USOO81881 01B2 (12) United States Patent (10) Patent No.: US 8,188,101 B2 Forsblom et al. (45) Date of Patent: May 29, 2012 (54) DIHYDROPYRIDOPYRIMIDINES FOR THE WO 2005054193 A1 6, 2005 TREATMENT OF AB-RELATED WO 2005115990 A1 12/2005 WO 200703.5873 A1 3, 2007 PATHOLOGES WO 2007042.299 A1 4/2007 WO 2007044698 A1 4/2007 (75) Inventors: Rickard Forsblom, Södertälje (SE): WO 2007 114771 A1 10, 2007 Kim Paulsen, Södertälje (SE); Didier WO 2007125364 A1 11, 2007 Rotticci, Södertälje (SE); Ellen W 392. A. 58. Santangelo, Södertälje (SE); Magnus WO 2007 149033 A1 12/2007 Waldman, Södertälje (SE) WO 2008006103 A2 1/2008 WO 2008097538 A1 8, 2008 (73) Assignee: AstraZeneca AB, Sodertalje (SE) WO 200809921.0 A1 8, 2008 WO 2008100412 A1 8, 2008 (*) Notice: Subject to any disclaimer, the term of this W. SESS A. 3. patent is extended or adjusted under 35 WO 2009032277 A1 3, 2009 U.S.C. 154(b) by 217 days. WO 2009073777 A1 6, 2009 WO 2009073779 A1 6, 2009 (21) Appl. No.: 12/613,935 WO 2009076337 A1 6, 2009 WO 2009087127 A1 T 2009 (22) Filed: Nov. 6, 2009 WO 2009 103652 A1 8, 2009 9 WO 2010070008 A1 6, 2010 O O WO 2010O752O4 A2 T 2010 (65) Prior Publication Data WO 2010O83141 A1 T 2010 WO 2010O892.92 A1 8, 2010 US 2010/O13O495 A1 May 27, 2010 WO 2010O94647 A1 8, 2010 Related U.S. Application Data WO 2010.132015 A1 11, 2010 (60) Provisional application No. 61/111,786, filed on Nov. OTHER PUBLICATIONS 6, 2008, provisional application No. 61/179,088, filed Aharony etal, J Pharmacol Exp. Ther 1995, 274(3), 1216-1221. on May 18, 2009, provisional application No. Beher, Curr top Med Chem 2008, 8(1), 34-37. 61/179,459, filed on May 19, 2009. Maggietal, J Pharmacol Exp Ther 1994, 271(3), 1489-1500. Weggen et al. Nature 2001, 414(6860), 212-216. (51) Int. Cl. A 6LX3/59 (2006.01) Primary Examiner — James O Wilson (52) U.S. Cl. ..................................... 514/264.1; 544/279 Assistant Examiner — Brian McDowell (58) Field of Classification Search ................... 544/279 (74) Attorney, Agent, or Firm — Kenneth F. Mitchell See application file for complete search history. (57) ABSTRACT (56) References Cited Dihydropyridopyrimidine compounds of formula (Ia) U.S. PATENT DOCUMENTS 2005/O197361 A1 9/2005 Jirgensons et al. (Ia) 2006, OOO4013 A1 1/2006 Kimura et al. 2008.0171771 A1 7/2008 Arnold et al. 2008/0280948 A1 11/2008 Baumann et al. 2009.0099.195 A1 4/2009 Bayrakdarian et al. 2009.00992.17 A1 4/2009 Berg et al. 2009/02O3697 A1 8, 2009 Kimura et al. 2010, O105904 A1 4/2010 Kimura et al. 2010/0292210 A1 11/2010 LO-Alfredsson et al. FOREIGN PATENT DOCUMENTS and therapeutically acceptable salts thereof, wherein R', R EP 1352659 A1 10, 2003 and Zare as defined in the specification; processes for making EP 1348707 B1 8, 2010 WO 2004O73705 A1 9, 2004 them and methods for using them in the treatment of AB WO 2004.110350 A2 12/2004 related pathologies. WO 2005O12304 A2 2, 2005 WO 2005O13985 A1 2, 2005 5 Claims, No Drawings US 8,188,101 B2 1. 2 DHYDROPYRIDOPYRIMIDNES FOR THE erates the N terminus of AB, is catalyzed by the transmem TREATMENT OF AB-RELATED brane aspartyl protease BACE1. The y-cleavage, generating PATHOLOGES the ABC termini and subsequent release of the peptide, is effected by a multi-subunit aspartyl protease named Y-secre This application claims the benefit of US Provisional Patent Applications Numbered 61/111,786 filed 6 Nov. 2008, tase. Both BACE1 and Y-secretase processes APP at different 61/179,088 filed 18 May 2009 and 61/179,459 filed 19May sites, resulting in AB peptides of different lengths and heter 2009. ologous N- and C-termini. The invention described herein covers all N-terminal variants of AB. Therefore, for the sake TECHNICAL FIELD OF THE INVENTION 10 of simplicity, all N-terminal variants will be covered by the denotation AB. The present invention relates to novel compounds and The activity of y-secretase causes the liberation of many AB pharmaceutically acceptable salt thereof. Furthermore, the peptides, such as AB37, AB38, AB39, AB40, A342 and AB43, present invention also relates to pharmaceutical compositions of which AB40 is the most common These peptides show a comprising said compounds, processes for making said com 15 different propensity to aggregate, and in particular AB42 is pounds and their use as medicaments for treatment and or prone to form oligomers and fibrillar deposits. Intriguingly, prevention of various diseases. In particular, the present human genetics strongly Support a key role for AB42 as a key invention relates to compounds, which interfer with Y-secre mediator of Alzheimer pathogenesis. Indeed, more than 150 tase and or its substrate and hence modulate the formation of different mutations causing familial Alzheimer's disease AB peptides. These compounds are used for treatment and or either result in an increase in the ratio of AB 42/40 peptides prevention of AB-related pathologies, such as Alzheimer's produced or affect the intrinsic aggregation behaviour of AB. disease, Downs syndrome and B-amyloid angiopathy, such as Based on this knowledge, A?42 has become a prime target for but not limited to cerebral amyloid angiopathy, hereditary therapeutic intervention in AD (Beher D. Curr Top Med Chem cerebral hemorrhage, disorders associated with cognitive 25 2008; 8(1):34-7). Targeting AB42 at the level of Y-secretase impairment, such as but not limited to MCI (“mild cognitive activity must however be conducted with caution since impairment'), Alzheimer's disease, memory loss, attention Y-secretase catalyses proteolysis of many proteins, which deficit symptoms associated with Alzheimer's disease, neu have important physiological functions. Among its many Sub rodegeneration associated with diseases such as Alzheimer's 30 strates is the Notch receptor family, which signaling is essen disease or dementia including dementia of mixed vascular tial for many different cell fate determination processes e.g. and degenerative origin, pre-senile dementia, senile dementia during embryogenesis and in the adult. As such, A?42 low and dementia associated with Parkinson's disease, progres ering strategies at the level of Y-secretase must be compatible sive Supranuclear palsy or cortical basal degeneration. with maintained Notch signaling. 35 Encouragingly, an enormous Scientific effort and progress BACKGROUND OF THE INVENTION have suggested that it is indeed possible to combine Y-secre tase interference and lowered AB42 production without The prime neuropathological event distinguishing Alzhe obtaining toxic side effects due to impaired Notch signaling imer's disease (AD) is deposition of the amyloid B-peptide 40 There have for instance been reports, which postulate that (AB) in brain parenchyma and cerebral vessels. A large body allosteric modulation of Y-secretase combines lowered AB42 of genetic, biochemical and in vivo data Support a pivotal role production with maintained Notch signaling (Weggen et al. for AB in the pathological cascade that eventually leads to Nature 414(6860), 212-216 (2003)). In addition, a number of AD. Patients usually present early symptoms (commonly compounds interfering with Y-secretase and AB production memory loss) in their sixth or seventh decades of life. The 45 have been suggested, in e.g. WO2005/054193, WO2005/ disease progresses with increasing dementia and elevated 001398, WO2004/073705, WO2007/135969, WO2007/ deposition of AB. In parallel, a hyperphosphorylated form of 139149, WO2005/115990, WO2008/097538, WO2008/ the microtubule-associated protein tau accumulates within 099210, WO2008/100412, WO2007/125364 and WO2009/ neurons, leading to a plethora of deleterious effects on neu 50 103652. ronal function. The prevailing working hypothesis regarding The present invention describes a new class of compounds, the temporal relationship between AB and tau pathologies said compounds will inhibit the AB40 and 42 production, states that AB deposition precedes tau aggregation in humans increase AB37 and AB38 levels and maintaining Notch sig and animal models of the disease. Within this context, it is naling. These compounds will thus be useful in the prevention worth noting that the exact molecular nature of AB, mediating 55 and/or treatment of Alzheimer's Disease (AD). this pathological function is presently an issue under intense study. Most likely, there is a continuum of toxic species DISCLOSURE OF THE INVENTION ranging from lower order AB oligomers to Supramolecular assemblies such as AB fibrils. It has been found that compounds of the Formula (I), herein The AB peptide is an integral fragment of the Type I protein 60 also referred to as the compounds of the (present) invention, APP (AB amyloid precursor protein), a protein ubiquitously are affecting the Y-secretase mediated processing of APP and expressed in human tissues. A? can be found in both plasma, thereby lowering the secretion of A?42 and AB40 peptides cerebrospinal fluid (CSF), and in the medium from cultured while causing an increase in the secreted levels of AB37 and cells, and is generated as a result of APP proteolysis. There 65 AB38 and maintaining Notch signaling. These compounds are two main cleavages of APP that results in AB production, can be used for treatment and/or prevention of AB-related the so-called B-, and Y-cleavages. The B-cleavage, which gen pathologies. US 8,188,101 B2 3 4 Hence, the present invention relates to a compound accord bocyclyl, C(O) heterocyclyl or SOC-alkyl, wherein said ing to formula (I) Calkyl, heterocyclyl, carbocyclyl or CalkylOC alkyl is optionally substituted with one to three substituents selected from halogen, cyano, hydroxy, amino, NHC R7 alkyl, N(Calkyl), NC(O)Calkyl, C(O)Calkoxy, M SOC-alkyl and heterocyclyl, Y R’ is selected from hydrogen, aryl, heteroaryl, C-alkylaryl, Calkylheteroaryl, Calkylcarbocyclyl, Calkylhet erocyclyl and carbocyclyl, wherein said aryl, heteroaryl, 10 Calkylcarbocyclyl, Calkylheterocyclyl, Calky W laryl, carbocyclyl or Calkylheteroaryl is optionally Sub stituted with one or more substituents selected from halo R2 R4 gen, cyano, hydroxy, nitro, Cigalkyl, C-galkoxy, carbocyclyl, heterocyclyl, CF.