JP2010500999A - Imidazoleamine as an inhibitor of beta-secretase - Google Patents

Abstract

の化合物、および患者におけるβ−アミロイド沈着またはβ−アミロイドレベルの上昇によって特徴付けられる疾患または障害の治療、予防または改善のためのその使用を提供する。The present invention relates to a compound of formula (I)

And its use for the treatment, prevention or amelioration of a disease or disorder characterized by elevated β-amyloid deposition or β-amyloid levels in a patient.

Description

BACKGROUND OF THE INVENTION Alzheimer's disease (AD), a progressive degenerative disease of the brain primarily related to aging, is a serious health care problem. Clinically, AD is characterized by memory, recognition, reasoning, judgment and loss of orientation. Also, as the disease progresses, motor, sensory and language skills are also affected, leading to widespread impairment of multiple cognitive functions. These loss of cognition occurs gradually, but typically leads to serious disability and eventually death in 4-12 years. AD patients exhibit characteristic β-amyloid deposition in the brain and cerebral blood vessels (β-amyloid angiopathy), as well as neurofibrillary tangles. Amyloidogenic plaques and vascular amyloid angiopathy are also characteristic of the brain of patients with trisomy 21 (Down syndrome), hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D), and other neurodegenerative disorders . Neurofibrillary tangles also occur in other dementia-induced disorders.

  A family of proteins known as β-amyloid is thought to be responsible for the pathology and subsequent cognitive decline in Alzheimer's disease. Proteolytic processing of amyloid precursor protein (APP) yields amyloid β (A-beta) peptide, in particular A-beta is N-terminal by β-secretase and C-terminal by one or more γ-secretases. Caused by cleavage of APP at Aspartyl protease enzyme, or β-secretase enzyme (BACE) activity correlates directly with the production of A-beta peptides from APP (Sinha et al., Nature, 1999, 402, 537-540). Research increasingly shows that inhibition of the β-secretase enzyme inhibits the production of A-beta peptides. Inhibition of β-secretase, and the resulting decrease in A-beta peptide, leads to a decrease in β-amyloid deposition in the brain and β-amyloid levels in the cerebral blood vessels, and an effective disease or disorder caused thereby. Can guide treatment.

Sinha et al., Nature, 1999, 402, 537-540.

Accordingly, an object of the present invention is an inhibitor of β-secretase and is useful as a therapeutic agent in the treatment, prevention or amelioration of a disease or disorder characterized by elevated β-amyloid deposition or β-amyloid levels in a patient It is to provide a compound.
Another object of the present invention is to provide therapeutic methods and pharmaceutical compositions useful for the treatment, prevention or amelioration of diseases or disorders characterized by elevated β-amyloid deposits or β-amyloid levels in patients.
A feature of the present invention is that the provided compounds can also be useful for studying and elucidating β-secretase enzymes.
These and other objects and features of the invention will become more apparent from the detailed description set forth below.

［式中、
Ｑは、Ｏ、ＳまたはＣＨ_２であり；
Ｗは、Ｏ、ＳまたはＣＨ_２であり；
Ｘは、Ｎ、ＮＯ、ＳＯ_ｍ、ＯまたはＣＨであり；
Ｙは、Ｎ、ＮＯ、ＳＯ_ｍ、ＯまたはＣＲ_１０であり；
Ｚは、Ｎ、ＮＯ、ＳＯ_ｍ、ＯまたはＣＲ_１１であり、但し、ＸがＣＨであり、ＹがＣＲ_１０であって、ＺがＣＲ_１１である場合、ＱおよびＷのうち１つはＯまたはＳであり；
ｍは、０、１または２であり；
ｎは、０または１であり；
Ｒ_１およびＲ_２は、各々、独立して、Ｈまたは置換されていてもよいＣ_１−Ｃ_４アルキル基であり；
Ｒ_３およびＲ_４は、各々、独立して、Ｈ、または置換されていてもよいＣ_１−Ｃ_４アルキル基であるか、またはＲ_３およびＲ_４は一緒になって、Ｏ、ＮおよびＳから選択される１または２個のヘテロ原子を含有していてもよい４−ないし７−員環を形成してもよく；
Ｒ_５およびＲ_６は、各々、独立して、Ｈ、ハロゲン、ＮＯ_２、ＣＮ、ＯＲ_１２、ＣＯ_２Ｒ_１３、ＣＯＲ_１４、ＮＲ_１７Ｒ_１８、ＳＯ_ｐＮＲ_１９Ｒ_２０、または各々、置換されていてもよいＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニルまたはＣ_３−Ｃ_８シクロアルキル基であり；
Ｒ_７およびＲ_８は、各々、独立して、Ｈ、ハロゲン、ＮＯ_２、ＣＮ、ＯＲ_１５、ＮＲ_１７Ｒ_１８、または、各々、置換されていてもよいＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_３−Ｃ_８シクロアルキルまたはシクロヘテロアルキル基であるか、または隣接する炭素原子に結合する場合、Ｒ_７およびＲ_８はそれらが結合する原子と一緒になって、Ｏ、ＮおよびＳから選択される１または２個のヘテロ原子を含有していてもよい置換されていてもよい５−ないし７−員環を形成していてもよく；
Ｒ_９は、Ｈ、ハロゲン、ＮＯ_２、ＣＮ、ＯＲ_１５、ＮＲ_１７Ｒ_１８、または各々、置換されていてもよいＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_３−Ｃ_８シクロアルキル、シクロヘテロアルキル、アリールまたはヘテロアリール基であり；
Ｒ_１０およびＲ_１１は、各々、独立して、Ｈ、または各々、置換されていてもよいＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_３−Ｃ_８シクロアルキル、シクロヘテロアルキルまたはアリール基であり；
Ｒ_１２、Ｒ_１３、Ｒ_１４およびＲ_１５は、各々、独立して、Ｈ、または各々、置換されていてもよいＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_３−Ｃ_８シクロアルキル、シクロヘテロアルキル、アリールまたはヘテロアリール基であり；
Ｒ_１７、Ｒ_１８、Ｒ_１９およびＲ_２０は、各々、独立して、Ｈ、Ｃ_１−Ｃ_４アルキル、Ｃ_３−Ｃ_８シクロアルキルであるか、またはＲ_１７およびＲ_１８もしくはＲ_１９およびＲ_２０は、それらが結合している原子と一緒になって、Ｏ、ＮおよびＳから選択される付加的なヘテロ原子を含有していてもよい５−ないし７−員環を形成していてもよく；
ｐは、０、１または２である］
で示されるイミダゾールアミン、またはその互変体、その立体異性体もしくはその医薬上許容される塩を提供する。 SUMMARY OF THE INVENTION The present invention provides compounds of formula I

[Where:
Q is O, S or CH ₂ ;
W is O, S or CH ₂ ;
X is N, NO, SO _m , O or CH;
Y is N, NO, SO _m , O or CR ₁₀ ;
Z is N, NO, SO _m , O or CR ₁₁ , provided that when X is CH, Y is CR ₁₀ and Z is CR ₁₁ , one of Q and W is O Or S;
m is 0, 1 or 2;
n is 0 or 1;
R ₁ and R ₂ are each independently H or an optionally substituted C ₁ -C ₄ alkyl group;
R ₃ and R ₄ are each independently H, or an optionally substituted C ₁ -C ₄ alkyl group, or R ₃ and R ₄ together are O, N and S May form a 4- to 7-membered ring which may contain 1 or 2 heteroatoms selected from:
R ₅ and R ₆ are each independently H, halogen, NO ₂ , CN, OR ₁₂ , CO ₂ R ₁₃ , COR ₁₄ , NR ₁₇ R ₁₈ , SO _p NR ₁₉ R ₂₀ , or each is substituted unprotected _C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl or _C 3 -C ₈ cycloalkyl group;
R ₇ and R ₈ are each independently H, halogen, NO ₂ , CN, OR ₁₅ , NR ₁₇ R ₁₈ , or each optionally substituted C ₁ -C ₆ alkyl, C _1- When it is a C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or cycloheteroalkyl group or attached to an adjacent carbon atom, R ₇ and R ₈ are Together with the atoms to which they are attached, they form an optionally substituted 5- to 7-membered ring which may contain 1 or 2 heteroatoms selected from O, N and S. May be;
R ₉ is H, halogen, NO ₂ , CN, OR ₁₅ , NR ₁₇ R ₁₈ , or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl. C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R ₁₀ and R ₁₁ are each independently H, or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C _{6. alkynyl,} C 3 -C ₈ cycloalkyl, cycloalkyl heteroalkyl or aryl group;
R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are each independently H, or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl. C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ are each independently H, C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, or R ₁₇ and R ₁₈ or R ₁₉ and R ₂₀ together with the atoms to which they are attached may form a 5- to 7-membered ring which may contain additional heteroatoms selected from O, N and S Often;
p is 0, 1 or 2]
Or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof.

  The present invention also provides a therapeutic method for the treatment, prevention or amelioration of a disease or disorder characterized by increased β-amyloid deposition or increased β-amyloid levels in a patient and the treatment, prevention or amelioration of the disease or disorder. Useful pharmaceutical compositions are provided.

Detailed Description of the Invention Alzheimer's disease (AD) is clinically manifested by progressive loss of memory, cognitive power, reasoning power, judgment and emotional stability, and gradually leads to severe mental deterioration and death. It is a major degenerative disease. Although the exact cause of AD is not known, there is increasing evidence that amyloid beta peptide (A-beta) plays a central role in the pathogenesis of the disease (DB Schenk; RE Rydel et al., Journal of Medicinal Chemistry, 1995, 21, 4141 and DJ Selkoe, Physiology Review, 2001, 81, 741). AD patients exhibit characteristic neuropathological markers such as senile plaques (and, in β-amyloid angiopathy, deposition in the cerebral blood vessels) and neurofibrillary tangles detected in the brain at necropsy. A-beta is a major component of senile plaques in AD brain. Furthermore, β-amyloid deposition and ductal β-amyloid angiopathy are also characteristic of individuals with Down syndrome, hereditary cerebral hemorrhage with Dutch amyloidosis, and other neurodegenerative and dementia-induced disorders. Overexpression of amyloid precursor protein (APP), altered cleavage of APP to A-beta or reduction of clearance of A-beta from the patient's brain is indicative of the level of soluble or fibrous form of A-beta in the brain Can rise. The β-site APP cleavage enzyme BACE1, also called memapsin-2 or Asp-2, was identified in 1999 (R. Vassar, BD Bennett et al., Nature, 1999, 402, 537). BACE1 is a membrane-bound aspartic protease with all the known functional properties and characteristics of β-secretase. In parallel with BACE1, it has been found that a second homologous aspartyl protease called BACE2 has β-secretase activity in vitro. Low molecular weight non-peptide non-substrate related inhibitors of BACE1 or β-secretase have been seriously investigated both as an aid in the study of β-secretase enzymes and as potential therapeutic agents.

［式中、
Ｑは、Ｏ、ＳまたはＣＨ_２であり；
Ｗは、Ｏ、ＳまたはＣＨ_２であり；
Ｘは、Ｎ、ＮＯ、ＳＯ_ｍ、ＯまたはＣＨであり；
Ｙは、Ｎ、ＮＯ、ＳＯ_ｍ、ＯまたはＣＲ_１０であり；
Ｚは、Ｎ、ＮＯ、ＳＯ_ｍ、ＯまたはＣＲ_１１であり、但し、ＸがＣＨであり、ＹがＣＲ_１０であって、ＺがＣＲ_１１である場合、ＱおよびＷのうち１つはＯまたはＳであり；
ｍは、０、１または２であり；
ｎは、０または１であり；
Ｒ_１およびＲ_２は、各々、独立して、Ｈまたは置換されていてもよいＣ_１−Ｃ_４アルキル基であり；
Ｒ_３およびＲ_４は、各々、独立して、Ｈ、または置換されていてもよいＣ_１−Ｃ_４アルキル基であるか、またはＲ_３およびＲ_４は一緒になって、Ｏ、ＮおよびＳから選択される１または２個のヘテロ原子を含有していてもよい４−ないし７−員環を形成してもよく；
Ｒ_５およびＲ_６は、各々、独立して、Ｈ、ハロゲン、ＮＯ_２、ＣＮ、ＯＲ_１２、ＣＯ_２Ｒ_１３、ＣＯＲ_１４、ＮＲ_１７Ｒ_１８、ＳＯ_ｐＮＲ_１９Ｒ_２０、または各々、置換されていてもよいＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニルまたはＣ_３−Ｃ_８シクロアルキル基であり；
Ｒ_７およびＲ_８は、各々、独立して、Ｈ、ハロゲン、ＮＯ_２、ＣＮ、ＯＲ_１５、ＮＲ_１７Ｒ_１８、または、各々、置換されていてもよいＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_３−Ｃ_８シクロアルキルまたはシクロヘテロアルキル基であるか、または隣接する炭素原子に結合する場合、Ｒ_７およびＲ_８はそれらが結合する原子と一緒になって、Ｏ、ＮおよびＳから選択される１または２個のヘテロ原子を含有していてもよい置換されていてもよい５−ないし７−員環を形成していてもよく；
Ｒ_９は、Ｈ、ハロゲン、ＮＯ_２、ＣＮ、ＯＲ_１５、ＮＲ_１７Ｒ_１８、または各々、置換されていてもよいＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_３−Ｃ_８シクロアルキル、シクロヘテロアルキル、アリールまたはヘテロアリール基であり；
Ｒ_１０およびＲ_１１は、各々、独立して、Ｈ、または各々、置換されていてもよいＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_３−Ｃ_８シクロアルキル、シクロヘテロアルキルまたはアリール基であり；
Ｒ_１２、Ｒ_１３、Ｒ_１４およびＲ_１５は、各々、独立して、Ｈ、または各々、置換されていてもよいＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_３−Ｃ_８シクロアルキル、シクロヘテロアルキル、アリールまたはヘテロアリール基であり；
Ｒ_１７、Ｒ_１８、Ｒ_１９およびＲ_２０は、各々、独立して、Ｈ、Ｃ_１−Ｃ_４アルキル、Ｃ_３−Ｃ_８シクロアルキルであるか、またはＲ_１７およびＲ_１８もしくはＲ_１９およびＲ_２０は、それらが結合している原子と一緒になって、Ｏ、ＮおよびＳから選択される付加的なヘテロ原子を含有していてもよい５−ないし７−員環を形成していてもよく；
ｐは、０、１または２である］
で示されるイミダゾールアミン化合物、またはその互変体、その立体異性体もしくはその医薬上許容される塩を提供する。 Surprisingly, it has now been found that imidazoleamine compounds of formula I exhibit β-secretase inhibition and selective inhibition of BACE1. Advantageously, the imidazolamine compound can be used as an effective therapeutic agent for the treatment, prevention or amelioration of a disease or disorder characterized by elevated β-amyloid deposits or β-amyloid levels in a patient. Accordingly, the present invention provides compounds of formula I:

[Where:
Q is O, S or CH ₂ ;
W is O, S or CH ₂ ;
X is N, NO, SO _m , O or CH;
Y is N, NO, SO _m , O or CR ₁₀ ;
Z is N, NO, SO _m , O or CR ₁₁ , provided that when X is CH, Y is CR ₁₀ and Z is CR ₁₁ , one of Q and W is O Or S;
m is 0, 1 or 2;
n is 0 or 1;
R ₁ and R ₂ are each independently H or an optionally substituted C ₁ -C ₄ alkyl group;
R ₃ and R ₄ are each independently H, or an optionally substituted C ₁ -C ₄ alkyl group, or R ₃ and R ₄ together are O, N and S May form a 4- to 7-membered ring which may contain 1 or 2 heteroatoms selected from:
R ₅ and R ₆ are each independently H, halogen, NO ₂ , CN, OR ₁₂ , CO ₂ R ₁₃ , COR ₁₄ , NR ₁₇ R ₁₈ , SO _p NR ₁₉ R ₂₀ , or each is substituted unprotected _C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl or _C 3 -C ₈ cycloalkyl group;
R ₇ and R ₈ are each independently H, halogen, NO ₂ , CN, OR ₁₅ , NR ₁₇ R ₁₈ , or each optionally substituted C ₁ -C ₆ alkyl, C _1- When it is a C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or cycloheteroalkyl group or attached to an adjacent carbon atom, R ₇ and R ₈ are Together with the atoms to which they are attached, they form an optionally substituted 5- to 7-membered ring which may contain 1 or 2 heteroatoms selected from O, N and S. May be;
R ₉ is H, halogen, NO ₂ , CN, OR ₁₅ , NR ₁₇ R ₁₈ , or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl. C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R ₁₀ and R ₁₁ are each independently H, or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C _{6. alkynyl,} C 3 -C ₈ cycloalkyl, cycloalkyl heteroalkyl or aryl group;
R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are each independently H, or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl. C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ are each independently H, C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, or R ₁₇ and R ₁₈ or R ₁₉ and R ₂₀ together with the atoms to which they are attached may form a 5- to 7-membered ring which may contain additional heteroatoms selected from O, N and S Often;
p is 0, 1 or 2]
Or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof.

［式中、Ｘ_１はＮＲ、ＯまたはＳであり、ＲはＨであるか、下記のような任意の置換基である］
を包含する。 As used herein and in the claims, the term halogen denotes F, Cl, Br or I and the term cycloheteroalkyl is the same or different selected from N, O and S. 5 represents a 5- to 7-membered cycloalkyl ring system containing one or two heteroatoms which may optionally contain one double bond. As used herein, examples of cycloheteroalkyl ring systems include the following rings:

[Wherein X ₁ is NR, O or S, and R is H or an optional substituent as described below]
Is included.

Similarly, as used herein and in the claims, the term heteroaryl refers to 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, O and S. Indicates 5- to 10-membered aromatic ring system contained. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolyl, benzothienyl, benzofuranyl, benzoisoxazolyl, and the like. The term aryl denotes, for example, an aromatic carbocyclic ring system consisting of 6 to 14 carbon atoms, such as phenyl, naphthyl, anthracenyl and the like. The term aryl (C ₁ -C ₄ ) alkyl refers to an aryl group as described above attached to a C ₁ -C ₄ alkyl group which may be straight or branched. The aryl (C ₁ -C ₄ ) alkyl group includes benzyl, phenethyl, naphthylmethyl and the like. The term haloalkyl, as used herein, refers to a C _n H _{2n + 1} group having 1 to 2n + 1 halogen atoms, which may be the same or different, and the term haloalkoxy is used herein. When used, represents an OC _n H _{2n + 1} group having 1 to 2n + 1 halogen atoms, which may be the same or different. Preferably, the term haloalkyl refers to CF ₃ and the term haloalkoxy refers to OCF ₃ .

As used herein and in the claims, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, cycloheteroalkyl, aryl, Where a term such as aryl (C ₁ -C ₄ ) alkyl or heteroaryl is indicated as optionally substituted, the substituents that may be present are considered for the development of a pharmaceutical compound, or for that compound Any one or more substituents conventionally used in modifications that affect structure / activity, persistence, absorbency, stability or other beneficial properties may be used. Specific examples of such substituents are halogen atoms, nitro, cyano, thiocyanate, cyanate, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, Includes alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamide, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl (eg, heteroaryl, cycloheteroalkyl), and cycloalkyl groups, preferably halogen atoms or lower alkyl or lower Including an alkoxy group (here, lower means 1 to 6 carbon atoms). Typically 0 to 3 substituents may be present. Where any of the above substituents represent or contain an alkyl substituent, this may be straight or branched, up to 12, preferably up to 6, more preferably 4 May contain up to carbon atoms.

  Pharmaceutically acceptable salts include compounds of formula I and pharmaceutically acceptable acids such as phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid. It may be any acid addition salt formed by acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and the like.

  The compounds of the present invention include esters, carbamates or other conventional prodrug forms, which are generally functional derivatives of the compounds of the present invention and are readily converted in vivo to the active forms of the present invention. The Correspondingly, the methods of the present invention encompass the treatment of the various pathologies described above using compounds of formula I or compounds not specifically disclosed, but which upon administration convert to compounds of formula I in vivo. Also encompassed are metabolites of the compounds of the invention which are defined as active species produced upon introduction of the compounds of the invention into a biological system.

The compounds of the invention may exist as one or more tautomers. One skilled in the art will appreciate that compounds of Formula I may also exist as the following tautomers (It).

  Tautomers can often be present in equivalent amounts to one another. Since these tautomers interconvert under environmental and physiological conditions, they provide the same useful biological effects. The present invention includes mixtures of such tautomers as well as individual tautomers of Formula I and Formula It.

  The compounds of the present invention may contain one or more asymmetric carbon atoms or one or more asymmetric (chiral) centers and can thus give rise to optical isomers and diastereomers. Thus, the present invention includes such optical isomers and diastereomers, as well as racemic and resolved enantiomerically pure stereoisomers, and other mixtures of R and S stereoisomers. As one skilled in the art will appreciate, one stereoisomer may be more active, or if one stereoisomer is abundant compared to other stereoisomers, or other stereoisomers When separated from the body, it may show beneficial effects. Furthermore, methods for separation or selective preparation of abundant stereoisomers are known to those skilled in the art. Accordingly, the present invention includes compounds of formula I, stereoisomers thereof, tautomers thereof and pharmaceutically acceptable salts thereof. The compounds of the invention may exist as mixtures of stereoisomers, individual stereoisomers, or optically active or enantiomerically pure forms.

In the absence of R ₁₁ , the point of attachment may be through Z in order to meet valence requirements.

  When n is 0, an example of a 5-membered ring is pyrazolyl, such as pyrazol-4-yl (ie, X and Y are N) and the ring may be substituted, for example, 1-ethylpyrazol-4-yl or 1- (2,2,2-trifluoroethyl) pyrazol-4-yl.

  When n is 1, an example of a 6-membered ring is pyridyl, such as pyrid-4-yl, or phenyl, which ring may be substituted, for example 2,6-diethylpyrid-4-yl Or 4-trifluoromethoxyphenyl.

Preferred compounds of the invention are those compounds of formula I wherein R ₁ and R ₂ are H. Another group of preferred compounds of the invention are those compounds of formula I, wherein R ₉ is an optionally substituted heteroaryl group. Also preferred are compounds of formula I, wherein X is N. A further group of preferred compounds of the invention are those compounds of formula I, wherein R ₉ is an optionally substituted heteroaryl group and is attached to the 3-position of the phenyl ring.

More preferred compounds of the invention are those compounds of formula I wherein R ₁ and R ₂ are H and R ₉ is an optionally substituted heteroaryl group. Another group of more preferred compounds of this invention are those compounds of formula I wherein R ₁ and R ₂ are H, R ₉ is an optionally substituted heteroaryl group and X is N. A further group of more preferred compounds of the invention are those of formula I wherein R ₁ and R ₂ are H and R ₉ is an optionally substituted heteroaryl group attached to the 3-position of the phenyl ring A compound.

Preferred compounds of formula I are:
8- [3- (2-fluoropyridin-3-yl) -phenyl] -8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo [1,5-a] pyrimidin-6-amine;
8- (2,6-Diethylpyridin-4-yl) -8- [3- (2-fluoropyridin-3-yl) -phenyl] -2,3,4,8-tetrahydro-imidazo [1,5- a] pyrimidine-6-amine;
8- (1-Ethyl-1H-pyrazol-4-yl) -8- [3- (2-fluoropyridin-3-yl) phenyl] -2,3,4,8-tetrahydro-imidazo [1,5- a] pyrimidine-6-amine;
8- [3- (2-Fluoropyridin-3-yl) phenyl] -8- [1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl] -2,3,4, 8-tetrahydroimidazo [1,5-a] pyrimidin-6-amine;
8- [3- (2-Fluoropyridin-3-yl) phenyl] -8- [4- (trifluoromethoxy) phenyl] -3,4-dihydro-8H-imidazo [5,1-c] [1, 2,4] oxadiazin-6-amine;
8- [3- (5-Fluoropyridin-3-yl) phenyl] -8- [4- (trifluoromethoxy) phenyl] -3,4-dihydro-8H-imidazo [5,1-c] [1, 2,4] oxadiazin-6-amine;
The tautomer, stereoisomer, or pharmaceutically acceptable salt thereof is included.

Advantageously, the present invention provides a process for the preparation of a compound of formula I (Ia) in which R ₉ is an optionally substituted aryl or heteroaryl group, wherein Hal is Cl or Br Substitution) with a leaving group selected from B (OH) ₂ , Sn (Bu) ₃ and Sn (CH ₃ ) _{3 in} the presence of a palladium catalyst and an inorganic base, optionally in the presence of a solvent. Provided is a method characterized by reacting with an aryl or heteroaryl group which may be substituted. The method is shown in flow diagram I.

［式中、Ａは、置換されていてもよいアリールまたはヘテロアリール基を示し、Ｗ’は、Ｂ（ＯＨ）_２、Ｓｎ（Ｂｕ）_３またはＳｎ（ＣＨ_３）_３であり、ＨａｌはＣｌまたはＢｒである。］ Flow diagram I

Wherein A represents an optionally substituted aryl or heteroaryl group, W ′ is B (OH) ₂ , Sn (Bu) ₃ or Sn (CH ₃ ) ₃ and Hal is Cl or Br. ]

Suitable palladium catalysts for use in the process of the present invention include Pd (0) or Pd (II) catalysts, such as dichlorobis (tri-o-tolylphosphine) palladium (II), Pd (OCOCH ₃ ) ₂ / tri -O-tolylphosphine, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) triphenylphosphine and the like are included.

Suitable inorganic bases for use in the method of the present invention include, hydroxide, carbonate or bicarbonate Na or K, and preferably, _Na 2 CO ₃ or _K 2 CO _3.

  Suitable solvents for use in the method of the present invention can solubilize polar or non-polar organic solvents such as toluene, diethoxyethyl ether, dioxane, ethylene glycol dimethyl ether, or Formula II or heteroaryl compounds. Any unreactive organic solvent is included.

Compounds of formula II can be prepared using conventional synthetic methods and, if necessary, standard separation or isolation techniques. For example, a compound of formula II (IIa) in which R ₁ and R ₂ are H and Q and W are CH ₂ is obtained by reacting a compound of formula III with a diamine of formula IV to give a bicyclic compound of formula V And may be prepared by reacting a compound of formula V with t-butyl hydroperoxide and ammonium hydroxide to give the desired compound of formula IIa. The reaction is shown in Flow Diagram II below.

［式中、ＨａｌはＣｌまたはＢｒである。］ Flow diagram II

[Wherein Hal is Cl or Br. ]

Similarly, compound of formula II (IIb) wherein R ₁ and R ₂ are H, R ₃ and R ₄ are H, Q is CH ₂ and W is O is a compound of formula III and 2 -(Aminooxy) ethanamine dihydrochloride is reacted in the presence of a base such as triethylamine and a solvent to give a bicyclic compound of formula VI, wherein the compound of formula VI is t-butyl hydroperoxide and ammonium hydroxide Can be prepared by reacting with to give the desired compound of formula IIb. The reaction is shown in Flow Diagram III.

［式中、ＨａｌはＣｌまたはＢｒである。］ Flow diagram III

[Wherein Hal is Cl or Br. ]

Compounds of formula II (IIc) in which R ₁ and R ₂ are H, R ₃ and R ₄ are H, Q is O and W is CH ₂ are Boc-protected with compounds of formula III Reaction with 2- (aminooxy) ethanamine to give a protected amine compound of formula VII, which is deprotected in the presence of an acid such as trifluoroacetic acid to give the corresponding formula VIII To obtain a free amine of formula VIII to cyclize the compound of formula VIII to obtain a bicyclic compound of formula IX and react the compound of formula IX with t-butyl hydroperoxide and ammonium hydroxide to give the desired compound of formula IIc Can be prepared. The reaction is shown in Flow Diagram IV.

［式中、Ｂｏｃは、ｔ−ブチルカルボニルオキシであり、ＨａｌはＣｌまたはＢｒである。］ Flow diagram IV

[Wherein Boc is t-butylcarbonyloxy and Hal is Cl or Br. ]

Compounds of formula IIa, IIb and IIc can be converted to the corresponding compounds of formula Ia (wherein R ₁ and R ₂ are H) using the procedure described in Flow Diagram I above.
A compound of formula III is prepared by reacting a halogenated heteroaryl compound of formula X with a benzonitrile compound of formula XI in the presence of a base, for example t-butyllithium, to give a methylamine of formula XII, Amine and thiophosgene are reacted in the presence of a base such as NaHCO ₃ to give a thiocyanate compound of formula XIII, and the thiocyanate compound of formula XIII and carbon disulfide in the presence of a base such as potassium t-butoxide. It can be readily prepared by reacting to obtain the desired compound of formula III. The reaction is shown in Flow Diagram V.

［式中、ＨａｌはＣｌまたはＢｒである。］ Flow diagram V

[Wherein Hal is Cl or Br. ]

Compounds of formula I in which R ₉ is other than an optionally substituted aryl or heteroaryl group have corresponding Hal substituted with the desired R ₉ substituent by the reactions shown in flow diagrams II-IV above. It can be prepared by using a compound of formula III.

Compounds of formula I in which R ₁ and R ₂ are other than H can be prepared using standard alkylation techniques, for example by converting compounds of formula I in which R ₁ and R ₂ are H with alkyl halides R ₁ -Hal. Reaction yields a compound of formula I (Id) in which R ₂ is H, optionally reacting the compound of formula Id with a _second alkyl halide R ₂ -Hal so that R ₁ and R ₂ are H Can be prepared by obtaining the desired compound of formula I.

  Advantageously, the compounds of the invention comprise β-amyloid deposits or β- in patients, including Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with Dutch amyloidosis, or other neurodegenerative or dementia-induced disorders. Useful for the treatment, prevention or amelioration of a disease or disorder characterized by elevated amyloid levels. Accordingly, the present invention provides a method for the treatment, prevention or amelioration of a disease or disorder characterized by elevated β-amyloid deposits or β-amyloid levels in a patient comprising the therapeutically effective amount of the above Provided is a method characterized in that it provides a compound of formula I. The compound may be provided by oral or parenteral administration or in any general manner known to be effective administration of therapeutic agents to patients.

  As used herein, the term “providing” relates to providing a compound or substance encompassed by the present invention, wherein such compound or substance is administered directly, or an equivalent amount of said compound or substance. Indicates administration of a prodrug, derivative or analog that forms the substance in the body.

  The therapeutically effective amount provided in the treatment of a particular CNS disorder will depend on the particular condition being treated, the patient's size, age and response pattern, severity of the disorder, the judgment of the physician in charge, etc. It can change. In general, the effective daily dose for oral administration may be about 0.01 to 1,000 mg / kg, preferably about 0.5 to 500 mg / kg. For parenteral administration, the effective amount is It may be about 0.1-100 mg / kg, preferably about 0.5-50 mg / kg.

  In actual practice, the compounds of the invention are provided by administering the compound or precursor thereof in solid or liquid form as such or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula I above.

  Suitable solid carriers for use in the compositions of the present invention are flavors, lubricants, solubilizers, suspending agents, bulking agents, lubricants, compression aids, binders, tablet disintegrants or capsules. It includes one or more substances that can also act as chelating materials. In powders, the carrier may be a finely divided solid mixed with the finely divided compound of formula I. In tablets, the compound of formula I may be mixed with a carrier having the necessary compression properties in suitable proportions and compressed into the desired shape and size. The powders and tablets may contain up to 99% by weight of the compound of formula I. Suitable solid carriers for use in the compositions of the present invention are calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting wax and ions Includes exchange resins.

  Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be used in the compositions of the invention. The compound of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or mixture thereof. The liquid composition comprises other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, It may contain a stabilizer, an osmotic pressure regulator and the like. Examples of liquid carriers suitable for oral and parenteral administration are water (especially containing the above-mentioned additives, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (monohydric and polyhydric alcohols, For example, glycols) or derivatives thereof, and oils (eg, fractionated coconut oil and peanut oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate or isopropyl myristate.

  Compositions of the invention that are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Compositions suitable for oral administration according to the present invention may be in either liquid or solid composition form.

  Alternatively, it may be desirable to use a sustained delivery device to avoid the need for the patient to take medication daily. The term “sustained delivery” is defined as delaying the release of an active agent, ie, a compound of the present invention, after being placed in the delivery environment until some time after the drug is released. One skilled in the art knows suitable sustained delivery devices. Examples of suitable sustained delivery devices include, for example, hydrogels (see, eg, US Pat. Nos. 5,266,325, 4,959,217 and 5,292,515), osmotic pumps, such as Among others, osmotic pumps, hydrophobic membrane materials such as those described by Alza (US Pat. Nos. 4,295,987 and 5,273,752) or Merck (European Patent 314,206), such as , Ethylene methacrylate (EMA) and ethylene vinyl acetate (EVA), bioresorbable polymer systems (see, eg, WO 98/44964, Bioxid and Cellomeda; US Pat. Nos. 5,756,127 and 5,854,388) See, for example, polyester, polyanhydride, or lactic acid / glycolic acid copoly It encompasses other bioresorbable implant devices that consist of over described (e.g., U.S. Patent No. 5,817,343 (Alkermes Inc.) refer) to. For use in such sustained delivery devices, the compounds of the invention may be formulated as described herein.

  In another aspect, the present invention provides a pharmaceutical kit for product delivery. Suitably, the kit contains a packaging or container with the compound formulated for the desired delivery route. For example, if the kit is designed for administration by inhalation, it can contain a suspension containing a compound of the invention formulated to deliver a predetermined dose by aerosol or spray by inhalation. Suitably, the kit may contain instructions for administration and an insert for the active agent. Optionally, the kit further contains instructions for monitoring the circulating level of the product and materials (eg, including reagents, well plates, containers, markers or labels, etc.) for performing such assays. You may do it. Such kits are easily packaged in a manner suitable for the treatment of the desired indication. For example, the kit may also contain instructions for use of a spray pump or other delivery device.

  Other components suitable for such kits will be readily apparent to those skilled in the art in view of the desired indication and delivery route. Administration may be repeated for a desired period of time, or as specified, daily, weekly or monthly.

  For a clearer understanding and to more clearly describe the present invention, specific examples are given below. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying principles of the invention in any way. Indeed, various modifications of the invention other than those shown and described herein will become apparent to those skilled in the art from the following examples and the above description. Such modifications are also intended to fall within the scope of the claims of the present invention.

  Unless otherwise specified, all “parts” refer to parts by weight. The term NMR refers to nuclear magnetic resonance. The terms DME and DMF refer to ethylene glycol dimethyl ether and dimethylformamide, respectively.

Example 1
Preparation of 8- [3- (2-fluoropyridin-3-yl) phenyl] -8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo [1,5-a] pyrimidin-6-amine

A) Preparation of Compound 1 A solution of tert-butyllithium (1.7M in pentane 30.0 mL, 51.0 mmol) in diethyl ether at −78 ° C. in 4-bromopyridine (25.7 mmol) in diethyl ether. Treat dropwise with solution, stir at −78 ° C. for 40 minutes, warm to 0 ° C., treat sequentially with methanol and sodium borohydride (1.94 g, 51.0 mmol), stir overnight at room temperature, saturated aqueous Diluted with ammonium chloride and concentrated under reduced pressure to remove most of the methanol and diethyl ether. The resulting aqueous residue was extracted with methylene chloride. The extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (silica, methylene chloride to 95: 5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give compound 1 as a yellow syrup (4.21 g, 69% yield). rate). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.54 (dd, J = 4.5, 1.5 Hz, 2H), 7.36-7.28 (m, 6H), 5.14 (s, 1H), 1.25 (s, 2H, br) ; ESI MS m / z 264 [C 12 H 11 BrN 2 + H] +

B) Preparation of compound 2 A mixture of potassium tert-butoxide (0.355 g, 3.16 mmol) in tetrahydrofuran was treated dropwise with a solution of 1 (0.665 g, 2.53 mmol) in tetrahydrofuran at -78 ° C. Stir for minutes, treat with carbon disulfide (0.635 g, 8.34 mmol), slowly warm to room temperature and stir at room temperature for 1 hour. The reaction mixture was cooled to −78 ° C., treated with di-2-pyridyl-thiocarbonate (0.880 g, 3.79 mmol), warmed to room temperature, stirred at room temperature overnight, and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, 97.5: 2.5 methylene chloride / methanol) to give compound 2 as a pink oil (0.310 g, 32% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.66 (dd, J = 4.5, 1.5 Hz, 2H), 7.57 (dt, J = 6.5, 2.0 Hz, 1H), 7.47 (D, J = 2.0 Hz, 1H), 7.34 (dd, J = 4.5, 1.5 Hz, 2H), 7.32-7.26 (m, 2H); ESI MS m / z 381 [C ₁₄ H ₉ BrN ₂ S ₃ + H] ⁺

C) Preparation of Compound 3 A mixture of 2 (0.310 g, 0.810 mmol) and 1,3-diaminopropane (0.181 g, 2.44 mmol) in ethanol was heated at 70 ° C. for 1 hour, cooled to room temperature, Concentrated to dryness. The resulting residue was purified by flash chromatography (silica, 97.5: 2.5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give compound 3 as a white solid (0.260 g, 83% yield). ¹ H NMR (500 MHz, CD ₃ OD) δ 8.57 (dd, J = 4.5, 1.5 Hz, 2H), 7.56-7.52 (m, 2H), 7.41 (dd, J = 4.5, 1.5 Hz, 2H), 7.36-7.33 (m, 2H), 3.86 (t, J = 6.0 Hz, 2H), 3.56 (t, J = 5. 5 Hz, 2H), 1.88 (tt, J = 6.0, 5.5 Hz, 2H); ESI MS m / z 387 [C ₁₇ H ₁₅ BrN ₄ S + H] ⁺

D) Preparation of Compound 4 A mixture of 3 (0.260 g, 0.670 mmol) and t-butyl hydroperoxide (1.73 g of 70% aqueous solution, 13.4 mmol) in methanol and aqueous concentrated ammonium hydroxide overnight at room temperature. Stir and concentrate under vacuum. The resulting residue was purified by flash chromatography (silica, 95: 5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give compound 4 as a white solid (0.210 g, 84% yield). ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48 (dd, J = 4.5, 1.5 Hz, 2H), 7.52 (t, J = 1.5 Hz, 1H), 7.46 (dt, J = 7.5, 1.5 Hz, 1H), 7.40 (dd, J = 4.5, 1.5 Hz, 2H), 7.32 (dt, J = 7.5, 1.5 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 3.69 (t, J = 6.0 Hz, 2H), 3.50 (t, J = 5.1 Hz, 2H), 1.86 (tt , J = 6.0, 5.1 Hz, 2H); ESI MS m / z 370 [C ₁₇ H ₁₆ BrN ₅ + H] ⁺

D) 8- [3- (2-Fluoropyridin-3-yl) phenyl] -8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo [1,5-a] pyrimidin-6-amine Preparation of 4 (0.100 g, 0.27 mmol), 2-fluoropyridine-3-boronic acid (0.076 g, 0.540 mmol), bis (triphenylphosphino) palladium (II) chloride (0.010 g, 0 .014 mmol), a 3: 1 DME / water mixture of triphenylphosphine (0.0071 g, 0.027 mmol) and sodium carbonate (0.086 g, 0.810 mmol) at reflux temperature for 2 hours, cooled to room temperature, Dilute with ethyl acetate and water. The phases were separated. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, 95: 5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give a white solid. The material was lyophilized from 2: 1 acetonitrile / water to give the title product as a white solid (0.082 g, 79% yield). mp 125-131 ° C.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.16 (dd, J = 4.5, 1.5 Hz, 2H), 8.16 (dt, J = 5.0, 1.5 Hz, 1H), 7.83 (Ddd, J = 9.5, 7.5, 2.0 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.52 (dt, J = 8.0, 1.5 Hz) , 1H), 7.47 (dd, J = 4.5, 1.5 Hz, 2H), 7.47-7.46 (m, 1H), 7.41 (t, J = 7.5 Hz, 1H) 7.24 (ddd, J = 7.5, 5.0, 2.0 Hz, 1H), 3.62-3.57 (m, 4H), 1.88 (m, 2H); ESI MS m / z 387 [C ₂₂ H ₁₉ FN ₆ + H] ⁺

Example 2
8- (2,6-Diethylpyridin-4-yl) -8- [3- (2-fluoropyridin-3-yl) phenyl] -2,3,4,8-tetrahydroimidazo [1,5-a] Preparation of pyrimidine-6-amine

Using substantially the same procedure described in Example 1 and using 4-bromo-2,6-diethylpyridine in Step A, the title product was obtained as a white solid (0.095 g). mp 174-176 ° C. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.16 (d, J = 4.2 Hz, 1H), 8.04-7.98 (m, 1H), 7.54-7.37 (m, 5H), 7.13 (s, 2H), 3.70 (t, J = 6.0 Hz, 2H), 3.50 (t, J = 6.0 Hz, 2H), 2.75 (q, J = 7.8 Hz) , 4H), 1.87 (t, J = 5.7 Hz, 2H), 1.23 (t, J = 7.8 Hz, 6H); ESI MS m / z 443 [C ₂₆ H ₂₇ FN ₆ + H] ⁺

Example 3
8- (1-Ethyl-1H-pyrazol-4-yl) -8- [3- (2-fluoropyridin-3-yl) phenyl] -2,3,4,8-tetrahydroimidazo [1,5-a Preparation of pyrimidine-6-amine

A) Preparation of Compound 1 A mixture of t-butyl lithium (16.2 mL of a 1.7 M solution in pentane, 27.5 mmol) and diethyl ether was cooled to −78 ° C. and taken over 15 minutes over 4-bromo-1- Treat dropwise with a solution of ethylpyrazole (2.3 g, 13.1 mmol) in diethyl ether, stir at −78 ° C. for 10 minutes and drop dropwise with a solution of 3-bromobenzonitrile (2.58 g, 14.1 mmol) in ether. Treated and stirred at -78 ° C for 45 minutes and allowed to warm to room temperature for 1 hour. The reaction mixture is treated with anhydrous methanol, cooled to 0 ° C., treated with sodium borohydride (0.991 g, 26.2 mmol), warmed to room temperature, stirred at room temperature for 1 hour, cooled to 0 ° C. and gaseous Quenched by careful addition of saturated ammonium chloride until evolution ceased to dissolve all precipitate. The reaction mixture was diluted with methylene chloride and water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash chromatography (silica, methylene chloride / methanol 95: 5) to give compound 1 as a colorless oil (1.91 g, 52% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54 (br s, 1H), 7.41-7.35 (m, 2H), 7.32-7.27 (m, 1H), 7.24-7 .16 (m, 2H), 5.11 (s, 1H), 4.10 (q, J = 7.3 Hz, 2H), 1.89 (br s, 2H), 1.44 (t, J = _{7.3Hz, 3H); ESI MS m} / z 263 [(C 12 H 14 BrN 3 -NH 2) + H] +

B) Preparation of Compound 2 A mixture of 1 (0.112 g, 0.40 mmol) in methylene chloride and saturated aqueous sodium bicarbonate was cooled in an ice bath and treated with thiophosgene (0.05 g, 0.44 mmol) for 30 minutes. Stir vigorously and dilute with methylene chloride. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give compound 2 as a yellow syrup (0.11 g, 84% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51-7.45 (m, 2H), 7.37 (s, 1H), 7.31-7.24 (m, 3H), 5.93 (s, 1H), 4.14 (q, J = 7.3 Hz, 2H), 1.47 (t, J = 7.3 Hz, 3H)

C) Preparation of Compound 3 A mixture of potassium t-butoxide (0.04 g, 0.37 mmol) in tetrahydrofuran at −78 ° C. over 2 minutes was taken over 2 (0.11 g, 0.34 mmol) and carbon disulfide (0. (04 g, 0.51 mmol) in tetrahydrofuran, stirred at −78 ° C. for 0.5 h, slowly warmed to room temperature, stirred at room temperature for 1 h, diluted with methylene chloride and water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give compound 3 as a yellow solid (0.089 g, 66% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.88-7.26 (m, 6H), 4.15, 4.06 (2q, J = 7.3 Hz, 2H), 1.41-1. _{39 (m, 3H); ESI} MS m / z 398 [C 14 H 12 BrN 3 S 3 + H] +

D) Preparation of compound 4 A mixture of 3 (0.50 g, 1.25 mmol) and 1,3-diaminopropane (0.28 g, 3.75 mmol) in ethanol was heated at 70 ° C. for 1 hour, cooled to room temperature, Evaporated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to give compound 4 as a pale yellow oil (0.38 g, 75% yield). ¹ H NMR (300 MHz, CDCl ₃ ) dδ 7.63 (s, 1H), 7.53-7.47 (m, 2H), 7.43-7.23 (m, 3H), 4.15 (q , J = 7.3 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.53-3.45 (m, 2H), 1.90-1.83 (m, 2H) , 1.43 (t, J = 7.3 Hz, 3H); ESI MS m / z 404 [C ₁₇ H ₁₈ BrN ₅ S + H] ⁺

E) Preparation of Compound 5 A mixture of Compound 4 (0.38 g, 0.94 mmol) and t-butyl hydroperoxide (3.6 g of 70% aqueous solution, 28.2 mmol) in methanol and aqueous concentrated ammonium hydroxide was mixed at room temperature. Stir overnight, treat with 10% aqueous sodium thiosulfate (30 mL) and concentrate under reduced pressure to remove most of the methanol. The resulting aqueous mixture was extracted with methylene chloride. The extracts were combined, washed sequentially with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (silica, 95: 5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give compound 5 as a colorless syrup (0.09 g, 25% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.66 (s, 1H), 7.48-7.34 (m, 4H), 7.17 (t, J = 7.8 Hz, 1H), 4.11 ( q, J = 7.3 Hz, 2H), 3.59 (t, J = 5.8 Hz, 2H), 3.58-3.52 (m, 2H), 1.91-1.80 (m, 2H) ), 1.46 (t, J = 7.3 Hz, 3H); ESI MS m / z 387 [C ₁₇ H ₁₉ BrN ₆ + H] ⁺

8- (1-Ethyl-1H-pyrazol-4-yl) -8- [3- (2-fluoropyridin-3-yl) phenyl] -2,3,4,8-tetrahydroimidazo [1,5-a Preparation of pyrimidine-6-amine 5 (0.090 g, 0.230 mmol), 2-fluoropyridine-3-boronic acid (0.065 g, 0.460 mmol), bis (triphenylphosphino) palladium (II) chloride (0.008 g, 0.011 mmol), triphenylphosphine (0.006 g, 0.022 mmol) and sodium carbonate (0.073 g, 0.690 mmol) in a 3: 1 DME / water mixture at reflux temperature for 1.5 hours. Heated, cooled to room temperature, diluted with ethyl acetate and water. The phases were separated. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, 95: 5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give an off-white solid (0.035 g). The material was lyophilized from 2: 1 acetonitrile / water to give a white solid that was mixed with dimethylformamide. The solid was purified by flash chromatography (silica, 95: 5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give a white solid that was lyophilized from 2: 1 acetonitrile / water to give the title The product was obtained as a white solid (0.034 g, 35% yield). mp 91-115 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.20-8.12 (m, 1H), 7.90-7.81 (m, 1H), 7.71 (brs, 1H), 7.59-7 .40 (m, 6H), 4.12 (q, J = 7.3 Hz, 2H), 3.70 (t, J = 6.0 Hz, 2H), 3.57 (t, J = 4.9 Hz, 2H), 1.95-1.82 (m, 2H ), 1.46 (t, J = 7.3Hz, 3H); ESI MS m / z 404 [C 22 H 22 FN 7 + H] +

Example 4
8- [3- (2-Fluoropyridin-3-yl) phenyl] -8- [1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl] -2,3,4, Preparation of 8-tetrahydroimidazo [1,5-a] pyrimidin-6-amine

Using substantially the same procedure described in Example 3, in step B, 1 (4-bromophenyl) -1-[(2,2,2-trifluoroethyl) pyrazol-4-yl] methylamine was Used to give the title product as a white solid. mp 106-116 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.17 (dd, J = 1.7, 1.6 Hz, 1H), 7.82 (m, 1H), 7.68 (d, J = 1.4 Hz, 1H) ), 7.63 (s, 1H), 7.59 (s, 1H), 7.57-7.41 (m, 3H), 7.23 (m, 1H), 4.68 (q, J = 8.4 Hz, 2H), 3.60 (t, J = 5.9 Hz, 2H), 3.54 (m, 2H), 1.85 (m, 2H); ESI MS m / z 458 [C ₂₂ H ₁₉ F ₄ N ₇ + H] ⁺

Example 5
8- [3- (2-Fluoropyridin-3-yl) phenyl] -8- [4- (trifluoromethoxy) -phenyl] -3,4-dihydro-8H-imidazo [5,1-c] [1 , 2,4] oxadiazin-6-amine

A) Preparation of Compound 1 4- (3-Bromophenyl) -4- [4- (trifluoromethoxy) phenyl] -1,3-thiazolidine-2,5-dithione (0.50 g, 1.08 mmol), 2 Of (aminooxy) ethanamine (0.48 g, 3.23 mmol, prepared as described in J. Med. Chem. 2000, 43 (12), 2347) and triethylamine (0.71 g, 7.00 mmol) The mixture in ethanol was stirred at ice bath temperature for 2 hours, warmed to room temperature, stirred at room temperature for 24 hours, heated to 70 ° C., stirred at 70 ° C. for 2 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic phase was washed successively with 1N HCl and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (silica, 1: 5 ethyl acetate / hexane) to give compound 1 as a white solid (0.277 g, 54% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53 (m, 2H), 7.39 (d, J = 8.9 Hz, 2H), 7.38-7.22 (m, 4H), 4.11 ( m, 2H), 4.03 (m , 2H); ESI MS m / z 472 [C 18 H 13 BrF 3 N 3 O 2 S + H] +

B) Preparation of Compound 2 A mixture of Compound 1 (0.27 g, 0.571 mmol) and t-butyl hydroperoxide (70% aqueous solution 1.47 g, 11.4 mmol) in methanol and aqueous concentrated ammonium hydroxide was mixed at room temperature. Stir overnight, treat with 10% aqueous sodium thiosulfate and concentrate to remove most of the methanol. The resulting aqueous mixture was extracted with methylene chloride. The extracts were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The concentrate was purified by flash chromatography (silica, 95: 5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give compound 2 as a white solid (0.166 g, 64% yield). . ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.70 (t, J = 1.8 Hz, 1H), 7.56 (m, 1H), 7.45-7.37 (m, 3H), 7.20- 7.13 (m, 3H), 3.99 (m, 2H), 3.77 (m, 2H); ESI MS m / z 456 [C 18 H 14 BrF 3 N 4 O 2 + H] +

C) 8- [3- (2-Fluoropyridin-3-yl) phenyl] -8- [4- (trifluoromethoxy) -phenyl] -3,4-dihydro-8H-imidazo [5,1-c] Preparation of [1,2,4] oxadiazin-6-amine 2 (0.16 g, 0.351 mmol), 2-fluoropyridine-3-boronic acid (0.089 g, 0.633 mmol), bis (triphenylphosphine chloride) Fino) palladium (II) (0.012 g, 0.018 mmol), triphenylphosphine (0.0092 g, 0.035 mmol) and sodium carbonate (0.112 g, 1.05 mmol) in a 3: 1 DME / water mixture 3 Heat at reflux for hours, cool to room temperature and dilute with ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The resulting concentrate was purified by flash chromatography (silica, 95: 5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give a white solid (0.12 g). The material was lyophilized from 2: 1 acetonitrile / water (6 mL) to give the title product as a white solid (0.109 g, 66% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16 (m, 1H), 7.83 (m, 1H), 7.71 (m, 1H), 7.61-7.56 (m , 3H), 7.46-7.41 (m, 2H), 7.25 (m, 1H), 7.15 (m, 2H), 4.00 (m, 2H), 3.78 (m, _{2H); ESI MS m / z} 472 [C 23 H 17 F 4 N 5 O 2 + H] +

Example 6
8- [3- (5-Fluoropyridin-3-yl) phenyl] -8- [4- (trifluoromethoxy) phenyl] -2,8-dihydro-3H-imidazo [1,5-b] [1, Preparation of 2,4] oxadiazin-6-amine

A) Preparation of Compound 1 4- (3-Bromophenyl) -4- [4- (trifluoromethoxy) phenyl] -1,3-thiazolidine-2,5-dithione (1.32 g, 2.84 mmol) and Boc A mixture of protected 2- (aminooxy) ethanamine (1.49 g, 8.53 mmol) in ethanol was stirred at 70 ° C. for 1.5 hours, cooled to room temperature and concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (silica, 1: 4 ethyl acetate / hexane) to give compound 1 as a white solid (1.12 g, 65% yield). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.72 (bs, 1 H), 7.56 (dt, J = 4.1, 1.6 Hz, 1 H), 7.49 (d, J = 1.8 Hz, 1 H ), 7.38 (d, J = 8.7 Hz, 2H), 7.30 (m, 3H), 4.68 (bs, 1H), 4.21 (t, J = 5.1 Hz, 2H), 3.37 (bs, 2H), 1.43 (s, 9H); ESI MS m / z 607 [C 23 H 23 BrF 3 N 3 O 4 S 2 + H] +

B) Preparation of Compound 2 A mixture of Compound 1 (1.12 g, 1.85 mmol), trifluoroacetic acid (6.0 mL) and methylene chloride was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. The concentrate was basified to pH 9 with 10% aqueous potassium carbonate and extracted with methylene chloride. The extracts were combined, dried over sodium sulfate and concentrated to give compound 2 as an off-white solid (0.842 g, 90% yield). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.21-7.60 (m, 6H), 7.11-7.25 (m, 2H), 4.22 (t, J = 5.3 Hz, 2H), 2.94 (t, J = 5.2 Hz, 2H), 1.62 (s, 2H); ESI MS m / z 507 [C ₁₈ H ₁₅ BrF ₃ N ₃ O ₂ S ₂ + H] ⁺

C) Preparation of compound 3 A solution of compound 2 (0.842 g, 1.66 mmol) in ethanol was heated at reflux for 1 hour, cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, 3: 1 hexane / ethyl acetate) to give compound 3 as an off-white solid (0.437 g, 56% yield). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.63 (m, 2H), 7.39 (dd, J = 4.6, 2.1 Hz, 2H), 7.28 (m, 2H), 7.23 ( d, J = 8.0 Hz, 2H), 4.11 (t, J = 2.9 Hz, 2H), 4.02 (t, J = 3.2 Hz, 2H); ESI MS m / z 473 [C ₁₈ H ₁₃ BrF ₃ N ₃ O ₂ S + H] ⁺

D) Preparation of Compound 4 A mixture of Compound 3 (0.434 g, 0.920 mmol) and t-butyl hydroperoxide (70% aqueous solution 3.55 g, 27.6 mmol) in methanol and aqueous concentrated ammonium hydroxide was mixed at room temperature. Stir overnight, treat with 10% aqueous sodium thiosulfate and concentrate to remove most of the methanol. The resulting aqueous mixture was extracted with methylene chloride. The extracts were combined, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography (silica, 95: 5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give compound 4 as an off-white solid (0.284 g, 68% yield). ). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.69 (t, J = 1.8 Hz, 1H), 7.55 (dd, J = 4.7, 2.1 Hz, 2H), 7.42 (dt, J = 5.2, 1.0 Hz, 1H), 7.40 (dt, J = 6.0, 1.0 Hz, 1H), 7.18 (m, 3H), 4.00 (t, J = 4. 5 Hz, 2H), 3.79 (t, J = 6.1 Hz, 2H); ESI MS m / z 456 [C ₁₈ H ₁₄ BrF ₃ N ₄ O ₂ + H] ⁺

E) 8- [3- (5-Fluoropyridin-3-yl) phenyl] -8- [4- (trifluoromethoxy) -phenyl] -2,8-dihydro-3H-imidazo [1,5-b] Preparation of [1,2,4] oxadiazin-6-amine Compound 4 (0.095 g, 0.209 mmol), Compound 5 (0.122 g, 0.313 mmol), and dichlorobis (triphenylphosphine) palladium (II) ( 0.007 g, 0.011 mmol) in DMF was degassed and then heated in a sealed tube at 150 ° C. for 1.5 hours. The mixture was cooled to room temperature and diluted with ethyl acetate and 5% aqueous LiCl. The organic phase was separated, washed with 5% aqueous LiCl, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, 95: 5: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give the title product as a white solid (0.050 g, 38% yield). rate). mp 120-135 ° C. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.67 (bs, 1H), 8.38 (d, J = 2.3 Hz, 1H), 7.78 (bs, 1H), 7.45-7.62 ( m, 6H), 7.18 (d , J = 8.3Hz, 2H), 4.05 (bs, 2H), 3.99 (bs, 2H); ESI MS m / z472 [C 23 H 17 F 4 N ₅ O ₂ + H] ⁺

Example 7
Evaluation of enzyme activity of test compounds and inhibition of hBACE1, MuBACE1 and hBACE2 by test compounds Assay conditions:
10 nM human BACE1 (or 10 nM murine BACE1, 1.5 nM human BACE2), 25 μM substrate (WABC-6, MW1549.6, manufactured by AnaSpec); final buffer conditions: 50 mM Na acetate, pH 4.5, 0.05% CHAPS, 25 % PBS; temperature: room temperature; reagent information: Na acetate is Aldrich (Cat. # 24, 124-5), CHAPS is Research Organics (Cat. # 1304C), 1X PBS is Mediatech (Cellgro) (Cat # 21-031-CV) ), The peptide substrate AbzSEVNLDAEFRDpa is AnaSpec (peptide name: WABC-6).

Determination of stock substrate (AbzSEVNLDAEEFRDpa) concentration:
A 25 mM stock solution in dimethyl sulfoxide (DMSO) is made using peptide weight and MW and diluted to 25 μM. The concentration is determined by the absorbance at 354 nm using the extinction coefficient ε 18172 M ⁻¹ cm ⁻¹ . The substrate stock is divided into small aliquots and stored at −80 ° C.
[Substrate ^{Stock] = ABS 354nm * 10 6/} 18172 (mM)

Determination of stock enzyme concentration:
Stock concentration of each enzyme by 280nm of ABS, 6M guanidinium hydrochloride (Research Organics Ltd., Cat. # 5134G-2) in pH 6, HBACE1 and MuBACE1 for ε 64150M ^-1 cm ^-1, hBACE2 about 62 870 M ^-1 cm Determined using ^-1 .
The extinction coefficient ε ^{280 nm} for each enzyme is known amino acid composition and Trp (5.69 M ⁻¹ cm ⁻¹ ) and Tyr (1.28 M ⁻¹ cm ⁻¹ ) residues (Anal. Biochem. 182, 319-326). Calculated based on the published extinction coefficient for.

Dilution and mixing steps:
Total reaction volume: 100 μL
1. Prepare 2X inhibitor dilution in buffer A (66.7 mM Na acetate, pH 4.5, 0.0667% CHAPS).
2. Prepare a 4X enzyme dilution in buffer A (66.7 mM Na acetate, pH 4.5, 0.0667% CHAPS).
3. Prepare 100 μM substrate dilution in 1 × PBS.
Immediately after adding 4.50 μL 2X inhibitor, 25 μL 100 μM substrate to each well of a 96-well plate (DYNEX Technologies, VWR #: 11311-046), add 25 μL 4X enzyme to the inhibitor and substrate mixer and take fluorescence reading Start.

Fluorescence reading:
Readings at λ _ex 320 nm and λ _em 420 nm are taken every 40 seconds for 30 minutes at room temperature to determine the linear slope (v _i ) for substrate cleavage rate.

Calculation of% inhibition:
% Inhibition = 100 ^* (1-v _i / v ₀ )
(V _i = substrate cleavage rate in the presence of inhibitor v ₀ = substrate cleavage rate in the absence of inhibitor)
IC ₅₀ determination:
% Inhibition = [(B ^* IC ₅₀ ⁿ ) + (100 ^* I ₀ ⁿ )] / (IC ₅₀ ⁿ + I ₀ ⁿ )

Fluorescence Kinetic Assay for Human Recombinant BACE2 The assay is used to provide kinetic and selectivity parameters for the analysis of test compounds.

Materials and methods:
Final assay conditions: 10 nM human BACE1 (or 10 nM murine BACE1, 1.5 nM human BACE2), 25 μM substrate (WABC-6, MW1549.6, from AnaSpec). Final buffer conditions: 50 mM Na acetate, pH 4.5, 0.05% CHAPS, 25% PBS. Temperature: room temperature. Reagent information: Na acetate: Aldrich, Cat. # 24, 124-5, CHAPS: Research Organics, Cat. # 1304C, 1XPBS: Mediatech (Cellgro), Cat # 21-031-CV, peptide substrate AbzSEVNLDAEEFRDpa: AnaSpec, peptide name: WABC-6.

Determination of stock substrate (AbzSEVNLDAEEFRDpa) concentration:
A 25 mM stock solution in DMSO is prepared using peptide weight and MW and diluted to 25 μM. The concentration is determined by the absorbance at 354 nm using the extinction coefficient ε 18172 M ⁻¹ cm ⁻¹ . The substrate stock is divided into small aliquots and stored at −80 ° C.
[Substrate ^{Stock] = ABS 354nm * 10 6/} 18172 (mM)

Determination of stock enzyme concentration:
Stock concentration of each enzyme by 280nm of ABS, 6M guanidinium hydrochloride (Research Organics Ltd., Cat. # 5134G-2) in pH 6, HBACE1 and MuBACE1 for ε 64150M ^-1 cm ^-1, hBACE2 about 62 870 M ^-1 cm Determined using ^-1 . (The extinction coefficient ε ^{280 nm} for each enzyme is the known amino acid composition and Trp (5.69 M ⁻¹ cm ⁻¹ ) and Tyr (1.28 M ⁻¹ cm ⁻¹ ) residues (Anal. Biochem. 182, 319-326). Calculated based on the extinction coefficient published for

Dilution and mixing steps: Total reaction volume: 100 μL
1. Prepare 2X inhibitor dilution in buffer A (66.7 mM Na acetate, pH 4.5, 0.0667% CHAPS).
2. Prepare a 4X enzyme dilution in buffer A (66.7 mM Na acetate, pH 4.5, 0.0667% CHAPS).
3. Immediately add 100 μM substrate dilution, 50 μL 2X inhibitor and 25 μL 100 μM substrate in 1 × PBS to each well of a 96-well plate (DYNEX Technologies, VWR #: 1131-046) with 25 μL 4X enzyme and In addition to the substrate mixer, start the fluorescence reading.

Fluorescence reading:
Readings at λ _ex 320 nm and λ _em 420 nm are taken every 40 seconds for 30 minutes at room temperature to determine the linear slope (v _i ) for substrate cleavage rate.

Analysis of% inhibition calculations:
% Inhibition = 100 ^* (1-v _i / v ₀ )
v _i = substrate cleavage rate in the presence of inhibitor v ₀ = substrate cleavage rate in the absence of inhibitor IC ₅₀ determination:
% Inhibition = [(B ^* IC ₅₀ ⁿ ) + (100 ^* I ₀ ⁿ )] / (IC ₅₀ ⁿ + I ₀ ⁿ )

The data obtained is shown in Table I below. Unless otherwise stated, IC ₅₀ values represent values obtained with 100% inhibition.

Table I

Results and Discussion:
As can be seen from the data shown in Table I above, the compounds of the present invention are potent and selective inhibitors of BACE1.

Claims (16)

Formula I

[Where:
Q is O, S or CH ₂ ;
W is O, S or CH ₂ ;
X is N, NO, SO _m , O or CH;
Y is N, NO, SO _m , O or CR ₁₀ ;
Z is N, NO, SO _m , O or CR ₁₁ , provided that when X is CH, Y is CR ₁₀ and Z is CR ₁₁ , one of Q and W is O Or S;
m is 0, 1 or 2;
n is 0 or 1;
R ₁ and R ₂ are each independently H or an optionally substituted C ₁ -C ₄ alkyl group;
R ₃ and R ₄ are each independently H, or an optionally substituted C ₁ -C ₄ alkyl group, or R ₃ and R ₄ together are O, N and S May form a 4- to 7-membered ring which may contain 1 or 2 heteroatoms selected from:
R ₅ and R ₆ are each independently H, halogen, NO ₂ , CN, OR ₁₂ , CO ₂ R ₁₃ , COR ₁₄ , NR ₁₇ R ₁₈ , SO _p NR ₁₉ R ₂₀ , or each is substituted unprotected _C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl or _C 3 -C ₈ cycloalkyl group;
R ₇ and R ₈ are each independently H, halogen, NO ₂ , CN, OR ₁₅ , NR ₁₇ R ₁₈ , or each optionally substituted C ₁ -C ₆ alkyl, C _1- When it is a C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or cycloheteroalkyl group or attached to an adjacent carbon atom, R ₇ and R ₈ are Together with the atoms to which they are attached, they form an optionally substituted 5- to 7-membered ring which may contain 1 or 2 heteroatoms selected from O, N and S. May be;
R ₉ is H, halogen, NO ₂ , CN, OR ₁₅ , NR ₁₇ R ₁₈ , or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl. C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R ₁₀ and R ₁₁ are each independently H, or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C _{6. alkynyl,} C 3 -C ₈ cycloalkyl, cycloalkyl heteroalkyl or aryl group;
R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are each independently H, or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl. C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ are each independently H, C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, or R ₁₇ and R ₁₈ or R ₁₉ and R ₂₀ together with the atoms to which they are attached may form a 5- to 7-membered ring which may contain additional heteroatoms selected from O, N and S Often;
p is 0, 1 or 2]
Or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein R ₁ and R ₂ are H. The compound according to claim 1 or 2, wherein R ₉ is an optionally substituted heteroaryl group. The compound according to claim 3, wherein R ₉ is bonded to the 3-position of the phenyl ring.   X is N, The compound of any one of Claims 1-4. The compound according to any one of claims 1 to 5, wherein R ₃ and R ₄ are H.   n is 0 and X and Y are N, The compound of any one of Claims 1-6. n is 1, X is CH or N, Y is a compound according to any one of claims 1 to 6 is _{CR 10.} 8- [3- (2-fluoropyridin-3-yl) -phenyl] -8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo [1,5-a] pyrimidin-6-amine;
8- (2,6-Diethylpyridin-4-yl) -8- [3- (2-fluoropyridin-3-yl) -phenyl] -2,3,4,8-tetrahydro-imidazo [1,5- a] pyrimidine-6-amine;
8- (1-Ethyl-1H-pyrazol-4-yl) -8- [3- (2-fluoropyridin-3-yl) phenyl] -2,3,4,8-tetrahydro-imidazo [1,5- a] pyrimidine-6-amine;
8- [3- (2-Fluoropyridin-3-yl) phenyl] -8- [1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl] -2,3,4, 8-tetrahydroimidazo [1,5-a] pyrimidin-6-amine;
8- [3- (2-Fluoropyridin-3-yl) phenyl] -8- [4- (trifluoromethoxy) phenyl] -3,4-dihydro-8H-imidazo [5,1-c] [1, 2,4] oxadiazin-6-amine;
8- [3- (5-Fluoropyridin-3-yl) phenyl] -8- [4- (trifluoromethoxy) phenyl] -3,4-dihydro-8H-imidazo [5,1-c] [1, 2,4] oxadiazin-6-amine;
2. A compound according to claim 1 which is one of its tautomers, its stereoisomers, or pharmaceutically acceptable salts thereof.   Providing the patient with a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 9, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof. A method for the treatment, prevention or amelioration of a disease or disorder characterized by β-amyloid deposition or elevated β-amyloid levels in a patient.   11. The method of claim 10, wherein the disease or disorder is selected from Alzheimer's disease, cognitive impairment, Down's syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, and neurodegenerative disorder.   11. The method of claim 10, wherein the disease or disorder is characterized by the formation of β-amyloid deposits or neurofibrillary tangles.   A method for modulating the activity of BACE, comprising contacting a BACE receptor with an effective amount of a compound according to any one of claims 1-9.   A method of treating Alzheimer's disease in a patient in need of treatment, characterized in that the patient is provided with an effective amount of a compound according to any one of claims 1-9.   A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 9, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof. Formula II

[Wherein Hal is Cl or Br, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , n, Q, W, X, Y and Z are As defined in Formula I above]
And a compound of formula A-W ′ (wherein A is an optionally substituted aryl or heteroaryl group, W ′ is B (OH) ₂ , Sn (n ^. Bu) ₃ and Sn and (CH _{3) 3} is a leaving group selected from), it may be the presence of a solvent, which comprises reacting in the presence of a palladium catalyst, even if R ₉ is optionally substituted A process for the preparation of a compound of formula I as defined in claim 1 which is a good aryl or heteroaryl group.