indole, isoindoline, Includes thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, tetrahydrocarboline, pyrimidine, pyrazine, tetrazole and pyrazole.

  Arylalkyl means an alkyl residue attached to an aryl ring. As generally understood, when referring to arylalkyl as a substituent, the point of attachment is meant to be an alkyl group. Examples of arylalkyl are benzoyl, phenethyl, phenylpropyl and naphthylethyl. Heteroarylalkyl means an alkyl residue attached to a heteroaryl ring. Examples include, for example, pyridinylmethyl, pyrimidinylethyl and the like.

  Heterocycle means a cycloalkyl or aryl residue in which 1 to 3 carbons are replaced by a heteroatom selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heterocycle includes spiroheterocycle. It should be noted that a heteroaryl is a subset of a heterocycle in which the heterocycle is aromatic. Examples of heterocyclyl residues are also piperazinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolylyl, benzimidazolyl , Tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl.

  Whenever a nitrogen-bonded or nitrogen-containing heterocycle is referred to, such heterocycle contains at least one nitrogen but also contains additional nitrogen atoms and / or other heteroatoms such as O and / or S Can do.

Aminoalkyl means an amino group linked to the core structure via an alkyl group, such as aminoamethyl, aminoethyl, aminopentyl and the like. Since the alkyl groups defined above can be linear or branched, aminoalkyl is, for example, —CH ₂ CH ₂ CH (CH ₃ ) CH ₂ NH ₂ , —CH ₂ C (CH ₃ ) ₂ CH _2. NH _{2 and the} like are included. Alkylaminoalkyl, secondary amine, which is attached to the core structure via an alkyl group, for example _-CH 2 _CH 2 NHCH _3, means such as -CH2CH2CH ₂ NHCH ₂ CH _3. Dialkylaminoalkyl refers to a tertiary amine linked to the core structure via an alkyl group, such as —CH ₂ N (CH ₃ ) ₂ , —CH ₂ CH ₂ CH ₂ N (CH ₃ ) CH ₂ CH _{3, and the} like.

  In substituted alkyl, aryl, cycloalkyl, heterocyclyl, etc., up to 3 H atoms in each residue are lower alkyl, halogen, haloalkyl, hydroxy, hydroxymethyl, lower alkoxy, perfluorolower alkoxy, carboxy, carbo Alkoxy (also called alkoxycarbonyl), carboxamide (also called alkylaminocarbonyl), sulfonamide, aminosulfonyl, alkylaminosulfonyl, cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, ureido, alkylureido, mercapto, alkylthio, Replacement with sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy or heteroaryloxy Its dependent alkyl, aryl, is intended to refer to a cycloalkyl or heterocyclyl.

  The term “halogen” means fluorine, chlorine, bromine or iodine.

  As used herein, “treatment” or “treating” a patient is intended to include prophylactic treatment. The term includes amelioration, prevention, and release from symptoms and / or effects associated with these disorders. The term “preventing” or “prevention” refers to pre-administration of a drug to prevent or blunt the attack. One of ordinary skill in the pharmaceutical arts (covered by the method claims of the present invention) recognizes that the term “prevention” is not an absolute term. In the pharmaceutical arts, this is understood as the prophylactic administration of a drug to reduce the likelihood or severity of a disease state, and this is the intended meaning.

Abbreviations The following abbreviations and terms have the meanings indicated throughout.
Ac = acetyl anh. = Anhydrous BNB = 4-bromomethyl-3-nitrobenzoic acid Boc = t-butyloxycarbonyl Bu = butyl CBZ = carbobenzooxy = benzyloxycarbonyl CDI = carbonyldiimidazole DBU = diazabicyclo [5.4.0] undec- 7-ene DCM = dichloromethane = methylene chloride = CH ₂ Cl ₂
DEAD = diethyl azodicarboxylate DIC = diisopropylcarbodiimide DIEA = N, N-diisopropylethylamine DMAP = 4-N, N-dimethylaminopyridine DMF = N, N-dimethylformamide DMSO = dimethyl sulfoxide DVB = 1,4-divinylbenzene EEDQ = 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline Et = ethyl FCC = flash column chromatography Fmoc = 9-fluorenylmethoxycarbonyl GC = gas chromatography HATU = O- (7-azabenzotriazole -1-yl) -1,1,3,3-
Tetramethyluronium hexafluorophosphate HOAc = acetic acid HOBt = hydroxybenzotriazole Me = methylmesyl = methanesulfonyl MTBE = methyl t-butyl ether NMO = N-methylmorpholine oxide PEG = polyethylene glycol Ph or κ = phenyl PhOH = phenol PfP = penta Fluorophenol PPTS = pyridinium p-toluenesulfonate PyBroP = bromo-tris-pyrrolidinophosphonium hexafluorophosphate rt = room temperature sat'd = saturated TBDMS = t-butyldimethylsilyl TFA = trifluoroacetic acid THF = tetrahydrofuran TIPSO = triisopropylsilanyl Oxy TMOF = Trimethylorthoformate TMS = Tri Methylsilyl tosyl = p-toluenesulfonyl Trt = triphenylmethyl

  While the invention may allow many different forms of embodiments, the preferred embodiments of the invention are shown. However, it should be understood that this disclosure is to be considered as illustrative of the principles of the invention and is not intended to limit the invention to the illustrated embodiments.

  It can be found that some members of the group of substances claimed for examination are not patentable to the inventors of the present application. As a result, the subsequent exclusion of the species from the applicant's claims should be considered a product of the patent procedure and does not reflect the concept or explanation of their invention by the inventor, but the present invention. Encompasses all members of substance group (I) that have not yet become public property.

  In general, the compounds of this invention may be prepared using readily available starting materials, reagents and conventional synthetic procedures, for example, by the methods illustrated in the general reaction schemes below, or by modifications thereof. . In these reactions it is also possible to use variants which are not mentioned here but are known per se.

General Synthesis of Prinones One method for preparing the prinone analogs of the present invention is shown in Scheme 1. Substitution of two chlorines in 2,4-dichloro-5-nitropyrimidine 1 usually occurs in a regioselective manner. Thus, it substituted a more reactive chlorine first 4-position by an amine R'NH ₂ leads to compounds 2. Addition of a second amine R ″ NH ₂ displaces the chlorine at the 2-position. Amine of nitro group in 3 using reagents well known in the art (eg Raney Ni / H ₂ , Fe / EtOH / aqueous AcOH, Na ₂ S ₂ O ₄ / NH ₄ OH / H ₂ O / dioxane) Cyclization using, for example, carbonyldiimidazole, following reduction to affords prinone 5.

The prinone analogs of the present invention can be prepared on a solid support (Scheme 2). For example, an acid cleavable linker can be attached to Argogel-NH ₂ resin. A resin having a linker is first reductively aminated using R′NH ₂ . Pyrimidine 2a, similarly prepared from the first step of Scheme 1, is then coupled to the amine coupled to the resin by a nucleophilic substitution reaction. Ring closure with 4-nitrophenyl chloroformate followed by reduction of the nitro group results in prinone. The product can then be released from the solid support by treatment with an acid such as trifluoroacetic acid.

General Synthesis of 1H-Imidazopyridinones The 1H-imidazopyridinone analogs of the present invention can be prepared by the method shown in Scheme 3. Sequential substitution of 2,6-dichloro-3-nitropyridine 6 with chlorine results in compound 8. Cyclization using, for example, triphosgene followed by reduction of the nitro group with reagents well known in the art provides 1H-imidazopyridinones 10.

The following are exemplary procedures for the preparation of some of the compounds of the present invention.
Synthesis of 9- (2,6-dichlorobenzyl) -2- (3-aminopropylamino) -7H-purin-8 (9H) -one (compound 120) 9- (2,6-dichlorobenzyl) -2- One possible method for (3-aminopropylamino) -7H-purin-8 (9H) -one (compound 120) is shown in Scheme 4 below and is described in detail in the following description.

N- (2,6-dichlorobenzyl) -2-chloro-5-nitropyrimidin-4-amine (11)
In a 500 mL round bottom flask, 2,4-dichloro-5-nitropyrimidine [5.0 g, 25.8 mmol] was charged under an argon atmosphere and dissolved in THF [anhydrous, 30 mL]. The resulting solution was cooled to -78 ° C. 2,6-Dichlorobenzylamine [4.54 g, 25.8 mmol] in THF [anhydrous, 25 mL] and N, N-diisopropylethylamine [9.9 mL, 56.7 mmol] were added dropwise over 20 minutes. The resulting pure white suspension was stirred at −78 ° C. for 50 minutes and then the cooling bath was removed. The mixture was slowly warmed over 30 minutes before the volatiles were removed in vacuo. The crude yellow-orange solid was dissolved in a minimum of MeOH and DCM and loaded onto a slurry of silica gel. Elution with a MeOH gradient in DCM (0-2%) gave the title compound 11 and its regioisomer (N- (2,6-dichlorobenzyl) -4-chloro-5-nitropyrimidin-2-amine) A first fraction [4.116 g] containing a ratio of 3: 7 by HPLC followed by a second fraction [4.38 g] containing only pure 11.

Data on N- (2,6-dichlorobenzyl) -2-chloro-5-nitropyrimidin-4-amine (11): ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.08 (s, 1H), 8 .67 (br s, 1H), 7.38 (d, 2H), 7.26 (t, 1H), 5.13 (d, 2H); MS (ESI) m / z 333.0 / 335.0 [M + H] ⁺ ; λ _max = 224.3 nm, 257.3 nm, 285-340 nm tail.

Data for N- (2,6-dichlorobenzyl) -4-chloro-5-nitropyrimidin-2-amine (positional isomer): [lambda] _max = 219.6 nm, 319.0 nm.
tert-Butyl-3- (4- (2,6-dichlorobenzylamino) -5-nitropyrimidin-2-ylamino) propylcarbamate (12)
A 100 mL round bottom flask was charged with 12 [700 mg, 2.08 mmol] and DMSO [anhydrous, 8 mL] at room temperature under an argon atmosphere. N- (3-aminopropyl) carbamic acid tert-butyl ester [362 mg, 2.08 mmol] in DMSO [anhydrous, 5 mL] and N, N-diisopropylethylamine [543 μL, 3.12 mmol] added dropwise over 3 minutes. did. The mixture was stirred for 1 hour and then volatiles were removed in vacuo. Dissolve the residue in ethyl acetate [30 mL] and wash with saturated aqueous NaCl [5 × 20 mL] to give crude 12 [quantitative yield] that can be followed without further manipulation in a reduction step. Used in.

tert-Butyl-3- (4- (2,6-dichlorobenzylamino) -5-aminopyrimidin-2-ylamino) propylcarbamate (13)
A 250 mL round bottom flask with one two-way cock was charged with 12 [980 mg, 2.08 mmol] and MeOH [25 mL] at room temperature. A suspension of Raney 2800 nickel in water [about 2-3 mL] was added. The flask was evacuated with vigorous stirring and subsequently filled with H ₂ [1 atm, balloon]. After 2.5 hours, H ₂ was removed and the suspension was filtered using fluted filter paper and washed with MeOH. Concentrate the aqueous methanol-containing filtrate to a residue by rotary evaporation and carefully dry in vacuo to give crude 13 [1.38 g, 100% yield +] as a tan foam / oil. Used in subsequent acylation / cyclization step without performing the above operations.

tert-Butyl-3- (9- (2,6-dichlorobenzyl) -8-oxo-8,9-dihydro-7H-purin-2-ylamino) propylcarbamate (14)
A 250 mL round bottom flask was charged with 13 [730 mg corrected, 1.66 mmol corrected] and THF [anhydrous, 18 mL] at room temperature under argon. Solid 1,1-carbonyldiimidazole [806 mg, 4.97 mmol] was added to the tan solution. After 75 minutes, the resulting orange suspension was concentrated in vacuo to a crude orange oil / solid from which 14 [302 mg] was flash chromatographed using a gradient of MeOH [0-7%] in DCM. Isolated by

9- (2,6-dichlorobenzyl) -2- (3-aminopropylamino) -7H-purine-8 (9H) -one (120)
A 250 mL round bottom flask was charged with 14 [207 mg, 443 μmol] and HCl / ethanol [14.5 wt / wt% solution, 10 mL]. The white suspension was stirred at room temperature overnight and then concentrated to near dryness by rotary evaporation. The contents were then coevaporated repeatedly with methanol to give a solid that was not pure white, from which a gradient of methanol [2-20%] in DCM with 0.5-3% aqueous NH ₃ was used. The pure 120 was isolated as the free base [113 mg, 69% yield] by flash chromatography. Pure 120 was obtained as HCl salt [82 mg] by treatment with free base [75 mg] in HCl / ethanol [14.5 wt / wt% solution, 5 mL] for 1 h followed by vacuum concentration.

Data on 9- (2,6-dichlorobenzyl) -2- (3-aminopropylamino) -7H-purin-8 (9H) -one (120): (120): ¹ H NMR (300 MHz, CD ₃ OD ): Δ 7.85 (s, 1H), 7.59-7.52 (m, 2H), 7.45 (dd, 1H), 5.45 (s, 2H), 3.52 (t, 2H) ), 3.04 (Br t, 2H), 1.92 (quintet, 2H); MS (ESI) m / z 367.0 / 369.0 [M + H] ⁺ .
Of (S) -3- (2,6-dichlorobenzyl) -5- (pyrrolidin-3-ylmethylamino) -1H-imidazo [4,5-b] pyridin-2 (3H) -one (compound 147) Synthesis of (R) -3- (2,6-dichlorobenzyl) -5- (pyrrolidin-3-ylmethylamino) -1H-imidazo [4,5-b] pyridin-2 (3H) -one (147) One possible way to do this is shown in Scheme 5 below and is described in detail below.

N- (2,6-dichlorobenzyl) -6-chloro-3-nitropyridin-2-amine (16)
To a mixture of 2,6-dichloro-3-nitropyridine (1.0 g, 5.18 mmol) and potassium carbonate (848 mg, 6.14 mmol) in 15 mL of MeCN was added 2,6-dichlorobenzylamine (0.63 mL, 5. 18 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 10 hours. The organic solvent was evaporated and the residue was purified by silica gel chromatography (EtOAc: Hex = 1: 10) to give 16 [511 mg].

Data for N- (2,6-dichlorobenzyl) -6-chloro-3-nitropyridin-2-amine (16): MS (ESI) m / z 331/333 [M + H] ⁺ .
(S) -tert-butyl 3-((6- (2,6-dichlorobenzylamino) -5-nitropyridin-2-ylamino) methyl) pyrrolidine-1-carboxylate (17)
16 (100 mg, 0.34 mmol), (S) -tert-butyl-3- (aminomethyl) pyrrolidine-1-carboxylate (0.4 g, 2.0 mmol), potassium carbonate (56.4 mg, 0 in 10 mL MeCN). .41 mmol) was stirred at reflux for 2 hours. The solvent was removed by vacuum and the residue was purified by silica gel chromatography (MeOH: DCM = 1: 10) to give 17 [46 mg, 27% yield].

Data on (S) -tert-butyl 3-((6- (2,6-dichlorobenzylamino) -5-nitropyridin-2-ylamino) methyl) pyrrolidine-1-carboxylate (17): MS (ESI) m / z 495/497 [M + H] ⁺ .
(S) -tert-butyl 3-((3- (2,6-dichlorobenzyl) -2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-5-ylamino) methyl) Pyrrolidine-1-carboxylate (18)
Carefully rinse a suspension of Raney® 2800 nickel in water [3 mL] under THF with THF (anhydrous, 8 inhalations-discharge) to remove most of the H ₂ O. did. THF [anhydrous, 5 mL] followed by Intermediate 6 (15 mg, 0.03 mmol) was added to the washed Raney nickel. The flask was filled with H ₂ [1 atm, balloon] and the suspension was stirred vigorously for 4 hours. A solution of triphosgene [3.8 mg] in THF [anhydrous, 2 mL] was then added to the reaction mixture containing the crude aniline. After 1 hour, the solvent was removed under vacuum and the crude residue was loaded onto a laboratory TLC plate (MeOH: DCM = 1: 10) from which pure 18 was isolated [8.9 mg, over 2 steps. Rate 60%].

(S) -tert-butyl 3-((3- (2,6-dichlorobenzyl) -2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-5-ylamino) methyl) Data for pyrrolidine-1-carboxylate (18): MS (ESI) m / z 491/493 [M + H] ⁺ .
(R) -3- (2,6-Dichlorobenzyl) -5- (pyrrolidin-3-ylmethylamino) -1H-imidazo [4,5-b] pyridin-2 (3H) -one (147)
Intermediate 18 [8.9 mg, 18 μmol] was treated with TFA-DCM [1: 1, 3 mL] at room temperature for 2 hours. The solvent was removed under vacuum and the residue was loaded onto a laboratory RP-HPLC column from which pure 147 [6.3 mg, 69% yield] was isolated as a TFA salt.

Data on (R) -3- (2,6-dichlorobenzyl) -5- (pyrrolidin-3-ylmethylamino) -1H-imidazo [4,5-b] pyridin-2 (3H) -one (147) : ¹ H NMR (300 MHz, CD ₃ OD): δ 7.62 (d, 2H), 7.50 (dd, 1H), 7.28 (d, 1H), 6.35 (d, 1H), 5 .53 (s, 2H), 3.35-3.55 (m, 9H), 3.15 (m, 1H), 2.75 (m, 1H), 2.33 (m, 1H), 1. 90 (m, 1 H); MS (ESI) m / z 392.0 / 394.0 [M + H] ⁺ .

Solid Phase Synthesis of Prinone Analogs One possible method of solid phase synthesis of the prinone analogs of the present invention is shown in Scheme 6 below and is described in detail in the following description.

Step 1: Reductive amination with primary amine 19-3.8 g (about 0.8 mmol / g, 3.0 mmol, 1. mmol) o-methoxybenzaldehyde conjugated to resin in 30 mL 1,2-dichloroethane (DCE). 0 eq.) In a 100 mL shaker container, 24 mmol (0.40 M, 1 amine (see Table 1 for 43 amines used in this library) 8.0 eq.) Was added. The resin suspension was shaken for 15 seconds, and 5.1 g (24 mmol, 0.40 M, 8.0 eq.) Of sodium triacetoxyborohydride was added followed by 30 mL of 1,2-dichloroethane. The suspension was shaken at 25 ° C. for 16 hours. The shaker vessel is then emptied and the resin is replaced with CH ₃ OH (1 time), CH ₂ Cl ₂ (2 times), CH ₃ OH (1 time), CH ₂ Cl ₂ (2 times), CH ₃ OH (1 time) ), CH ₃ OH (1 × 30 min) and CH ₂ Cl ₂ (2 ×). Secondary amine 20 bound to the resulting resin gave a positive result in the bromophenol blue staining test. The resin was vacuum dried.

Step 2: N-acylation with 4-amino-2-chloro-5-nitropyrimidine 25 mL DMF and 2.18 mL N, N-diisopropylethylamine (12.5 mmol, 0.25 M, 3 mL) in a 100 mL shaker vessel. Secondary amine 20 bound to the resin in .4 eq.) (About 0.7 mmol / g, 3.7 mmol, 1.0 eq.) To 4-amino-2-chloro-5 in 25 mL DMF. -A solution of 12.5 mmol (0.25 M, 3.4 eq.) Of nitropyrimidine was added. The mixture was shaken at 25 ° C. for 16 hours. Empty shaker and remove resin from DMF (2 times), CH ₂ Cl ₂ (1 time), DMF (1 time), CH ₂ Cl ₂ (2 times), CH ₃ OH (2 times) and CH ₂ Cl ₂ (twice). Nitropyrimidine 21 bound to the resulting resin gave a negative result in the bromophenol blue staining test. The resin was vacuum dried.

Step 3: Reduction of the nitro group To a solution of 5.22 g (30.0 mmol, 0.5 M, 45 eq.) Of sodium hydrosulfite in 40 mL of H ₂ O was added 20 mL of 1,4-dioxane, followed by a saturated aqueous solution of ammonia 1 .86 mL was added. This solution was added to a medium shaker container containing 1.1 g (about 0.6 mmol / g, 0.66 mmol, 1.0 eq.) Of 5-nitropyrimidine 21 bound to the resin. The resin suspension was shaken at 25 ° C. for 2 hours. The shaker vessel was emptied and the resin was washed with H ₂ O: 1,4-dioxane 2: 1 (volume: volume) (once). The shaker vessel was recharged with 40 mL of freshly prepared 0.5 M sodium hydrosulfite solution in 40 mL of H ₂ O and 20 mL of 1,4-dioxane and 0.93 mL of a saturated aqueous solution of ammonia prepared as described above. The resin suspension was shaken at 25 ° C. for 16 hours. Empty the shaker vessel and remove the resin from H ₂ O: 1,4-dioxane 2: 1 (volume: volume) (twice), anhydrous CH ₃ OH (twice), anhydrous DMF (twice), CH ₂ Cl Washed with ₂ (twice) and anhydrous THF (twice). The 5-aminopyrimidine 22 bound to the resulting resin gave a positive result in the bromophenol blue staining test. The resin was vacuum dried.

Step 4: Formation of the prionone ring 1.54 g (approx. 0.6 mmol / g, 0.93 mmol, 1.0 eq.) Of 5-aminopyrimidine 22 bound to the resin in 30 mL of CH ₂ Cl ₂ in a medium shaker vessel. ) And 5.23 mL (30 mmol, 0.5 M, 32.2 eq.) Of N, N-diisopropylethylamine to 60 g (30 mmol, 0.5 M) of p-nitrophenyl chloroformate in 30 mL of CH ₂ Cl ₂ . 32.2 eq.) Solution was added. The resulting resin suspension was shaken at 25 ° C. for 18 hours. The shaker vessel is then emptied and the resin is washed with CH ₂ Cl ₂ (2 times), CH ₃ OH (2 times), CH ₂ Cl ₂ (2 times), CH ₃ OH (2 times), and CH ₂ Cl ₂ ( 2 times). The resulting resin gave a negative result in the bromophenol blue staining test and was used without drying. To this resin was added 60 mL of a solution of 1.68 g (30 mmol, 0.5 M, 32.2 eq.) KOH in 15 mL H ₂ O and 45 mL DMSO. The resulting resin suspension was shaken for 18 hours. The shaker vessel is then emptied and the resin is H ₂ O; DMSO 1: 3 (volume / volume), CH ₃ OH (2 times), DMF (2 times), CH ₃ OH (2 times) and CH ₂ Cl ₂ Washed using (twice). Prinone 23 bonded to the obtained resin was vacuum-dried.

Step 5: Cleavage from resin To Prinone 23 (0.5 g) bound to the resin, 10 mL of a 1: 1 mixture (volume / volume) of CH ₂ Cl ₂ / TFA was added. The mixture was stirred at 25 ° C. for 1 hour. The resin was removed by filtration and the filtrate was evaporated to give 24, which was purified by flash chromatography or semi-experimental HPLC.

PKCθ IMAP Assay The activity of the compounds described in the present invention can be determined by the following procedure. This procedure describes a kinase assay in which phosphorylation of a peptide fluorescently labeled with full-length human recombinant active PKCθ is measured by fluorescence polarization using a commercially available IMAP reagent.

  The PKCθ used was made from a full-length human cDNA (Accession No. LO1087) with the His-6 sequence encoded at the C-terminus. PKCθ was expressed using a baculovirus expression system. The protein was purified using Ni-NTA affinity chromatography to obtain a protein having a purity of 91%.

Substrate for this assay is a fluorescently-labeled peptide having the sequence LHQRRGSIKQAKVHHVK (FITC) -NH _2. The peptide stock solution is 2 mM in water.

  IMAP reagents are obtained from IMAP Assay Bulk Kit, product # R8063 or # R8125 (Molecular Devices, Sunnyvale, Calif.). The kit material includes 5 × IMAP binding buffer and IMAP binding reagent. The binding solution is prepared as a 1: 400 dilution of IMAP binding reagent in 1 × IMAP binding buffer.

The substrate / ATP buffer for this assay consists of 20 mM HEPES, pH 7.4, containing 5 mM MGCl ₂ and 0.01% Tween-20. In addition, this buffer contains 100 nM substrate, 20 μM ATP, and 2 mM DTT that are freshly added just prior to use. The kinase buffer containing PKCθ consists of 20 mM HEPES, pH 7.4 with 0.01% Tween-20. This buffer also contains 2 ng / μL PKCθ and 2 mM DTT, which are freshly added just prior to use.

  The plate used is Corning 3710 (Corning Incorporated, Corning, NY). These are black polystyrene 384 wells with an untreated flat bottom. Sequential dilutions are performed in Nunc V bottom 96 well plates (Cat # 442587, Nunc A / S, Roskilde, Denmark).

  The assay procedure begins with the preparation of a 10 mM stock solution of the compound in 100% DMSO. Stock solutions and control compounds are serially diluted 1: 3.16 in DMSO for a total of 11 times (37 μL of compound in 80 μL of DMSO). After serial dilution is complete, further dilution is performed by taking 4 μL of compound and adding it to 196 μL of substrate / ATP buffer. The 10 μL aliquots of compound are then transferred to Coastar 3710 plates. The kinase reaction is initiated by the addition of 10 μL PKCθ. The reaction is allowed to incubate for 1 hour at ambient temperature. The reaction is then quenched by the addition of 60 μL of binding solution. Incubate the plate at ambient temperature for an additional 30 minutes. The assay is measured using the Acquest ™ Ultra-HTS Assay Detection System (Molecular Devices) in a fluorescence polarization mode using 485 nm excitation and 530 nm emission.

  Table 1 shows some examples of compounds of the present invention. These compounds were synthesized using one of the appropriate procedures described above. The molecular weight of the compound was confirmed by mass spectrometry (m / z). The compounds in Table 1 were tested using the PKCθIMAP assay described above.

All compounds in Table 1 below exhibited PKCθIMAP assay IC ₅₀ values of 10 μM or less. 100 entries in series exhibited _{IC 50} values less than 100 nM, 200 series entries exhibited _{IC 50} values of less than 1 [mu] M, 300 series entry gave the following _{IC 50} values 10 [mu] M.

  Table 2 shows the results of testing the selectivity for inhibition of PKCθ by the compounds of the present invention. The data in Table 2 show the values obtained for PKCθ isoform selectivity by showing Ki Pan Vera (PV) potency against PKCθ, PKCδ and PKCα. For PKCθ Ki Pan Vera (PV), the entry identified by “A” had a value of less than 100 nM and the entry identified by “B” had a value of less than 1 μM. For PKCδ and PKCα Ki Pan Vera (PV), the entry identified by “1” has a value greater than 15 nM, the entry identified by “2” has a value greater than 100 nM, The entry identified with “3” had a value greater than 1 μM, and the entry identified with “4” had a value greater than 10 μM.

  Table 2 also shows the selectivity of the compounds of the present invention by showing their IC50 values for their kinase SGK. An entry identified by “1” has a value greater than 15 nM, an entry identified by “2” has a value greater than 100 nM, and an entry identified by “3” is greater than 1 μM And the entry identified by “4” had a value greater than 10 μM. In Table 2, “nd” means “not measured”.

  The compounds of the present invention were also tested in vivo. Table 3 below shows Goldberg et al. (2003), J. MoI. Med. Chem. FIG. 4 shows the results of anti-CD3 induced interleukin-2 (IL-2) production in mice performed according to the protocol disclosed in Volume 46, pages 1337-1349.

  IL-2 is a T cell-derived lymphokine that regulates the immune system's immune effects on many cells, including cytotoxic T cells, natural killer cells, activated B cells and lymphokine activated cells. This is a powerful T cell mitogen required for T cell proliferation and promotes the progression of these cells from the G1 phase to the S phase of the cell cycle. This is a growth factor for all subpopulations of T lymphocytes, as well as promoting NK cell growth. It also acts as a growth factor for B cells and promotes antibody synthesis.

  Because of this effect on T and B cells, IL-2 is a major central regulator of the immune response. This plays a role in anti-inflammatory responses, tumor monitoring and blood generation. This not only affects the production of other cytokines, including the secretion of IL-1, TNF-α and TNF-β, but also promotes the synthesis of IFN-γ in peripheral leukocytes. Although IL-2 is useful in the immune response, it also causes various problems. IL-2 damages the blood brain barrier and cerebrovascular endothelium. These effects can be the root cause of neuropsychiatric side effects seen under IL-2 therapy, such as fatigue, disorientation and depression. This also alters the electrophysiological behavior of the nerve.

  T cells that are not capable of producing IL-2 become inactive (anergic). This can render them inactive to any antigenic stimulus they receive in the future. As a result, agents that inhibit IL-2 production can be used for immunosuppression or to treat or prevent inflammation and immune disorders. This approach has been clinically validated with immunosuppressive drugs such as cyclosporine, FK506, RS61443.

  The data presented in Tables 1-3 show the utility of the compounds of the invention in inhibiting PKCθ and their autoimmune diseases such as rheumatoid arthritis, lupus erythematosus and multiple sclerosis, asthma and inflammatory bowel disease, etc. Have demonstrated utility for the treatment of T cell mediated diseases including inflammatory diseases, transplant rejection, gastrointestinal cancer and diabetes.

  Some of the compounds described herein contain one or more asymmetric centers and are therefore defined as (R)-or (S)-in enantiomeric, diastereomeric, and other absolute stereochemical terms. The resulting stereoisomer can be obtained. The present invention is meant to include all such possible diastereomers as well as their racemic and optically pure forms. Optically active (R)-and (S) -isomers can be prepared using homo-chiral synthons or homo-chiral reagents, or optically resolved using conventional techniques. Unless the compound described herein contains an olefinic double bond or other geometrically asymmetric center and is otherwise specified, geometrical isomers of (E)-and (Z)- Including both. Similarly, all tautomers are intended to be included.

  The present invention includes a compound of formula (I) in the form of a salt. Suitable salts include those formed using both organic and inorganic salts. Such salts are usually pharmaceutically acceptable, but pharmaceutically unacceptable salts may also be useful in the preparation and purification of the compound in question. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compound of the present invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention are acetate, benzenesulfonate (besylate), benzoate, camphorsulfonate, citrate, ethanesulfonate, fumaric acid Salt, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucolate, nitrate, pamoic acid Salt, pantothenate, phosphate, succinate, sulfate, tartrate, p-toluenesulfonate, and the like. Where the compound contains an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the invention are metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or Organic salts made from lysine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine are included.

  While it may be possible for compounds of formula (I) or their salts and solvates to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, one or more pharmaceutically acceptable carriers and optionally one or more. Pharmaceutical compositions are provided that include other therapeutic ingredients. The carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient thereof.

  The formulations should be suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including cutaneous, buccal, sublingual and intraocular) administration. Including. The most appropriate route may depend on the condition and disorder of the recipient. The formulation can conveniently be provided in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of bringing the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (“active ingredient”) into association with a carrier which constitutes one or more additional ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

  Formulations of the present invention suitable for oral administration include as individual units containing a predetermined amount of each active ingredient, such as capsules, cachets or tablets, in aqueous or non-aqueous liquids, as powders or granules. Or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be provided as a bolus, electuary or paste.

  A tablet may be made by compression or molding, optionally with one or more additional ingredients. Compressed tablets are compressed in a suitable machine by optionally mixing the active ingredients in free-flow form, such as powders or granules, with a binder, lubricant, inert diluent, lubricant, surfactant or dispersant. Can be prepared. Molded tablets may be made by moistening a mixture of the powdered compound with an inert liquid diluent and molding in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.

  Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions, which are antioxidants, buffers, bacteriostats and solutes that make the formulation isotonic with the blood of the intended recipient. May be contained. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending and thickening agents. Formulations can be provided in unit-dose containers or multi-dose containers, such as sealed ampoules and vials, and are placed in a sterile liquid carrier such as saline, phosphate buffered saline (PBS) just prior to use. ) And the like that need only be added, etc., can be stored in a freeze-dried (lyophilized) state. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

  Formulations for rectal administration may be presented as a suppository with common carriers such as cocoa butter or polyethylene glycol.

  Formulations for topical administration in the mouth, such as the oral cavity or sublingual, include lozenges containing sucrose and active ingredients in a flavored base such as acacia or tragacanth, and bases such as seratin and glycerin or sucrose and acacia Contains candy containing active ingredients in it.

  Preferred unit dosage formulations are those containing an effective dosage of the active ingredient or an appropriate divided amount thereof.

  A pharmaceutical composition usually comprises a “pharmaceutically acceptable inert carrier”, the expression of which includes one or more of starch, polyol, granulating agent, microcrystalline cellulose, diluent, lubricant, binder, disintegrant, etc. It shall contain a plurality of inert excipients. If desired, tablet dosages of the disclosed compositions can be coated by standard aqueous or non-aqueous techniques. “Pharmaceutically acceptable carrier” also encompasses controlled release means. The compositions of the present invention may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweeteners, colorants, flavors, desiccants, plasticizers, pigments and the like.

  The compound of formula (I) is preferably administered orally or by injection (intravenous or subcutaneous). The exact amount of the compound administered to the patient is the responsibility of the attending physician. However, the dosage used will depend on a number of factors including the age and sex of the patient, the precise disorder being treated and this severity. Also, the route of administration can vary depending on the symptoms and the severity.

  The contents of each reference cited herein are hereby incorporated by reference in their entirety, including the contents of the references cited within the primary reference.

Claims (33)

[Where:
Q is selected from N and CH;
R ¹ is a nitrogen-bonded heterocyclyl, substituted nitrogen-bonded heterocyclyl and

(Where
n is an integer from 2 to 6,
R ²¹ is independently selected at each occurrence from —H, C ₁ -C ₄ alkyl and —OH;
R ²² is independently selected at each occurrence from —H, C ₁ -C ₄ alkyl and a bond to R ²⁴ ;
R ²³ is selected from —H, C ₁ -C ₄ alkyl and a bond to R ²⁴ ;
R ²⁴ is selected from —H, C ₁ -C ₄ alkyl, or, together with either R ²² or R ²³ , a 5-7 membered nitrogen-containing optionally substituted with C ₁ -C ₄ alkyl Heterocycle is formed. )
Selected from
R ² is selected from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl. ]
A compound represented by formula I or a salt thereof. R ¹ is

Wherein R ⁹ is amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl and di [(C ₁ -C ₆ ) alkyl Selected from amino (C ₁ -C ₆ ) alkyl.
The compound according to claim 1 or a salt thereof. R ¹ is

Is,
The compound according to claim 1 or a salt thereof. R ²² is independently selected at each occurrence from —H and C ₁ -C ₄ alkyl;
R ²⁴ together with R ²³ forms a 5-7 membered nitrogen-containing heterocycle optionally substituted with C ₁ -C ₄ alkyl.
The compound according to claim 3 or a salt thereof. R ²² is independently selected at each occurrence from —H and C ₁ -C ₄ alkyl;
R ²³ is selected from —H, C ₁ -C ₄ alkyl;
R ²⁴ is H or C ₁ -C ₄ alkyl,
The compound according to claim 3 or a salt thereof. R ²² is independently selected at each occurrence from —H, C ₁ -C ₄ alkyl and a bond to R ²⁴ ;
R ²³ is selected from H, C ₁ -C ₄ alkyl;
R ²⁴ together with one occurrence of R ²² forms a 5-7 membered nitrogen-containing heterocycle optionally substituted with C ₁ -C ₄ alkyl.
The compound according to claim 3 or a salt thereof. R ² is

Wherein R ¹⁰ , R ¹¹ and R ¹² are independently selected from —H, halogen, —OCH ₃ , —OCF ₃ , —CF ₃ , C ₁ -C ₄ alkyl and phenyl;
L is C ₀ -C ₁₀ alkyl. ),
The compound according to claim 1 or a salt thereof. R ² is

Wherein R ¹⁰ , R ¹¹ and R ¹² are independently selected from —H, halogen, —OCH ₃ , —OCF ₃ , —CF ₃ and C ₁ -C ₄ alkyl;
R ¹⁵ and R ¹⁶ are independently selected from —H and C ₁ -C ₄ alkyl. ),
The compound according to claim 7 or a salt thereof.   A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier.

[Where:
Q is selected from N and CH;
R ¹ is

Selected from
(Where
R ⁴ is

And -M-NR < ⁷ > R < ⁸ > (wherein
R ⁵ , R ⁶ and R ⁹ are independently selected from —H, C ₁ -C ₄ alkyl, —OH, —OCH ₃ , halogen and aminoalkyl;
R ⁷ and R ⁸ are independently selected from —H, C ₁ -C ₄ alkyl and aminoalkyl;
L ¹ is C ₀ -C ₁₀ alkyl optionally substituted with —OH, provided that —OH cannot be bonded to a carbon atom that is also bonded to N;
M is a C ₂ -C ₁₀ alkyl which is optionally substituted with -OH, however -OH can not be bonded at a carbon atom which is also bound to N. )),
R ² is

Selected from (where
R ¹⁰ , R ¹¹ and R ¹² are each independently —H, halogen, —OCH ₃ , —OCF ₃ , —CF ₃ ,
Is selected from C ₁ -C ₄ alkyl and phenyl,
L is C ₀ -C ₁₀ alkyl. )],
A compound represented by formula I or a salt thereof. R ⁴ is

Selected from (where
R ⁵ , R ⁶ and R ⁹ are independently selected from —H, C ₁ -C ₄ alkyl, —OH, —OCH ₃ , halogen and aminoalkyl;
R ⁷ and R ⁸ are independently selected from —H, C ₁ -C ₄ alkyl and aminoalkyl;
R ¹³ and R ¹⁴ are independently selected from —H, —OH and C ₁ -C ₄ alkyl, provided that —OH cannot be bound to a carbon atom that is also bound to N. ),
The compound according to claim 10 or a salt thereof. R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from —H and C ₁ -C ₄ alkyl;
R ⁹ is —R ¹⁷ —NR ⁷ R ⁸ (wherein
R ¹⁷ is C ₁ -C ₄ alkyl. ),
The compound according to claim 11 or a salt thereof. R ⁴ is

Selected from (where
R ⁷ and R ⁸ are independently selected from —H and —CH ₃ ;
R ¹⁸ is selected from —H and —OH. ),
The compound or its salt of Claim 12. R ² is

Selected from (where
R ¹⁰ , R ¹¹ and R ¹² are independently selected from —H, halogen, —OCH ₃ , —OCF ₃ , —CF ₃ and C ₁ -C ₄ alkyl;
R ¹⁵ and R ¹⁶ are independently selected from —H and C ₁ -C ₄ alkyl. ),
The compound according to claim 10 or a salt thereof.   A pharmaceutical composition comprising the compound according to claim 10 or a salt thereof and a pharmaceutically acceptable carrier.

[Where:
Q is selected from N and CH;
R ¹ is

Selected from
(Where
R ⁴ is

Selected from
(Where
R ⁵ , R ⁶ and R ⁹ are independently selected from —H, C ₁ -C ₄ alkyl, —OH, —OCH ₃ , halogen and aminoalkyl;
R ⁷ and R ⁸ are independently selected from —H, C ₁ -C ₄ alkyl and aminoalkyl;
R ¹³ and R ¹⁴ are independently selected from —H, —OH and C ₁ -C ₄ alkyl, provided that —OH cannot be bound to a carbon atom that is also bound to N. )),
R ² is

Selected from (where
R ¹⁰ , R ¹¹ and R ¹² are independently selected from —H, halogen, —OCH ₃ , —OCF ₃ , —CF ₃ and C ₁ -C ₄ alkyl;
R ¹⁵ and R ¹⁶ are independently selected from —H and C ₁ -C ₄ alkyl. ]]
A compound represented by formula I or a salt thereof. R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from —H and C ₁ -C ₄ alkyl;
R ⁹ is —R ¹⁷ —NR ⁷ R ⁸ (wherein
R ¹⁷ is C ₁ -C ₄ alkyl. ),
The compound according to claim 16 or a salt thereof. R ⁴ is

Selected from (where
R ⁷ and R ⁸ are independently selected from —H and —CH ₃ ;
R ¹⁸ is selected from —H and —OH. ),
The compound or its salt of Claim 17.   18. A compound according to claim 17 or a salt thereof, wherein Q is N.   18. A compound according to claim 17 or a salt thereof, wherein Q is CH.   A pharmaceutical composition comprising the compound according to claim 16 or a salt thereof and a pharmaceutically acceptable carrier.   17. A T cell mediated comprising administering a therapeutically effective amount of a compound according to any of claims 1, 10 and 16 or a salt thereof to a patient suffering from a T cell mediated disease. How to treat the disease.   23. The method of claim 22, wherein the T cell mediated disease is an autoimmune disease.   24. The method of claim 23, wherein the autoimmune disease is rheumatoid arthritis.   24. The method of claim 23, wherein the autoimmune disease is lupus erythematosus.   24. The method of claim 23, wherein the autoimmune disease is multiple sclerosis.   23. The method of claim 22, wherein the T cell mediated disease is an inflammatory disease.   28. The method of claim 27, wherein the inflammatory disease is asthma.   28. The method of claim 27, wherein the inflammatory disease is inflammatory bowel disease.   23. The method of claim 22, wherein the T cell mediated disease is transplant rejection.   A method of treating cancer comprising administering to a patient suffering from cancer a therapeutically effective amount of a compound according to any of claims 1, 10 and 16 or a salt thereof.   32. The method of claim 31, wherein the cancer is gastrointestinal cancer.   17. A method for treating diabetes comprising administering to a patient suffering from diabetes a therapeutically effective amount of a compound according to any of claims 1, 10 and 16 or a salt thereof.