HK1127036A

HK1127036A - Novel 2-aminopyrimidinone or 2-aminopyridinone derivatives and their use

Info

Publication number: HK1127036A
Application number: HK09106139.0A
Authority: HK
Inventors: Jeffrey Albert; Phil Edwards; James Empfield
Original assignee: 阿斯利康(瑞典)有限公司; 阿斯特克斯医疗公司
Priority date: 2005-11-15
Filing date: 2006-11-13
Publication date: 2009-09-18

Description

Novel 2-aminopyrimidinone derivatives or 2-aminopyridinone derivatives and use thereof

Technical Field

The present invention relates to novel compounds and pharmaceutical compositions thereof. Furthermore, the present invention relates to a therapeutic method for the treatment and/or prevention of: a β -related pathologies (a β -related pathology), such as down syndrome (down syndrome) and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), Alzheimer Disease (Alzheimer Disease), memory loss, attention deficit symptoms associated with Alzheimer Disease, neurodegeneration associated with diseases such as Alzheimer Disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's Disease, progressive supranuclear palsy or cortical basal degeneration.

Background

Several groups have identified and isolated aspartic proteases with β -secretase activity (Hussain et al, 1999, Lin et al, 2000, Yan et al, 1999, Sinha et al, 1999 and Vassar et al, 1999). Beta-secretase is also known in the relevant literature as Asp2(Yan et al, 1999), beta-site APP-cleaving enzyme (BACE) (Vassar et al, 1999) or memapsin-2(Lin et al, 2000). Identification of BACE has employed a variety of experimental approaches, such as EST database analysis (Hussain et al 1999), expression cloning (Vassar et al, 1999), identification of human homologs from public databases of predicted c.elegans proteins (Yan et al 1999) and eventual use of inhibitors to purify proteins derived from human brain (Sinha et al 1999). Thus, five groups used three different experimental approaches to identify the same enzyme, and thus it was firmly believed that BACE is a β -secretase. The following patent documents are also mentioned: WO96/40885, EP871720, U.S. Pat. Nos. 5,942,400 and 5,744,346, EP855444, US6,319,689, WO99/64587, WO99/31236, EP1037977, WO00/17369, WO01/23533, WO0047618, WO00/58479, WO00/69262, WO01/00663, WO01/00665 and US6,313,268.

It was found that BACE is a pepsin-like aspartic protease, a mature enzyme consisting of an N-terminal catalytic domain, a transmembrane domain and a small cytoplasmic domain. BACE has optimal activity at pH 4.0-5.0 (Vassar et al, 1999) and is slightly inhibited by standard pepsin inhibitors (e.g., pepstatin). It has been shown that the catalytic domain, minus the transmembrane and cytoplasmic domains, is active on the substrate peptide (Lin et al, 2000). BACE is a membrane-bound type 1 protein that is synthesized as a partially active zymogen and is abundantly expressed in brain tissue. It is thought to represent the major beta-secretase activity and is considered to be the rate-limiting step in the production of amyloid-beta-protein (a β). Thus, BACE is of particular interest in the pathology of alzheimer's disease and in the development of drugs for the treatment of alzheimer's disease.

A β or amyloid- β -protein is the major component of brain plaques, which are characteristic of Alzheimer's disease (De Strooper et al, 1999). A β is a 39-42 residue peptide formed by the specific cleavage of a class I transmembrane protein (called APP or amyloid precursor protein). The a β -secretase activity cleaves this protein between residues Met671 and Asp672 (numbering the 770aa isoform of APP), forming the N-terminus of a β. Secondary cleavage of the peptide is associated with gamma-secretase, thereby forming the C-terminus of the a β peptide.

Alzheimer's Disease (AD) is estimated to afflict more than twenty million people in the world and is believed to be the most prevalent form of dementia. Alzheimer's disease is a progressive dementia in which large deposits, i.e., amyloid plaques and neurofibrillary tangles, formed from accumulated protein breakdown products accumulate in the brain. Amyloid plaques are thought to be responsible for the decline in intelligence found in alzheimer's patients.

The probability of developing alzheimer's disease increases with age, and as the aging population of developed countries increases, this disease becomes an increasingly serious problem. In addition to this, there is a familial association with alzheimer's disease, and therefore any individual with a double mutation of APP (known as the Swedish mutation, where the mutated APP constitutes a rather improved substrate for BACE) is much more likely to develop AD, and at a young age is also much more likely to develop AD (see also US6,245,964 and US5,877,399 relating to transgenic rodents including APP-Swedish). Therefore, there is also a strong need to develop compounds that can be used in these individuals in a prophylactic manner.

The gene encoding APP is found on chromosome 21, which is also found as an extra copy in down syndrome. Patients with down syndrome tend to have alzheimer's disease at a young age, and patients with down syndrome over 40 years of age almost all show alzheimer-type pathology (Oyama et al, 1994). This is thought to be due to the extra copy of the APP gene found in these patients, which causes overexpression of APP, thus increasing APP β levels, leading to a high incidence of alzheimer's disease in this population. Thus, inhibitors of BACE are useful for reducing alzheimer-type pathology in patients with down's syndrome.

Thus, drugs that reduce or block BACE activity should be able to reduce A β levels and levels of fragments of A β in the brain or elsewhere where A β or fragments thereof are deposited, thus slowing the formation of amyloid plaques and the progression of AD or other patients involving the deposition of A β or fragments thereof (Yankner, 1996; Desstrooper and Konig, 1999). Therefore, BACE is an important candidate target for the development of drugs for the treatment and/or prevention of the following diseases: a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

Thus, by inhibiting BACE with inhibitors (e.g., the compounds provided herein), it is useful to inhibit the deposition of a β and portions thereof.

The therapeutic potential to inhibit a β deposition has prompted many research groups to isolate and characterize secretases and to identify their potential inhibitors (see, for example, WO01/23533 a2, EP0855444, WO00/17369, WO00/58479, WO00/47618, WO00/77030, WO01/00665, WO01/00663, WO01/29563, WO02/25276, US5,942,400, US6,245,884, US6,221,667, US6,211,235, WO02/02505, WO02/02506, WO02/02512, WO 02/518, WO02/02520, WO 02/0264, WO05/058311, WO05/097767 and US/2005 0282826).

Disclosure of Invention

The compounds of the invention exhibit improved properties, such as improved hERG selectivity, compared to potential inhibitors known in the art.

The present application provides novel compounds of formula Ia or Ib or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof:

wherein

W is C or N;

q is selected from C_3-12Cycloalkyl radical, C_3-12Cycloalkenyl radical, C_6-14Aryl or C_5-15A heterocyclic group;

R¹each independently selected from H, halogen, C_2-6Alkenyl radical, C_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl or C_5-15Heterocyclyl, wherein said C is_1-6Alkyl radical, said C_3-12Cycloalkyl radical, said C_6-10Aryl radical, said C_1-6alkyl-C_6-10Aryl or said C_5-15The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, CN, NH₂、OH、COOH、OC_1-6Alkyl radical, CH₂OH、SO₂H、S(＝O)、C_2-6Alkenyl radical, C_1-6alkyl-R^a、OC_1-6alkyl-R^a、C(＝O)C_1-6alkyl-R^a、C(＝O)OC_1-6alkyl-R^a、C(＝O)NH₂、C(＝O)NHC_1-6alkyl-R^a、C(＝O)N(C_1-6alkyl-R^a)₂、S(＝O)C_1-6alkyl-R^a、S(＝O)NHC_1-6alkyl-R^a、S(＝O)N(C_1-6alkyl-R^a)₂、SO₂C_1-6alkyl-R^a、SO₂NHC_1-6alkyl-R^a、SO₂N(C_1-6alkyl-R^a)₂、NH(C_1-6Alkyl) -R^a、N(C_1-6alkyl-R^a)₂、NHC(＝O)C_1-6Alkyl radical, C_6-10aryl-R^a、OC_6-10aryl-R^a、C(＝O)C_6-10aryl-R^a、C(＝O)OC_6-10aryl-R^a、C(＝O)NHC_6-10aryl-R^a、C(＝O)N(C_6-10aryl-R^a)₂、S(＝O)C_6-10aryl-R^a、S(＝O)NHC_6-10aryl-R^a、S(＝O)N(C_6-10aryl-R^a)₂、SO₂C_6-10aryl-R^a、SO₂NHC_6-10aryl-R^a、SO₂N(C_6-10aryl-R^a)₂、NH(C_6-10Aryl) -R^a、N(C_6-10aryl-R^a)₂、NC(＝O)C_6-10Aryl radical, C_5-6heterocyclyl-R^a、OC_5-6heterocyclyl-R^a、C(＝O)C_5-6heterocyclyl-R^a、C(＝O)OC_5-6heterocyclyl-R^a、C(＝O)NHC_5-6heterocyclyl-R^a、C(＝O)N(C_5-6heterocyclyl-R^a)₂、S(＝O)C_5-6heterocyclyl-R^a、S(＝O)NHC_5-6heterocyclyl-R^a、S(＝O)N(C_5-6heterocyclyl-R^a)₂、SO₂C_5-6heterocyclyl-R^a、SO₂NHC_5-6heterocyclyl-R^a、SO₂N(C_5-6heterocyclyl-R^a)₂、NH(C_5-6heterocyclyl-R^a)、N(C_5-6heterocyclyl-R^a)₂、NHC(＝O)C_5-6Heterocyclic radical, SO₂R^a、S(＝O)R^a、N(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、N(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、N(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、C(＝O)(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)O(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、C(＝O)O(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)O(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、S(＝O)(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、S(＝O)(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、S(＝O)(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、SO₂(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、SO₂(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a) Or SO₂(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)；

R^aEach independently selected from H, halogen, CN, NH₂、OH、C_1-6Alkyl, OC_1-6Alkyl, C (═ O) C_1-6Alkyl, C (═ O) OC_1-6Alkyl, C (═ O) NH₂、C(＝O)NHC_1-6Alkyl, C (═ O) N (C)_1-6Alkyl radical)₂、SOC_1-6Alkyl, SONHC_1-6Alkyl, SON (C)_1-6Alkyl radical)₂、SO₂C_1-6Alkyl, SO₂NHC_1-6Alkyl, SO₂N(C_1-6Alkyl radical)₂、NH(C_1-6Alkyl group), N (C)_1-6Alkyl radical)₂、NC(＝O)C_1-6Alkyl radical, C_5-6Aryl, OC_5-6Aryl, C (═ O) C_5-6Aryl, C (═ O) OC_5-6Aryl, C (═ O) NH₂、C(＝O)NHC_5-6Aryl, C (═ O) N (C)_5-6Aryl radical)₂、SO₂C_5-6Aryl, SO₂NHC_5-6Aryl, SO₂N(C_5-6Aryl radical)₂、NH(C_5-6Aryl group), N (C)_5-6Aryl radical)₂、NC(＝O)C_5-6Aryl radical, C_5-6Heterocyclic group, OC_5-6Heterocyclyl, C (═ O) C_5-6Heterocyclyl group, C (═ O) OC_5-6Heterocyclyl, C (═ O) NH₂、C(＝O)NHC_5-6Heterocyclyl, C (═ O) N (C)_5-6Heterocyclic radical)₂、S(＝O)C_5-6Heterocyclyl, S (═ O) NHC_5-6Heterocyclyl, S (═ O) N (C)_5-6Heterocyclic radical)₂、SO₂NHC_5-6Heterocyclic radical, SO₂N(C_5-6Heterocyclic radical)₂、NH(C_5-6Heterocyclic group), N (C)_5-6Heterocyclic radical)₂、NC(＝O)C_5-6Heterocyclyl, C (═ O) NHC_1-6Alkyl radical C_5-6Aryl, NR^bR^b、C(＝O)R^b、C(＝O)NR^bR^b、OC(＝O)NR^bR^b、S(＝O)R^b、S(＝O)NR^bR^bOr SO₂NR^bR^b；

R^bEach independently selected from H, C_1-6Alkyl radical, C_5-6Aryl or C_5-6A heterocyclic group;

each V is independently selected from NH, O, S (═ O), SO₂、NHS(＝O)、NHSO₂、S(＝O)NH、SO₂NH、NHC(＝O)、C(＝O)NH、NR^aSO₂、NR^aS(＝O)、NR^aC(O)、C(O)NR^a、S(O)₂NR^a、S(＝O)NR^a、OC_1-6Alkylene radical, C_2-6Alkenylene or C_1-6Alkylene, wherein said OC_1-6Alkylene radical, C_2-6Alkenylene and C_1-6Alkylene is optionally substituted by 1,2 or 3 independently selected from R^aSubstituted with the substituent(s);

x and Y are each independently selected from NH, O, S (═ O), SO₂、NHS(＝O)、NHSO₂、S(＝O)NH、SO₂NH、NHC(＝O)、C(＝O)NH、NR^aSO₂、NR^aS(＝O)、NR^aC(O)、C(O)NR^a、S(O)₂NR^a、S(＝O)NR^aOr C_1-6Alkylene, wherein said C_1-6Alkylene is optionally substituted by 1,2 or 3 independently selected from R^aSubstituted with the substituent(s);

z is

m is 0, 1,2 or 3;

n, q, r and u are each independently 0 or 1;

s is 1 or 2;

R²selected from H, halogen, C_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl radical, C_5-10Heterocyclyl or C_1-6alkyl-C_5-10Heterocyclyl, wherein said C is_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl radical, C_5-10Heterocyclyl and C_1-6alkyl-C_5-10The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, CN, NH₂、OH、C_1-6alkyl-R^a、OC_1-6alkyl-R^a、C(＝O)C_1-6alkyl-R^a、C(＝O)OC_1-6alkyl-R^a、C(＝O)NH₂、C(＝O)NHC_1-6alkyl-R^a、C(＝O)N(C_1-6alkyl-R^a)₂、S(＝O)C_1-6alkyl-R^a、S(＝O)NHC_1-6alkyl-R^a、S(＝O)N(C_1-6alkyl-R^a)₂、SO₂C_1-6alkyl-R^a、SO₂NHC_1-6alkyl-R^a、SO₂N(C_1-6alkyl-R^a)₂、NH(C_1-6Alkyl) -R^a、N(C_1-6alkyl-R^a)₂、NHC(＝O)C_1-6Alkyl radical, C_5-6aryl-R^a、OC_5-6aryl-R^a、C(＝O)C_5-6aryl-R^a、C(＝O)OC_5-6aryl-R^a、C(＝O)NH₂、C(＝O)NHC_5-6aryl-R^a、C(＝O)N(C_5-6aryl-R^a)₂、S(＝O)C_5-6aryl-R^a、S(＝O)NHC_5-6aryl-R^a、S(＝O)N(C_5-6aryl-R^a)₂、SO₂C_5-6aryl-R^a、SO₂NHC_5-6aryl-R^a、SO₂N(C_5-6aryl-R^a)₂、NH(C_5-6Aryl) -R^a、N(C_5-6aryl-R^a)₂、NHC(＝O)C_5-6Aryl radical, C_5-6heterocyclyl-R^a、OC_5-6heterocyclyl-R^a、C(＝O)C_5-6heterocyclyl-R^a、C(＝O)OC_5-6heterocyclyl-R^a、C(＝O)NH₂、C(＝O)NHC_5-6heterocyclyl-R^a、C(＝O)N(C_5-6heterocyclyl-R^a)₂、SO₂C_5-6heterocyclyl-R^a、SO₂NHC_5-6heterocyclyl-R^a、SO₂N(C_5-6heterocyclyl-R^a)₂、S(＝O)C_5-6heterocyclyl-R^a、S(＝O)NHC_5-6heterocyclyl-R^a、S(＝O)N(C_5-6heterocyclyl-R^a)₂、NH(C_5-6Heterocyclyl) -R^a、N(C_5-6heterocyclyl-R^a)₂Or NHC (═ O) C_5-6A heterocyclic group;

R³is selected from R¹、C_1-6Alkyl radical R^c、C_1-6Alkyl radical NR^cR^c、C_1-6Alkyl OR^c、C_1-6Alkyl SR^c、C_1-6Alkyl NHC_1-6Alkyl radical C_5-6Aryl radical R^d、C_1-6Alkyl NHC_6-10Aryl radical R^d、C_1-6Alkyl NHC (O) C_6-10Aryl radical R^d、C_1-6Alkyl OC_1-6Alkyl radical C_5-6Aryl radical R^d、C_1-6Alkyl group SC_1-6Alkyl radical C_5-6Aryl radical R^d、C_1-6Alkyl radical C_5-9Heterocyclic radical R^d、C_1-6Alkyl radical C_3-9Cycloalkyl radical R^d、C_1-6Alkyl NHC_1-6Alkyl radical C_5-9Heterocyclic radical R^d、C_1-6Alkyl NHC_5-9Heterocyclic radical (R)^d)_t、C_1-6Alkyl NHC (O) C_5-9Heterocyclic radical R^d、C_1-6Alkyl OC_1-6Alkyl radical C_5-9Heterocyclic radical R^d、C_1-6Alkyl group SC_1-6Alkyl radical C_5-9Heterocyclic radical R^d、C_1-6Alkyl NHC_1-6Alkyl radical C_3-9Cycloalkyl radical R^d、C_1-6Alkyl OC_1-6Alkyl radical C_3-9Cycloalkyl radical R^dOr C_1-6Alkyl group SC_1-6Alkyl radical C_3-9Cycloalkyl radical R^d；

R⁴Each independently selected from H, halogen, C_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl radical, C_5-10Heterocyclyl or C_1-6alkyl-C_5-10Heterocyclyl, wherein said C is_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl radical, C_5-10Heterocyclyl and C_1-6alkyl-C_5-10The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, CN, NH₂、OH、C_1-6alkyl-R^a、OC_1-6alkyl-R^a、C(＝O)C_1-6alkyl-R^a、C(＝O)OC_1-6alkyl-R^a、C(＝O)NH₂、C(＝O)NHC_1-6alkyl-R^a、C(＝O)N(C_1-6alkyl-R^a)₂、S(＝O)C_1-6alkyl-R^a、S(＝O)NHC_1-6alkyl-R^a、S(＝O)N(C_1-6Alkyl radical-R^a)₂、SO₂C_1-6alkyl-R^a、SO₂NHC_1-6alkyl-R^a、SO₂N(C_1-6alkyl-R^a)₂、NH(C_1-6Alkyl) -R^a、N(C_1-6alkyl-R^a)₂Or NHC (═ O) C_1-6An alkyl group;

t is 0, 1,2, 3, 4 or 5;

R^ceach independently selected from H, C (═ O) C_1-4Alkyl, C (═ O) C_1-4Alkyl OC_1-4Alkyl, C (═ O) C_1-4Alkyl C (═ O) OC_1-4Alkyl, C (═ O) C_1-4Alkyl C (═ O) OH, C (═ O) C_1-4Alkyl OC (═ O) C_1-4Alkyl radical, C_5-6Aryl radical R^d、C_5-9Heterocyclic radical R^d、C_3-9Cycloalkyl radical R^d、C(＝O)C_5-6Aryl radical R^d、C(＝O)C_5-9Heterocyclic radical R^d、C(＝O)C_3-9Cycloalkyl radical R^d、C_1-4alkyl-C_5-6Aryl radical R^d、C_1-4alkyl-C_5-9Heterocyclic radical R^dOr C_1-4alkyl-C_3-9Cycloalkyl radical R^d(ii) a And is

R^dSelected from H, C_1-3Alkyl, NH₂、OH、COOH、OC_1-3Alkyl or OC_1-3An alkyl group OH;

provided that when the compound has formula Ib, W is N, u is 1, and R is³When is H, [ R ]¹-(V)_n]_m-Q is not poly-C_1-4Alkyl-substituted cyclohexenyl or nitro-substituted furyl.

In some embodiments, the compound has formula Ia.

In some embodiments, the compound has formula Ib.

In some embodiments, W is N.

In some embodiments, R³Selected from H, C_1-6Alkyl radical, C_1-6Alkyl radical NR^cR^c、C_1-6Alkyl OR^c、C_1-6Alkyl NHC_1-6Alkyl radical C_6-10Aryl radical R^d、C_1-6Alkyl NHC (O) C_6-10Aryl radical R^d、C_1-6Alkyl OC_1-6Alkyl radical C_5-6Aryl radical R^d、C_1-6Alkyl radical C_6-10Aryl radical R^d、C_1-6Alkyl radical C_5-9Heterocyclic radical R^dOr C_1-6Alkyl radical C_3-9Cycloalkyl radical R^d. In some embodiments, R³Selected from H, C_1-6Alkyl radical, C_1-6Alkyl radical NR^cR^cOr C_1-6alkyl-C_5-9Heterocyclic radical R^d. In some embodiments, R³Is C_1-3An alkyl group.

In some embodiments, Q is C_6-10Aryl radical, C_3-10Cycloalkyl or C_3-10A cycloalkenyl group. In some embodiments, Q is C₆Aryl or C_3-10A cycloalkenyl group.

In some embodiments, - [ X ]]_q-[Y]_rIs OC_1-3Alkylene, N (C)_1-3Alkyl) C_1-3Alkylene radical, C_1-3Alkylene OC_1-3Alkylene radical, C_1-3Alkylene radical N (H) C_1-3Alkylene or C_1-3Alkylene, said group being optionally substituted with OH.

In some embodiments, q is 0, R is 0, and R is⁴Each is H.

In some embodiments, m is 1, V is S, n is 0 or 1, and R is¹Is C_6-10Aryl or C_5-15Heterocyclyl, wherein said aryl and heterocyclyl are each optionally substituted with 1 or 2 substituents independently selected from: halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl, OC_1-4Alkyl, OC_1-4Haloalkyl, -C (O) H, COOH, OC_1-4alkyl-C_6-10Aryl, OH, NHC (═ O) C_1-4Alkyl radicals and-C₆aryl-OC_1-4An alkyl group.

In some embodiments, m is 1, n is 0, and R is¹Is C_6-10Aryl, wherein said aryl is optionally substituted with 1 or 2 substituents independently selected from: halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl, OC_1-4Alkyl, OC_1-4Haloalkyl, -C (O) H, COOH, OC_1-4alkyl-C_6-10Aryl, OH, NHC (═ O) C_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

In some embodiments, R¹Independently selected from H, halogen, C₆Aryl or C_5-6Heterocyclyl, wherein said C is₆Aryl or C_5-6The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, OH, NH₂、CN、C(＝O)NH₂、C_1-6Alkyl, OC_1-6Alkyl radical, C_1-4Alkyl OH, C_1-4Alkyl OC_1-3Alkyl radical, CH₂OH、SO₂H、SO₂NHC(CH₃)₃、SO₂C_1-6Alkyl, SO₂NHC_1-6Alkyl, OC_1-3Alkyl OC_1-3Alkyl, OC_1-3Alkyl OH, OC_1-3Alkyl OC (═ O) C_1-3Alkyl, C (═ O) C_1-6Alkyl, C (═ O) OC_1-6Alkyl, C (═ O) NH₂、C_5-6Heterocyclic group, OC_5-6Aryl radical, -C₆aryl-OC_1-4Alkyl or OC_1-6alkyl-C_5-6An aryl group; r²Is H or C_1-6An alkyl group; r³Is H or C_1-3An alkyl group; and R is⁴Each is H.

In some embodiments, Q is C₆Aryl or C_5-9A heterocyclic group; w is N; r¹Independently selected from H, halogen, C₆Aryl or C_5-6Heterocyclyl, wherein said C is₆Aryl or C_5-6The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, OH, NH₂、CN、C(＝O)NH₂、C_1-6Alkyl, OC_1-6Alkyl radical, C_1-4Alkyl OH, C_1-4Alkyl OC_1-3Alkyl radical, CH₂OH、SO₂H、SO₂NHC(CH₃)₃、SO₂C_1-6Alkyl, SO₂NHC_1-6Alkyl, OC_1-3Alkyl OC_1-3Alkyl, OC_1-3Alkyl OH, OC_1-3Alkyl OC (═ O) C_1-3Alkyl, C (═ O) C_1-6Alkyl, C (═ O) OC_1-6Alkyl, C (═ O) NH₂、C_5-6Heterocyclic group, OC_5-6Aryl radical, -C₆aryl-OC_1-4Alkyl or OC_1-6alkyl-C_5-6An aryl group; and R is²Is C_1-3An alkyl group.

In some embodiments, Q is C_6-10An aryl group; w is N; - [ X ]]_q-[Y]_rIs OC_1-3An alkylene group; m is 1; n is 0; and R is¹Is C_6-10Aryl radical, said C_6-10Aryl is optionally substituted with 1 or 2 substituents independently selected from: OC_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

In some embodiments, Q is C_3-10A cycloalkenyl group; w is N; - [ X ]]_q-[Y]_r-is absent; m is 1; n is 0; and R is¹Is C_6-10Aryl radical, said C_6-10Aryl is optionally substituted with 1 or 2 substituents independently selected from: OC_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

In some embodiments, Q is C_6-10Aryl radical, C_3-10Cycloalkyl or C_3-10A cycloalkenyl group; w is N; - [ X ]]_q-[Y]_rIs OC_1-3Alkylene, N (C)_1-3Alkyl) C_1-3Alkylene radical, C_1-3Alkylene OC_1-3Alkylene radical, C_1-3Alkylene radical N (H) C_1-3Alkylene or C_1-3Alkylene, said group being optionally substituted with OH; m is 1; v is S; n is 0 or 1; and R is¹Is C_6-10Aryl or C_5-15Heterocyclic ringsWherein said aryl and heterocyclyl are each optionally substituted with 1 or 2 substituents independently selected from: halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl, OC_1-4Alkyl, OC_1-4Haloalkyl, -C (O) H, COOH, OC_1-4alkyl-C_6-10Aryl, OH, NHC (═ O) C_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

In some embodiments, the compound is:

2-amino-6- [ (Z) -2- (3' -methoxybiphenyl-3-yl) vinyl ] -3-methylpyrimidin-4 (3H) -one;

2-amino-6- [ (E) -2- (3' -methoxybiphenyl-3-yl) vinyl ] -3-methylpyrimidin-4 (3H) -one;

2-amino-6- [ (Z) -2- (3-bromophenyl) vinyl ] -3-methylpyrimidin-4 (3H) -one;

2-amino-6- [ (E) -2- (3-bromophenyl) vinyl ] -3-methylpyrimidin-4 (3H) -one;

or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof.

The present invention also provides a composition comprising a compound of formula Ia or Ib, or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

The present invention also provides methods of modulating the activity of BACE comprising contacting BACE with a compound of formula Ia or Ib, or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof.

The present invention also provides a method of treating or preventing an a β -related pathology in a patient, comprising administering to said patient a therapeutically effective amount of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof.

The present invention also provides a compound of formula Ia or Ib or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, for use as a medicament as described herein.

The present invention also provides a compound of formula Ia or Ib or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, for use in the manufacture of a medicament as described herein.

Detailed Description

in some embodiments, W is C or N. In some embodiments, W is N.

In some embodiments, Q is selected from C_3-12Cycloalkyl radical, C_3-12Cycloalkenyl radical, C_6-14Aryl or C_5-15Heterocyclyl or any subgroup thereof (subgroup). In some embodiments, Q is C_6-10Aryl radical, C_3-10Cycloalkyl or C_3-10A cycloalkenyl group. In some embodiments, Q is C₆Aryl or C_3-10A cycloalkenyl group. In some embodiments, Q is C₆Aryl or C_5-9A heterocyclic group. In some embodiments, Q is C_6-10And (4) an aryl group. In some embodiments, Q is C_3-10A cycloalkenyl group.

In some embodiments, R¹Each independently selected from H, halogen, C_2-6Alkenyl radical, C_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl or C_5-15Heterocyclyl or any subclass thereof, wherein said C_1-6Alkyl radical, said C_3-12Cycloalkyl radical, said C_6-10Aryl radical, said C_1-6alkyl-C_6-10Aryl or said C_5-15The heterocyclic group is optionally substituted by 1,2 or 3 substituents independently selected fromGeneration: halogen, CN, NH₂、OH、COOH、OC_1-6Alkyl radical, CH₂OH、SO₂H、S(＝O)、C_2-6Alkenyl radical, C_1-6alkyl-R^a、OC_1-6alkyl-R^a、C(＝O)C_1-6alkyl-R^a、C(＝O)OC_1-6alkyl-R^a、C(＝O)NH₂、C(＝O)NHC_1-6alkyl-R^a、C(＝O)N(C_1-6alkyl-R^a)₂、S(＝O)C_1-6alkyl-R^a、S(＝O)NHC_1-6alkyl-R^a、S(＝O)N(C_1-6alkyl-R^a)₂、SO₂C_1-6alkyl-R^a、SO₂NHC_1-6alkyl-R^a、SO₂N(C_1-6alkyl-R^a)₂、NH(C_1-6Alkyl) -R^a、N(C_1-6alkyl-R^a)₂、NHC(＝O)C_1-6Alkyl radical, C_6-10aryl-R^a、OC_6-10aryl-R^a、C(＝O)C_6-10aryl-R^a、C(＝O)OC_6-10aryl-R^a、C(＝O)NHC_6-10aryl-R^a、C(＝O)N(C_6-10aryl-R^a)₂、S(＝O)C_6-10aryl-R^a、S(＝O)NHC_6-10aryl-R^a、S(＝O)N(C_6-10aryl-R^a)₂、SO₂C_6-10aryl-R^a、SO₂NHC_6-10aryl-R^a、SO₂N(C_6-10aryl-R^a)₂、NH(C_6-10Aryl) -R^a、N(C_6-10aryl-R^a)₂、NC(＝O)C_6-10Aryl radical, C_5-6heterocyclyl-R^a、OC_5-6heterocyclyl-R^a、C(＝O)C_5-6heterocyclyl-R^a、C(＝O)OC_5-6heterocyclyl-R^a、C(＝O)NHC_5-6heterocyclyl-R^a、C(＝O)N(C_5-6heterocyclyl-R^a)₂、S(＝O)C_5-6heterocyclyl-R^a、S(＝O)NHC_5-6heterocyclyl-R^a、S(＝O)N(C_5-6heterocyclyl-R^a)₂、SO₂C_5-6heterocyclyl-R^a、SO₂NHC_5-6heterocyclyl-R^a、SO₂N(C_5-6heterocyclyl-R^a)₂、NH(C_5-6heterocyclyl-R^a)、N(C_5-6heterocyclyl-R^a)₂、NHC(＝O)C_5-6Heterocyclic radical, SO₂R^a、S(＝O)R^a、N(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、N(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、N(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、C(＝O)(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)O(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、C(＝O)O(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)O(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、S(＝O)(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、S(＝O)(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、S(＝O)(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、SO₂(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、SO₂(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a) Or SO₂(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a) Or any subclass thereof. In some embodiments, R¹Independently selected from H, halogen, C₆Aryl or C_5-6Heterocyclyl, wherein said C is₆Aryl or C_5-6The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, OH, NH₂、CN、C(＝O)NH₂、C_1-6Alkyl, OC_1-6Alkyl radical, C_1-4Alkyl OH, C_1-4Alkyl OC_1-3Alkyl radical, CH₂OH、SO₂H、SO₂NHC(CH₃)₃、SO₂C_1-6Alkyl, SO₂NHC_1-6Alkyl, OC_1-3Alkyl OC_1-3Alkyl, OC_1-3Alkyl OH, OC_1-3Alkyl OC (═ O) C_1-3Alkyl, C (═ O) C_1-6Alkyl, C (═ O) OC_1-6Alkyl, C (═ O) NH₂、C_5-6Heterocyclic group, OC_5-6Aryl radical, -C₆aryl-OC_1-4Alkyl or OC_1-6alkyl-C_5-6And (4) an aryl group. In some embodiments, R¹Is C_6-10Aryl or C_5-15Heterocyclyl, wherein said aryl and heterocyclyl are each optionally substituted with 1 or 2 substituents independently selected from: halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl, OC_1-4Alkyl, OC_1-4Haloalkyl, -C (O) H, COOH, OC_1-4alkyl-C_6-10Aryl, OH, NHC (═ O) C_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group. In some embodiments, R¹Is C_6-10Aryl radical, said C_6-10Aryl is optionally substituted with 1 or 2 substituents independently selected from: OC_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

In some embodiments, R^aEach independently selected from H, halogen, CN, NH₂、OH、C_1-6Alkyl, OC_1-6Alkyl, C (═ O) C_1-6Alkyl, C (═ O) OC_1-6Alkyl, C (═ O) NH₂、C(＝O)NHC_1-6Alkyl, C (═ O) N (C)_1-6Alkyl radical)₂、SOC_1-6Alkyl, SONHC_1-6Alkyl, SON (C)_1-6Alkyl radical)₂、SO₂C_1-6Alkyl, SO₂NHC_1-6Alkyl, SO₂N(C_1-6Alkyl radical)₂、NH(C_1-6Alkyl group), N (C)_1-6Alkyl radical)₂、NC(＝O)C_1-6Alkyl radical, C_5-6Aryl, OC_5-6Aryl, C (═ O) C_5-6Aryl, C (═ O) OC_5-6Aryl, C (═ O) NH₂、C(＝O)NHC_5-6Aryl, C (═ O) N (C)_5-6Aryl radical)₂、SO₂C_5-6Aryl, SO₂NHC_5-6Aryl, SO₂N(C_5-6Aryl radical)₂、NH(C_5-6Aryl group), N (C)_5-6Aryl radical)₂、NC(＝O)C_5-6Aryl radical, C_5-6Heterocyclic group, OC_5-6Heterocyclyl, C (═ O) C_5-6Heterocyclyl group, C (═ O) OC_5-6Heterocyclyl, C (═ O) NH₂、C(＝O)NHC_5-6Heterocyclyl, C (═ O) N (C)_5-6Heterocyclic radical)₂、S(＝O)C_5-6Heterocyclyl, S (═ O) NHC_5-6Heterocyclyl, S (═ O) N (C)_5-6Heterocyclic radical)₂、SO₂NHC_5-6Heterocyclic radical, SO₂N(C_5-6Heterocyclic radical)₂、NH(C_5-6Heterocyclic group), N (C)_5-6Heterocyclic radical)₂、NC(＝O)C_5-6Heterocyclyl, C (═ O) NHC_1-6Alkyl radical C_5-6Aryl, NR^bR^b、C(＝O)R^b、C(＝O)NR^bR^b、OC(＝O)NR^bR^b、S(＝O)R^b、S(＝O)NR^bR^bOr SO₂NR^bR^bOr any subclass thereof.

In some embodiments, R^bEach independently selected from H, C_1-6Alkyl radical, C_5-6Aryl or C_5-6Heterocyclyl or any subclass thereof.

In some embodiments, each V is independently selected from NH, O, S (═ O), SO₂、NHS(＝O)、NHSO₂、S(＝O)NH、SO₂NH、NHC(＝O)、C(＝O)NH、NR^aSO₂、NR^aS(＝O)、NR^aC(O)、C(O)NR^a、S(O)₂NR^a、S(＝O)NR^a、OC_1-6Alkylene radical, C_2-6Alkenylene or C_1-6Alkylene or any subclass thereof, wherein said OC is_1-6Alkylene radical, C_2-6Alkenylene and C_1-6Alkylene is optionally substituted by 1,2 or 3 independently selected from R^aOr any subclass thereof.

In some embodiments, X and Y are each independently selected from NH, O, S (═ O), SO₂、NHS(＝O)、NHSO₂、S(＝O)NH、SO₂NH、NHC(＝O)、C(＝O)NH、NR^aSO₂、NR^aS(＝O)、NR^aC(O)、C(O)NR^a、S(O)₂NR^a、S(＝O)NR^aOr C_1-6Alkylene or any subclass thereof, wherein said C_1-6Alkylene is optionally substituted by 1,2 or 3 independently selected from R^aOr any subclass thereof.

In some embodiments, Z is

In some embodiments, m is 0, 1,2, or 3, or any subclass thereof.

In some embodiments, n, q, r, and u are each independently 0 or 1.

In some embodiments, s is 1 or 2.

In some embodiments, R²Selected from H, halogen, C_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl radical, C_5-10Heterocyclyl or C_1-6alkyl-C_5-10Heterocyclyl or any subclass thereof, wherein said C_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl radical, C_5-10Heterocyclyl and C_1-6alkyl-C_5-10The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, CN, NH₂、OH、C_1-6alkyl-R^a、OC_1-6alkyl-R^a、C(＝O)C_1-6alkyl-R^a、C(＝O)OC_1-6alkyl-R^a、C(＝O)NH₂、C(＝O)NHC_1-6alkyl-R^a、C(＝O)N(C_1-6alkyl-R^a)₂、S(＝O)C_1-6alkyl-R^a、S(＝O)NHC_1-6alkyl-R^a、S(＝O)N(C_1-6alkyl-R^a)₂、SO₂C_1-6alkyl-R^a、SO₂NHC_1-6alkyl-R^a、SO₂N(C_1-6alkyl-R^a)₂、NH(C_1-6Alkyl) -R^a、N(C_1-6alkyl-R^a)₂、NHC(＝O)C_1-6Alkyl radical, C_5-6aryl-R^a、OC_5-6aryl-R^a、C(＝O)C_5-6aryl-R^a、C(＝O)OC_5-6aryl-R^a、C(＝O)NH₂、C(＝O)NHC_5-6aryl-R^a、C(＝O)N(C_5-6aryl-R^a)₂、S(＝O)C_5-6aryl-R^a、S(＝O)NHC_5-6aryl-R^a、S(＝O)N(C_5-6aryl-R^a)₂、SO₂C_5-6aryl-R^a、SO₂NHC_5-6aryl-R^a、SO₂N(C_5-6aryl-R^a)₂、NH(C_5-6Aryl) -R^a、N(C_5-6aryl-R^a)₂、NHC(＝O)C_5-6Aryl radical, C_5-6heterocyclyl-R^a、OC_5-6heterocyclyl-R^a、C(＝O)C_5-6heterocyclyl-R^a、C(＝O)OC_5-6heterocyclyl-R^a、C(＝O)NH₂、C(＝O)NHC_5-6heterocyclyl-R^a、C(＝O)N(C_5-6heterocyclyl-R^a)₂、SO₂C_5-6heterocyclyl-R^a、SO₂NHC_5-6heterocyclyl-R^a、SO₂N(C_5-6heterocyclyl-R^a)₂、S(＝O)C_5-6heterocyclyl-R^a、S(＝O)NHC_5-6heterocyclyl-R^a、S(＝O)N(C_5-6heterocyclyl-R^a)₂、NH(C_5-6Heterocyclyl) -R^a、N(C_5-6heterocyclyl-R^a)₂Or NHC (═ O) C_5-6Heterocyclyl or any subclass thereof. In some embodiments, R²Is C_1-3An alkyl group.

In some embodiments, R³Is selected from R¹、C_1-6Alkyl radical R^c、C_1-6Alkyl radical NR^cR^c、C_1-6Alkyl OR^c、C_1-6Alkyl SR^c、C_1-6Alkyl NHC_1-6Alkyl radical C_5-6Aryl radical R^d、C_1-6Alkyl NHC_6-10Aryl radical R^d、C_1-6Alkyl NHC (O) C_6-10Aryl radical R^d、C_1-6Alkyl OC_1-6Alkyl radical C_5-6Aryl radical R^d、C_1-6Alkyl group SC_1-6Alkyl radical C_5-6Aryl radical R^d、C_1-6Alkyl radical C_5-9Heterocyclic radical R^d、C_1-6Alkyl radical C_3-9Cycloalkyl radical R^d、C_1-6Alkyl NHC_1-6Alkyl radical C_5-9Heterocyclic radical R^d、C_1-6Alkyl NHC_5-9Heterocyclic radical (R)^d)_t、C_1-6Alkyl NHC (O) C_5-9Heterocyclic radical R^d、C_1-6Alkyl OC_1-6Alkyl radical C_5-9Heterocyclic radical R^d、C_1-6Alkyl group SC_1-6Alkyl radical C_5-9Heterocyclic radical R^d、C_1-6Alkyl NHC_1-6Alkyl radical C_3-9Cycloalkyl radical R^d、C_1-6Alkyl OC_1-6Alkyl radical C_3-9Cycloalkyl radical R^dOr C_1-6Alkyl group SC_1-6Alkyl radical C_3-9Cycloalkyl radical R^d. In some embodiments, R³Selected from H, C_1-6Alkyl radical, C_1-6Alkyl radical NR^cR^c、C_1-6Alkyl OR^c、C_1-6Alkyl NHC_1-6Alkyl radical C_6-10Aryl radical R^d、C_1-6Alkyl NHC (O) C_6-10Aryl radical R^d、C_1-6Alkyl OC_1-6Alkyl radical C_5-6Aryl radical R^d、C_1-6Alkyl radical C_6-10Aryl radical R^d、C_1-6Alkyl radical C_5-9Heterocyclic radical R^dOr C_1-6Alkyl radical C_3-9Cycloalkyl radical R^d. In some embodiments, R³Selected from H, C_1-6Alkyl radical, C_1-6Alkyl radical NR^cR^cOr C_1-6alkyl-C_5-9Heterocyclic radical R^d. In some embodiments, R³Is H or C_1-3An alkyl group.

In some embodiments, R³Is C_1-3An alkyl group.

In some embodiments, R⁴Each independently selected from H, halogen, C_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl radical, C_5-10Heterocyclyl or C_1-6alkyl-C_5-10Heterocyclyl or any subclass thereof, wherein said C_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl radical, C_5-10Heterocyclyl and C_1-6alkyl-C_5-10The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, CN, NH₂、OH、C_1-6alkyl-R^a、OC_1-6alkyl-R^a、C(＝O)C_1-6alkyl-R^a、C(＝O)OC_1-6alkyl-R^a、C(＝O)NH₂、C(＝O)NHC_1-6alkyl-R^a、C(＝O)N(C_1-6alkyl-R^a)₂、S(＝O)C_1-6alkyl-R^a、S(＝O)NHC_1-6alkyl-R^a、S(＝O)N(C_1-6alkyl-R^a)₂、SO₂C_1-6alkyl-R^a、SO₂NHC_1-6alkyl-R^a、SO₂N(C_1-6alkyl-R^a)₂、NH(C_1-6Alkyl) -R^a、N(C_1-6alkyl-R^a)₂Or NHC (═ O) C_1-6Alkyl groups or any subclass thereof. At one endIn some embodiments, R⁴Each is H.

In some embodiments, t is 0, 1,2, 3, 4, or 5.

In some embodiments, R^cEach independently selected from H, C (═ O) C_1-4Alkyl, C (═ O) C_1-4Alkyl OC_1-4Alkyl, C (═ O) C_1-4Alkyl C (═ O) OC_1-4Alkyl, C (═ O) C_1-4Alkyl C (═ O) OH, C (═ O) C_1-4Alkyl OC (═ O) C_1-4Alkyl radical, C_5-6Aryl radical R^d、C_5-9Heterocyclic radical R^d、C_3-9Cycloalkyl radical R^d、C(＝O)C_5-6Aryl radical R^d、C(＝O)C_5-9Heterocyclic radical R^d、C(＝O)C_3-9Cycloalkyl radical R^d、C_1-4alkyl-C_5-6Aryl radical R^d、C_1-4alkyl-C_5-9Heterocyclic radical R^dOr C_1-4alkyl-C_3-9Cycloalkyl radical R^dOr any subclass thereof.

In some embodiments, R^dSelected from H, C_1-3Alkyl, NH₂、OH、COOH、OC_1-3Alkyl or OC_1-3Alkyl OH or any subclass thereof.

However, when the compound has formula Ib, W is N, u is 1, and R is³When is H, [ R ]¹-(V)_n]_m-Q is not poly-C_1-4Alkyl-substituted cyclohexenyl or nitro-substituted furyl.

In some embodiments, the compound has formula Ia.

In some embodiments, the compound has formula Ib.

In some embodiments, - [ X ]]_q-[Y]_rIs OC_1-3Alkylene, N (C)_1-3Alkyl) C_1-3Alkylene radical, C_1-3Alkylene OC_1-3Alkylene radical, C_1-3Alkylene radical N (H) C_1-3Alkylene or C_1-3Alkylene group ofThe groups are optionally substituted with OH. In some embodiments, - [ X ]]_q-[Y]_rIs OC_1-3An alkylene group. In some embodiments, - [ X ]]_q-[Y]_r-is absent.

In some embodiments, q is 0, R is 0, and R is⁴Each is H.

In some embodiments, m is 1, V is S, n is 0 or 1, and R is¹Is C_6-10Aryl or C_5-15Heterocyclyl, wherein said aryl and heterocyclyl are each optionally substituted with 1 or 2 substituents independently selected from: halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl, OC_1-4Alkyl, OC_1-4Haloalkyl, -C (O) H, COOH, OC_1-4alkyl-C_6-10Aryl, OH, NHC (═ O) C_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

In some embodiments, Q is C_3-10A cycloalkenyl group;w is N; - [ X ]]_q-[Y]_r-is absent; m is 1; n is 0; and R is¹Is C_6-10Aryl radical, said C_6-10Aryl is optionally substituted with 1 or 2 substituents independently selected from: OC_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

In some embodiments, Q is C_6-10Aryl radical, C_3-10Cycloalkyl or C_3-10A cycloalkenyl group; w is N; - [ X ]]_q-[Y]_rIs OC_1-3Alkylene, N (C)_1-3Alkyl) C_1-3Alkylene radical, C_1-3Alkylene OC_1-3Alkylene radical, C_1-3Alkylene radical N (H) C_1-3Alkylene or C_1-3Alkylene, said group being optionally substituted with OH; m is 1; v is S; n is 0 or 1; and R is¹Is C_6-10Aryl or C_5-15Heterocyclyl, wherein said aryl and heterocyclyl are each optionally substituted with 1 or 2 substituents independently selected from: halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl, OC_1-4Alkyl, OC_1-4Haloalkyl, -C (O) H, COOH, OC_1-4alkyl-C_6-10Aryl, OH, NHC (═ O) C_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

In some embodiments, the compound is:

2-amino-6- [ [3- (3-methoxyphenyl) phenoxy ] methyl ] -3-methyl-3H-pyrimidin-4-one;

2-amino-6- [2- [3- (3-methoxyphenyl) phenyl ] -3-bicyclo [2.2.1] hept-5-enyl ] -3-methyl-3H-pyrimidin-4-one;

The compounds of the present invention also include pharmaceutically acceptable salts, tautomers and in vivo hydrolysable precursors of the compounds of formula Ia or Ib. The compounds of the present invention also include hydrates and solvates.

The compounds of the invention are useful as medicaments. In some embodiments, the present invention provides a compound of formula Ia or Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, for use as a medicament. In some embodiments, the present invention provides a compound described herein for use as a medicament for treating or preventing an a β -related pathology. In other embodiments, the a β -related pathology is downs syndrome, a β -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), alzheimer disease, memory loss, attention deficit symptoms associated with alzheimer disease, neurodegeneration associated with alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

In some embodiments, the present invention provides a compound of formula Ia or Ib, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, for use in the manufacture of a medicament for use in the treatment or prevention of an a β -related pathology. In other embodiments, a β -related pathologies include, for example, down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

In some embodiments, the present invention provides methods of inhibiting the activity of BACE comprising contacting BACE with a compound of the present invention. BACE is thought to represent the major β -secretase activity and is considered to be the rate-limiting step in the production of amyloid- β -protein (A β). Thus, inhibition of BACE with inhibitors (e.g., compounds provided herein) may be useful for inhibiting the deposition of a β and portions thereof. Since deposition of a β and portions thereof is associated with diseases such as alzheimer's disease, BACE is an important candidate target for the development of drugs for the treatment and/or prevention of the following diseases: a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

In some embodiments, the present invention provides methods for treating: an a β -related pathology, such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration, comprising administering to a mammal (including a human) a therapeutically effective amount of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof.

In some embodiments, the present invention provides methods for preventing: an a β -related pathology, such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration, comprising administering to a mammal (including a human) a therapeutically effective amount of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof.

In some embodiments, the present invention provides methods for treating or preventing the following diseases by administering to a mammal (including a human) a compound of formula Ia or Ib, or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof, and a cognitive and/or memory enhancing agent: a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

In some embodiments, the present invention provides methods of treating or preventing the following diseases by administering to a mammal (including a human) a compound of formula Ia or Ib, or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof, each of which is provided herein, and a cholinesterase inhibitor or an anti-inflammatory agent: a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

In some embodiments, the present invention provides methods of treating or preventing the following diseases by administering a compound of the present invention and an atypical antipsychotic to a mammal (including a human): a β -related pathologies such as down's syndrome and β -amyloid angiopathy, such as, but not limited to, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as, but not limited to, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with diseases such as alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration or any other disease, disorder or condition described herein. Atypical antipsychotics include, but are not limited to, Olanzapine (Olanzapine) (commercially available as Zyprexa), Aripiprazole (Aripiprazole) (commercially available as Abilify), Risperidone (Risperidone) (commercially available as Risperdal), Quetiapine (Quetiapine) (commercially available as seroque), Clozapine (Clozapine) (commercially available as Clozaril), Ziprasidone (Ziprasidone) (commercially available as Geodon), and Olanzapine/Fluoxetine (Olanzapine/Fluoxetine) (commercially available as symbax).

In some embodiments, a mammal or human being treated with a compound of the invention has been diagnosed with a particular disease or disorder, such as those described herein. In these cases, the mammal or human being treated is in need of such treatment. However, the diagnosis need not be done previously.

The anti-dementia treatment as defined herein may be applied as a sole therapy or may involve conventional chemotherapy in addition to the compounds of the present invention. Such chemotherapy may include one or more of the following classes of drugs: acetylcholinesterase inhibitors, anti-inflammatory drugs, cognition and/or memory enhancing drugs or atypical antipsychotics.

Such combination therapy may be carried out by the simultaneous, sequential or separate administration of the individual therapeutic ingredients. These combinations use the compounds of the present invention.

Cognition enhancing drugs, memory enhancing drugs, and cholinesterase inhibitors include, but are not limited to, donepezil (Aricept), galantamine (remininyl or Razadyne), rivastigmine (rivastigmine), tacrine (Cognex), and memantine (memantine) (Namenda, Axura, or Ebixa).

The invention also includes pharmaceutical compositions comprising, as an active ingredient, one or more compounds of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient.

When used in pharmaceutical compositions, medicaments, manufacture of medicaments, to inhibit the activity of BACE or to treat or prevent a β -related pathology, the compounds of the invention include compounds of formula Ia or Ib and pharmaceutically acceptable salts, tautomers and in vivo hydrolysable precursors thereof. The compounds of the present invention also include hydrates and solvates.

The definitions set forth herein are intended to clarify the terminology used throughout this application. The term "present application" refers to the entire application.

The term "optionally substituted" as used herein means that the substitution is optional and thus may be unsubstituted with respect to the designated atom or group. Where substitution is desired, such substitution means that any number of hydrogens on the designated atom or group is replaced with a selection from the designated group, provided that the designated atom or group's normal valency is not exceeded, and that the result of the substitution is a stable compound. For example, if methyl (i.e. CH)₃) Is optionally substituted, then 3 hydrogens on carbon atoms may be replaced. Examples of suitable substituents include, but are not limited to: halogen, CN, NH₂、OH、SO、SO₂、COOH、OC_1-6Alkyl radical, CH₂OH、SO₂H、C_1-6Alkyl, OC_1-6Alkyl, C (═ O) C_1-6Alkyl, C (═ O) OC_1-6Alkyl, C (═ O) NH₂、C(＝O)NHC_1-6Alkyl, C (═ O) N (C)_1-6Alkyl radical)₂、SO₂C_1-6Alkyl, SO₂NHC_1-6Alkyl, SO₂N(C_1-6Alkyl radical)₂、NH(C_1-6Alkyl group), N (C)_1-6Alkyl radical)₂、NHC(＝O)C_1-6Alkyl, NC (═ O) (C)_1-6Alkyl radical)₂、C_5-6Aryl, OC_5-6Aryl, C (═ O) C_5-6Aryl, C (═ O) OC_5-6Aryl, C (═ O) NHC_5-6Aryl, C (═ O) N (C)_5-6Aryl radical)₂、SO₂C_5-6Aryl, SO₂NHC_5-6Aryl, SO₂N(C_5-6Aryl radical)₂、NH(C_5-6Aryl group), N (C)_5-6Aryl radical)₂、NC(＝O)C_5-6Aryl, NC (═ O) (C)_5-6Aryl radical)₂、C_5-6Heterocyclic group, OC_5-6Heterocyclyl, C (═ O) C_5-6Heterocyclyl group, C (═ O) OC_5-6Heterocyclyl, C (═ O) NHC_5-6Heterocyclyl, C (═ O) N (C)_5-6Heterocyclic radical)₂、SO₂C_5-6Heterocyclic radical, SO₂NHC_5-6Heterocyclic radical, SO₂N(C_5-6Heterocyclic radical)₂、NH(C_5-6Heterocyclic group), N (C)_5-6Heterocyclic radical)₂、NC(＝O)C_5-6Heterocyclyl or NC (═ O) (C)_5-6Heterocyclic radical)₂。

The various compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention includes all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) -isomers, (L) -isomers, racemic mixtures thereof, and other mixtures thereof, which are encompassed within the scope of the present invention. Additional asymmetric carbon atoms may be present in a substituent (e.g., alkyl). All such isomers and mixtures thereof are intended to be included in the present invention. The compounds described herein may have asymmetric centers. The compounds of the invention containing asymmetrically substituted atoms may be isolated in optically active or racemic forms. How to prepare optically active forms is well known in the art, for example by resolution of racemic forms, or by synthesis from optically active starting materials. Separation of the racemic material can be achieved by methods known in the art, if desired. Multiple geometric isomers of olefins, C ═ N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the invention are described and may be separated into a mixture of isomers or into separate isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended to be included in the invention, unless the specific stereochemistry or isomeric form is specifically indicated.

When a bond connecting substituents is shown to intersect a bond connecting two atoms in a ring, the substituent may be attached to any atom on the ring. When a substituent is listed without indicating through which atom the substituent is attached to the rest of the compound of a given structure, the substituent may be attached through any atom in the substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

"alkyl" or "alkylene" used herein alone or as a suffix or prefix is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms (or, if a specific number of carbon atoms is provided, that specific number). For example, "C_1-6Alkyl "denotes an alkyl group having 1,2, 3, 4, 5 or 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. It should be understood that as used herein, "C" is_1-3Alkyl groups "(whether terminal substituents or alkylene groups linking two substituents) specifically include straight and branched methyl, ethyl and propyl groups.

As used herein, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like. The term "alkenylene" refers to a divalent linking alkenyl group.

As used herein, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl, propynyl, and the like. The term "alkynylene" refers to a divalent linking alkynyl group.

As used herein, "aromatic" refers to a hydrocarbon group having one or more polyunsaturated carbon rings with aromatic character (e.g., 4n +2 delocalized electrons) and including up to about 14 carbon atoms.

The term "aryl" as used herein refers to an aromatic ring structure of 5 to 14 carbon atoms. The ring structure containing 5, 6, 7 and 8 carbon atoms may be a monocyclic aromatic group, such as phenyl. The ring structure containing 8, 9, 10, 11, 12, 13, or 14 carbon atoms can be a polycyclic group in which at least one carbon is common to any two adjacent rings herein (e.g., the rings are "fused rings"), such as naphthyl. The aromatic ring may be substituted with the substituents described above at one or more ring positions. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, or cycloalkynyl. The terms "ortho", "meta" and "para" apply to 1, 2-, 1, 3-and 1, 4-disubstituted benzenes, respectively. For example, the names "1, 2-dimethylbenzene" and "o-dimethylbenzene" have the same meaning.

As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon having a specified number of carbon atoms, including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups may include monocyclic groups or polycyclic (e.g., having 2, 3, or 4 fused or bridged rings) groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinanyl, norcarane-yl, adamantyl, and the like. Included within the definition of cycloalkyl are also those having one or more ring members fused to (i.e. having common usage with) the cycloalkyl ringA bond of (b) such as a benzo derivative of cyclopentane (i.e., indanyl), a benzo derivative of cyclopentene, a benzo derivative of cyclohexane, and the like. The term "cycloalkyl" also includes saturated cyclic groups having the specified number of carbon atoms. These cyclic groups may include fused or bridged polycyclic ring systems. Preferred cycloalkyl groups have 3 to 10 carbon atoms in their ring structure, more preferably 3, 4, 5 and 6 carbons in the ring structure. For example, "C_3-6Cycloalkyl "represents a group such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein, "cycloalkenyl" refers to a cyclic-containing hydrocarbon group having at least one carbon-carbon double bond in the ring and 3 to 12 carbon atoms.

As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

"counter ion" is used to denote a small negatively or positively charged species, such as chloride (Cl)^-) Bromine ion (Br)^-) Hydroxyl ion (OH)^-) Acetate ion (CH)₃COO^-) Sulfate ion (SO)₄ ^2-) Tosylate ion (CH)₃-phenyl-SO₃ ^-) Benzenesulfonate ion (phenyl-SO)₃ ^-) Sodium ion (Na)⁺) Potassium ion (K)⁺) Ammonium ion (NH)₄ ⁺) And the like.

The term "heterocyclyl" or "heterocyclic" or "heterocycle" as used herein refers to ring-containing monovalent and divalent structures having one or more heteroatoms independently selected from N, O and S as part of the ring structure and including from 3 to 20 atoms, more preferably from 3 to 7 membered rings in the ring. The number of ring-forming atoms in the heterocyclic group is given in the scope of the present application. E.g. C_5-10The heterocyclic group means a ring structure including 5 to 10 ring-forming atoms, at least one of which is N, O or S. Heterocyclyl groups may be saturated or partially saturated or unsaturated (containing one or more double bonds), and in the case of polycyclic systems, heterocyclyl groups may contain more than one ring. At the present applicationThe heterocyclic ring described may be substituted on a carbon or heteroatom as long as the resulting compound is stable. If specifically indicated, the nitrogen of the heterocyclic group may optionally be quaternized. It is understood that when the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms cannot be adjacent to each other.

Examples of heterocyclyl groups include, but are not limited to, 1H-indazole, 2-pyrrolidinone, 2H, 6H-1, 5, 2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidinonyl, 4 aH-carbazole, 4H-quinolizinyl, 6H-1, 2, 5-thiadiazinyl, acridinyl, azabicyclo, azetidine, azepane, aziridine, azooctazocyclotetranyl, benzimidazolyl, benzodioxolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolonyl, carbazolyl, 4 aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, and the like, Cinnolinyl, diazacycloheptane, decahydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, dioxolane, furyl (furyl), 2, 3-dihydrofuran, 2, 5-dihydrofuran, dihydrofuro [2, 3-b ] tetrahydrofuran, furyl (furanyl), furazanyl, homopiperidinyl (homopiperidinyl), imidazolidine, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, 3H-indolyl (indolynyl), indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, morpholinyl, diazananyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, cinnolinyl, 2, 3-oxadiazolyl, 2-dihydrofuranyl (furyl), 2, 3-dihydrofuranyl, 2-dihydrofuranyl, 2, 5-dihydrofuranyl, 2, 3-dihydrofuranyl, furazanyl, 1,2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, ethylene oxide, oxazolidinyl, perimidine, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, purinyl, pyranyl, pyrrolidinyl, pyrroline, pyrrolidine, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, N-oxide-pyridinyl, pyrimidinyl, pyrrolidinyl dione, pyrrolinyl, pyrrolyl, pyridine, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, Tetrahydrofuryl, tetramethylpiperidinyl, tetrahydroquinoline, tetrahydroisoquinolinyl, tetrahydrothiophene, thiatetrahydroquinolinyl, 6H-1, 2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, thienylcyclopropane, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1, 3, 4-triazolyl, and xanthenyl.

As used herein, "heteroaryl" refers to an aromatic heterocyclic ring having at least one ring heteroatom (e.g., sulfur, oxygen, or nitrogen). Heteroaryl groups include monocyclic ring systems and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, heteroaryl groups have from 1 to about 20 carbon atoms, and in other embodiments from about 3 to about 20 carbon atoms. In some embodiments, heteroaryl groups contain 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, heteroaryl groups have 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom.

As used herein, "alkoxy" or "alkyloxy" refers to an alkyl group as defined above having the specified number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy, and propargyloxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above having the specified number of carbon atoms attached through a sulfur bridge.

The term "carbonyl" as used herein is known in the art and includes groups that can be represented by the general formula:

wherein X is a bond or represents oxygen or sulphur, and R represents hydrogen, alkyl, alkenyl, - (CH)₂)_m-R "or a pharmaceutically acceptable salt, R' represents hydrogen, alkyl, alkenyl or- (CH)₂)_m-R ", wherein m is an integer less than or equal to 10; and R "is alkyl, cycloalkyl, alkenyl, aryl or heteroaryl. In the case where X is oxygen and R' are not hydrogen, the above formula represents an "ester". Where X is oxygen and R is as defined above, the group referred to herein as carboxyl, especially when R' is hydrogen, the above formula represents "carboxylic acid". In the case where X is oxygen and R' is hydrogen, the above structural formula represents a "formate". Generally, the above formula represents a "thiocarbonyl" group in the case where the oxygen atom of the above formula is replaced with sulfur. In the case where X is sulfur and R' are not hydrogen, the above formula represents a "thioester". In the case where X is sulfur and R is hydrogen, the above structural formula represents a "thiocarboxylic acid". In the case where X is sulfur and R' is hydrogen, the above structural formula represents a "thioformate". In another aspect, where X is a bond and R is not hydrogen, the above structural formula represents a "keto group. In the case where X is a bond and R is hydrogen, the above structural formula represents an "aldehyde group".

The term "sulfonyl" as used herein refers to a group that can be represented by the general formula:

wherein R represents, but is not limited to, hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.

Some substituents used herein are described as a combination of two or more groups. For example, the expression "C (═ O) C_3-9Cycloalkyl radical R^d"refers to the structure:

wherein p is 1,2, 3, 4, 5, 6 or 7 (i.e., C)_3-9Cycloalkyl), said C_3-9Cycloalkyl radicals by R^dSubstituted, and "C (═ O) C_3-9Cycloalkyl radical R^d"is attached via the carbon atom of the carbonyl group, which is to the left of the expression.

The phrase "protecting group" as used herein refers to a temporary substituent that protects a potentially reactive functional group from undesirable chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and the corresponding acetals and ketals of aldehydes and ketones. A review of the field of protecting group chemistry has been made (Greene, T.W.; Wuts, P.G.M.protective Groups in Organic Synthesis, 3^rded.；Wiley：New York，1999)。

As used herein, "pharmaceutically acceptable" refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified (i.e., also includes a counterion) by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines), inorganic or organic base salts of acidic residues (e.g., carboxylic acids), and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, which are prepared, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids (e.g., hydrochloric acid, phosphoric acid, etc.) and salts prepared from organic acids (e.g., lactic acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, etc.).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, these salts can be prepared by the following method: reacting the free acid form or free base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both; non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile may be used.

As used herein, "in vivo hydrolysable precursor" refers to an in vivo hydrolysable (or cleavable) ester of a compound of formula Ia or Ib, e.g. an amino acid ester, C, containing a carboxyl or hydroxyl group_1-6Alkoxymethyl esters (e.g. methoxymethyl ester), C_1-6Alkanoyloxymethyl esters (e.g. pivaloyloxymethyl ester), C_3-8Cycloalkoxy-carbonyloxy C_1-6Alkyl esters (e.g. 1-cyclohexylcarbonyloxyethyl ester), acetoxymethoxy ester or phosphoramide.

As used herein, "tautomer" refers to other structural isomers that exist in equilibrium due to hydrogen atom migration, such as keto-enol tautomerism, wherein the resulting compound has the properties of a ketone and an unsaturated alcohol.

As used herein, "stable compound" and "stable structure" refer to a compound that is sufficiently stable to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

The invention also includes isotopically-labeled compounds of the invention. An "isotopically labeled" or "radiolabeled" compound is a compound of the invention having the following characteristics: wherein one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in the compounds of the present invention include, but are not limited to²H (also written as D, representing deuterium),³H (also written as T, representing tritium),¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、¹⁸F、³⁵S、³⁶Cl、⁸²Br、⁷⁵Br、⁷⁶Br、⁷⁷Br、¹²³I、¹²⁴I、¹²⁵I and¹³¹I. the radionuclide that is incorporated into these radiolabeled compounds depends on the particular application of the radiolabeled compound. For example, for in vitro receptor labeling and competition assays, binding is provided³H、¹⁴C、⁸²Br、¹²⁵I、¹³¹I or³⁵The compounds of S are generally most useful. In the case of a radiological imaging application,¹¹C、¹⁸F、¹²⁵I、¹²³I、¹²⁴I、¹³¹I、⁷⁵Br、⁷⁶br or⁷⁷Br is generally most useful.

It is to be understood that a "radiolabeled compound" is a compound to which at least one radionuclide is bound. In some embodiments, the radionuclide is selected from³H、¹⁴C、¹²⁵I、³⁵S and⁸²Br。

the anti-dementia treatment as defined herein may be applied as a sole therapy or as a conventional chemotherapy including the compounds of the present invention.

The compounds of the invention may be administered as follows: oral, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingual, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intravenous, epidural, intrathecal, intracerebroventricular, and injection into the joints.

When determining the most appropriate individual dosage regimen and dosage level for a particular patient, the dosage will depend upon the route of administration, the severity of the disease, the age and weight of the patient and other factors normally considered by the attending physician.

An effective amount of a compound of the present invention for treating dementia is an amount sufficient to symptomatically alleviate symptoms of dementia in a warm-blooded animal, particularly a human, slow the progression of dementia, or reduce the risk of worsening in a patient with symptoms of dementia.

For preparing pharmaceutical compositions from the compounds of the present invention, inert pharmaceutically acceptable carriers can be either solid or liquid. Solid formulations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents, and may also be an encapsulating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

To prepare suppository compositions, a low melting wax (e.g., a mixture of fatty acid glycerides and cocoa butter) is first melted and the active ingredient is then dispersed therein, for example, by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, which is then allowed to cool and solidify.

Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sucrose, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.

Some of the compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases, and such salts are also within the scope of the present invention. For example, such conventional non-toxic salts include those derived from inorganic acids (e.g., hydrochloric acid, phosphoric acid, etc.) and salts prepared from organic acids (e.g., lactic acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, trifluoroacetic acid, etc.).

In some embodiments, the present invention provides a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment (including prophylactic treatment) of mammals, including humans, formulated generally in accordance with standard pharmaceutical practice as a pharmaceutical composition.

In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain, or be combined (administered simultaneously or sequentially) with one or more pharmacological ingredients having therapeutic value for one or more of the conditions described herein.

The term "composition" is intended to include a formulation of an active ingredient or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. For example, the present invention can be formulated into the following forms by methods known in the art: for example tablets, capsules, aqueous or oily solutions, suspensions, emulsions, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation and sterile aqueous or oily solutions or suspensions or sterile emulsions for parenteral use, including intravenous, intramuscular or infusion.

Liquid compositions include solutions, suspensions, and emulsions. As examples of liquid preparations suitable for parenteral administration, mention may be made of sterile aqueous solutions or sterile water-propylene glycol solutions of the active compounds. Liquid compositions may also be formulated as aqueous polyethylene glycol solutions. Aqueous solutions for oral administration can be prepared by the following method: the active ingredient is dissolved in water and suitable colorants, flavors, stabilizers, and thickeners are added as desired. Aqueous suspensions for oral use can be prepared by the following process: finely divided active ingredient is dispersed in water together with a viscous substance such as natural/synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents known in the pharmaceutical art.

The pharmaceutical composition may be in unit dosage form. In this form, the composition is divided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, for example, tablets, capsules, and powders packaged in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or can be the appropriate number of any of these packaged forms. The compositions may be formulated for any suitable route and method of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for administration of: oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. For convenience, the formulations may be in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

For solid compositions, conventional non-toxic solid carriers can be used, including, for example, pharmaceutical grades of mannitol, lactose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like. Liquid compositions useful for administration can be prepared, for example, by the following method: the active compounds as defined above and optional pharmaceutical excipients are dissolved, dispersed, etc. in a carrier, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming a solution or suspension. If desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and the like. The actual methods of preparing these dosage forms are known to, or will be apparent to, those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack publishing company, Easton, Pennsylvania, 15th Edition, 1975.

The compounds of the present invention may be derivatized in a variety of ways. As used herein, "derivatives" of a compound include salts (e.g., pharmaceutically acceptable salts), any complexes (e.g., inclusion complexes or chelates with compounds such as cyclodextrins, etc.), or with compounds such as Mn²⁺And Zn²⁺A complex formed by a plasma metal ion), an ester (e.g. an in vivo hydrolysable ester), a free acid or base, a polymorph of a compound, a solvate (e.g. hydrate), a prodrug or lipid, a coupling partner (coupling partner) and a protecting group. For example, "prodrug" refers to any compound that can be converted in vivo to a biologically active compound.

Salts of the compounds of the present invention are preferably physiologically well tolerated and non-toxic salts. Many examples of salts are known to those skilled in the art. All such salts are within the scope of the present invention and reference to the compounds includes the salt forms of the compounds.

Compounds having acidic groups (e.g., carboxylate, phosphate, or sulfate) can form salts with alkali or alkaline earth metals (e.g., Na, K, Mg, and Ca) or organic amines (e.g., triethylamine and tris (2-hydroxyethyl) amine). Compounds having basic groups, such as amines, can form salts with inorganic acids, such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids, such as acetic acid, citric acid, benzoic acid, fumaric acid or tartaric acid. Compounds having both acidic and basic groups can form internal salts.

Acid addition salts can be prepared with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with the following acids: hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid and lactobionic acid.

If the compounds are anionic or have functional groups which form anions (for example COOH can form COO)^-) Salts can then be prepared with the appropriate cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions (e.g., Na)⁺And K⁺) Alkaline earth metal cations (e.g. Ca)²⁺And Mg²⁺) And other cations (e.g., Al)³⁺). Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH)₄ ⁺) And substituted ammonium ions (e.g. NH)₃R⁺、NH₂R²⁺、NHR³⁺Or NR⁴⁺). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine and amino acids (e.g. lysine and arginine). An example of a common quaternary ammonium ion is N (CH)₃)₄ ⁺。

Where the compounds contain amine functional groups, these compounds may form quaternary ammonium salts, for example, by the following method: the compound is reacted with an alkylating agent according to methods well known to the skilled person. These quaternary ammonium compounds are within the scope of the present invention.

The compounds comprising amine functionality may also form N-oxides. The compounds comprising amine functional groups to which the present application relates also include N-oxides.

In the case where the compound comprises several amine functional groups, one or more nitrogen atoms may be oxidized to the N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles.

The N-oxide can be prepared by the following method: the corresponding amines are treated with an oxidizing agent, such as hydrogen peroxide or a peracid, such as peroxycarboxylic acid, see for example Advanced Organic Chemistry, by JerryMarch, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the method of l.w. destination (syn.comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

Esters can be prepared between the hydroxyl or carboxyl group of a compound and a suitable carboxylic acid or alcohol reaction partner (interaction partner) using techniques well known in the art. Examples of esters are compounds comprising a group-C (═ O) OR, where R is an ester substituent, e.g. C_1-7Alkyl radical, C_3-20Heterocyclyl or C_5-20Aryl, preferably C_1-7An alkyl group. Specific examples of ester groups include, but are not limited to, -C (═ O) OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)OC(CH₃)₃and-C (═ O) OPh. Examples of acyloxy (trans esters) are represented by-OC (═ O) R, where R is an acyloxy substituent, such as C_1-7Alkyl radical, C_3-20Heterocyclyl or C_5-20Aryl, preferably C_1-7An alkyl group. Specific examples of acyloxy include, but are not limited to, -OC (═ O) CH₃(acetoxy), -OC (═ O) CH₂CH₃、-OC(＝O)C(CH₃)₃-OC (═ O) Ph and-OC (═ O) CH₂Ph。

Derivatives that are prodrugs of a compound may be converted in vivo or in vitro to one of the parent compounds. Typically, at least one biological activity of a compound is reduced in a prodrug form of the compound and can be activated by converting the prodrug, thereby releasing the compound or a metabolite thereof. Some prodrugs are esters (e.g., physiologically acceptable metabolically labile esters) of the active compound. During metabolism, the ester group (-C (═ O) OR) is cleaved, giving the active drug. These esters can be prepared, for example, by esterification of any carboxyl group (-C (═ O) OH) of the parent compound, if necessary, protection of any other reactive group of the parent compound in advance, followed by deprotection as necessary.

Examples of such metabolically labile esters include those represented by the formula-C (═ O) OR, where R is C_1-7Alkyl (e.g. -Me (methyl), -Et (ethyl), -nPr (n-propyl), -iPr (isopropyl), -nBu (n-butyl), -sbu (sec-butyl), -iBu (isobutyl), -tBu (tert-butyl)), C_1-7Aminoalkyl radicals (e.g. aminoethyl, 2- (N, N-diethylamino) ethyl, 2- (4-morpholino) ethyl) and acyloxy-C_1-7Alkyl (e.g., acyloxymethyl, acyloxyethyl, pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 1- (1-methoxy-1-methyl) ethyl-carbonyloxyethyl, 1- (benzoyloxy) ethyl, isopropoxy-carbonyloxymethyl, 1-isopropoxy-carbonyloxyethyl, cyclohexyl-carbonyloxymethyl, 1-cyclohexyl-carbonyloxyethyl, cyclohexyloxy-carbonyloxymethyl, 1-cyclohexyloxy-carbonyloxyethyl, (4-tetrahydropyranyloxy) carbonyloxymethyl, 1- (4-tetrahydropyranyloxy) carbonyloxyethyl, (4-tetrahydropyranyl) carbonyloxymethyl and 1- (4-tetrahydropyranyl) carbonyloxyethyl).

In addition, some prodrugs are activated by enzymes to give the active compound or compounds which give the active compound after further chemical reaction (e.g. in ADEPT, GDEPT, LIDEPT etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Other derivatives include coupling partners for compounds wherein the compound is attached to the coupling partner, for example by chemical coupling or physical association with the compound. Examples of coupling partners include a marker molecule or reporter molecule, a carrier substance, carrier or transport molecule, an effector, a drug, an antibody or an inhibitor. The coupling partner may be covalently attached to the compounds of the invention through a suitable functional group of the compound, such as a hydroxyl, carboxyl or amino group. Other derivatives include formulating the compound with liposomes.

In the case where the compound contains a chiral center, various optical forms of the compound (e.g., enantiomers, epimers, and diastereomers, as well as racemic mixtures) are within the scope of the present invention.

The compounds may exist in a number of different geometric and tautomeric forms and reference to a compound includes all such forms. For the avoidance of doubt, where a compound may exist in one of several geometric or tautomeric forms and only one form is specifically described or shown, all other forms are still included within the scope of the invention.

The amount of the compound administered will vary with the patient being treated, and will range from about 100ng/kg body weight to 100mg/kg body weight per day, preferably from 10pg/kg to 10mg/kg per day. For example, the dosage can be readily determined by one skilled in the art based on the disclosure herein and the knowledge in the art. Thus, the skilled person is readily able to determine the amount of the compound and optional additives, vehicles and/or carriers in the composition, and also the amount administered in the method of the invention.

The compounds of the present invention have been shown to inhibit β -secretase (including BACE) activity in vitro. It has been shown that inhibitors of beta-secretase can be used to block the formation or accumulation of a beta peptide and therefore have beneficial effects in the treatment of alzheimer's disease and other neurodegenerative diseases associated with elevated levels of a beta peptide and/or deposition of a beta peptide. Thus, it is believed that the compounds of the present invention are useful in the treatment of alzheimer's disease and dementia-related disorders. Thus, the compounds of the present invention and their salts are expected to have activity against age-related diseases such as alzheimer's disease and other a β -related pathologies such as down's syndrome and β -amyloid angiopathy. It is expected that the compounds of the present invention are most likely to be used in combination with a wide variety of cognitive deficit enhancing agents, but may also be used as single agents.

In general, the compounds of the invention have been identified as having an IC of 100 micromolar or less than 100 micromolar in one or both of the assays described below₅₀The value is obtained.

IGEN assay

The enzyme was diluted 1: 30 in 40mM MES pH 5.0. Stock substrate was diluted to 12. mu.M in 40mM MES pH 5.0. The PALMEB solution was added to the substrate solution (dilution 1: 100). DMSO stock solutions of compounds or DMSO alone were diluted to the desired concentration in 40mM MES pH 5.0. The assay was performed in 96-well PCR plates (Nunc). A DMSO (3 μ L) solution of compound was added to the plate, followed by addition of enzyme (27 μ L), and preincubated with compound for 5 minutes. The reaction was then initiated with substrate (30. mu.L). The final dilution of the enzyme was 1: 60; the final concentration of substrate was 6. mu.M (Km 150. mu.M). After 20 minutes at room temperature, the reaction was stopped by: mu.L of the reaction mixture was removed and then diluted 1: 25 in 0.20M Tris pH 8.0. The compound was added to the plate manually and then all remaining liquid manipulations were performed on the CyBi-Well instrument.

All antibodies and streptavidin-coated beads were diluted in PBS (containing 0.5% BSA and 0.5% tween 20). The product was quantified by the following method: mu.L of a neo-epitope antibody (neoepitope antibody) at a dilution of 1: 5000 was added to 50. mu.L of a reaction mixture at a dilution of 1: 25. Then, 100. mu.L of PBS (0.5% BSA, 0.5% Tween 20) containing 0.2mg/mLIGEN beads and a ruthenium-labeled goat anti-rabbit (Ru-Gar) antibody at a dilution of 1: 5000 was added. The final dilution of the neo-epitope antibody was 1: 20000, the final dilution of Ru-Gar was 1: 10000, and the final concentration of the beads was 0.1 mg/mL. After 2 hours incubation at room temperature, the mixture was read on an IGEN instrument using the CindyAB40 program. DMSO alone was added to define 100% activity. In a single-prick assay (single-poke assay), 20 μ M of control inhibitor was used to define 0% of the control activity, and 100nM of inhibitor defined 50% of the control activity. Control inhibitors were also used in dose response assays, their IC₅₀Was 100 nM.

Fluorescence measurement

The enzyme was diluted 1: 30 in 40mM MES pH 5.0. Stock substrate was diluted to 30. mu.M in 40mM MES pH 5.0. Dissolving PALMEB in waterThe solution was added to the substrate solution (dilution 1: 100). The enzyme and substrate stock solutions were kept on ice until they were placed in the stock plates. All liquid manipulations were performed using a Platemate-plus instrument. Enzyme (9 μ L) was added to the plate, followed by 1 μ L of compound in DMSO, and pre-incubation for 5 minutes. When testing the dose response curve of compounds, dilutions were made in clean DMSO, and DMSO stock was then added as described above. Substrate (10. mu.L) was added, and then the reaction was carried out at room temperature for 1 hour in the absence of light. The assay was performed in a Corning 384 well plate (round bottom, low volume, non-binding surface) (Corning # 3676). The final dilution of the enzyme was 1: 60; the final concentration of substrate was 15. mu.M (Km 25. mu.M). The fluorescence of the product was measured on a Victor II plate reader using a protocol-labeled Edans peptide with an excitation wavelength of 360nm and an emission wavelength of 485 nm. The DMSO control defined a 100% activity level, 0% activity was defined using 50 μ M of a control inhibitor (which completely blocked enzyme function). Control inhibitors were also used in dose response assays, their IC₅₀Was 95 nM.

Beta-secretase Whole cell assay

Production of HEK-Fc 33-1:

the cDNA encoding the full length BACE was fused in frame to the Fc portion of human IgG1 (starting at amino acid 104) together with a three amino acid linker (Ala-Val-Thr). The BACE-Fc construct was then cloned into a GFP/pGEN-IRES-neoK vector (a vector proprietary to AstraZeneca) for protein expression in mammalian cells. The expression vector was stably transfected into HEK-293 cells using the calcium phosphate method. Cell populations were selected using 250. mu.g/mL G-418. Limited dilution cloning was performed to obtain homogeneous cell lines. Clones were characterized by the level of APP expression and the level of secreted a β in conditioned media using a self-developed ELISA assay. A β secretion by BACE/Fc clone Fc33-1 was moderate.

Cell culture:

HEK293 cells stably expressing human BACE (HEK-Fc33) were grown at 37 ℃ in DMEM containing 10% heat-inhibited FBS, 0.5mg/mL of an antibacterial-antifungal solution and 0.05mg/mL of the selective antibiotic G-418(selection antibiotic G-418).

A β 40 release assay:

when the fusion rate was between 80 and 90%, cells were harvested. 100 μ L of cells (cell density 150 ten thousand/mL) were added to a clear flat bottom white 96 well cell culture plate (Costar 3610) or a clear flat bottom 96 well cell culture plate (Costar 3595) containing 100 μ L of inhibitor in the cell culture medium, with a final concentration of DMSO of 1%. After incubation of the plates at 37 ℃ for 24 hours, 100 μ L of cell culture medium was transferred to a round bottom 96-well plate (Costar 3365) to quantify Α β 40 levels. The cell culture plate was stored and used for ATP measurement in the following ATP measurement. To each well of the round bottom plate, 50. mu.L of a detection solution (containing 0.2. mu.g/mL of R.alpha.A.beta.40 antibody and 0.25. mu.g/mL of biotinylated 4G8 antibody (prepared in DPBS containing 0.5% BSA and 0.5% Tween 20)) was added, followed by incubation at 4 ℃ for at least 7 hours. Then, 50. mu.L of a solution (prepared in the same buffer as above) containing 0.062. mu.g/mL ruthenium-labeled goat anti-rabbit antibody and 0.125mg/mL streptavidin-coated Dyna beads (Dynabead) was added to each well. The plates were shaken for 1 hour at 22 ℃ on a plate shaker, and then the plates were measured for ECL counts in an IGEN M8 analyzer. The standard curve of Abeta was obtained by the following method: a β stock solution of known concentration was serially diluted 2-fold in the same cell culture medium as the cell-based assay.

ATP determination:

as noted above, after transferring 100 μ Ι _ of medium from the cell culture plate for Α β 40 detection, the plate still containing the cells was stored for cytotoxicity assay using an assay kit for measuring total cellular ATP (ViaLight)^TMPlus) (Cambrex Bioscience). Briefly, 50 μ L of cytolytic reagent was added to each well of the plate. The plates were incubated at room temperature for 10 minutes. Add 100. mu.L of reconstituted (reconstituted) ViaLight^TMPlus reagent was used for ATP measurements, and after 2 minutes the luminosity (luminescence) of each well was read in LJL platesMeasured in Wallac or Wallac Topcount.

BACE Biacore protocol

Preparing a sensing chip:

BACE was determined on a Biacore 3000 instrument by attaching either a peptide Transition State Isostere (TSI) or a scrambled version of the peptide TSI to the surface of a Biacore CM5 sensor chip. The surface of the CM5 sensor chip had 4 different channels available for coupling peptides. The scrambled peptide KFES-inhibin-ETIAEVENV (KFES-statin-ETIAEVENV) was coupled to channel 1, while the TSI inhibitor KTEEISEVN-inhibin-VAEF (KTEEISEVN-statin-VAEF) was coupled to channel 2 of the same chip. Both peptides were dissolved at 0.2mg/mL in 20mM sodium acetate (pH 4.5) and the solution was centrifuged at 14000rpm to remove all particles. The carboxyl groups on the dextran layer are activated by the following method: a1: 1 mixture of 0.5M N-ethyl-N' - (3-dimethylaminopropyl) -carbodiimide (EDC) and 0.5M N-hydroxysuccinimide (NHS) was injected at a rate of 5 μ L/min for 7 minutes. Then, a stock solution of the control peptide was injected into channel 1 at a rate of 5 μ L/min for 7 minutes, and then the remaining activated carboxyl groups were blocked by the following method: 1M ethanolamine was injected at a rate of 5. mu.L/min for 7 minutes.

Determination protocol:

BACE Biacore assay was performed by diluting BACE to 0.5. mu.M in sodium acetate buffer pH 4.5 (running buffer minus DMSO). Diluted BACE was mixed with DMSO or DMSO dilutions of compounds at a final DMSO concentration of 5%. The BACE/inhibitor mixture was incubated at 4 ℃ for 1 hour and then injected at a rate of 20. mu.L/min into channels 1 and 2 of a CM5 Biacore chip. When BACE is bound to the chip, the signal is measured in Response Units (RU). BACE binding to TSI inhibitors on channel 2 generates a certain signal. The presence of a BACE inhibitor reduces this signal by binding to BACE thereby inhibiting BACE interaction with the peptide TSI on the chip. Any binding to channel 1 was non-specific and was subtracted from the response value of channel 2. The DMSO control was defined as 100% and the effect of the compound was reported as percent inhibition relative to the DMSO control.

hERG assay

Cell culture:

the reaction mixture (Persson, Carlsson, Duker,&jacobson, 2005) expressing hERG in F-12Ham Medium at 37 ℃ in a humidified atmosphere (5% CO)₂) Medium containing L-glutamine, 10% Fetal Calf Serum (FCS) and 0.6mg/ml hygromycin (all from Sigma-Aldrich) to half confluency. Prior to use, the monolayers were washed with a 3ml aliquot of prewarmed (37 ℃) Versene 1: 5000 (Invitrogen). After aspirating this solution, the flask was incubated in an incubator at 37 ℃ for 6 minutes with another 2ml of Versene 1: 5000. Then, the cells were detached from the bottom of the flask by gentle tapping, and 10ml of Dulbecco's phosphate buffered saline (containing calcium (0.9mM) and magnesium (0.5mM)) (PBS; Invitrogen) was added to the flask, which was then pipetted into a 15ml centrifuge tube, followed by centrifugation (50g, 4 minutes). The resulting supernatant was discarded and the pellet was carefully resuspended in 3ml of PBS. A0.5 ml aliquot of the cell suspension was removed and the number of viable cells (based on Trypan blue exclusion) was determined in an automated reader (Cedex; Innovatis) so that the volume of cell resuspension could be adjusted with PBS to obtain the desired final cell concentration. When this parameter is referred to, the cell concentration at that point in the assay is quoted. For use in IonWorks^TMCHO-Kv1.5 cells with adjusted voltage offset (voltage offset) on HT were cultured and prepared for use in the same manner.

Electrophysiology:

the principle and operation of this device is described in (Schroeder, Neagle, Trezise,&worley, 2003). Briefly, the technique is described in 384 well plates (PatchPlates)^TM) A basis in which aspiration is used to position the cells over a small hole separating two independent fluid chambers and to hold the cells thereon, thereby attempting to record in each well. Once carried outUpon closure, the PatchPlate is applied^TMThe solution on the bottom side becomes a solution containing amphotericin B. This solution can penetrate the cell patch (patch of cell membrane) covering the hole in each well, thereby allowing the perforated whole-cell patch clamp recording to be actually performed.

Using beta-Test IonWorks^TMHT (essen instrument). This apparatus cannot warm the solution, and therefore operates at room temperature (about 21 ℃ C.) as follows. The container at the "buffer" position contained 4ml of PBS, while the container at the "cell" position contained the CHO-hERG cell suspension described above. Place 96-well plate (V-bottom, Greiner Bio-one) containing the compound to be tested (3 times its final test concentration) in the "plate 1" position, and PatchPlate^TMClamping to PatchPlate^TMLocation. Each compound plate is designed into 12 columns, so that 10 concentration-action curves formed by connecting 8 points can be constructed; the remaining two columns on the plate were occupied with vehicle (final concentration of DMSO 0.33%) to define the assay baseline, and cisapride (final concentration of 10 μ M) above the maximum blocking concentration to define the 100% inhibition level. Then, IonWorks^TMHT jet head (F head) 3.5. mu.l of PBS was added to PatchPlate^TMAnd its bottom side is perfused with an "internal" solution having the following composition (in mM): potassium Gluconate (K-Gluconate)100, KCl 40, MgCl₂3.2, EGTA 3 and HEPES 5 (all Sigma-Aldrich; pH was adjusted to 7.25-7.30 using 10M KOH). After start-up and debubbling, the electronic head (E head) surrounds the PatchPlate^TMMoving, a drill hole test method (i.e., applying a voltage pulse to determine if a hole in each well is open) is performed. Then, the F head sends 3.5. mu.l of the above cell suspension to PatchPlate^TMAnd the cells have 200 seconds to reach the hole in each well and seal the hole. Thereafter, the E head around PatchPlate^TMMoved to determine the resulting closed resistance in each well. Next, PatchPlate^TMBecomes an "inlet" solution, said "inlet" being"solution has the following composition (in mM): KCl 140, EGTA 1, MgCl₂1 and HEPES20 (pH adjusted to 7.25-7.30 using 10M KOH) together with 100. mu.g/ml amphotericin B (Sigma-Aldrich). After a duration of 9 minutes for perforating the membrane, the E heads each wrap around the PatchPlate^TMTo obtain the hERG current measurement before compound addition. Then, F head from the compound plate each hole of 3.5 u l solution to PatchPlate^TM4 wells (final concentration of DMSO in each well is 0.33%). This is achieved by the following method: moving from the most dilute wells of the compound plate to the most concentrated wells of the compound plate to minimize the effect of any compound carryover. After about 3.5 minutes of incubation, the E head surrounds the PatchPlate^TMAll 384 wells are moved to obtain the hERG current measurement after compound addition. In this way, a non-cumulative concentration-effect curve can be obtained, wherein the effect of each concentration of test compound depends on the recording of 1 to 4 cells, provided that acceptance criteria (see below) are met in a sufficient percentage of wells.

The hERG current before and after compound addition was induced by a single voltage pulse consisting of 20 seconds hold at-70 mV, change to-60 mV in 160 millisecond steps (to evaluate leakage), change back to-70 mV in 100 millisecond steps, change to +40mV in 1 second steps, change to-30 mV in 2 second steps, and finally change to-70 mV in 500 millisecond steps. The membrane potential was not clamped any between the voltage pulses before and after the compound addition. The leakage value is subtracted from the current value, which depends on evaluating the current caused at the +10mV step at the beginning of the voltage pulse scheme. One of two ways to IonWorks^TMAny voltage offset in HT is adjusted. When compound potency was determined, a depolarization voltage ramp was applied to CHO-kv1.5 cells, and a voltage was noted at which the current trace (current trace) appeared to be an inflection point (i.e., at which activation of the channel due to the ramping protocol was observed). The electricity in which the above-described phenomenon occurs has previously been determined in conventional electrophysiology using the same voltage commandsAnd found to be-15 mV (data not shown), an offset potential (offset) can be entered into the IonWorks^TMIn the HT software, this value is used as a reference point. When determining the basic electrophysiological properties of hERG, any bias is adjusted by: in IonWorks^TMThe hERG tail current reversal potential (reciprocal potential) was determined in HT, compared to the value determined in conventional electrophysiology (-82 mV; see FIG. 1c), and then at IonWorks^TMThe necessary offset adjustments are made in the HT software. The current signal is collected at a frequency of 2.5 kHz.

By taking the 40 ms average of the current (baseline current) at the-70 mV initial hold period and subtracting the average from the peak of the tail current response, with IonWorks^TMHT software from the deduction of leakage value of the trace automatically measured before and after the scanning hERG current magnitude. The acceptance criteria for the current induced in each well were: the blocking resistance before scanning is larger than 60M omega, the hERG tail current amplitude before scanning is larger than 150pA, and the blocking resistance after scanning is larger than 60M omega. The degree of inhibition of hERG current was evaluated by the following method: for each well, the values of hERG current after scanning are divided by the values of hERG current before the respective scanning.

Preparation method

The compounds of the present invention can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. The compounds of the invention can be synthesized using the following methods: the methods described below, along with synthetic methods known in the art of synthetic organic chemistry, or variations on these methods as would be understood by one of skill in the art. These methods include, but are not limited to, those described below. All documents cited in this application are incorporated herein by reference in their entirety.

The novel compounds of the present invention can be prepared using the reactions and techniques described herein. The reaction is carried out in a solvent appropriate to the reagents and materials used and to the conversion carried out. In addition, in the description of the synthetic methods described below, it should be understood that all of the suggested reaction conditions (including selection of solvent, reaction atmosphere, reaction temperature, duration of experiment and operation process) are selected as standard conditions for the reaction, which can be easily understood by those skilled in the art. It will be appreciated by those skilled in the art of organic synthesis that the functional groups present in the various parts of the molecule must be compatible with the reagents and reactions proposed. These limitations on substituents that are not compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods must be used.

The starting materials for the examples contained in this application are either commercially available or readily prepared by standard methods from known materials. For example, the following reactions are illustrative of, but not limiting to, the preparation of some of the starting materials and examples referred to herein.

The general process for preparing the compounds of the invention is as follows:

the invention will now be illustrated by the following non-limiting examples.

Normal phase chromatographic conditions: for selected compounds and intermediates, flash chromatography was used as the purification method. Isco CombiFlash Sq 16 × instrument: preassembled with disposable RediSep SiO₂Chromatographic columns of the stationary phase (sizes 4, 12, 40 and 120 grams); performing gradient elution with the selected mixture of the two solvents at a flow rate of 5-125 mL/min; UV detection (range 190 and 760nm) or timed collection; the flow cell path length was 0.1 mm.

The microwave heating method comprises the following steps: a Personal Chemistry Smith Synthesizer unit (single mode, 2.45GHz, max. 300W) was used to microwave heat the reaction.

LC-MS HPLC conditions: the chromatographic column is Agilent Zorbax SB-C82mm ID x 50 mm; the flow rate is 1.4 mL/min; a gradient from 95% a to 90% B over 3 minutes for 1 minute, gradually to 95% a over 1 minute for 1 minute, where a is 2% acetonitrile in water (containing 0.1% formic acid) and B is 2% water in acetonitrile (containing 0.1% formic acid); UV-DAD is 210-400 nm.

Abbreviations: APCI: atmospheric pressure chemical ionization; DME: 1, 2-dimethoxyethane; DMF: n, N-dimethylformamide; HPLC: high pressure liquid chromatography; NMR: nuclear magnetic resonance; GMF: glass Microfiber Filter (Glass Microfiber Filter).

General experimental details: for mass spectral data, the reported results are for the parent ion (M +1) (in M/z), unless otherwise indicated. In case of isotopic splitting (e.g. in case the compound comprises bromine) resulting in multiple peaks, only the main peak in the cluster of peaks (cluster) is indicated. The reported NMR data are the key resonance signals, recorded in the indicated deuterated solvents, and the chemical shifts are reported in parts per million relative to tetramethylsilane.

Scheme 1

Example 1

2-amino-6- [ (Z) -2- (3' -methoxybiphenyl-3-yl) vinyl ] -3-methylpyrimidin-4 (3H) -one (scheme 1, H)

The thick-walled glass bottle is filled with a stirrer and the geometric isomer 2-amino-6- [ (Z) -2- (3-bromophenyl) vinyl]-3-methylpyrimidin-4 (3H) -one (scheme 1, F) and 2-amino-6- [ (E) -2- (3-bromophenyl) vinyl]-mixture of 3-methylpyrimidin-4 (3H) -one (scheme 1, G) (ca. 1: 1, 18mg, 0.06mmol), 3-methoxyphenylboronic acid (9.2mg, 0.07mmol), bis (triphenylphosphine) palladium (II) dichloride (ca. 1mg, 0.001mmol), Cs₂CO₃(39mg0.12mmol) and DME/H2O/ethanol (7: 3: 2; about 1.2 mL). The reaction flask was sealed and then microwave irradiation was applied and held at 150 ℃ for 10 minutes. The resulting black slurry was filtered through a 0.7 μ M GMF filter over Celite/MgSO₄The pad was filtered, washed thoroughly with ethanol and dichloromethane (3X 1ml each) and then concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)₂Is 4 g; gradient elution was from 30% ethyl acetate/hexane to 100% ethyl acetate/hexane over 24 minutes; flow rate 20mL/min), and concentration to give 2-amino-6- [ (Z) -2- (3' -methoxybiphenyl-3-yl) ethenyl]3-methylpyrimidin-4 (3H) -one (2.7mg, 28% (based on 1: 1 starting mixture stoichiometry)) as a clean film.¹HNMR(300MHz，CDCl₃)δ3.39(s，3H)，3.85(s，3H)，4.97(br s，2H)，5.93(s，1H)，6.25(d，J＝12.5Hz，1H)，6.80(d，J＝12.5Hz，1H)，6.88(dd，J＝8.1，2.2Hz，1H)，7.05(t，J＝1.9Hz，1H)，7.12(d，J＝7.8Hz，1H)，7.30-7.35(m，3H)，7.45(dd，J＝1.6，3.5Hz，1H)，7.61(s，1H)；m/z(ES+)M+1＝334.1；HPLCt_R＝1.82min。

The desired 2-amino-6- [ (Z) -2- (3-bromophenyl) vinyl ] -3-methylpyrimidin-4 (3H) -one (scheme 1, F) and 2-amino-6- [ (E) -2- (3-bromophenyl) vinyl ] -3-methylpyrimidin-4 (3H) -one (scheme 1, G) were prepared as follows.

4, 4-diethoxy-3-oxobutanoic acid ethyl ester (scheme 1, A)

To a stirred suspension of sodium hydride (5.12g, 213mmol) in anhydrous tetrahydrofuran (250mL) was added dropwise a mixture of ethyl acetate (15.3mL, 156mmol) and ethyl diethoxyacetate (25mL, 142mmol) at 50 ℃ under an argon atmosphere over 30 minutes. After the addition was complete, the reaction mixture was refluxed for 4 hours, then cooled to ambient temperature while stirring was continued for another 16 hours. The mixture was concentrated by rotary evaporation toAbout the initial volume of 1/3, which was then rapidly added to aqueous acetic acid (about 145mL, 15% v/v) at 0 ℃ for quenching, followed by extraction with diethyl ether (4X 100 mL). The combined organic extracts were washed with water (1X 20mL), saturated aqueous sodium carbonate (3X 50mL), water (2X 20mL) and brine (1X 30mL) followed by MgSO₄Drying and concentration in vacuo afforded the desired ethyl 4, 4-diethoxy-3-oxobutanoate (scheme 1, a) as a clean yellow oil, which is a 4: 1 mixture of keto-enol tautomers (25.05g, 81%).¹H NMR(300MHz，CDCl₃)δ1.22-1.30(m，9H)，3.53-3.76(m，5.6H)，4.19(q，J＝7.6Hz，2H)，4.67(s，0.8H)，4.92(s，0.2H)，5.45(s，0.2H)，11.88(s，0.2H)。

2-amino-6- (diethoxymethyl) pyrimidin-4 (3H) -one (scheme 1, B)

To a stirred solution of ethyl 4, 4-diethoxy-3-oxobutanoate (scheme 1, a) (about 25g, 114mmol) in ethanol (600mL) was added guanidine carbonate (10.42g, 57.8mmol), washed with additional ethanol (200mL), after which the reaction mixture was heated at reflux for 18 h. After cooling, the resulting white crystals were collected by filtration and washed with cold ethanol. The filtrate was then concentrated to a reduced volume by rotary evaporation and then cooled to give a further few batches of white crystals, which were collected by filtration and then washed with cold ethanol. Several batches of white crystals were dried under high vacuum at ambient temperature overnight to give the title compound (15.5g, 64%) as a white solid.¹H NMR(300MHz，DMSO-d₆)δ1.13(t，J＝7.1Hz，6H)，3.45-3.58(m，4H)，4.90(s，1H)，5.62(s，1H)，6.57(br s，2H)，10.73(br s，1H)；m/z(ES+)M+1＝214.1；HPLCt_R＝0.70min。

2-amino-6- (diethoxymethyl) -3-methylpyrimidin-4 (3H) -one (scheme 1, C)

To a suspension of 2-amino-6- (diethoxymethyl) pyrimidin-4 (3H) -one (scheme 1, B) (1.02g, 4.8mmol) in anhydrous ethanol (30mL) was added solid potassium hydroxide (484mg, 8.6mmol), which was stirred until a homogeneous solution was reached. Methyl iodide (1.08mL, 17.3mmol) was added in one portion, and the reaction mixture was then heated to 78 ℃ in a sealed tube for 17 hours. Upon completion, the mixture was concentrated in vacuo to a slightly golden residue, which was then subjected to flash chromatography (SiO)₂Is 40 g; gradient elution was from 2% methanol/CH₂Cl₂After 25min, the mixture became 5% methanol/CH₂Cl₂Flow rate 60mL/min) gave 2-amino-6- (diethoxymethyl) -3-methylpyrimidin-4 (3H) -one (scheme 1, C) (833mg, 76%) as a pale yellow solid.¹H NMR(300MHz，CDCl₃)δ1.25(t，J＝7.1Hz，6H)，2.01(br s，2H)，3.44(s，3H)，3.55-3.68(m，4H)，5.07(s，1H)，6.18(s，1H)；m/z(ES+)M+1＝228.3；HPLC t_R＝0.87min。

N- [4- (diethoxymethyl) -1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl ] acetamide (scheme 1, D)

To a stirred solution of 2-amino-6- (diethoxymethyl) -3-methylpyrimidin-4 (3H) -one (scheme 1, C) (1.33g, 5.83mmol) in dichloromethane (40mL) was added acetic anhydride (2.2mL, 23.2mmol) and N, N-dimethylpyridin-4-amine (71mg, 0.58mmol) at ambient temperature. After 5 h, the reaction mixture was washed with water (1X 20mL) and MgSO₄Dried and then concentrated in vacuo. Flash chromatography (SiO) of the viscous yellow residue₂Is 40 g; gradient elution is 10% ethyl acetate-Hexane was held for 2 minutes and then changed from 10% ethyl acetate/hexane to 100% ethyl acetate/hexane over 20 minutes; flow 60mL/min) gave the title compound N- [4- (diethoxymethyl) -1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl]Acetamide (scheme 1, D) (1.1g, 70%) as an off-white solid.¹H NMR(300MHz，CDCl₃)δ1.29(t，J＝7.1Hz，6H)，2.24(s，3H)，3.46(s，3H)，3.65(m，J＝7.1Hz，4H)，5.28(s，1H)，6.05(s，1H)，13.76(br s，1H)；m/z(ES+)M+1＝270.3；HPLC t_R＝1.30min。

N- (4-formyl-1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl) acetamide (scheme 1, E)

The glass bottle is filled with a stirrer and N- [4- (diethoxymethyl) -1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl]Acetamide (scheme 1, D) (500mg, 1.86mmol) and formic acid (4 mL). The bottle was immersed in a preheated oil bath and held at 100 ℃ for 20 minutes before concentration by rotary evaporation. The residue was taken up in hot ethyl acetate, cooled, filtered and then washed thoroughly with diethyl ether. The filtrate was then concentrated, treated with diethyl ether and then filtered. The mother liquor was concentrated and then dried in vacuo to give the title compound (148mg, 41%) as a white solid.¹H NMR(300MHz，DMSO-d₆)δ2.17(s，3H)，3.35(s，3H)，6.81(s，1H)，9.75(s，1H)，10.89(s，1H)；HPLC t_R＝0.91min。

2-amino-6- [ (Z) -2- (3-bromophenyl) vinyl ] -3-methylpyrimidin-4 (3H) -one (scheme 1, F)

Under argon at 0 deg.CTo a stirred suspension of N- (4-formyl-1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl) acetamide (scheme 1, E) (331mg, 1.70mmol) and (3-bromo-benzyl) -triphenylphosphonium chloride (793mg, 1.70mmol) (Beak, et al, Tetrahedron, 1994, 50, 5999) in anhydrous tetrahydrofuran (10mL) was rapidly added a solution of potassium tert-butoxide in 2-methyl-2-propanol (1.0M, 3.56mL, 3.56mmol) by syringe under an atmosphere. Warmed to ambient temperature and then stirred for 22 hours. The reaction was quenched by addition of aqueous HCl (0.5N) to adjust the pH to about 5, diluted with water, and extracted with dichloromethane (3 × 20 mL). The combined organic phases were separated by MgSO₄Drying and then concentrating in vacuo to give a residue which is subjected to flash chromatography (SiO)₂Is 12 g; gradient elution was from 35% ethyl acetate/hexane to 100% ethyl acetate/hexane over 20 minutes; flow rate 40 mL/min). The resulting film was triturated with methanol to give 2-amino-6- [ (Z) -2- (3-bromophenyl) vinyl group]-3-methylpyrimidin-4 (3H) -one (scheme 1, F) (21mg, 4%) as an off-white solid.¹H NMR(300MHz，DMSO-d₆)δ2.49(s，3H)，3.90(s，2H)，4.74(s，1H)，5.41(d，J＝12.5Hz，1H)，5.86(d，J＝12.5Hz，1H)，6.31(app t，J＝7.8Hz，1H)，6.41(d，J＝7.8Hz，1H)，6.50(d，J＝7.8Hz，1H)，6.62(s，1H)；m/z(ES+)M+1＝306.0；HPLC t_R＝1.53min。

2-amino-6- [ (E) -2- (3-bromophenyl) vinyl ] -3-methylpyrimidin-4 (3H) -one (scheme 1, G)

By the above process to obtain 2-amino-6- [ (Z) -2- (3-bromophenyl) vinyl]Reaction of (E) -3-methylpyrimidin-4 (3H) -one (scheme 1, F) also gave 2-amino-6- [ (E) -2- (3-bromophenyl) vinyl]-3-methylpyrimidin-4 (3H) -one. The title material (21mg, 4%) was obtained as a white solid.¹H NMR(300MHz，DMSO-d₆)δ2.52(s，3H)，3.90(s，2H)，5.01(s，1H)，6.00(d，J＝15.7Hz，1H)，6.40(app t，J＝7.8Hz，1H)，6.57(d，J＝7.8Hz，1H)，6.65(d，J＝6.6Hz，1H)，6.69(d，J＝15.7Hz，1H)，6.85(s，1H)；m/z(ES+)M+1＝306.0；HPLCt_R＝1.71min。

Example 2

2-amino-6- [ (E) -2- (3' -methoxybiphenyl-3-yl) vinyl ] -3-methylpyrimidin-4 (3H) -one (scheme 1, I)

The title compound (5.6mg, 57% (based on 1: 1 starting mixture stoichiometry)) was obtained by the preparative reaction of the compound of example 1 as an off-white solid.¹H NMR(300MHz，CDCl₃)δ3.45(s，3H)，3.88(s，3H)，4.96(br s，2H)，5.99(s，1H)，6.82(d，J＝15.7Hz，1H)，6.92(dd，J＝8.1，1.9Hz，1H)，7.13(t，J＝2.0Hz，1H)，7.19(d，J＝7.7Hz，1H)，7.37(t，J＝8.0Hz，1H)，7.44(d，J＝7.5Hz，1H)，7.51-7.54(m，2H)，7.67(d，J＝15.7Hz，1H)，7.73(s，1H)；m/z(ES+)M+1＝334.1；HPLC t_R＝1.99min。

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also within the scope of the appended claims. Each of the documents cited in this application, including but not limited to journal articles, U.S. and non-U.S. patents, patent application publications, international patent application publications, and the like, is hereby incorporated by reference in its entirety.

Claims

1. A compound of formula Ia or Ib, or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof:

wherein

W is C or N;

R¹each independently selected from H, halogen, C_2-6Alkenyl radical, C_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl or C_5-15Heterocyclyl, wherein said C is_1-6Alkyl radical, said C_3-12Cycloalkyl radical, said C_6-10Aryl radical, said C_1-6alkyl-C_6-10Aryl or said C_5-15The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, CN, NH₂、OH、COOH、OC_1-6Alkyl radical, CH₂OH、SO₂H、S(＝O)、C_2-6Alkenyl radical, C_1-6alkyl-R^a、OC_1-6alkyl-R^a、C(＝O)C_1-6alkyl-R^a、C(＝O)OC_1-6alkyl-R^a、C(＝O)NH₂、C(＝O)NHC_1-6alkyl-R^a、C(＝O)N(C_1-6alkyl-R^a)₂、S(＝O)C_1-6alkyl-R^a、S(＝O)NHC_1-6alkyl-R^a、S(＝O)N(C_1-6alkyl-R^a)₂、SO₂C_1-6alkyl-R^a、SO₂NHC_1-6alkyl-R^a、SO₂N(C_1-6alkyl-R^a)₂、NH(C_1-6Alkyl) -R^a、N(C_1-6alkyl-R^a)₂、NHC(＝O)C_1-6Alkyl radical, C_6-10aryl-R^a、OC_6-10aryl-R^a、C(＝O)C_6-10aryl-R^a、C(＝O)OC_6-10aryl-R^a、C(＝O)NHC_6-10aryl-R^a、C(＝O)N(C_6-10aryl-R^a)₂、S(＝O)C_6-10aryl-R^a、S(＝O)NHC_6-10aryl-R^a、S(＝O)N(C_6-10aryl-R^a)₂、SO₂C_6-10aryl-R^a、SO₂NHC_6-10aryl-R^a、SO₂N(C_6-10aryl-R^a)₂、NH(C_6-10Aryl) -R^a、N(C_6-10aryl-R^a)₂、NC(＝O)C_6-10Aryl radical, C_5-6heterocyclyl-R^a、OC_5-6heterocyclyl-R^a、C(＝O)C_5-6heterocyclyl-R^a、C(＝O)OC_5-6heterocyclyl-R^a、C(＝O)NHC_5-6heterocyclyl-R^a、C(＝O)N(C_5-6heterocyclyl-R^a)₂、S(＝O)C_5-6heterocyclyl-R^a、S(＝O)NHC_5-6heterocyclyl-R^a、S(＝O)N(C_5-6heterocyclyl-R^a)₂、SO₂C_5-6heterocyclyl-R^a、SO₂NHC_5-6heterocyclyl-R^a、SO₂N(C_5-6heterocyclyl-R^a)₂、NH(C_5-6heterocyclyl-R^a)、N(C_5-6heterocyclyl-R^a)₂、NHC(＝O)C_5-6Heterocyclic radical, SO₂R^a、S(＝O)R^a、N(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、N(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、N(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、C(＝O)(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)O(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、C(＝O)O(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、C(＝O)O(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、S(＝O)(C_1-6alkyl-R^a)(C^6-10aryl-R^a)、S(＝O)(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a)、S(＝O)(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)、SO₂(C_1-6alkyl-R^a)(C_6-10aryl-R^a)、SO₂(C_1-6alkyl-R^a)(C_6-10heteroaryl-R^a) Or SO₂(C_6-10aryl-R^a)(C_6-10heteroaryl-R^a)；

z is

Or

m is 0, 1,2 or 3;

n, q, r and u are each independently 0 or 1;

s is 1 or 2;

R⁴Each independently selected from H, halogen, C_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl radical, C_5-10Heterocyclyl or C_1-6alkyl-C_5-10Heterocyclyl, wherein said C is_1-6Alkyl radical, C_3-12Cycloalkyl radical, C_6-10Aryl radical, C_1-6alkyl-C_6-10Aryl radical, C_5-10Heterocyclyl and C_1-6alkyl-C_5-10The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, CN, NH₂、OH、C_1-6alkyl-R^a、OC_1-6alkyl-R^a、C(＝O)C_1-6alkyl-R^a、C(＝O)OC_1-6alkyl-R^a、C(＝O)NH₂、C(＝O)NHC_1-6alkyl-R^a、C(＝O)N(C_1-6alkyl-R^a)₂、S(＝O)C_1-6alkyl-R^a、S(＝O)NHC_1-6alkyl-R^a、S(＝O)N(C_1-6alkyl-R^a)₂、SO₂C_1-6alkyl-R^a、SO₂NHC_1-6alkyl-R^a、SO₂N(C_1-6alkyl-R^a)₂、NH(C_1-6Alkyl) -R^a、N(C_1-6alkyl-R^a)₂Or NHC (═ O) C_1-6An alkyl group;

t is 0, 1,2, 3, 4 or 5;

with the proviso that when said compound has the formula Ib, W is N, u is 1, and R³When is H, [ R ]¹-(V)_n]_m-Q is not poly-C_1-4Alkyl-substituted cyclohexenyl or nitro-substituted furyl.

2. The compound of claim 1, wherein the compound has formula Ia.

3. The compound of claim 1, wherein the compound has formula Ib.

4. The compound of claim 1, wherein W is N.

5. The compound of claim 1, wherein R³Selected from H, C_1-6Alkyl radical, C_1-6Alkyl radical NR^cR^c、C_1-6Alkyl OR^c、C_1-6Alkyl NHC_1-6Alkyl radical C_6-10Aryl radical R^d、C_1-6Alkyl NHC (O) C_6-10Aryl radical R^d、C_1-6Alkyl OC_1-6Alkyl radical C_5-6Aryl radical R^d、C_1-6Alkyl radical C_6-10Aryl radical R^d、C_1-6Alkyl radical C_5-9Heterocyclic radical R^dOr C_1-6Alkyl radical C_3-9Cycloalkyl radical R^d。

6. The compound of claim 1, wherein R³Selected from H, C_1-6Alkyl radical, C_1-6Alkyl radical NR^cR^cOr C_1-6alkyl-C_5-9Heterocyclic ringsRadical R^d。

7. The compound of claim 1, wherein R³Is C_1-3An alkyl group.

8. The compound of claim 1 wherein Q is C_6-10Aryl radical, C_3-10Cycloalkyl or C_3-10A cycloalkenyl group.

9. The compound of claim 1 wherein Q is C₆Aryl or C_3-10A cycloalkenyl group.

10. The compound of claim 1 wherein- [ X [ ]]_q-[Y]_rIs OC_1-3Alkylene, N (C)_1-3Alkyl) C_1-3Alkylene radical, C_1-3Alkylene OC_1-3Alkylene radical, C_1-3Alkylene radical N (H) C_1-3Alkylene or C_1-3Alkylene, said group being optionally substituted with OH.

11. The compound of claim 1, wherein q is 0, R is 0, and R is⁴Each is H.

12. The compound of claim 1, wherein m is 1, V is S, n is 0 or 1, and R is¹Is C_6-10Aryl or C_5-15Heterocyclyl, wherein said aryl and heterocyclyl are each optionally substituted with 1 or 2 substituents independently selected from: halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl, OC_1-4Alkyl, OC_1-4Haloalkyl, -C (O) H, COOH, OC_1-4alkyl-C_6-10Aryl, OH, NHC (═ O) C_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

13. The compound of claim 1, wherein m is 1, n is 0, and R is¹Is C_6-10Aryl, wherein said aryl isIs optionally substituted with 1 or 2 substituents independently selected from: halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl, OC_1-4Alkyl, OC_1-4Haloalkyl, -C (O) H, COOH, OC_1-4alkyl-C_6-10Aryl, OH, NHC (═ O) C_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

14. The compound of claim 1, wherein

R¹Independently selected from H, halogen, C₆Aryl or C_5-6Heterocyclyl, wherein said C is₆Aryl or C_5-6The heterocyclyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, OH, NH₂、CN、C(＝O)NH₂、C_1-6Alkyl, OC_1-6Alkyl radical, C_1-4Alkyl OH, C_1-4Alkyl OC_1-3Alkyl radical, CH₂OH、SO₂H、SO₂NHC(CH₃)₃、SO₂C_1-6Alkyl, SO₂NHC_1-6Alkyl, OC_1-3Alkyl OC_1-3Alkyl, OC_1-3Alkyl OH, OC_1-3Alkyl OC (═ O) C_1-3Alkyl, C (═ O) C_1-6Alkyl, C (═ O) OC_1-6Alkyl, C (═ O) NH₂、C_5-6Heterocyclic group, OC_5-6Aryl radical, -C₆aryl-OC_1-4Alkyl or OC_1-6alkyl-C_5-6An aryl group; and is

R²Is H or C_1-6An alkyl group;

R³is H or C_1-3An alkyl group; and is

R⁴Each is H.

15. The compound of claim 1, wherein

Q is C₆Aryl or C_5-9A heterocyclic group;

w is N;

R²Is C_1-3An alkyl group.

16. The compound of claim 3, wherein

Q is C_6-10An aryl group;

w is N;

-[X]_q-[Y]_ris OC_1-3An alkylene group;

m is 1;

n is 0; and is

R¹Is C_6-10Aryl radical, said C_6-10Aryl is optionally substituted with 1 or 2 substituents independently selected from: OC_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

17. The compound of claim 3, wherein

Q is C_3-10A cycloalkenyl group;

w is N;

-[X]_q-[Y]_r-is absent;

m is 1;

n is 0; and is

R¹Is C_6-10Aryl radical, said C_6-10Aryl is optionally selected from 1 or 2 independentlyThe following substituents: OC_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

18. The compound of claim 2, wherein

Q is C_6-10Aryl radical, C_3-10Cycloalkyl or C_3-10A cycloalkenyl group;

w is N;

-[X]_q-[Y]_ris OC_1-3Alkylene, N (C)_1-3Alkyl) C_1-3Alkylene radical, C_1-3Alkylene OC_1-3Alkylene radical, C_1-3Alkylene radical N (H) C_1-3Alkylene or C_1-3Alkylene, said group being optionally substituted with OH;

m is 1;

v is S;

n is 0 or 1; and is

R¹Is C_6-10Aryl or C_5-15Heterocyclyl, wherein said aryl and heterocyclyl are each optionally substituted with 1 or 2 substituents independently selected from: halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl, OC_1-4Alkyl, OC_1-4Haloalkyl, -C (O) H, COOH, OC_1-4alkyl-C_6-10Aryl, OH, NHC (═ O) C_1-4Alkyl and-C₆aryl-OC_1-4An alkyl group.

19. A compound, or a pharmaceutically acceptable salt, tautomer or in vivo hydrolysable precursor thereof, selected from the group consisting of:

2-amino-6- [ (Z) -2- (3-bromophenyl) vinyl ] -3-methylpyrimidin-4 (3H) -one; and

2-amino-6- [ (E) -2- (3-bromophenyl) vinyl ] -3-methylpyrimidin-4 (3H) -one.

20. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable excipient, carrier or diluent.

21. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use as a medicament.

22. Use of a compound according to any one of claims 1 to 19 as a medicament for the treatment or prevention of an a β -related pathology.

23. Use of a compound according to any one of claims 1 to 19 as a medicament for the treatment or prevention of an a β -related pathology, wherein said a β -related pathology is down's syndrome, a β -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

24. Use of a compound according to any one of claims 1 to 19 in the manufacture of a medicament for the treatment or prevention of an a β -related pathology.

25. Use of a compound according to any one of claims 1 to 19 in the manufacture of a medicament for the treatment or prevention of an a β -related pathology, wherein said a β -related pathology is down's syndrome, a β -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), alzheimer's disease, memory loss, attention deficit symptoms associated with alzheimer's disease, neurodegeneration associated with alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

26. A method of inhibiting activity of BACE comprising contacting said BACE with a compound of any one of claims 1 to 19.

27. A method of treating or preventing an a β -related pathology in a mammal, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 19.

28. The method of claim 27, wherein said a β -related pathology is downs syndrome, a β -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), alzheimer disease, memory loss, attention deficit symptoms associated with alzheimer disease, neurodegeneration associated with alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

29. The method of claim 27, wherein the mammal is a human.

30. A method of treating or preventing an a β -related pathology in a mammal, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 19 and at least one cognitive enhancing drug, memory enhancing drug, or cholinesterase inhibitor.

31. The method of claim 30, wherein said a β -related pathology is downs syndrome, a β -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), alzheimer disease, memory loss, attention deficit symptoms associated with alzheimer disease, neurodegeneration associated with alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, dementia associated with parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

32. The method of claim 30, wherein the mammal is a human.