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. OCF, OC-alkyl, C(O) C1-alkyl, CalkylOC-alkyl, SOC-alkyl, R3 R5 15 SONHC alkyl, SON(Calkyl). SON-heterocyclyl, C(O)NH2, C(O)NHC alkyl, C(O)N(Calkyl), C(O)N- A heterocyclyl, Calkenyl and Calkynyl, wherein said Calkyl, Calkoxy, CalkylOC-alkyl, heterocyclyl, carbocyclyl, Calkenyl or C-alkynyl is optionally Sub wherein stituted with cyano, hydroxy, methoxy, halogen, SOC E is alkyl, amino, NHC alkyl, N(Calkyl), heterocyclyl or aryl; O RandR may, when Y is NR, optionally form together with 25 the nitrogen atom a saturated, partially saturated or unsat urated ring system, wherein said ring system is optionally Substituted with one or more groups selected from halogen, hydroxy, cyano, CalkylOC-alkyl and Calkyl, wherein X and V are independently selected from nitrogen wherein said CalkylOC alkyl or Calkyl is option or CH and wherein at least one of X or V is nitrogen: 30 ally Substituted with halogen, cyano, hydroxy: W is C(R) -, - O - or - N(R)–: R" is selected from hydrogen, C-alkyl, Calkoxy, C2-alk R is hydrogen, Calkyl or Calkoxy, wherein said enyl, C-alkynyl, carbocyclyl, heterocyclyl, C(O)R. Calkyl is Substituted with halogen, cyano, hydroxy, C(O)N(R), C(O)CHN(R), C(O)heterocyclyl, C(O) amino, NHC alkyl, N(Calkyl), heterocyclyl, NC(O) carbocyclyl, C(O)OR, SOR, SOheterocyclyl, Calkyl, C(O)Calkoxy or SOC-alkyl: 35 SOcarbocyclyl and SON(R), wherein said Calkyl, Y is C(R)(R') , N(R) or - O : Calkoxy, Calkenyl, C-alkynyl, carbocyclyl or het R'' and Rare independently selected from hydrogen, halo erocyclyl is optionally substituted with one or more sub gen, Calkyl, CalkylOC-alkyl, carbocyclyl, hetero stituents selected from halogen, hydroxy, cyano, amino, cyclyl and Calkoxy, wherein said Calkyl, Calky C(O)OR, NHC, alkyl, NHCalkoxy, N(Calkyl). 1OC-alkyl, carbocyclyl, heterocyclyl or Calkoxy is 40 N(Calkoxy), SC alkyl, SOC-alkyl, SOC-alkyl, optionally substituted with one or more substituents Calkyl, Calkoxy, heterocyclyl and carbocyclyl, Selected from halogen, cyano, hydroxy, heterocyclyl, R is selected from hydrogen, hydroxy, halogen, cyano, N(Coalkyl), NC(O)Calkyl; Calkyl, Calkoxy, carbocyclyl and heterocyclyl, O wherein said Calkyl, Calkoxy, cycloalkyl or hetero R'' and R' may form together with the carbonatom they are 45 cyclyl is optionally substituted with one or more substitu attached to a saturated, partially unsaturated or saturated ents selected from halogen, cyano, hydroxy or methoxy; ring system, wherein said ring system may contain one or R. R. Rand Rare independently selected from hydrogen, more heteroatoms selected from N, O and S, and wherein if cyano, Calkoxy, Calkoxy, halogen, OCH, OCF, said ring system contains an nitrogen atom that nitrogen OCFH, OCFH and hydroxy: may optionally be substituted with a group selected from 50 A is a 5-7 membered heteroaryl, wherein at least one of the Calkyl and C(O)Calkyl and wherein said ring is ring forming atoms is selected from nitrogen and the optionally Substituted with one or more groups selected remaining ring forming atoms are selected from carbon, from halogen, cyano, hydroxy: nitrogen, Sulphur and oxygen, and wherein said A is O optionally substituted with one or more substituents R'' and R may form together a saturated, partially unsatur 55 selected from halogen, Calkyl, SR', NR'R'', OR', ated or Saturated bicyclic ring system, wherein said bicy Calkenyl and Calkynyl and wherein said Calkyl, clic ring system may contain Zero to three heteroatoms Calkenyl or C-alkynyl is optionally Substituted with selected from N, O and S, and wherein said bicyclic ring halogen, hydroxy, cyano or Calkoxy; system is optionally substituted with one to three substitu R'' and R'' are independently selected from hydrogen, ents selected from halogen, cyano, hydroxy, Calkoxy, 60 Calkyl, CF, CFH and CFH: amino, NHC alkyl, N(Calkyl). NC(O)Calkyl, B is a 5 to 7 membered non-aromatic saturated ring, wherein SOC-alkyl and heterocyclyl, and wherein if said bicy one of the ring forming atom is selected from —N(R')—, clic ring system contains an nitrogen atom that nitrogen —C(R)-, -S(O), or —O— and the other ring form may optionally be substituted by a group selected from ing atoms are carbon, wherein one —CH2— group can Calkyl and C(O)Calkyl; 65 optionally be replaced by a C(O)— and wherein said R is selected from hydrogen, C-alkyl, C-alkylOC. ring is optionally substituted with one to three substituents alkyl, C(O)Calkyl, C(O) cycloalkyl, heterocyclyl, car selected from halogen, cyano, hydroxy, amino, Calkyl, US 8,188,101 B2 5 6 Calkoxy, NHC alkyl, NHC alkylOC-alkyl, N(C. optionally Substituted with one or more groups selected alkyl), N(CalkylOC-alkyl), carbocyclyl and hetero from halogen, cyano, hydroxy: cyclyl, wherein said Calkyl, Calkoxy, NHC alkyl, O NHC alky1OC-alkyl, N(Calkyl), N(Calky1OC R'' and R7 may form together a saturated, partially unsatur alkyl), carbocyclyl or heterocyclyl is optionally substi ated or Saturated bicyclic ring system, wherein said bicy clic ring system may contain Zero to three heteroatoms tuted with one or more Substituents selected from halogen, selected from N, O and S, and wherein said bicyclic ring hydroxy or cyano; system is optionally substituted with one to three substitu n is selected from 0, 1, 2: ents selected from halogen, cyano, hydroxy, Calkoxy, E and B will together form a bicyclic ring system; amino, NHC alkyl, N(Calkyl). NC(O)Calkyl, provided that the following compounds are excluded: 10 SOC-alkyl and heterocyclyl, and wherein if said bicy a compound according to formula (I), wherein V and X are clic ring system contains an —NH-moiety that nitrogen N.Y is NR; B contains a N(R')—moiety, R is hydrogen, may optionally be substituted by a group selected from Calkyl and C(O)Calkyl; alkylor cycloalkyl, and R is arylalkyl, optionally substituted R is selected from hydrogen, C-alkyl, C-alkylOC. with a group containing a linker selected from O or S; and 15 alkyl, C(O)Calkyl, C(O) cycloalkyl, heterocyclyl, car as a free base or a pharmaceutically acceptable salt thereof. bocyclyl, C(O) heterocyclyl or SOC-alkyl, wherein said The present invention also relates to a compound according Calkyl, heterocyclyl, carbocyclyl or CalkylOC to formula (I) alkyl is optionally substituted with one to three substituents selected from halogen, cyano, hydroxy, amino, NHC alkyl, N(Calkyl), NC(O)Calkyl, C(O)Calkoxy, (I) R7 SOC-alkyl and heterocyclyl, A R’ is selected from hydrogen, aryl, heteroaryl, C-alkylaryl, Y Calkylheteroaryl, Calkylcarbocyclyl, Calkylhet erocyclyl and carbocyclyl, wherein said aryl, heteroaryl, 25 Calkylcarbocyclyl, Calkylheterocyclyl, Calky laryl, carbocyclyl or Calkylheteroaryl is optionally Sub W stituted with one or more substituents selected from halo gen, cyano, hydroxy, nitro, Calkyl, Calkoxy, R2 R4 carbocyclyl, heterocyclyl, CF. OCF, OC-alkyl, C(O) 30 Calkyl, CalkylOC-alkyl, SOC-alkyl, SONHC alkyl, SON(Calkyl), SON-heterocyclyl, R3 R5 C(O)NHC(O)NHC alkyl, C(O)N(Calkyl), C(O)N- heterocyclyl, Calkenyl and Calkynyl, wherein said A Calkyl, Calkoxy, CalkylOC-alkyl, heterocyclyl, 35 carbocyclyl, Calkenyl or C-alkynyl is optionally Sub wherein stituted with cyano, hydroxy, methoxy, halogen, SOC E is alkyl, amino, NHC alkyl, N(Calkyl), heterocyclyl or aryl; O 40 RandR may, when Y is NR, optionally form together with the nitrogen atom a saturated, partially saturated or unsat urated ring system, wherein said ring system is optionally Substituted with one or more groups selected from halogen, hydroxy, cyano, CalkylOC-alkyl and Calkyl, wherein X and V are independently selected from nitrogen 45 wherein said CalkylOC alkyl or Calkyl is option or CH and wherein at least one of X or V is nitrogen: ally Substituted with halogen, cyano, hydroxy: W is C(R) -, - O - or - N(R)–: R" is selected from hydrogen, Calkyl, Calkoxy, Calk R is hydrogen, Calkyl or Calkoxy, wherein said enyl, Coalkynyl, carbocyclyl, heterocyclyl, C(O)R. Calkyl is substituted with halogen, cyano, hydroxy, C(O)N(R), C(O)CHN(R), C(O)heterocyclyl, C(O) amino, NHC alkyl, N(Calkyl), heterocyclyl, NC(O) 50 carbocyclyl, C(O)OR, SOR, SOheterocyclyl, Calkyl, C(O)Calkoxy or SOC-alkyl, SO.carbocyclyl and SON(R), wherein said Calkyl, Y is C(R)(R') , N(R) or - O : Calkoxy, Calkenyl, C-alkynyl, carbocyclyl or het R'' and Rare independently selected from hydrogen, halo erocyclyl is optionally substituted with one or more sub gen, Calkyl, C-alkylOC-alkyl, carbocyclyl, hetero stituents selected from halogen, hydroxy, cyano, amino, cyclyl and Calkoxy, wherein said Calkyl, Calky 55 C(O)OR, NHC, alkyl, NHCalkoxy, N(Calkyl). 1OC-alkyl, carbocyclyl, heterocyclyl or Calkoxy is N(Calkoxy), SC alkyl, SOC-alkyl, SOC-alkyl, optionally substituted with one or more substituents Calkyl, Calkoxy, heterocyclyl and carbocyclyl, Selected from halogen, cyano, hydroxy, heterocyclyl, R is selected from hydrogen, hydroxy, halogen, cyano, N(Coalkyl), NC(O)Calkyl; Calkyl, Calkoxy, carbocyclyl and heterocyclyl, O 60 wherein said Calkyl, Calkoxy, cycloalkyl or hetero R'' and R' may form together with the cabon atom they are cyclyl is optionally substituted with one or more substitu attached to a saturated, partially unsaturated or saturated ents selected from halogen, cyano, hydroxy or methoxy; ring system, wherein said ring system may contain one or R. R. Rand Rare independently selected from hydrogen, more heteroatoms selected from N, O and S, and wherein if cyano, Calkyl, Calkoxy, halogen, OCH, OCF, said ring system contains an —NH-moiety that nitrogen 65 OCFH, OCFH and hydroxy: may optionally be substituted with a group selected from A is a 5-7 membered heteroaryl, wherein at least one of the Calkyl and C(O)Calkyl and wherein said ring is ring forming atoms is selected from nitrogen and the US 8,188,101 B2 7 8 remaining ring forming atoms are selected from carbon, According to one embodiment of the present invention, Y nitrogen, Sulphur and oxygen, and wherein said A is is —O—. optionally substituted with one or more substituents According to one embodiment of the present invention, Y selected from halogen, Calkyl, SR', NR'R'', OR', is C(R')(R') . Calkenyl and C alkynyl and wherein said Calkyl, According to another embodiment of the present invention, Calkenyl or Calkynyl is optionally Substituted with R'' and Rare independently selected from hydrogen, halo halogen, hydroxy, cyano or Calkoxy; gen, Calkyl, CalkylOC-alkyl, carbocyclyl and hetero R'' and R'' are independently selected from hydrogen, cyclyl y, wherein said Calkyl, CalkylOC-alkyl, car Calkyl, CF, CFH and CFH: bocyclyl or heterocyclyl is optionally substituted with one or B is a 5 to 7 membered non-aromatic ring, wherein one of the 10 more substituents selected from halogen, cyano, hydroxy, ring forming atom is selected from —N(R')—, heterocyclyl, N(Coalkyl), NC(O)C alkyl. —C(R)-, -S(O), or —O— and the other ring form According to one embodiment of the present invention, R ing atoms are carbon, wherein one —CH2— group can and Rare hydrogen. optionally be replaced by a C(O)— and wherein said 15 According to one embodiment of the present invention, R ring is optionally substituted with one to three substituents is selected from hydrogen, cyano, Calkyl, halogen and Selected from halogen, cyano, hydroxy, amino, Calkyl, Calkoxy. Calkoxy, NHC alkyl, NHC alkylOC-alkyl, N(C. According to one embodiment of the present invention, R alkyl), N(CalkylOC-alkyl), carbocyclyl and hetero is selected from hydrogen, cyano, Calkyl, halogen and cyclyl, wherein said Calkyl, Calkoxy, NHC alkyl, Calkoxy. NHC alkylOC-alkyl, N(Calkyl), N(CalkylOC According to one embodiment of the present invention, A alkyl), carbocyclyl or heterocyclyl is optionally Substi is selected from oxazolyl, imidazolyl pyrazolyl, isoxazolyl, tuted with one or more Substituents selected from halogen, oxadiazolyl pyridinyl, pyrimidinyl, pyrryl, thiazolyl, triaz hydroxy or cyano; olyl and thiadiazolyl. n is selected from 0, 1, 2: 25 According to another embodiment of the present invention, E and B will together form a bicyclic ring system; A is selected from oxazolyl, imidazolyl and pyrazolyl. provided that the following compounds are excluded: According to another embodiment of the present invention, a compound according to formula (I), wherein V and X are A is substituted with Calkyl or halogen. N;Y is NR: R is hydrogen, 30 According to one embodiment of the present invention, B alkyl or cycloalkyl, and R7 is arylalkyl, optionally substi is a non-aromatic 6 membered ring, wherein one of the ring tuted with a group containing a linker selected from O or S forming atom is N(R') and five of the ring forming atoms are and B contains a N(R')— moiety and carbon. a compound according to formula (I), wherein V and X are According to one embodiment of the present invention, B N: Y is NR; R is hydrogen, alkyl or cycloalky and R is 35 is a non-aromatic 6 membered ring, wherein one of the ring arylalkyl and wherein R7 and R will together form a ring, forming atom is O and five of the ring forming atoms are said ring is piperidyl, piperazinyl or morpholinyl and is carbon. optionally Substituted with hydroxy, OXO or a group contain According to one embodiment of the present invention, B ing—C(O) and B contains a —N(R')— moiety; is a non-aromatic 6 membered ring, wherein one of the ring as a free base or a pharmaceutically acceptable salt thereof. 40 forming atom is C(R) and five of the ring forming atoms are According to one embodiment of the present invention, X carbon, and wherein R is selected from hydrogen and is nitrogen. Calkyl wherein said Calkyl is optionally Substituted According to one embodiment of the present invention, V with one or more substituents selected from halogen. is nitrogen. According to one embodiment of the present invention, the According to one embodiment of the present invention, X 45 ring system formed by E and B is selected from and V are nitrogen. 5,6,7,8-tetrahydropyrido4,3-dipyrimidine: According to one embodiment of the present invention, W is NR. 5,6,7,8-tetrahydropyrido 3,4-dipyrimidine: According to another embodiment of the present invention, 6,7-dihydro-5H-pyrrolo3,4-dpyrimidine: R is hydrogen. 50 6,7,8,9-tetrahydro-5H-pyrimidoA,5-diazepine; According to one embodiment of the present invention, Y 6,7,8,9-tetrahydro-5H-pyrimidoA.5-cazepine; is N(R)-. 6,7,8,9-tetrahydro-5H-pyrimido 5,4-cazepine; According to another embodiment of the present invention, 5,6,7,8-tetrahydropyrido 2,3-dipyrimidine: R is selected from hydrogen, C-alkyl, C-alkylOC. 55 5,6,7,8-tetrahydroquinazoline; alkyl, C(O)Calkyl, heterocyclyl and carbocyclyl, wherein said Calkyl, heterocyclyl, carbocyclyl or CalkylOC 7,8-dihydro-5H-thiopyrano.4.3-dpyrimidine 6-oxide; alkyl is optionally substituted with one to three substituents 7,8-Dihydro-5H-pyrano.4.3-dpyrimidine: selected from halogen, cyano, hydroxy, amino, NHC alkyl, and 6,7-dihydro-5H-pyrrolo2,3-dipyrimidine. N(Calkyl). NC(O)Calkyl and heterocyclyl; 60 According to another embodiment of the present invention, According to another embodiment of the present invention, said ring system is R and R' will form together with the nitrogen atom a par 5,6,7,8-tetrahydropyrido4,3-dipyrimidine tially saturated or unsaturated ring system, wherein said ring 5,6,7,8-tetrahydroquinazoline; system is optionally Substituted with one or more groups 7,8-dihydro-5H-thiopyrano.4.3-dpyrimidine 6-oxide; selected from halogen, hydroxy, cyano, CalkylOC alkyl 65 and Calkyl, wherein said CalkylOC-alkyl or Calkyl 7,8-Dihydro-5H-pyrano.4.3-dpyrimidine: is optionally substituted with hydroxy. or 5,6,7,8-tetrahydropyrido3,4-dpyrimidine. US 8,188,101 B2 9 10 According to one embodiment of the present invention, A is a 5 membered heteroaryl, wherein at least one of the ring E is forming atoms is selected from nitrogen and the remaining ring forming atoms are selected from carbon, nitrogen, and oxygen, and wherein said A is optionally Substituted with one or more substituents selected from halogen or Calkyl and wherein said Calkyl is optionally Substi O tuted with halogen, hydroxy, cyano or Calkoxy; B is a 6 membered non-aromatic ring, wherein one of the ring forming atom is selected from —N(R')— or -O- and W is N(R) ; 10 R is hydrogen; the other ring forming atoms are carbon, wherein said ring Y is C(R)(R') , N(R) or - O : is optionally substituted with one to three substituents R'' and Rare independently selected from hydrogen, halo selected from halogen, cyano, hydroxy, amino, Calkyl, gen, Calkyl, CalkylOC-alkyl, carbocyclyl and het Calkoxy, NHC alkyl, NHC alkylOC-alkyl, N(C. erocyclyl, wherein said Calkyl, CalkylOC-alkyl, 15 alkyl), N(CalkylOC-alkyl), carbocyclyl and hetero carbocyclyl or heterocyclyl is optionally substituted with cyclyl one or more Substituents selected from halogen, cyano, According to one embodiment of the present invention, hydroxy, heterocyclyl, N(Coalkyl), NC(O)Calkyl, E is R is selected from hydrogen, C-alkyl, C-alkylOC. alkyl, C(O)Calkyl, C(O) cycloalkyl, heterocyclyl, car bocyclyl and C(O)heterocyclyl, wherein said Calkyl, heterocyclyl, carbocyclyl or CalkylOC-alkyl is optionally substituted with one to three substituents Selected from halogen, cyano, hydroxy, amino, NHC alkyl, N(Calkyl), NC(O)Calkyl, C(O)Calkoxy, 25 SOC-alkyl and heterocyclyl; wherein X and V are nitrogen; R’ is selected from hydrogen, aryl, heteroaryl, C-alkylaryl, W is - O - or - N(R)–: Calkylheteroaryl, Calkylcarbocyclyl, Calkylhet R is hydrogen; erocyclyl and carbocyclyl, wherein said aryl, heteroaryl, Y is C(R')(R') , N(R) or - O : Calkylcarbocyclyl, Calkylheterocyclyl, Calky 30 R'' and R' are independently selected from hydrogen, laryl, carbocyclyl or Calkylheteroaryl is optionally Sub Calkyl, CalkylOC-alkyl, wherein said Calkyl or stituted with one or more substituents selected from halo CalkylOC-alkyl is optionally substituted with one or gen, cyano, hydroxy, nitro, Calkyl, Calkoxy, more Substituents selected from halogen, cyano, hydroxy, carbocyclyl, heterocyclyl, CF. OCF, OC-alkyl, C(O) heterocyclyl, N(Coalkyl), NC(O)Calkyl; Calkyl, CalkylOC-alkyl, SOC-alkyl, 35 R is selected from hydrogen, Calkyl and carbocyclyl, SONHC alkyl, SON(Calkyl), SON-heterocyclyl, wherein said Calkyl, is optionally Substituted with one C(O)NHC(O)NHC alkyl, C(O)N(Calkyl), C(O)N- to three Substituents selected from cyano, hydroxy and heterocyclyl, Calkenyl and C-alkynyl, wherein said heterocyclyl; Calkyl, Calkoxy, CalkylOC-alkyl, heterocyclyl, R’ is selected from hydrogen, aryl, C-alkylaryl, C-alkyl carbocyclyl, Calkenyl or C-alkynyl is optionally Sub 40 heteroaryl, Calkylcarbocyclyl, Calkylheterocyclyl stituted with cyano, hydroxy, methoxy, halogen, SOC and carbocyclyl, wherein said aryl, Calkylcarbocyclyl, alkyl, amino, NHC alkyl, N(Calkyl), heterocyclyl or Calkylheterocyclyl, Calkylaryl, carbocyclyl or aryl; Calkylheteroaryl is optionally substituted with one or O more substituents selected from hydroxy, halogen, RandR may, when Y is NR, optionally form together with 45 Calkyl, C(O)Calkyl, wherein said Calkyl is option the nitrogen atom a saturated, partially saturated or unsat ally substituted with hydroxy: urated ring system, wherein said ring system is optionally O Substituted with one or more groups selected from halogen, RandR may, when Y is NR, optionally form together with hydroxy, cyano, CalkylOC-alkyl and Calkyl, the nitrogen atom a saturated, partially saturated or unsat wherein said CalkylOC alkyl or Calkyl is option 50 urated ring system, wherein said ring system is optionally ally Substituted with halogen, cyano, hydroxy: Substituted with one or more groups selected from R" is selected from hydrogen, C-alkyl, Cigalkoxy, carbocy CalkylOC-alkyl and Calkyl, wherein said Calky clyl, heterocyclyl, C(O)R. C(O)N(R), C(O)CHN(R), 1OC-alkyl or Calkyl is optionally substituted with C(O)heterocyclyl, C(O)carbocyclyl, C(O)CR, SOR, hydroxy, wherein said Calkyl, Calkoxy, carbocyclyl or hetero 55 R" is selected from hydrogen, Calkyl, C(O)R’, C(O)N cyclyl is optionally substituted with one or more substitu (R), C(O)CHN(R), C(O)CR and SOR, wherein ents selected from halogen, hydroxy, cyano, amino, C(O) said Calkyl, is optionally Substituted with one hydroxy OR, NHC, alkyl, NHCalkoxy, N(Calkyl), N(C. or heterocyclyl; alkoxy), SC-alkyl, SOC-alkyl, SOC-alkyl, R is selected from Calkyl and carbocyclyl, wherein said Calkyl, Calkoxy, heterocyclyl and carbocyclyl; 60 Calkyl is optionally Substituted with one or more Sub R is selected from hydrogen, hydroxy, halogen, cyano, stituents selected from halogen, cyano, hydroxy or meth Calkyl, Calkoxy, carbocyclyl and heterocyclyl, oxy; wherein said Calkyl, Calkoxy, cycloalkyl or hetero R. R. Rand Rare independently selected from hydrogen cyclyl is optionally substituted with one or more substitu and Calkoxy. ents selected from halogen, cyano, hydroxy or methoxy; 65 A is a 5 membered heteroaryl, wherein at least one of the ring R. R. RandR are independently selected from hydrogen, forming atoms is selected from nitrogen and the remaining Calkyl, Calkoxy, halogen and hydroxy, ring forming atoms are selected from carbon, nitrogen, US 8,188,101 B2 11 12 Sulphur and oxygen, and wherein said A is optionally Sub R'' is hydrogen or C-alkyl wherein said Calkyl is option stituted with one or more substituents selected from halo ally substituted with one or more substituents selected gen, Calkyl, SR', NR'R'', OR', Calkenyl and from halogen Calkynyl and wherein said Calkyl, Calkenyl or A is a 5 membered heteroaryl, wherein at least one of the ring Calkynyl is optionally substituted with halogen, 5 forming atoms is selected from nitrogen and the remaining hydroxy, cyano or Calkoxy; ring forming atoms are selected from carbon, nitrogen and B is a 6 membered non-aromatic ring, wherein one of the ring oxygen, and wherein said A is optionally Substituted with forming atom is selected from N(R') , —C(R) , one C-alkyl, —S(O), or —O— and the other ring forming atoms are carbon, wherein one —CH2— group can optionally be 10 B is a 6 non-aromatic ring, wherein one of the ring forming replaced by a —C(O)—and wherein said ring is optionally atom is selected from N(R') , —O , S(O) , Substituted with one to three substituents selected from —C(R')—and the other ring forming atoms are carbon, halogen, cyano, hydroxy, amino, Calkyl, Calkoxy, and wherein said ring is optionally Substituted with one to NHC alkyl, NHC alkylOC-alkyl, N(Calkyl). three substituents selected from Calkyl. N(CalkylOC-alkyl), carbocyclyl and heterocyclyl 15 According to one embodiment of the present invention, wherein said Calkyl, Calkoxy, NHC alkyl, NHC E is alkylOC-alkyl, N(Calkyl), N(CalkylOC-alkyl). carbocyclyl or heterocyclyl is optionally substituted with one or more Substituents selected from halogen, hydroxy and cyano; n is 1. According to one embodiment of the present invention, E is 25 wherein X and V are nitrogen; W is - O - or - N(R)–: R is hydrogen; Y is C(R')(R') , N(R) or - O : 30 R'' and Rare hydrogen; R is selected from hydrogen, C-alkyl and carbocyclyl, wherein X and V are nitrogen; wherein said Calkyl, is optionally Substituted with one W is O— or - N(R)–: to three Substituents selected from cyano, hydroxy and R is hydrogen; 35 heterocyclyl; Y is C(R)(R') , N(R) or - O : R’ is selected from hydrogen, aryl, C-alkylaryl, Calky R'' and R' are independently selected from hydrogen, lheteroaryl, Calkylheterocyclyl and carbocyclyl, wherein Calkyl, Calkylalkoxy: said aryl, Calkylaryl or carbocyclyl is optionally substi R is selected from hydrogen, C-alkyl and carbocyclyl, tuted with one substituent selected from hydroxy, Calkyl wherein said Calkyl, is optionally Substituted with one 40 and C(O)Calkyl, wherein said Calkyl is optionally Sub to three Substituents selected from cyano, hydroxy and stituted with hydroxy: heterocyclyl: R’ is selected from hydrogen, aryl, C-alkylaryl, C-alkyl O heteroaryl, Calkylcarbocyclyl, Calkylheterocyclyl RandR may, when Y is NR, optionally form together with and carbocyclyl, wherein said aryl, Calkylcarbocyclyl, 45 the nitrogen atom a saturated, partially saturated or unsat Calkylheterocyclyl, Calkylaryl, carbocyclyl or urated ring system, wherein said ring system is optionally Calkylheteroaryl is optionally substituted with one or Substituted with one or more groups selected from more substituents selected from hydroxy, halogen, Calkyl, wherein said Calkyl is optionally substituted Calkyl, C(O)Calkyl, wherein said Calkyl is option with hydroxy: ally substituted with hydroxy: 50 R" is selected from hydrogen, Calkyl, C(O)R’, C(O)N O (R), C(O)CHN(R), C(O)CR and SOR, wherein RandR may, when Y is NR, optionally form together with said Calkyl, is optionally Substituted with one hydroxy the nitrogen atom a saturated, partially saturated or unsat or heterocyclyl; urated ring system, wherein said ring system is optionally R is Calkyl or carbocyclyl, wherein said Calkyl is Substituted with one or more groups selected from 55 optionally substituted with one e substituent selected from CalkylOC-alkyl and Calkyl, wherein said Calky hydroxy or methoxy; 1OC-alkyl or Calkyl is optionally substituted with hydroxy: R. R. RandR are independently selected from hydrogen R" is selected from hydrogen, Calkyl, C(O)R. C(O)N and Calkoxy. (R), C(O)CHN(R), C(O)CR and SOR, wherein 60 A is a 5 membered heteroaryl, wherein at least one of the ring said Calkyl, is optionally substituted with one hydroxy forming atoms is selected from nitrogen and the remaining or heterocyclyl: ring forming atoms are selected from carbon, nitrogen and R is selected from Calkyl and carbocyclyl, wherein said oxygen, and wherein said A is optionally Substituted with Calkyl is optionally substituted with one or more Sub one C-alkyl, stituents selected from hydroxy or methoxy; 65 B is a 6 membered non-aromatic ring, wherein one of the ring R. R. Rand Rare independently selected from hydrogen forming atom is selected from -O-, or —N(R')— and and Calkoxy: the other ring forming atoms are carbon. US 8,188,101 B2 13 14 The present invention also relates to a compound according R’ is selected from hydrogen, aryl, heteroaryl, C-alkylaryl, to formula (Ia) Calkylheteroaryl, Calkylheterocyclyl, Calkyl, halogenatedCalkyl, and C-carbocyclyl, wherein said aryl, heteroaryl, Calkyl or carbocyclyl is optionally and

(Ia) independently substituted with one to three R' groups, fluoro, hydroxy, alkoxy, cyano, hydroxyalkyl, or C(O)Cl. 6alkyl, wherein said Calkyl is optionally substituted with hydroxy: O 10 RandR may, when Y is NR, optionally form together with the nitrogen atom a saturated, partially saturated or unsat urated ring system, wherein said ring system is optionally and independently substituted by one to three R' groups; wherein R is selected from phenyl substituted by a heteroaryl R'' and Rare independently selected from Calkyl, halo group and wherein the phenyl group and the heteroaryl group 15 genated Calkyl, Calkoxy, halgogenated Calkoxy, are optionally and independently substituted by one to three Z is selected from CH-(R), N-(R), O, S, S(O), and S(O); R" is selected from C-galkyl and halogenated Cigalkyl; R is selected from hydrogen, Calkyl, cyano substituted Calkyl, Calkanoyl, hydroxy Substituted Calkanoyl, O , or O C(R')(R') : amino Substituted Calkanoyl, Calkoxy substituted R" is selected from halogen, Calkyl, halogenated Calkyl, Calkanoyl, C-carbocyclyl-carbonyl, (Calkyl)car Calkoxy, halogenated Calkoxy, bamoyl, Calkylsulfonyl, Calkoxy-carbonyl, R is selected from hydrogen, C-alkyl, halogenated or a pharmaceutically acceptable salt thereof. Calkyl and C-carbocyclyl, wherein said Calkyl, is 25 Further, one embodiment of the present invention is a com optionally substituted with one to three substituents pound of formula Ia wherein R' is selected from phenyl Selected from cyano, hydroxy and heterocyclyl, substituted by a heteroaryl group and wherein the phenyl R’ is selected from hydrogen, aryl, heteroaryl, C-alkylaryl, group is further optionally substituted with a Calkoxy Calkylheteroaryl, Calkylheterocyclyl, halogenated group or a halogenated Calkoxy group and the heteroaryl Calkyl, Calkyl and C-carbocyclyl, wherein said 30 group is optionally substituted by a Calkyl group or a aryl, heteroaryl, Calkyl or carbocyclyl is optionally and halogenated Calkyl group; R is Y R7; independently substituted with one to three R' groups, Y is C(R'2)(R') or C(R'2)(R') O : fluoro, hydroxy, alkoxy, cyano, hydroxyalkyl or C(O)Cl. R’ is selected from hydrogen, aryl, heteroaryl, Calkylaryl, alkyl, wherein said Calkyl is optionally substituted with 35 Calkylheteroaryl, Calkylheterocyclyl, Calkyl, haloge hydroxy; or natedC-alkyland C-carbocyclyl, wherein said aryl, het RandR may, when Y is NR, optionally form together with eroaryl, Calkylaryl, Calkyl, halogenatedCalkyl or the nitrogen atom a saturated, partially saturated or unsat carbocyclyl is optionally substituted with one substituent urated ring system, wherein said ring system is optionally selected from hydroxy, alkoxy, cyano, Calkyl, haloge and independently substituted by one to three R' groups 40 nated Calkyl and C(O)Calkyl, wherein said Calkyl R'' and Rare independently selected from Calkyl, halo is optionally substituted with hydroxy: genated Calkyl, Calkoxy, halgogenated Calkoxy. R'' and Rare independently selected from Calkyl, halo Z is selected from CH-(R), N-(R), O, S, S(O), and genated Calkyl, Calkoxy, halgogenated Calkoxy, S(O); Z is selected from CH-(R), N-(R) and O; R" is selected from Cigalkyl and halgonated C-alkyl: 45 R" is selected from Cigalkylandhalogenated Cigalkyl; and R is selected from hydrogen, C-alkyl, cyano substituted R is selected from hydrogen, C-alkyl, cyano substituted Calkyl, halogenated Calkyl, Calkanoyl, hydroxy Calkyl, Calkanoyl, hydroxy substituted Calkanoyl. Substituted Calkanoyl, dialkylamino Substituted Ceal amino Substituted Calkanoyl, Calkoxy Substituted kanoyl, Calkoxy substituted Calkanoyl, C-carbocy Calkanoyl, C-carbocyclyl-carbonyl, (Calkyl)car clyl-carbonyl, (Calkyl)carbamoyl, Calkylsulfonyl, 50 bamoyl, Calkylsulfonyl, Calkoxy-carbonyl, Calkoxycarbonyl, or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof. Further, one embodiment of the present invention is a com Further, one embodiment of the present invention is a com pound of formula Ia wherein R' is selected from 3-methoxy pound of formula Ia wherein R' is selected from phenyl 4-(4-methylimidazol-1-yl)phenyl, 4-(1-methylpyrazol-4-yl) substituted by a heteroaryl group and wherein the phenyl 55 phenyl, 4-(2-methylimidazol-1-yl)phenyl, or 4-oxazol-5- group and the heteroaryl group are optionally and indepen ylphenyl: dently substituted by one to three R groups; R’ is selected from 2-fluoro-1-(fluoromethyl)ethoxyme thyl, (2-fluorophenyl)methyl, (2-hydroxy-2-phenyl ethyl)-methyl-amino, (2R)-2-(hydroxymethyl)indolin-1- 60 y1, (2S)-2-(hydroxymethyl)indolin-1-yl, (3-acetylphenyl) O , or O C(R)(R') : amino, (3-methoxyphenyl)methyl, (4-fluorophenyl) R" is selected from halogen, Calkyl, halogenated Calkyl, methyl, (4-fluorophenyl)-methyl-amino, (2R)- Calkoxy, halogenated Calkoxy, norbornan-2-yl)amino, (2R)-tetrahydrofuran-2-yl) R is selected from hydrogen, C-alkyl, halogenated methylamino, (2S)-tetrahydrofuran-2-yl)methylamino, Calkyl and C-carbocyclyl, wherein said Calkyl, is 65 1-(hydroxymethyl)cyclopentyl)amino. 2-(hydroxym optionally substituted with one to three substituents ethyl)phenylmethyl-methyl-amino, 3-(hydroxymethyl) Selected from cyano, hydroxy and heterocyclyl, phenylamino. 1-(3,5-dimethylpyrazol-1-yl)ethyl, 1-hy

US 8,188,101 B2 21 22 is the integer 0 (zero) the group to which the subscript refers as Sulfur, oxygen, or nitrogen. Heteroaryl groups include to indicates that the group may be absent, i.e. there is a direct monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) bond between the groups. systems. Examples of heteroaryl groups include without limi As used herein, “alkenyl', used alone or as a suffix or tation, pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, prefix, is intended to include both branched and straight chain pyridazinyl, triazinyl, furyl (i.e. furanyl), quinolyl, iso aliphatic hydrocarbon groups comprising at least one carbon quinolyl, thienyl, imidazolyl, thiazolyl, indolyl pyrryl. carbon double bond ( C=C ) and having from 2 to 12 oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isox carbon atoms or if a specified number of carbon atoms is azolyl pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thia provided then that specific number would be intended. For 10 diazolyl, isothiazolyl, benzothienyl, purinyl, carbazolylben example “C. alkenyl denotes alkenyl having 2, 3, 4, 5 or 6 Zimidazolyl, indolinyl, imidazothiazolyland the like. In some carbon atoms. embodiments, the heteroaryl group has from 1 to 16 carbon As used herein, “alkynyl', ", used alone or as a suffix or atoms, and in further embodiments from 3 to 16 carbon prefix, is intended to include both branched and straight chain atoms. In some embodiments, the heteroaryl group contains 3 aliphatic hydrocarbon groups comprising at least one carbon 15 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some carbon triple bond ( C=C ) and having from 2 to 12 embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 carbon atoms or if a specified number of carbon atoms is heteroatoms. In some embodiments, the heteroaryl group has provided then that specific number would be intended. For 1 heteroatom. example “C-alkynyl denotes alkynyl having 2, 3, 4, 5 or 6 A "heterocyclyl is a saturated or partially unsaturated carbon atoms. monocyclic ring containing 4-7 atoms of which at least one As used herein, “carbocyclyl', used alone or as suffix or atom is chosen from nitrogen, Sulphur or oxygen, which may, prefix, is intended to include cyclic non-aromatic hydrocar unless otherwise specified, be carbon or nitrogen linked, bon groups from 3 to 14 ring carbon atoms, wherein a wherein a —CH2— group can optionally be replaced by a —CH2—group can optionally be replaced by a —C(O)—. In 25 —C(O)—, or a ring nitrogen and/or Sulphur atom may be one embodiment, 'carbocyclyl is a monocyclic ring contain optionally oxidised to form the N-oxide and or the S-oxides. ing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. In one aspect of the present invention, "heterocyclyl is a Examples of carbocyclyls include cyclopropyl, cyclobutyl, saturated monocyclic ring containing 4 or 5 or 6 atoms. cyclopentyl, cyclohexyl, cycloheptyl 1-oxocyclopentyl, Examples of heterocyclic groups include without limitation cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phe 30 areaZetidyl, morpholino, piperidyl, tetrahydropyranyl, 1,4- nyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. According dioxanyl, 1,3-dioxolanyl, 1,2-oxathiolanyl, piperazinyl, pyr to one embodiment, the cycloalkyl group can comprise rolidinyl, tetrahydrofuranyl and thiomorpholino. cycloalkyl groups that are substituted with other rings includ As used herein, the phrase “protecting group” means tem ing fused ring. Example of cycloalkyl groups that are substi 35 porary Substituents, which protect a potentially reactive func tuted with fused rings include, but are not limited to, ada tional group from undesired chemical transformations. mantly, bornyl, camphenyl, bicycle 2.2.2]octyl, Examples of Such protecting groups include esters of car tetrahydronaphthyl and indanyl groups. boxylic acids, silyl ethers of alcohols, and acetals and ketals The term “alkoxy’, unless stated otherwise, refers to radi of aldehydes and ketones respectively. The field of protecting cals of the general formula —O R, wherein R is selected 40 group chemistry has been extensively reviewed (e.g. Jarow from a hydrocarbon radical. For example “C. alkoxy” icki, K. Kocienski, P. Perkin Trans. 1, 2001, issue 18, p. denotes alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms. 2109). Examples of alkoxy include, but are not limited to, methoxy, As used herein, “pharmaceutically acceptable' is ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and isobutoxy. 45 employed herein to refer to those compounds, materials, As used herein, the term “aryl” refers to an aromatic ring compositions, and/or dosage forms which are, within the structure made up of from 5 to 14 carbon atoms. Ring struc Scope of sound medical judgment, Suitable for use in contact tures containing 5, 6, 7 and 8 carbon atoms would be single with the tissues of human beings and animals without exces ring aromatic groups, for example, phenyl. Ring structures sive toxicity, irritation, allergic response, or other problem or containing 8, 9, 10, 11, 12, 13, or 14 would be polycyclic, for 50 complication, commensurate with a reasonable benefit/risk example naphthyl. The aromatic ring can be substituted at one ratio. or more ring positions with Such Substituents as described As used herein, “pharmaceutically acceptable salts' refer above. The term “aryl also includes polycyclic ring systems to derivatives of the disclosed compounds wherein the parent having two or more cyclic rings in which two or more carbons 55 compound is modified by making acid or base salts thereof. are common to two adjoining rings (the rings are “fused Examples of pharmaceutically acceptable salts include, but rings’) wherein at least one of the rings is aromatic and, for are not limited to, mineral or organic acid salts of basic example, the other cyclic rings can be cycloalkyls, cycloalk residues such as amines; alkali or organic salts of acidic enyls, cycloalkynyls, aryls and/or heterocyclyls. residues such as carboxylic acids; and the like. The pharma As used herein, “halo' or “halogen' or “halogenated 60 ceutically acceptable salts include the non-toxic salts or the refers to fluoro, chloro, bromo, and iodo. "Counterion' is quaternary ammonium salts of the parent compound formed, used to represent a small, negatively charged species such as for example, from non-toxic inorganic or organic acids. For chloride, bromide, hydroxide, acetate, Sulfate, tosylate, ben example, such non-toxic salts include those derived from eZenSulfonate, and the like. 65 inorganic acids such as hydrochloric acid. As used herein, "heteroaryl” refers to a heteroaromatic The pharmaceutically acceptable salts of the present inven heterocycle having at least one heteroatom ring member Such tion can be synthesized from the parent compound that con US 8,188,101 B2 23 24 tains a basic or acidic moiety by chemical methods. Gener The present invention also relates to the use of a compound ally, Such salts can be prepared by reacting the free acid or according to formula (I) base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic (I) Solvent, or in a mixture of the two; generally, nonaqueous R7 media like diethyl ether, ethyl acetate, ethanol, isopropanol, A or acetonitrile are used. A variety of compounds in the present invention may exist 10 in particular geometric or stereoisomeric forms. The present W CO invention takes into account all such compounds, including cis- and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of 15 R3 R5 this invention. Additional asymmetric carbon atoms may be present in a Substituent Such as an alkyl group. All Such A isomers, as well as mixtures thereof, are intended to be included in this invention. The compounds herein described wherein may have asymmetric centers. Compounds of the present E is invention containing an asymmetrically Substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by Synthesis from optically 25 active starting materials, or synthesis using optically active OV reagents. When required, separation of the racemic material can be achieved by methods known in the art. Many geomet X and V are independently selected from nitrogen or CH ric isomers of olefins, C=N double bonds, and the like can and wherein at least one of X or V is nitrogen; also be present in the compounds described herein, and all 30 W is C(R) -, - O - or - N(R)–: Such stable isomers are contemplated in the present invention. R" is hydrogen, Calkyl or Caalkoxy, wherein said C is and trans geometric isomers of the compounds of the Calkyl is Substituted with halogen, cyano, hydroxy, present invention are described and may be isolated as a amino, NHC alkyl, N(Calkyl), heterocyclyl, NC(O) mixture of isomers or as separated isomeric forms. All chiral, 35 Calkyl, C(O)Calkoxy or SOC-alkyl, diastereomeric, racemic forms and all geometric isomeric Y is C(R')(R') , N(R) or - O : forms of a structure are intended, unless the specific stere R'' and Rare independently selected from hydrogen, halo ochemistry or isomeric form is specifically indicated. gen, Calkyl, CalkylOC-alkyl, carbocyclyl, hetero As used herein, “tautomer means other structural isomers cyclyl and Calkoxy, wherein said Calkyl, Calky that exist in equilibrium resulting from the migration of a 40 1OC-alkyl, carbocyclyl, heterocyclyl or Calkoxy is hydrogen atom. For example, keto-enol tautomerism where optionally substituted with one or more substituents the resulting compound has the properties of both a ketone selected from halogen, cyano, hydroxy, heterocyclyl, and an unsaturated alcohol. N(Coalkyl), NC(O)Calkyl; Compounds of the invention further include hydrates and O Solvates. 45 R'' and R' may form together with the cabon atom they are The present invention further includes isotopically-labeled attached to a saturated, partially unsaturated or saturated compounds of the invention. An "isotopically” or “radio ring system, wherein said ring system may contain one or labeled compound is a compound of the invention where one more heteroatoms selected from N, O and S, and wherein if or more atoms are replaced or Substituted with an atom having said ring system contains an —NH-moiety that nitrogen an atomic mass or mass number different from the atomic 50 may optionally be substituted with a group selected from mass or mass number typically found in nature (i.e., naturally Calkyl and C(O)Calkyl and wherein said ring is occurring). Suitable radionuclides that may be incorporated optionally Substituted with one or more groups selected in compounds of the present invention include but are not from halogen, cyano, hydroxy: limited to H (also written as D for deuterium), H (also O written as T for tritium), ''C, C, C, N, N, O, 7O, 55 R'' and R may form together a saturated, partially unsatur 18O, 18F 35S, 36C1, 82Br, 75 Br, 76Br, 77Br, 123, 1241, 125 and ated or Saturated bicyclic ring system, wherein said bicy ''I. The radionuclide that is incorporated in the instant radio clic ring system may contain Zero to three heteroatoms labeled compounds will depend on the specific application of selected from N, O and S, and wherein said bicyclic ring that radio-labeled compound. For example, for in vitro recep system is optionally substituted with one to three substitu tor labeling and competition assays, compounds that incor 60 ents selected from halogen, cyano, hydroxy, Calkoxy, porate H, C, Br, I, I, or S will generally be most amino, NHC alkyl, N(Calkyl). NC(O)Calkyl, useful. For radio-imaging applications 'C, F, I, I, SOC-alkyl and heterocyclyl, and wherein if said bicy *I, I, 7Br 7Br or 77Br will generally be most useful. clic ring system contains an —NH-moiety that nitrogen It is understood that a “radio-labeled compound is a com may optionally be substituted by a group selected from pound that has incorporated at least one radionuclide. In some 65 Calkyl and C(O)Calkyl; embodiments the radionuclide is selected from the group R is selected from hydrogen, C-alkyl, C-alkylOC. consisting of H, C, "'I, S and Br. alkyl, C(O)Calkyl, C(O)Clscycloalkyl, heterocyclyl, US 8,188,101 B2 25 26 carbocyclyl, C(O)Cheterocyclyl or SOC-alkyl, amino, Calkyl, Calkoxy, NHC alkyl, NHC alky wherein said Calkyl, heterocyclyl, carbocyclyl or 1OC-alkyl, N(Calkyl), N(CalkylOC-alkyl), car Calky1OC-alkyl is optionally Substituted with one to bocyclyl and heterocyclyl wherein said Calkyl, three Substituents selected from halogen, cyano, hydroxy, Calkoxy, NHC alkyl, NHC alkylOC-alkyl, N(C. amino, NHC alkyl, N(Calkyl), NC(O)Calkyl, alkyl), N(CalkylOC-alkyl), carbocyclyl or heterocy C(O)Calkoxy, SOC-alkyl and heterocyclyl: R’ is selected from hydrogen, aryl, heteroaryl, C-alkylaryl, clyl is optionally substituted with one or more substituents Calkylheteroaryl, Calkylcarbocyclyl, Calkylhet selected from halogen, hydroxy, cyano; erocyclyl and carbocyclyl, wherein said aryl, heteroaryl, n is selected from 0, 1, 2: Calkylcarbocyclyl, Calkylheterocyclyl, Calky E and B will together form a bicyclic ring system; laryl, carbocyclyl or Calkylheteroaryl is optionally Sub 10 as a free base or a pharmaceutically acceptable salt thereof; stituted with one or more substituents selected from halo for the manufacture of a medicament for treating or pre gen, cyano, hydroxy, nitro, Cigalkyl, Cigalkoxy, venting an AB-related pathology. carbocyclyl, heterocyclyl, CF. OCF, OC-alkyl, C(O) Compounds of the present invention may be administered Coalkyl, Calky1OC-alkyl, SOC-alkyl, orally, parenteral, buccal, vaginal, rectal, inhalation, insuffla SONHC alkyl, SON(Calkyl), SON-heterocyclyl, 15 tion, Sublingually, intramuscularly, Subcutaneously, topi C(O)NHC(O)NHC alkyl, C(O)N(Calkyl), C(O)N- cally, intranasally, intraperitoneally, intrathoracially, intrave heterocyclyl, Calkenyl and Calkynyl, wherein said nously, epidurally, intrathecally, intracerebroVentricularly Calkyl, Calkoxy, CalkylOC-alkyl, heterocyclyl, and by injection into the joints. carbocyclyl, Calkenyl or C-alkynyl is optionally Sub The dosage will depend on the route of administration, the stituted with cyano, hydroxy, methoxy, halogen, SOC severity of the disease, age and weight of the patient and other alkyl, amino, NHC alkyl, N(Calkyl), heterocyclyl or factors normally considered by the attending physician, when aryl; determining the individual regimen and dosage level as the O most appropriate for a particular patient. RandR may, when Y is NR, optionally form together with The quantity of the compound to be administered will vary the nitrogen atom a saturated, partially saturated or unsat 25 for the patient being treated and will vary from about 100 urated ring system, wherein said ring system is optionally ng/kg of body weight to 100 mg/kg of body weight per day Substituted with one or more groups selected from halogen, and preferably will be from 10 pg/kg to 50 mg/kg per day. For hydroxy, cyano, CalkylOC-alkyl and Calkyl, instance, dosages can be readily ascertained by those skilled wherein said Calky1OC-alkyl and Calkyl is option in the art from this disclosure and the knowledge in the art. ally Substituted with halogen, cyano, hydroxy: 30 Thus, the skilled artisan can readily determine the amount of R" is selected from hydrogen, C-calkyl, Calkoxy, compound and optional additives, vehicles, and/or carrier in Calkenyl, C-alkynyl, carbocyclyl, heterocyclyl, C(O)R. compositions and to be administered in methods of the inven C(O)N(R), C(O)CHN(R), C(O)heterocyclyl, C(O)car tion. bocyclyl, C(O)OR, SOR, SOheterocyclyl, The treatment of AB-related pathology defined herein may SOcarbocyclyl and SON(R), wherein said Calkyl, 35 be applied as a sole therapy or may involve, in addition to the Calkoxy, Calkenyl, C2-alkynyl, carbocyclyl or hetero compound of the invention, conjoint treatment with conven cyclyl is optionally substituted with one or more substituents tional therapy of value in treating one or more disease condi selected from halogen, hydroxy, cyano, amino, C(O)OR, tions referred to herein. Such conventional therapy may NHC alkyl, NHC alkoxy, N(Calkyl), N(Calko include one or more of the following categories of agents: Xy), SC-alkyl, SOC-alkyl, SOC-alkyl, Calkyl, 40 acetyl cholinesterase inhibitors, anti-inflammatory agents, Calkoxy, heterocyclyl and carbocyclyl, cognitive and/or memory enhancing agents or atypical antip R is selected from hydrogen, hydroxy, halogen, cyano, sychotic agents. Cognitive enhancing agents, memory Calkyl, Calkoxy, carbocyclyl and heterocyclyl, enhancing agents and acetyl choline esterase inhibitors wherein said Calkyl, Calkoxy, cycloalkyl or hetero includes, but not limited to, onepezil (Aricept), galantamine cyclyl is optionally substituted with one or more substitu 45 (Reminyl or Razadyne), rivastigmine (Exelon), tacrine (Cog ents selected from halogen, cyano, hydroxy or methoxy; nex) and memantine (Namenda, AXura or Ebixa). Atypical R. R. RandR are independently selected from hydrogen, antipsychotic agents includes, but not limited to, Olanzapine cyano, Calkyl, Calkoxy, halogen, OCH, OCF, (marketed as Zyprexa), Aripiprazole (marketed as Abilify), OCFH, OCFH and hydroxy: Risperidone (marketed as Risperdal), Quetiapine (marketed A is a 5-7 membered heteroaryl, wherein at least one of the 50 as Seroquel), Clozapine (marketed as CloZaril), Ziprasidone ring forming atoms is selected from nitrogen and the (marketed as Geodon) and Olanzapine/Fluoxetine (marketed remaining ring forming atoms are selected from carbon, as Symbyax). nitrogen, Sulphur and oxygen, and wherein said A is Such conjoint treatment may be achieved by way of the optionally substituted with one or more substituents simultaneous, sequential or separate dosing of the individual selected from halogen, Calkyl, SR', NR'R'', OR', 55 components of the treatment. Such combination products Calkenyl and Calkynyl and wherein said Calkyl, employ the compounds of the invention. Calkenyl or Calkynyl is optionally Substituted with Additional conventional therapy may include one or more halogen, hydroxy, cyano or Calkoxy; of the following categories of agents: R'' and R'' are independently selected from hydrogen, (i) antidepressants such as agomelatine, amitriptyline, amox Calkyl, CF, CFH and CFH: 60 apine, bupropion, citalopram, clomipramine, desipramine, B is a 5 to 7 membered saturated or partly saturated ring, doxepin dulloxetine, elzasonan, escitalopram, fluvoxam wherein one of the ring forming atom is selected from ine, fluoxetine, gepirone, imipramine, ipsapirone, mapro N(R') , —C(R) , S(O), or—O and the other tiline, nortriptyline, nefazodone, paroxetine, phenelzine, ring forming atoms are carbon, wherein one —CH2— protriptyline, ramelteon, reboxetine, robalZotan, Sertraline, group can optionally be replaced by a —C(O)— and 65 Sibutramine, thionisoxetine, tranylcypromaine, traZodone, wherein said ring is optionally substituted with one to three trimipramine, Venlafaxine and equivalents and pharmaceu Substituents selected from halogen, cyano, hydroxy, tically active isomer(s) and metabolite(s) thereof. US 8,188,101 B2 27 28 (ii) atypical antipsychotics including for example quetiapine tobarbital, phenobarbital, propofol, ramelteon, roletamide, and pharmaceutically active isomer(s) and metabolite(s) triclofos, secobarbital, Zaleplon, Zolpidem and equivalents thereof. and pharmaceutically active isomer(s) and metabolite(s) (iii) antipsychotics including for example amisulpride, arip thereof. iprazole, asenapine, benzisoxidil, bifeprunoX, carbam 5 aZepine, clozapine, chlorpromazine, debenzapine, dival (xiv) mood stabilizers including for example carbamazepine, proex, dulloxetine, esZopiclone, haloperidol, illoperidone, divalproex, gabapentin, lamotrigine, lithium, olanzapine, lamotrigine, loxapine, mesoridazine, olanzapine, paliperi quetiapine, valproate, valproic acid, Verapamil, and done, perlapine, perphenazine, phenothiazine, phenylbu equivalents and pharmaceutically active isomer(s) and tylpiperidine, pimozide, prochlorperazine, risperidone, 10 metabolite(s) thereof. sertindole, Sulpiride, Suproclone, Suriclone, thioridazine, Such combination products employ the compounds of this trifluoperazine, trimetozine, Valproate, valproic acid, Zopi invention within the dosage range described herein and the clone, Zotepine, Ziprasidone and equivalents and pharma other pharmaceutically active compound or compounds ceutically active isomer(s) and metabolite(s) thereof. within approved dosage ranges and/or the dosage described in (iv) anxiolytics including for example alnespirone, aza 15 the publication reference. pirones, benzodiazepines, barbiturates such as adina Zolam, alprazolam, balezepam, bentazepam, bromazepam, Methods of Preparation for Compounds of the Present Inven brotizolam, buspirone, clonazepam, cloraZepate, chlor tion diazepoxide, cyprazepam, diazepam, diphenhydramine, Preparation of the compounds of formula (I) will be illus estazolam, fenobam, flunitrazepam, flurazepam, fos trated below. azepam, lorazepam, lormetazepam, meprobamate, mida In each of the following preparation methods, when a Zolam, nitrazepam, oxazepam, prazepam, quaZepam, defined group changes under reaction conditions or is not reclazepam, tracazolate, trepipam, temazepam, triazolam, Suitable for carrying out the method, the preparation can be uldazepam, Zolazepam and equivalents and pharmaceuti easily carried out by Subjecting the group to a procedure cally active isomer(s) and metabolite(s) thereof. 25 (v) anticonvulsants including for example carbamazepine, conventionally employed in organic synthetic chemistry, Valproate, lamotrogine, gabapentin and equivalents and Such as protection and/or deprotection of a functional group pharmaceutically active isomer(s) and metabolite(s) (for example see, Protection Groups in Organic Synthesis, T. thereof. W. Green, Wiley & Sons Inc. (1999)). (vi) Alzheimer's therapies including for example donepezil, 30 Where necessary the order of reation process steps such as memantine, tacrine and equivalents and pharmaceutically introduction of substituents can be altered. Solvent, tempera active isomer(s) and metabolite(s) thereof. ture, pressure, and other reaction conditions may readily be (vii) Parkinson's therapies including for example deprenyl, selected by one of ordinary skill of the art. Starting materials L-dopa, Requip, Mirapex. MAOB inhibitors such as sel are commercially available or readily prepared by one skilled egine and rasagiline, comP inhibitors such as Tasmar, A-2 35 in the art. Compounds of formula (I) can be prepared, for inhibitors, dopamine reuptake inhibitors, NMDA antago nists, Nicotine agonists, Dopamine agonists and inhibitors example, using the Methods of Preparation 1 to 4. of neuronal nitric oxide synthase and equivalents and phar Compounds of formula (AI) can be prepared, for example, maceutically active isomer(s) and metabolite(s) thereof. by using the Methods of Preparation 1 to 5. In the method of (viii) migraine therapies including for example almotriptan, 40 preparation below, PG represents a protective group or any amantadine, bromocriptine, butalbital, cabergoline, suitable R' defined as in formula (I). PG can be replaced or dichloralphenaZone, eletriptan, froVatriptan, lisuride, exchanged prior to, during or immediately following the pro naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, cessing mentioned below. Sumatriptan, Zolmitriptan, Zomitriptan, and equivalents Method of Preparation 1: and pharmaceutically active isomer(s) and metabolite(s) 45 thereof. (ix) stroke therapies including for example abciximab, acti vase, NXY-059, citicoline, crobenetine, desmoteplaser o1 epinotan, traxoprodil and equivalents and pharmaceuti J| -W NH2 cally active isomer(s) and metabolite(s) thereof. O -- He (X) urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalZo tan, Solifenacin, tolterodine and and equivalents and phar 4 maceutically active isomer(s) and metabolite(s) thereof. (Ia) (II) (xi) neuropathic pain therapies including for example gaba 55 pentin, lidoderm, pregablin and equivalents and pharma ceutically active isomer(s) and metabolite(s) thereof. (xii) nociceptive pain therapies such as celecoxib, etori coxib, lumiracoxib, rofecoxib, Valdecoxib, diclofenac, loxo profen, naproxen, paracetamol and equivalents and pharma 60 O ceutically active isomer(s) and metabolite(s) thereof. (xiii) insomnia therapies including for example agomelatine, HN He allobarbital, alonimid, amobarbital, benzoctamine, but abarbital, capuride, chloral, cloperidone, clorethate, dex J| N O clamol, ethchlorVynol, etomidate, glutethimide, 65 Yw N halazepam, hydroxyZine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pen US 8,188,101 B2 29 30 -continued -continued J2 -R y1 R7 y1 R7 o1 SO HY- R7 Y (V) 5 N21 He- N21

N N J2 N J Sw CG)4. sul-UW N or (VIII) - or (AI) 10 (IV) (AI) wherein wherein J°W is a substituted ArNR or ArO; Y, B, RandR areas defined for the compound of formula (I) J-W is a substituted ArNR, ArO or ArC(R) 15 above. J’ is CF, CH, or aryl. Compounds of formula (VI) can be prepared, for example, Y. R. Rand Bareas defined for the compound of formula (I) according to the method described in US 2007/0037834. above. Thus, compound of formula (VI) can be obtained by reacting Condensation of cyclic beta-keto ester of formula (Ia) with a beta-keto ester of formula (Ia) with one equivalent to an an appropriate Substituted guanidine or Substituted acetamide excess of urea in the presence of a base (such as Sodium or of formula (II) in presence of a Suitable base (such as sodium potassium alkoxides). Compounds of formula (VII) can be or potassium alkoxides) provides pyrimidinone of formula prepared by reacting a compound of formula (VI) with an (III). Pyrimidinone of formula (III) is converted into the sul excess of a chlorinating agent. Examples of chlorinating fonate of formula (IV) using reagents (such as triflate anhy 25 agents are phosphorus oxychloride and phosphorus pen dride or 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfo tachloride. Compounds of formula (VIII) can be prepared by nyl)methanesulfonamide or Sulphonyl chloride) in presence reacting compounds of formula (VII) with one equivalent to a of a suitable base (such as 1,8-diazabicyclo[5.4.0]undec-7- large excess of a compound of formula (V) optionally in ene and triethylamine). presence of a base. Examples of suitable bases are triethy 30 lamine, pyridine and Sodium carbonates. Displacement of the sulphonate of formula (IV) in pres Compound of formula (VIII) can also be obtained by using ence of an appropriate nucleophile (V) such as amine, alcohol the “Buchwald-Hartwig cross-coupling' method as an alter and thiol afford compounds of formula (AI). The conditions native to the thermal displacement mentioned above. In said for displacing the sulphonate of formula (IV) will depend on method are compounds of formula (VII) reacted with a reac the nature of the reactivity of formula (V) and are generally by 35 tant of formula (V), which may be an amine, thiol or alcohol the skilled person (see for examples European J. Med. Chem; in the presence of a suitable base (such as CsCO or potassium 2007, 42, 256, and Synlett: 1997, 12: 1400; and Org. Lett. tert-butoxide), a suitable catalyst (such as Pd(OAc)) and a 2000, 2,927). suitable ligand (such as triphenylphosphine or BINAP) to Cross-coupling reaction is an alternative method for con provide compound of formula (VIII) (see for examples Acc. Verting a compound of formula (IV) into a compound of 40 Chem. Res. 1998, 31, 803-818 and J. Am. Chem. Soc., 125, formula (I). Compounds of formula (IV) and of formula (V) 6653). are heated in presence of a catalyst (such as Pd(OAc) and Method of Preparation 3: Pd(dba), a ligand (such as BINAP. dppf and Xantphos), a suitable base (such as potassium tert-butoxide and CsCO) in 45 a suitable solvent (see for examples Accounts of Chemical O R7 -R Research, 2002, 35, 717; and J. Am. Chem. Soc. 2003, 125, HO1 Y 6653). (Va) Method of Preparation 2: 50 O s Jin W lsN J Nw l N2 1. (III) (BI) O NH2 O -- N 55 wherein NH2 2 J'W is a substituted ArNR, ArO or ArC(R): O B. R and Rare as defined for the compounds of formula (I) (Ia) above. O C HYR7 60 Compounds of formula (BI) can be prepared in one step using the “Mitsunobu' method (see for examples Tetra. Lett. 1994, 35, 2819 and Synlett. 2005, 18, 2808). Trialkyl or triaryl phosphine (Such as triphenyphosphine or tributylphos O1. N C ls N phine) and a suitable dialkyl azodicarboxylate (such as 65 DEAD) are added to a compound of formula (II) in the pres (VI) (VII) ence of an appropriate alcohol of formula (Va) in a suitable solvent (such as THF) to afford compound of formula (BI). US 8,188,101 B2 31 32 Method of Preparation 4: nucleophile of formula (XVI) such as amine, alcohol and thio, provides compound of formula (AI). Method of Preparation 5 o1 J2

O -- O Stepte 1 R ls -- p 4. GE NH N X O 10 (XVI) (XVII) (Ia) (XI) R7 SOJ2 y1 O o1 2 W. NH -- 1 2 Step 2 O 15 2 n ) J2 s)2 O J2 S lsN Ns l N G) (XVIII) (II) (XII) (XIII) 1 R7 y1 R7 N1 N J2 D J Yw lsCG)N Ns N 25 (XIV) (Ic) y1 R7 -R JIW Y wherein 30 Y is C(R)(R'), C(R)(R') O - C(R')(R') N1 N (XVI) N(R) ; J2 2 J° is a substituted aryl; A. N ID 'S lCG) 2 W is carbon or nitrogen; / \, W N X is C1 or imidazolyl; 35 B is as defined for the compound of formula (I) above; (XV) (AI) R", Rand Rare as defined for the compound of formula (Ia) above: wherein J W is a substituted ArNR or ArO; Step 1 J’ is alkyl or arylalkyl: A suitable base (such as lithium diisoprylamide, lithium B. R. RandY areas defined for the compound of formula (I) 40 bis(trimethylsilyl)amide) is added to a solution of ketone of above. formula (XVII) in a suitable solvent (such as hexane, THF) Condensation of cyclic beta-keto ester of formula (Ia) with preferably below room temperature followed by addition of an appropriate thiourea of formula (XI) in presence of a the acid chloride or other activated form such as imidazolyl of Suitable base (such as sodium or potassium alkoxides) pro formula (XVI) to afford a diketone of formula (XVIII). vides a compound of formula (XII). A compound of formula 45 Step 2 (XII) is converted into the sulphonate of formula (XIII) using Condensation of diketone of formula (XVIII) with an reagents (such as triflate anhydride, 1,1,1-trifluoro-N-phe appropriate compound of formula (II) in presence of a Suit nyl-N-(trifluoromethylsulfonyl)methanesulfonamide or a able base (such as sodium or potassium alkoxides) provides a Sulphonyl chloride) in presence of an Suitable base (such as compound of formula (Ic). Condensation is preferably per 1,8-diazabicyclo5.4.0]undec-7-ene or triethylamine). Dis 50 formed between rt and 150° C. in a suitable solvent (such as placement of the sulphonate of formula (XIII) in presence of ethanol or DMF). an appropriate nucleophile of formula (V) Such as amine, Examples have been named using CambridgeSoft Med alcohol and thiol affords a compound of formula (XIV). Chem ELN v2.1. The compound of formula (XIV) can also be obtained by the “Buchwald-Hartwig cross-coupling method as an alter 55 ABBREVIATIONS native to the thermal displacement mentioned above. Com pound of formula (XIII) is reacted with a reactant of formula app apparent (V), which may be an amine, thiol or alcohol, in the presence aq. Aqueous ofa suitable base (such as CsCO or potassium tert-butoxide), Ar Argon (or Argon atmosphere) a Suitable catalyst (such as Pd(OAc)) and a Suitable ligand 60 br broadened (such as triphenylphosphine or BINAP) to provide the com BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl pound of formula (VIII). CI chemical ionization Conversion of compound of formula (XIV) to the corre ö chemical shift in parts per million (ppm) downfield from the sponding sulphone of formula (XV) can be obtained by react standard ing a compound of formula (XIV) with an oxidation agent 65 d doublet (such as m-chloroperbenzoic acid) in a suitable solvent. Dis DCM dichloromethane placement of a compound of formula (XV) with a suitable DIPEAN,N-diisopropylethylamine US 8,188,101 B2 33 34 DMA N,N-dimethylacetamide General Procedure for Boc Deprotection of Amines DMF N,N-dimethylformamide The boc protected amines were dissolved in DCM (5 mL). DME 1,2-dimethoxyethane TFA (10 eq) was added and the reactions were heated to reflux DMSO dimethyl sulfoxide for 2 h. The mixtures were neutralized with sat NaHCO and dppf 1,1'-bis(diphenylphosphino) ferrocene the phases were separated. The organic phases, in all cases EI electron impact except two, contained the deprotected products. The organic eq equivalents phases were separated, dried with MgSO and the solvents ES electro-spray were evaporated. Where the deproteced product could be ELS electro-spray found in the aqueous phase both phases were evaporated EtO diethyl ether 10 together and used as Such. EtOH ethanol General Procedure for N-acetylation HCl hydrochloric acid Acetic anhydride (1 eq) was added to a solution of the HBTU O-Benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium secondary amine (1 eq) in DCM (and in some cases a few hexafluorophosphate 15 drops of MeOH). After 2 hours the solvents were evaporated HPLC high performance liquid chromatography and the residues redissolved in MeOH (1 mL) and then trans LC liquid chromatography ferred into a 48 pos MTP. The products were purified on UV LHMDS lithium hexamethyldisilazide or MS-triggered preparative HPLC. m multiplet General Procedure for Preparation of Acid Chlorides mCPBA meta-chloroperbenzoic acid The carboxylic acid (1 eq) was dissolved in thionyl chlo MeCN acetonitrile ride (3 eq) and heated to reflux for 1 h. The excess thionyl MeOH methanol chloride was evaporated and used as such. MP-CNBH Macroporous cyanoborohydride MS mass spectroscopy Example 1 NMR nuclear magnetic resonance 25 o.n. Over-night Pd(dba), bis(dibenzylideneacetone)palladium 2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahy Pd(OAc), palladium(II) acetate dropyrido4.3-dpyrimidin-4-yl)(phenyl)aminoetha Pd(PPh) tetrakis(triphenylphosphine)palladium(0) nol PDA photodiode array detector 30 prep. Preparative q quartet rt. Room temperature (ca 21-25°C.) S singlet t triplet 35

THF tetrahydrofuran TEA triethylamine TFA trifluoroacetic acid TLC thin layer chromatography UV ultra violet 40 Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxan thene

EXAMPLES 45 Below follows a number of non-limiting examples of com pounds of the invention. General Procedure for the Preparation of Pyrimidines The diketone (1 eq), the guanidine (1 eq) and potassium carbonate (2 eq) was slurrified in EtOH. The reaction was 50 heated to 130° C. in the microwave oven. DCM and water were added and the organic phase was separated. The crude products were used as such or purified by preparative HPLC. Hydrochloric acid (2 M, 2 ml) was added to a solution of General Procedure for the Preparation of Diketones tert-butyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol The ketone were dissolved in toluene and cooled to 0°C. 55 5-yl)phenylamino)-7,8-dihydropyrido4,3-dipyrimidine-6 LHMDS (1.1 eq) was added and after 2 min the acid chlorides (5H)-carboxylate (150 mg, 0.28 mmol. Example 1a) in were added. The reactions were quenched after 5 min with 5 methanol (4 mL). Water (2 mL) was added and the solution eq acetic acid in water. The organic phase was separated and was stirred at 70° C. for 30 min. The residual solvent was reduced under vacuum. The crude products were purified evaporated under reduced pressure and the crude product with flash column chromatography (a gradient of EtOAC in 60 dissolved in DMSO. Purification by preparative HPLC Heptane). afforded 2-((2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tet General Procedure for Reductive Amination rahydropyrido4.3-dipyrimidin-4-yl)(phenyl)amino)ethanol To the amine, the aldehyde, 0.1 eq acetic acid and 2 eq (72 mg, 54.8%). MS (ESI+)/(ESI-) m/z 429/427 MP-cyanoborohydride were added 2 ml MeOH. After 2 h 'HNMR (500MHz, DMSO-d) 8 ppm 2.56 (t, 2 H)2.73 (s, stirring at rt the solid reagent was filtered off and the solvent 65 2 H)2.78 (t, 2 H)3.66 (t, 2 H)4.02 (t, 2 H)4.83 (br. s. 1 H) was evaporated. The crude products were purified on MS 7.10-7.20 (m, 3 H) 731-7.38 (m.2 H) 7.50 (s, 1 H) 7.60 (d. 2 triggered preparative HPLC. H) 7.87 (d. Hz, 2 H) 8.35 (s, 1 H) 9.44 (s, 1 H) US 8,188,101 B2 35 36 Example la 4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido4.3-d pyrimidine-6(5H)-carboxylate (1.700 g, 80%). MS (ESI+)/ tert-Butyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4- (ESI-) m/z 542/540 (oxazol-5-yl)phenylamino)-7,8-dihydropyrido4.3-d pyrimidine-6(5H)-carboxylate 5 Example 1c

tert-Butyl 4-hydroxy-2-(4-(oxazol-5-yl)pheny lamino)-7,8-dihydropyrido4,3-dipyrimidine-6(5H)- 10 carboxylate

W O

15

2-(Phenylamino)ethanol (0.051 g, 0.37 mmol) was added to tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluorom ethylsulfonyloxy)-7,8-dihydropyrido4.3-dpyrimidine-6 (5H)-carboxylate (0.2g, 0.37 mmol. Example 1b) in DMSO 25 Sodium ethoxide (0.106 g, 1.55 mmol) was added to 1-tert (3 mL). The reaction mixture was heated in a microwave butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (0.400 g, reactor at 70° C. for 3 h. Water (1 mL) was added to the 1.55 mmol. Example 3c) and 1-(4-(oxazol-5-yl)phenyl) solution and the precipitate was washed with water and fil tered to give tert-butyl 4-((2-hydroxyethyl)(phenyl)amino)- guanidine (obtained from Example 1e, 0.314g, 1.55 mmol) in 2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido4.3-d ethanol (4 mL) and heated in a microwave reactor at 100° C. 30 for 15 minutes. The suspension was diluted with ethanol (5 pyrimidine-6(5H)-carboxylate (150 mg, 77%). No further mL) and the precipitated product was filtered off and washed purification. MS (ESI+)/(ESI-) m/z 529/527 with cold ethanol to give tert-butyl 4-hydroxy-2-(4-(oxazol 5-yl)phenylamino)-7,8-dihydropyrido4,3-dipyrimidine-6 Example 1b (5H)-carboxylate (0.480g, 75%). No further purification. MS 35 (ESI+)/(ESI-) M/Z 410/408 tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluo romethylsulfonyloxy)-7,8-dihydropyrido4.3-dpyri Example 1d midine-6(5H)-carboxylate 40 1-tert-Butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate

45 50 ---, 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (1.396 g, 3.91 mmol) was added to tert 55 butyl 4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihy dropyrido4,3-dipyrimidine-6(5H)-carboxylate (1.6 g., 3.91 Di-tert-butyl dicarbonate (2.227g, 10.20 mmol) was added mmol. Example 3b) and 1,8-diazabicyclo[5.4.0]undec-7-ene to a solution of methyl 4-oxopiperidine-3-carboxylate (2.000 (0.589 ml, 3.91 mmol) in DCM (20 mL). 4-Dimethylami 60 g, 10.20 mmol) and triethylamine (2.84 mL. 20.41 mmol) in nopyridine (0.01 g, 0.08 mmol) was added and the solution DCM (20 mL) cooled on an ice-bath. One DMAP crystal was was stirred for 30 minutes at rt. The solvent was removed added and the suspension was stirred for 15 minutes. The under reduced pressure and the crude was redissolved in Solution was poured onto ice and washed with Saturated aq. DCM, washed with H2O, dried (MgSO), filtered and con NaHCO and H2O. The organic layer was dried (MgSO) centrated under reduced pressure. The crude mixture was 65 filtered and concentrated to give 1-tert-butyl 3-methyl 4-ox recrystallized from in ethanol with the addition of a few drops opiperidine-1,3-dicarboxylate (2.500 g, 95%). No further of water to give tert-butyl 2-(4-(oxazol-5-yl)phenylamino)- purification. MS (ESI+)/(ESI-) m/z 258/256 US 8,188,101 B2 37 38 Example le Example 3

1-(4-(Oxazol-5-yl)phenyl)guanidine N2-(4-(Oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8-tet rahydropyrido4.3-dipyrimidine-2,4-diamine N NH NH 10

7 O O

{ 15 N

Hydrochloric acid (4.04 mL. 24.35 mmol) was added to a solution of 4-(oxazol-5-yl)aniline (5g. 31.22 mmol) and car bodiimide (1.444 g., 34.34 mmol) in ethanol (50 mL). The Aniline (0.017 mL, 0.18 mmol) was added to tert-butyl resulting mixture was heated to reflux for 5 h. The reaction 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfony mixture was concentrated under reduced pressure and potas loxy)-7,8-dihydropyrido4,3-dipyrimidine-6(5H)-carboxy sium carbonate (2.59 g, 18.73 mmol) in water (50.00 mL) was late (0.1 g, 0.18 mmol. Example 1b) in DMSO (4 mL). The added. The formed crystals were filtered off, washed with solution was heated in a microwave reactor at 80° C. for 1 h. several portions of potassium carbonate (aq) and dried over 25 HCl (2M aq, 1.5 mL) was added and the reaction was stirred night under reduced pressure. The crude solid was slurried in in an open vessel at 76° C. for 30 min. The reaction was DCM and filtered to give 1-(4-(oxazol-5-yl)phenyl)guani allowed to cool and DMSO was added to the solution. The dine (7.00 g, 86%). No further purification. MS (ESI+)/ product was purified by preparative HPLC to give N2-(4- (ESI-) m/z. 203/201 (oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido 30 4,3-dipyrimidine-2,4-diamine (0.017 g, 24%). Example 2 "H NMR (500 MHz, DMSO-d) & ppm 2.55-2.60 (m.2 H) 2.96-3.03 (m, 2 H)3.69-3.75 (m, 2 H) 7.11 (t, 1H) 7.36 (t, 2 H) 7.46-7.51 (m, 3 H) 7.64 (d. 2 H) 7.80 (d. 2H)8.20 (s, 1 H) 2-((6-Methyl-2-(4-(oxazol-5-yl)phenylamino)-5.6.7. 35 8-tetrahydropyrido4.3-dipyrimidin-4-yl)(phenyl) 8.35 (s, 1 H) 9.26 (s, 1 H) MS (ESI+)/(ESI-) m/z 385/383 amino)ethanol Example 4

40 6-Methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-phenyl-5. 6,7,8-tetrahydropyrido4.3-dpyrimidine-2,4-diamine

7 No 45

7 No 50

Triethylamine (0.038 ml, 0.27 mmol) was added to 2-((2- (4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido4. 3-dipyrimidin-4-yl)(phenyl)amino)ethanol (0.058 g., 0.14 55 mmol. Example 1) in DMF (2 mL). Methyl iodide (9.28 ul, Triethylamine (0.022 mL, 0.16 mmol) was added to N2 0.15 mmol) was added and the reaction mixture was stirred (4-(oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropy for 1 hat 25°C. The solution was concentrated under reduced rido4,3-dipyrimidine-2,4-diamine (0.06 g., 0.16 mmol. pressure and the product purified by preparative HPLC to give 60 Example 3) in DMF (1 mL) and dioxane (1 mL). 2-((6-methyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tet Iodomethane (0.031 g, 0.22 mmol) was added and the reac rahydropyrido4.3-dipyrimidin-4-yl)(phenyl)amino)ethanol tion stirred at 25° C. for 1 h. Solvent was removed under (0.022 g, 36.7%). MS (ESI+)/(ESI-) m/z. 443/441 reduced pressure and the crude product redissolved in "H NMR (500 MHz, MeOD) 8 ppm 2.17 (s.3 H)2.64 (s.2 DMSO. The crude product was purified by preparative HPLC H) 2.69 (t, 2 H) 2.84 (t, 2 H) 3.80 (t, 2 H) 4.15 (t, 2 H) 65 to give 6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-phenyl-5. 7.20-7.27 (m, 3 H) 736-7.45 (m, 3 H) 7.66 (d. 2H) 7.81 (d. 2 6,7,8-tetrahydropyrido4,3-dipyrimidine-2,4-diamine H) 8.20 (s, 1 H) (0.014g, 23%). US 8,188,101 B2 39 40 "H NMR (500 MHz, MeOD) 8 ppm 2.60 (s, 3 H)2.83 (d. Solvent was removed under reduced pressure and the crude 2 H)2.88 (d. 2 H)3.55 (s, 2 H) 7.17 (t, 1H) 7.32-7.41 (m, 3 product redissolved in EtOAc, washed with saturated H) 7.50 (d, 2 H) 7.58 (d. 2 H) 7.68 (d. 2 H) 8.19 (s, 1 H) MS NaHCO and H2O. The organic layer was dried (MgSO), (ESI+)/(ESI-) m/z 399/397 filtered and concentrated to give tert-butyl 4-(benzylamino)- 2-(4-(oxazol-5-yl)phenylamino)-5,6-dihydropyrido 3,4-d Example 5 pyrimidine-7(8H)-carboxylate (0.120 g, 87%). No further purification. N4-Benzyl-N2-(4-(oxazol-5-yl)phenyl)-5,6,7,8-tet rahydropyrido3,4-dipyrimidine-2,4-diamine MS (ESI+)/(ESI-) m/z 499/497 10 Example 5b tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluo romethylsulfonyloxy)-5,6-dihydropyrido 3,4-dpyri midine-7(8H)-carboxylate 15

25 Hydrogen chloride (2 mL, 0.20 mmol, 2Maq) was added to a solution of tert-butyl 4-(benzylamino)-2-(4-(oxazol-5-yl) phenylamino)-5,6-dihydropyrido 3,4-dpyrimidine-7(8H)- carboxylate (0.1 g, 0.20 mmol. Example 5a) in MeOH (5 mL) and heated in an open reaction vessel to 76° C. for 1 h. The 30 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) residual solvent was removed under reduced pressure, the methanesulfonamide (0.698 g, 1.95 mmol) was added to tert crude product was redissolved in DMSO and purified by butyl 4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-5,6-dihy preparative HPLC to give N4-benzyl-N2-(4-(oxazol-5-yl) dropyrido 3,4-dipyrimidine-7(8H)-carboxylate (0.8 g. 1.95 phenyl)-5,6,7,8-tetrahydropyrido 3,4-dipyrimidine-2,4-di mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.292 mL, amine (38 mg, 47.5%). MS (ESI+)/(ESI-) m/z 399/397 35 1.95 mmol) in DCM (30 mL). 4-Dimethylaminopyridine "H NMR (600 MHz, DMSO-d) 8 ppm 2.33 (t, 2 H)2.97 (t, (0.024g, 0.20 mmol) was added and the solution was stirred 2 H)3.55 (s, 2 H)4.65 (d. 2 H) 7.17-7.28 (m, 2 H) 7.30-7.37 for 30 minutes. Solvent was removed under reduced pressure (m, 4H) 742-749 (m, 3 H) 7.71 (d. 2H)8.33 (s, 1 H) 9.05 (s, and the crude product dissolved in DCM and washed with 1H) HO. The organic layer was dried (MgSO), filtered and 40 concentrated. The crude mixture was dissolved in ethanol and Example 5a precipitated upon addition of a few drops of water to give tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluorometh tert-Butyl 4-(benzylamino)-2-(4-(oxazol-5-yl)pheny ylsulfonyloxy)-5,6-dihydropyrido 3,4-dpyrimidine-7(8H)- lamino)-5,6-dihydropyrido 3,4-dipyrimidine-7(8H)- carboxylate (0.850 g., 80%). No further purification. MS carboxylate 45 (ESI+)/(ESI-) m/z 542/540 Example 5c tert-Butyl 4-hydroxy-2-(4-(oxazol-5-yl)pheny 50 lamino)-5,6-dihydropyrido 3,4-dipyrimidine-7(8H)- carboxylate

55 7 No OH N e lsN 60 sy O Benzylamine (0.030g, 0.28 mmol) was added to tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfony Sodium ethoxide (0.476 g, 7.00 mmol) was added to 1-tert loxy)-5,6-dihydropyrido 3,4-dipyrimidine-7(8H)-carboxy 65 butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (1.899 g, late (0.15g, 0.28 mmol. Example 5b) in dioxane (10 mL) and 7.00 mmol. Example 1 d) and 1-(4-(oxazol-5-yl)phenyl) DMF (0.5 mL). The reaction was stirred at rt over night. The guanidine (1.415 g, 7.00 mmol. Example le) in ethanol (10 US 8,188,101 B2 41 42 mL). The reaction vial was heated a microwave reactor at (4-(oxazol-5-yl)phenyl)-5,6,7,8-tetrahydropyrido4.3-dpy 100° C. for 15 minutes. The suspension was diluted with rimidine-2,4-diamine (0.090g, 75%). MS (ESI+)/(ESI-) m/z. ethanol (5 ml) and the precipitated crude product was filtered 399/397 off and washed with cold ethanol to give tert-butyl 4-hy 'HNMR (600 MHz, DMSO-d)8 ppm 2.47 (t, 2H)2.94 (t, droxy-2-(4-(oxazol-5-yl)phenylamino)-5,6-dihydropyrido 2 H) 3.57 (s, 2 H)4.64 (d. 2 H) 7.14 (t, 1 H) 7.21 (t, 1 H) 3,4-dpyrimidine-7(8H)-carboxylate (1.200 g, 41.9%). No 7.29-7.39 (m, 4H) 742-749 (m, 3 H) 7.71 (d. 2 H)8.33 (s, 1 further purification. MS (ESI+)/(ESI-) m/z 410/408 H) 9.06 (s, 1 H) Example 5d Example 6a 10 1-tert-Butyl 4-ethyl tert-Butyl 4-(benzylamino)-2-(4-(oxazol-5-yl)pheny 3-oxopiperidine-1,4-dicarboxylate lamino)-7,8-dihydropyrido4,3-dipyrimidine-6(5H)- carboxylate

15 u

x-r 25 Di-tert-butyl dicarbonate (3.19 g, 14.60 mmol) was added to a solution of ethyl 3-oxopiperidine-4-carboxylate (2.5 g. 14.60 mmol) and triethylamine (2.030 mL, 14.60 mmol) in DCM (50 mL) cooled on an ice-bath. One DMAP crystal was 30 Benzylamine (0.061 mL, 0.55 mmol) was added to tert added and the suspension was stirred for 15 minutes. The butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethyl solution was poured onto ice and neutralised with HCl (2M, sulfonyloxy)-7,8-dihydropyrido4,3-dipyrimidine-6(5H)- aq). The organic layer was washed with HCl (0.1M), H2O, carboxylate (0.3 g, 0.55 mmol. Example 3c) in dioxane (4 dried (MgSO), filtered and concentrated to give 1-tert-butyl mL) and the reaction mixture was stirred over night at 25°C. 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2.60 g. 65.6%). 35 The solvent was removed under reduced pressure and the MS (ESI-) m/z 270 reaction mixture was redissolved in DCM and washed with water. The organic layer was dried (MgSO), filtered and Example 6 concentrated to give tert-butyl 4-(benzylamino)-2-(4-(OX azol-5-yl)phenylamino)-7,8-dihydropyrido4.3-dpyrimi N4-Benzyl-N2-(4-(oxazol-5-yl)phenyl)-5,6,7,8-tet 40 dine-6(5H)-carboxylate (0.238 g, 86%). MS (ESI+)/(ESI-) rahydropyrido4.3-dipyrimidine-2,4-diamine m/Z. 499/497 Example 7 45 N2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phe nyl)-N4-phenyl-5,6,7,8-tetrahydropyrido4.3-dpyri midine-2,4-diamine

50

55

Hydrochloric acid (2Maq, 2 ml) was added to a solution of tert-butyl 4-(benzylamino)-2-(4-(oxazol-5-yl)phenylamino)- 7,8-dihydropyrido4.3-dpyrimidine-6(5H)-carboxylate 60 (0.15 g, 0.30 mmol. Example 6a) in MeCH (4 mL). The reaction was heated in an open reaction vessel to 76°C. for 1 Aniline (0.032 g, 0.34 mmol) was added to a solution of hand the product precipitated out from the Solution as it was tert-butyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phe cooled. The crude product was filtered off and washed with nylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropy water. The crude salt was dissolved in water and precipitated 65 rido4.3-dpyrimidine-6(5H)-carboxylate (0.2g, 0.34 mmol. when saturated NaHCO was added. The product was filtered Example 7a) in DMF (2 mL). The solution was stirred at 70° off and purified by preparative HPLC to give N4-benzyl-N2 C. for 1 h. HCl 2Maq (2 ml) was added and the solution US 8,188,101 B2 43 44 heated to 76° C. for 1 h. Solvent was concentrated under The reaction was heated in the microwave oven for 20 minat reduced pressure and purified on preparative HPLC to give 100° C. Solvent was evaporated under reduced pressure. The N2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N4 crude was dissolved in minimal volume of EtOH and few phenyl-5,6,7,8-tetrahydropyrido4,3-dipyrimidine-2,4-di drops of water added to allow the product to precipitate. The amine (0.060 g, 41.0%). MS (ESI+)/(ESI-) m/z 428/426 precipitated product was filtered and dried to give tert-butyl "H NMR (500 MHz, DMSO-d) & ppm 2.13 (s.3 H) 2.56 4-hydroxy-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl) (t, 2 H)2.97 (t, 2 H)3.52 (s.3 H)3.70 (s, 2 H)6.99 (s, 1 H) phenylamino)-7,8-dihydropyrido4.3-dpyrimidine-6(5H)- 7.01-7.11 (m.2 H) 728-7.38 (m, 3 H) 7.61 (d. 1 H) 7.65 (d. 2 carboxylate (0.400 g, 39.4%). MS (ESI+)/(ESI-) m/z 453/ H) 7.70 (s, 1 H) 8.16 (s, 1 H) 9.18 (s, 1 H) 450 10 Example 7a Example7c tert-Butyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1- 1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phe yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8- nyl)guanidine dihydropyrido4,3-dipyrimidine-6(5H)-carboxylate 15

25 3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline hydro chloride (3 g, 12.52 mmol), cyanamide (0.684g, 16.27 mmol) and hydrochloric acid (1.564 mL, 18.77 mmol) in ethanol (20 mL) were heated to reflux o.n. The reaction mixture was tert-Butyl 4-hydroxy-2-(3-methoxy-4-(4-methyl-1H-imi 30 concentrated under reduced pressure before the resulting dazol-1-yl)phenylamino)-7,8-dihydropyrido4.3-dpyrimi mixture was poured on a solution of potassium carbonate dine-6(5H)-carboxylate (0.5g, 1.10 mmol. Example 7b), 1,1, (1.730 g, 12.52 mmol) in water (60 mL) and left in refrigera 1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) toro.n. The formed carbonate-salt was filtered off, and dried methanesulfonamide (0.395 g, 1.10 mmol), 1,8-diazabicyclo in vacuum oven o.n. The solid was washed with several por 5.4.0]undec-7-ene (0.165 ml, 1.10 mmol) and 35 4-dimethylaminopyridine (0.013 g, 0.11 mmol) in DCM (20 tions of DCM, dried and used as such in next step. mL) were stirred at rt for 1 h. Solvent was evaporated under MS (ESI+)/(ESI-) m/z 246/244 reduced pressure and the crude product was purified on a Example 7d silica gel column using DCM/MeOH (9/1) as eluent. Col lected fractions were pooled and solvent evaporated under 40 3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine reduced pressure to give tert-butyl 2-(3-methoxy-4-(4-me thyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsul fonyloxy)-7,8-dihydropyrido4.3-dpyrimidine-6(5H)-car boxylate (0.400 g, 61.9%). MS (ESI+) m/z 585 45 Example 7b tert-Butyl 4-hydroxy-2-(3-methoxy-4-(4-methyl-1H imidazol-1-yl)phenylamino)-7,8-dihydropyrido4.3- NH2 dpyrimidine-6(5H)-carboxylate 50 10% Pd/C was added to a solution of 1-(2-methoxy-4- nitro-phenyl)-4-methyl-1H-imidazole (616 mg, 2.6 mmol. Example 7e) in ethyl acetate (20 mL). The resulting mixture 55 was shaken under hydrogen atmosphere overnight at 35 psi and room temperature. The mixture was filtered through a pad of celite and washed with ethylacetate (2x15 mL). The filtrate was concentrated to 10 mL and diluted with ether (50 mL). 2M HCl in dioxane (2 mL) was added to the resulting solution 60 at 0°C. under stirring and continued the stirring for another hour at room temperature. The separated solid was filtered, washed with ether (3x15 mL) and dried under high vacuum to In a microwave vial was 1-tert-butyl 3-methyl 4-oxopip afford the title compound as HCl salt (603 mg, 95%). eridine-1,3-dicarboxylate (0.577 g, 2.24 mmol. Example7c), 'HNMR (400 MHz, methanol-da) 8 ppm 2.42 (s.3 H)3.93 Sodium ethoxide (0.153 g, 2.24 mmol), and 1-(3-methoxy 65 (s.3 H), 6.91 (dd. 1 H), 7.05 (d. 1 H), 7.44-7.67 (m, 2H), 9.10 4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (0.55 g, (d. 1 H), 2.24 mmol) added in ethanol (10 mL) to give a Suspension. Mol. Formula: CHNO.1.8 HCl US 8,188,101 B2 45 46 Elemental Analysis: Found C 48.99, H 5.86, N 15.27: under reduced pressure. The crude product was dissolved in Calcd. C 49.14, H 5.55, N 15.63 MS m/z. M+H 204 MeOH/DMSO and purified by preparative HPLC to give 2-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny Example 7e lamino)-4-(phenylamino)-7,8-dihydropyrido4.3-dipyrimi din-6(5H)-yl)ethanol (0.018 g., 53.5%). MS (ESI+)/(ESI-) 1-(2-Methoxy-4-nitro-phenyl)-4-methyl-1H-imida m/Z 472/470 Zole and 1-(2-methoxy-4-nitro-phenyl)-5-methyl "H NMR (500 MHz, DMSO-d) & ppm 2.13 (s.3 H)2.64 1H-imidazole (t, 2H)2.68 (t, 2 H)2.76 (t, 2 H)3.45 (s.2H)3.51 (s.3 H)3.64 (q,2H)4.51 (t, 1H)6.99 (s, 1 H) 7.03-7.10 (m.2 H) 7.29-7.38 10 (m, 3 H) 7.59-7.66 (m, 3 H) 7.68 (br.s., 1 H)8.25 (s, 1 H).9.20 (s, 1 H) Example 9

15 (S)-(1-(6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl) phenylamino)-5,6,7,8-tetrahydropyrido4.3-dpyri midin-4-yl)indolin-2-yl)methanol

Chiral A mixture of 4-methyl imidazole (500 mg, 6 mmol),

2-fluoro-5-nitro anisole (1.02 g, 5.9 mmol) and potassium carbonate (1.68 g. 12 mmol) in DMF (15 mL) was heated overnight at 85°C. in a sealed tube. The reaction mixture was cooled, transferred into a round bottom flask using ethyl 25 acetate and concentrated under high vacuum to 5 mL. Volume. The residue was suspended in water and extracted with dichloromethane (3x25 mL). The organic extracts were com bined, washed with brine, dried over anhydrous MgSO, fil tered and concentrated to give an orange Solid. The Solid was 30 dissolved in dichloromethane (10 mL) and diluted with hex (S)-Indolin-2-ylmethanol (25.5 mg, 0.17 mmol) was added ane until the solution became slightly turbid. The turbid solu to a solution of 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl) tion was left at room temperature. The separated orange Solid phenylamino)-5,6,7,8-tetrahydropyrido4,3-dipyrimidin-4- was filtered, washed with hexane to give 1-(2-methoxy-4- 35 yl trifluoromethanesulfonate (80 mg 0.17 mmol. Example nitro-phenyl)-4-methyl-1H-imidazole and 1-(2-methoxy-4- 9a) in DMSO (1 mL). The reaction was heated to 80°C. for 2 nitro-phenyl)-5-methyl-1H-imidazole (577 mg, 43%). h. The solution was allowed to cool down, filtered and the "H NMR (400 MHz, methanol-da) 8 ppm 2.25 (s.3 H)4.02 product was purified on preparative HPLC to give (S)-(1-(6- (s.3 H) 7.21 (s, 1 H) 7.62 (d. 1 H) 7.92-8.02 (m.2 H) 8.04 (s, methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5, 1H) 40 6,7,8-tetrahydropyrido4,3-dipyrimidin-4-yl)indolin-2-yl) methanol (22.00 mg, 27.6%). MS (ESI+)/(ESI-) m/z 468/466 Example 8 H NMR (500 MHz, MeOD) 8 ppm 2.31 (s.3 H)2.41 (s.3 2-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl) H)2.66 (s, 1 H)2.80-2.87(m, 1 H)2.87-2.94 (m, 1 H)2.98 (t, phenylamino)-4-(phenylamino)-7,8-dihydropyrido4. 2H)3.13 (dd. 1 H)3.23-3.28 (m, 1 H)3.42 (d. 1 H)3.65 (dd. 3-dipyrimidin-6(5H)-yl)ethanol 45 1H)3.82 (dd. 1 H)4.73-4.80 (m, 1 H) 6.65 (d. 1 H) 6.85 (t, 1 H) 6.93 (d. 1 H) 7.07 (t, 1 H) 7.12 (d. 1 H) 7.21 (d. 1 H) 7.24-729 (m, 2 H) 7.78-7.89 (m, 2 H) Example 9a 50 6-Methyl-2-(4-(2-methyl-1H-imidazol-1-yl)pheny lamino)-5,6,7,8-tetrahydropyrido4.3-dpyrimidin-4- yl trifluoromethanesulfonate

55

Acetic acid (0.803 uL, 0.01 mmol) was added to a solution 60 of N2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)- N4-phenyl-5,6,7,8-tetrahydropyrido4,3-dipyrimidine-2,4- diamine (Example 7, 0.03 g, 0.07 mmol) and 2-hydroxyac etaldehyde (4.21 mg, 0.07 mmol) in MeCH (5 mL). The reaction mixture was stirred for 10 min and sodium 65 cyanoborohydride (4.41 mg, 0.07 mmol) added. The reaction was stirred for an additional 15 min and solvent evaporated US 8,188,101 B2 47 48 6-Methyl-2-(4-(2-methyl-1H-imidazol-1-yl)pheny (20 mL). The solution was stirred at 75° C. for 30 min allow lamino)-5,6,7,8-tetrahydropyrido4,3-dipyrimidin-4-ol (0.4 ing the EtOH to evaporate. The solution was made basic with g, 1.19 mmol. Example 9b), 1,1,1-trifluoro-N-phenyl-N-(tri potassium carbonate(s) and EtOAc (20 mL) was added. After fluoromethylsulfonyl)methanesulfonamide (0.425 g, 1.19 stirring 10 min the precipitated product was filtered off and mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.179 mL, 1.19 dried to give 2-(4-(2-methyl-1H-imidazol-1-yl)pheny mmol) and 4-dimethylaminopyridine (0.015g, 0.12 mmol) in lamino)-5,6,7,8-tetrahydropyrido4,3-dipyrimidin-4-ol DCM (10 mL) was stirred at room temperature for 30 min. (1.300 g, 74.1%). MS (ESI+)/(ESI-) m/z 323/321 Solvent was evaporated under reduced pressure and the crude dissolved in minimal volume of EtOH, the desired product Example 9d precipitated when a few drops of water were added. The 10 precipitate was filtered and washed carefully with ice-cold ethanol to give 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl) tert-Butyl 4-hydroxy-2-(4-(2-methyl-1H-imidazol-1- phenylamino)-5,6,7,8-tetrahydropyrido4,3-dipyrimidin-4- yl)phenylamino)-7,8-dihydropyrido4.3-dpyrimi yl trifluoromethanesulfonate (0.500 g, 90%). MS (ESI+)/ 15 dine-6(5H)-carboxylate (ESI-) m/z 469/467 Example 9b

6-Methyl-2-(4-(2-methyl-1H-imidazol-1-yl)pheny lamino)-5,6,7,8-tetrahydropyrido4.3-dpyrimidin-4- ol

25 1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (1.4 g, 6.50 mmol. Example 9e), 1-tert-butyl-3-methyl 4-oxopip eridine-1,3-dicarboxylate (1.673 g. 6.50 mmol) and sodium 30 ethoxide (0.443 g. 6.50 mmol) were placed in a microwave vial and ethanol (1 mL) added. The vial was heated in a microwave oven at 100° C. for 20 min. Solvent was evapo A suspension of 2-(4-(2-methyl-1H-imidazol-1-yl)pheny rated under reduced pressure and the crude dissolved in lamino)-5,6,7,8-tetrahydropyrido4,3-dipyrimidin-4-ol (1.4 35 EtOAc. The organic solution was washed with sat NaHCO g, 4.34 mmol. Example 9c), formaldehyde (0.423 g, 5.21 and HO. The organic layer was dried over NaSO filtered mmol) and acetic acid (0.025 mL, 0.43 mmol) in MeOH (25 and evaporated to give tert-butyl-4-hydroxy-2-(4-(2-methyl mL) was stirred for 10 min. Sodium cyanoborohydride (0.273 1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido4.3-d g, 4.34 mmol) was added and the reaction was stirred for an pyrimidine-6(5H)-carboxylate (2.300 g, 84%). MS (ESI+)/ additional 10 min after which water (2 mL) was added. Sol 40 (ESI-) m/z 423/421 vent was evaporated and EtOAc (2 mL) was added followed by the addition of potassium carbonate Solution (sat. aq., 1 Example 9e mL). The solution was stirred and the formed precipitate was filtered off to give 6-methyl-2-(4-(2-methyl-1H-imidazol-1- yl)phenylamino)-5,6,7,8-tetrahydropyrido4.3-dpyrimidin 45 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine 4-ol (0.500 g, 34.2%). MS (ESI+)/(ESI-) m/z 337/335

Example 9c NH 2-(4-(2-Methyl-1H-imidazol-1-yl)phenylamino)-5,6, 50 "N. 7,8-tetrahydropyrido4.3-dpyrimidin-4-ol NH

55 M

To a solution of 4-(2-methyl-1H-imidazol-1-yl)aniline (2 60 g, 11.55 mmol) in ethanol (25 mL) was added cyanamide (0.728 g. 17.32 mmol) and hydrochloric acid (1.422 mL, 17.32 mmol). The reaction mixture was refluxed for 4 h. An additional 1 eq of hydrochloric acid (1.422 ml, 17.32 mmol) tert-Butyl 4-hydroxy-2-(4-(2-methyl-1H-imidazol-1-yl) was added and precipitation occurred. The precipitated prod phenylamino)-7,8-dihydropyrido4.3-dpyrimidine-6(5H)- 65 uct was filtered off and washed with DCM to give 1-(4-(2- carboxylate (2.3 g 5.44 mmol. Example 9d) was added to a methyl-1H-imidazol-1-yl)phenyl)guanidine (1.600 g, solution of hydrogen chloride (10 mL, 5.44 mmol) in ethanol 64.4%). MS (ESI+)/(ESI-) m/z 216/214

US 8,188,101 B2 59 60 Example 26 and dried in a vacuum oven overnight at 40° C. yielding 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahy 1-(4-(Cyclohexylamino)-2-(4-(oxazol-5-yl)pheny dropyrido4,3-dipyrimidin-4-yl trifluoromethanesulfonate lamino)-7,8-dihydropyrido4,3-dipyrimidin-6(5H)- (0.720 g, 18%). yl)ethanone MS (ESI) (M+1) m/z 484.2 Example 26b

10

1-(4-Hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8- W O dihydropyrido4,3-dipyrimidin-6(5H)-yl)ethanone

15 /S O le 6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tet rahydropyrido4.3-dipyrimidin-4-yl trifluoromethane sulfonate (35 mg 0.07 mmol) in DMSO (1 mL) was dis pensed in a library plate. Cyclohexanamine (6.94 mg. 0.07 mmol) was added and the reaction mixture was stirred over 1-(4-(Oxazol-5-yl)phenyl)guanidine (2.7 g 13.35 mmol), night at 80° C. before it was filtered and purified by prepara 25 methyl 1-acetyl-4-oxopiperidin-3-carboxylate (2.66 g. 13.35 tive HPLC to give 1-(4-(cyclohexylamino)-2-(4-(oxazol-5- mmol) and sodium ethoxide (0.946g, 13.35 mmol) in ethanol yl)phenylamino)-7,8-dihydropyrido4,3-dipyrimidin-6 (15 mL) were heated in a microwave reactor at 100° C. for 15 (5H)-yl)ethanone (11.2 mg, 36%). minutes. The reaction mixture was allowed to reach room temperature and water was added. The solid obtained was Mixture of rotamers: 30 filtered, washed with water and dried in a vaccum oven yield "H NMR (500 MHz, CDC1) 8 ppm 1.18-1.35 (m), 1.40 ing 1-(4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihy 1.53 (m), 1.70-1.91 (m), 2.09-2.18 (m), 2.20-2.27 (m) 2.68 dropyrido4,3-dipyrimidin-6(5H)-yl)ethanone (2.90 g, 2.82 (m), 3.69-3.78 (m), 3.84-3.92 (m), 3.98-4-12 (m), 4.15 61.8%). 4.25 (m), 4.34 (s), 7.27-7.29 (m), 7.56-7.62 (m), 7.70-7.72 MS (ESI) (M+1) m/z 352.2 (m), 7.89 (s) 35 H NMR (500 MHz, MeOD) 8 ppm 1.90 (s, 7 H) 2.20 (d. Total no of protons in spectrum: 27 3 H)2.63 (t, 1H)2.72 (t, 1H)3.74-3.85 (m, 3 H)4.41 (d. 2 H) Ratio major:minor: 0.7:0.4 7.34-7.43 (m, 3 H) 7.56 (s, 1 H) 7.64 (dd, 2 H) 7.75-7.85 (m, Example 26a 4 H) 8.20 (d. 1 H) 8.28 (s, 1 H) 40 6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8- Example 26c tetrahydropyrido4.3-dpyrimidin-4-yl trifluo romethanesulfonate Methyl 1-acetyl-4-oxopiperidine-3-carboxylate 45

50

55

1-(4-Hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihy Methyl 4-oxo-3-piperidinecarboxylate hydrochloride (10 dropyrido4,3-dipyrimidin-6(5H)-yl)ethanone (2.9 g, 8.25 g, 51.65 mmol) was dissolved in dichloromethane (130 mL). mmol) was dissolved in dichloromethane (50 mL) and 1.8- 60 Triethylamine (7.20 mL, 51.65 mmol) was added followed by diazabicyclo5.4.0]undec-7-ene (1.232 mL, 8.25 mmol). acetic anhydride (4.87 mL, 51.65 mmol). The reaction mix N-phenyltrifluoromethane-sulfonimide (3.24 g, 9.08 mmol) ture was stirred at room temperature for 2 h. The organic was added followed by 4-dimethylaminopyridine (1.01 mg, phase was washed with water, dried over MgSO filtered and 8.25 umol). The reaction mixture was stirred at room tem concentrated to give methyl 1-acetyl-4-oxopiperidine-3-car perature for 4 h. The solvent was evaporated under reduced 65 boxylate (6.10g, 59.3%), which was used in the next step as pressure and the crude dissolved in ethanol. Water was added Such. until the product precipitated. The solid obtained was filtered MS (ESI) (M+1) m/z 200.1

US 8,188,101 B2 69 70 (phenyl)amino)-2-(4-(1-methyl-1H-pyrazol-4-yl)pheny (0.108 g., 0.17 mmol) and potassium carbonate (1.837 g. lamino)-7,8-dihydropyrido4,3-dipyrimidine-6(5H)-car 13.29 mmol) in DMF (5 mL), water (2.5 mL) and ethanol boxylate (0.882g, 90%). MS (ESI) (M+H) m/z 542 (0.833 mL) were charged in a thick wall glass, which was sealed and heated at 110° C. for 20 minutes. The raction Example 38c mixture was allowed to cool down, the crude was filtered through celite and the filtercake washed with ethanol. The tert-Butyl 2-(4-(1-methyl-1H-pyrazol-4-yl)pheny solvent was evaporated under reduced pressure. The crude lamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydro was used in the next step without further purification. MS pyrido4,3-dipyrimidine-6(5H)-carboxylate 10 (ESI) (M+1) m/z 423 Example 38e

tert-Butyl 2-(4-bromophenylamino)-4-hydroxy-7,8- 15 dihydropyrido4.3-dpyrimidine-6(5H)-carboxylate

Br

25 tert-Butyl 4-hydroxy-2-(4-(1-methyl-1H-pyrazol-4-yl) phenylamino)-7,8-dihydropyrido4.3-dpyrimidine-6(5H)- carboxylate (1 g, 2.37 mmol) was dissolved in dichlo romethane (25 mL). 2,3,4,6,7,8,9,10-octahydropyrimido1, 30 2-aazepine (0.360 g, 2.37 mmol) was added followed by 1-tert-Butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)-meth (1 g, 3.89 mmol), 1-(4-bromophenyl)guanidine (0.832g, 3.89 anesulfonamide (0.846g, 2.37 mmol). Few crystals of 4-dim mmol) and sodium ethoxide (0.264 g. 3.89 mmol) in ethanol ethylaminopyridine was added and the reaction mixture was (8 mL) were heated to 100° C. in a microwave reactor for 15 stirred for 4 h. The solvent was evaporated under reduced 35 minutes. The reaction mixture was allowed to reach room pressure and the crude purified by flash chromatography temperature, the solid obtained was filtered and washed with (ISCO) using dichlorometane and methanol (0-10%) as elu cold ethanol and dried in a vacuum oven yielding tert-butyl ent and the solvent was evaporated under reduced pressure 2-(4-bromophenylamino)-4-hydroxy-7,8-dihydropyrido4, yielding tert-butyl 2-(4-(1-methyl-1H-pyrazol-4-yl)pheny 3-dipyrimidine-6(5H)-carboxylate (1.45 g, 72%). The com lamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido 40 pound was used in the next step without purification. MS 4,3-dipyrimidine-6(5H)-carboxylate (1.020 g, 78%). MS (ESI) (M+H) m/z 423 (ESI) (M+H) m/z 555 Example 38d Example 38f tert-Butyl 4-hydroxy-2-(4-(1-methyl-1H-pyrazol-4- 45 yl)phenylamino)-7,8-dihydropyrido4.3-dpyrimi 1-(4-Bromophenyl)guanidine dine-6(5H)-carboxylate

50

H N NH2

NH 55 Br

Hydrochloric acid (1.503 mL, 9.07 mmol) was added to 60 4-bromoaniline (2g, 11.63 mmol) and carbodiimide (0.538g. 12.79 mmol) in ethanol (10 mL) heated to reflux for 90 min. tert-Butyl 2-(4-bromophenylamino)-4-hydroxy-7,8-dihy The solvent was removed under reduced pressure and potas dropyrido4,3-dipyrimidine-6(5H)-carboxylate (1.4 g 3.32 sium carbonate (0.964 g. 6.98 mmol) in water (10.00 mL) was mmol), 1-methyl-4-(4.4.5.5-tetramethyl-1,3,2-dioxaboro 65 added. Crystals were filtered off and washed with several lan-2-yl)-1H pyrazole (0.691 g, 3.32 mmol), dichloro1,1'- portions of DCM to give the title compound (1.9 g, 60%). bis(di-tert-butylphosphino) ferrocenepalladium (II), Pd-118 US 8,188,101 B2 71 72 Example 39 methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido 4.3-dpyrimidin-6(5H)-yl)ethanol (18.10 mg, 19.7%). MS 2-((2-(4-(1-Methyl-1H-pyrazol-4-yl)phenylamino)- (ES+) (M+H)+=441.3 6-propyl-5,6,7,8-tetrahydropyrido4,3-dipyrimidin H NMR (400 MHz, chloroform-d) 8 ppm 2.36 (s, 3 H) 4-yl)(phenyl)amino)ethanol 2.72-2.80 (m, 2 H)2.89 (dd, 4H)3.61 (s, 2 H)3.68-3.75 (m, 2 H)3.98 (s, 2 H) 6.98 (d. 1 H) 7.04 (d. 1 H) 7.14 (m, 2 H) 723-7.27 (m.2 H)7.27-7.31 (m, 1 H) 7.31-7.38 (m.2 H) 7.67

(m, 2 H) 7.90 (s, 1 H) 10 Example 41a 4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)- 5,6,7,8-tetrahydropyrido4.3-dpyrimidin-2-amine

15

2-((2-(4-(1-Methyl-1H-pyrazol-4-yl)phenylamino)-5,6,7, 8-tetrahydropyrido4.3-dpyrimidin-4-yl)(phenyl)amino) ethanol (40 mg 0.09 mmol. Example 38a) was dissolved in methanol (2 mL). Acetic acid (1.037 uL, 0.02 mmol) was added followed by propionaldehyde (0.013 mL, 0.18 mmol). The reaction mixture was stirred for 30 minutes at room temperature before sodium cyanoborohydride (11.39 mg, 25 0.18 mmol) was added. The solvent was evaporated under reduced pressure, the crude dissolved in few drops of dim tert-Butyl 4-benzyl-2-(4-(2-methyl-1H-imidazol-1-yl) ethylformamide and acetonitrile, filtered and purified by pre phenylamino)-7,8-dihydropyrido4.3-dpyrimidine-6(5H)- parative HPLC yielding 2-((2-(4-(1-methyl-1H-pyrazol-4- carboxylate (270 mg. 0.54 mmol) was dissolved in methanol yl)phenylamino)-6-propyl-5,6,7,8-tetrahydropyrido4.3-d 30 (3 mL). Hydrochloric acid (0.017 mL, 0.54 mmol) was added pyrimidin-4-yl)(phenyl)amino)ethanol (7.6 mg, 15.4%) as and the reaction mixture was stirred at 75° C. for 1 h. The acetic acid salt. Solvent was evaporated under reduced pressure yielding MS (ESI) (M+1) m/z 484 4-benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7, H NMR (500 MHz, chloroform-d) 8 ppm 0.82 (t, 3 H) 8-tetrahydropyrido4.3-dpyrimidin-2-amine (150 mg. 1.30-1.40 (m, 2 H)2.02 (s.3 H)2.21-2.28 (m.2 H)2.68 (s. 2 35 69.6%) which was used in the subsequent step as such. H)2.72 (t, 2 H)2.87 (t, 2 H)3.75 (t, 2 H)3.95 (s.3 H)4.17 (t, 2H) 7.18-7.25 (m, 3 H) 7.37 (t, 2 H) 7.43 (d, 2 H) 7.57-7.61 "H NMR (400 MHz, chloroform-d) 8 ppm 2.34 (s, 3 H) (m, 3 H) 7.74 (s, 1 H) 8.13 (br. s. 1 H) 2.81 (t, 2 H)3.16 (t, 2 H)3.91 (s. 2H)3.94 (s, 2 H) 6.98 (dd. 3 H) 7.12 (d, 2 H) 7.21-7.26 (m, 3 H) 728-7.34 (m, 2 H) Example 41 40 Example 41b 2-(4-Benzyl-2-(4-(2-methyl-1H-imidazol-1-yl)phe nylamino)-7,8-dihydropyrido4.3-dpyrimidin-6 tert-Butyl 4-benzyl-2-(4-(2-methyl-1H-imidazol-1- (5H)-yl)ethanol yl)phenylamino)-7,8-dihydropyrido4.3-dpyrimi 45 dine-6(5H)-carboxylate

50

55

4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6, 7,8-tetrahydropyrido4,3-dipyrimidin-2-amine (75 mg 0.19 60 1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (224 mmol) was dissolved in methanol (2 mL). Acetic acid (10.83 mg, 1.04 mmol), tert-butyl 4-oxo-3-(2-phenylacetyl)piperi uL, 0.19 mmol) was added followed by glycoaldehyde (11.36 dine-1-carboxylate (330 mg, 1.04 mmol) and sodium ethox mg, 0.19 mmol) and sodium cyanoborohydride (11.89 mg, ide (70.8 mg, 1.04 mmol) in ethanol (5 mL) were heated to 0.19 mmol). The reaction mixture was stirred at room tem 110° C. in a microwave reactor for 1 h 20 min. The reaction perature for 1 hand the solvent was evaporated under reduced 65 was allowed to reach room temperature and the solvent was pressure. The crude was dissolved in methanol, filtered and evaporated under reduced pressure. The crude was dissolved purified by preparative HPLC yielding 2-(4-benzyl-2-(4-(2- in ethylacetate and washed with water. The organic phase was US 8,188,101 B2 73 74 dried under MgSO and the solvent evaporated under reduced H NMR (400 MHz, chloroform-d) 8 ppm 3.57 (t, 2 H) pressure yielding tert-butyl 4-benzyl-2-(4-(2-methyl-1H 3.72 (br. S., 2H)3.86-3.90 (m, 1H)4.39 (s, 1 H)4.47-4.53 (m, imidazol-1-yl)phenylamino)-7,8-dihydropyrido4.3-dpyri 1 H) 7.25 (s, 1 H) 728-7.37 (m, 5 H) midine-6(5H)-carboxylate (280 mg, 54.2%) which was used in the Subsequent step as such. 5 Example 41e MS m/z (ES+) 497 (M+H)+ tert-Butyl 4-morpholino-5,6-dihydropyridine-1 (2H)-carboxylate Example 41c 1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine 10

15 O

le

4-(2-Methylimidazol-1-yl)phenylamine (10 g, 57.73 >-l. mmol) was dissolved in ethanol (100 mL). Nitric acid (3.96 mL, 57.73 mmol) was carefully added followed by cyana tert-Butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mide (2.427g, 57.73 mmol). The reaction mixture was heated 25 mmol) was dissolved in toluene (25 mL). Morpholine (2.186 to reflux overnight. Extra cyanamide (1.942 g, 46.19 mmol) mL, 25.09 mmol) was added and the reaction mixture was heated overnight in a atmosphere of argon in a Dean-Stark and nitric acid (2.98 mL, 46.19 mmol) were added and then reflux apparatus. The mixture was allowed to reach room the reaction mixture was refluxed for 16 hours. The reaction temperature and it was evaporated to dryness yielding tert mixture was allowed to reach room temperature and ethyl 30 butyl 4-morpholino-5,6-dihydropyridine-1 (2H)-carboxylate ether (100 mL) was added. The mixture was refrigerated for (6.70 g, 99%). 2 h and the solid obtained was filtered off and washed with H NMR (400 MHz, chloroform-d) 8 ppm 1.46 (s, 9 H) ethyl ether yielding 1-(4-(2-methyl-1H-imidazol-1-yl)phe 2.16 (br.s., 2H)2.77-2.82 (m, 4H)3.54 (t, 2H)3.72-3.77 (m, nyl)guanidine (9.40 g, 76%). 4 H)3.94 (br. S., 2 H)4.56 (br. s. 1 H) 35 H NMR (500 MHz, DMSO-d) 8 ppm 2.53 (s.3 H) 7.49 Example 42 (m.2 H) 7.60 (s, 4H) 7.68 (m, 2H)7.81 (dd, 2 H) 9.90 (s, 1 H) 4-Benzyl-6-methyl-N-(4-(2-methyl-1H-imidazol-1- Example 41d yl)phenyl)-5,6,7,8-tetrahydropyrido4.3-dpyrimidin 2-amine 40 tert-Butyl 4-oxo-3-(2-phenylacetyl)piperidine-1-carboxylate

45

50

>s- 4-benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6, 55 7,8-tetrahydropyrido4,3-dipyrimidin-2-amine (75 mg 0.19 tert-Butyl 4-morpholino-5,6-dihydropyridine-1 (2H)-car mmol. Example 41a) was dissolved in methanol (2 mL). boxylate (6.7 g. 24.97 mmol) was dissolved in dioxane (60 Acetic acid (10.83 uL, 0.19 mmol) was added followed by mL) under an atmosphere of argon. 2-Phenylacetyl chloride formaldehyde (0.014 mL, 0.19 mmol). The reaction mixture (3.64 mL. 27.46 mmol) was added dropwise and the reaction was stirred at room temperature for 15 minutes and MP mixture was refluxed overnight. 60 CNBH was added. The reaction was stirred for 1 h, the The reaction was allowed to reach room temperature and MP-CNBH was filtered off and the solvent was evaporated the solid was filtered off. The filtrated was concentrated under under reduced pressure. The crude was dissolved in metha reduced pressure and purified by flash chromatography using nol, filtered and purified by preparative HPLC yielding dichlorometane and methanol as eluent, yielding tert-butyl 4-benzyl-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phe 4-oxo-3-(2-phenylacetyl)piperidine-1-carboxylate (0.510 g, 65 nyl)-5,6,7,8-tetrahydropyrido4.3-dpyrimidin-2-amine 6.44%). (23.00 mg, 27%). MS m/z (ES-) 316 (M-H)- MS m/z (ES+) 411 (M+H)+

US 8,188,101 B2 107 108 vent was evaporated under reduced pressure. The crude was Example 71 dissolved in ethyl acetate and washed with water. The organic phase was dried under MgSO and concentrated under reduced pressure yielding tert-butyl 4-hydroxy-2-(4-(2-me 6-Methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)- thyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido4. 5 4-(1-phenylethyl)-5,6,7,8-tetrahydropyrido4.3-d 3-dipyrimidine-6(5H)-carboxylate (1,970 g, 55.8%). The pyrimidin-2-amine product was used as such in the subsequent step. MS (ES+) m/Z 423.3 (M+H)+ Example 69e 10 ISOMER2 1-tert-Butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate

15

ill 25 a = unknown absolute Methyl 4-oxo-3-piperidinecarboxylate hydrochloride (5 g, 25.82 mmol) was dissolved in dichloromethane (50 mL) and Chiral separation gave isomer 2 (P2)-(+) optical rotation triethylamine (3.60 mL. 25.82 mmol). Di-tert-butyl dicarbon (PDR-Chiral Detector) ate (5.93 mL. 25.82 mmol) was carefully added and the 30 reaction mixture was stirred at room temperature for 2 h. The 1H NMR (600 MHz, CHLOROFORM-d) 8 ppm 1.66 (d. 3 reaction mixture was washed with 2M HCl (aq) and brine. H)2.35 (s.3 H)2.44 (s.3 H)2.59-2.68 (m, 1 H)2.73 (dt, 1H) The organic phase was dried under MgSO and concentrated 2.81-2.96 (m, 2 H)3.27 (d. 1 H)3.58 (d. 1 H) 4.14 (q, 1 H) under reduced pressure yielding 1-tert-butyl 3-methyl 4-ox 6.99 (d. 2H) 7.14-7.23 (m, 4H) 728 (br. s.3 H) 7.76 (d. 2H) opiperidine-1,3-dicarboxylate (6.55 g, 99%). 35 MS (ES+) m/Z 425.2 (M+H)+ MS (ES+) m/z 256.1 (M-H)- 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.48 (s.9 H) 1.49 (s.3 H)2.38 (t, 2 H)3.57 (t, 2H)3.77 (s, 1 H)3.78 (s, Example 71a 3 H)4.06 (br. S., 2 H) 11.98 (s, 1 H) 40 Example 70 N-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)-4-(1-phe nylethyl)-5,6,7,8-tetrahydropyrido4.3-dpyrimidin 6-Methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)- 2-amine 4-(1-phenylethyl)-5,6,7,8-tetrahydropyrido4.3-d pyrimidin-2-mine 45 ISOMER 1

50

55 a = unknown absolute tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)pheny lamino)-4-(1-phenylethyl)-7,8-dihydropyrido4,3-dipyrimi Chiral separation gave isomer 1 (P1)=(-) optical rotation 60 dine-6(5H)-carboxylate (612 mg, 1.20 mmol) was dissolved (PDR-Chiral Detector) in methanol (10 mL). Hydrochloric acid (0.098 mL, 1.20 1H NMR (600 MHz, CHLOROFORM-d) & ppm 1.66 (d. 3 mmol) was added and the reaction mixture was stirred at 75° H)2.35 (s.3 H)2.45 (s.3 H)2.60-2.67 (m, 1 H)2.73 (dt, 1H) C. for 1 h. The solvent was evaporated under reduced pressure 2.82-2.95 (m, 2 H)3.27 (d. 1 H)3.58 (d. 1 H) 4.14 (q, 1 H) and the crude N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4- 6.98 (s, 1 H) 7.01 (s, 1 H) 7.19 (d, 4H) 7.28 (d. 3 H) 7.76 (d. 65 (1-phenylethyl)-5,6,7,8-tetrahydropyrido4.3-dpyrimidin 2H) 2-amine (490 mg, 100%) was used as such in the subsequent MS (ES+) m/Z 425.3 (M+H)+ step. MS (ES+) m/z. 411 (M+H)+ US 8,188,101 B2 109 110 Example 71b Example 72

tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)pheny (S)-(1-(6-Methyl-2-(4-(2-methyl-1H-imidazol-1-yl) lamino)-4-(1-phenylethyl)-7,8-dihydropyrido4.3-d phenylamino)-5,6,7,8-tetrahydropyrido4.3-dpyri pyrimidine-6(5H)-carboxylate 5 midin-4-yl)indolin-2-yl)methanol

10 Chiral

15

1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (700 mg, 3.25 mmol, example 9e), tert-butyl 4-oxo-3-(2-phenyl propanoyl)piperidine-1-carboxylate (1293 mg, 3.90 mmol) (S)-(1-(2-(4-(2-Methyl-1H-imidazol-1-yl)phenylamino)- and sodium ethoxide (221 mg, 3.25 mmol) in ethanol (6 mL) 5,6,7,8-tetrahydropyrido4,3-dipyrimidin-4-yl)indolin-2-yl) were heated to 110° C. in a microwave reactor for 4 h. The 25 methanol (49 mg, 0.11 mmol) was dissolved in methanol (3 solvent was evaporated and the crude was dissolved in ethyl mL). Acetic acid (6.18 uL, 0.11 mmol) was added followed acetate and washed with water. The organic phase was dried by formaldehyde (0.016 mL, 0.22 mmol). The reaction mix under MgSO and the solvent was evaporated under reduced ture was allowed to stirred at room temperature for 15 min pressure. Purification by flash chromatography using dichlo utes and sodium cyanoborohydride (13.58 mg, 0.22 mmol) romethane and methanol (0-10%) as eluent gave tert-butyl 30 was added. After 1 h the solvent was evaporated and the crude 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(1-phe dissolved in few drops of methanol, filtered and purified by nylethyl)-7,8-dihydropyrido4,3-dipyrimidine-6(5H)-car preparative HPLC to give (S)-(1-(6-methyl-2-(methyl(4-(2- boxylate (612 mg, 36.9%). MS (ES+) m/z 511 (M+H)+ methyl-1H-imidazol-1-yl)phenyl)amino)-5,6,7,8-tetrahy dropyrido4,3-dipyrimidin-4-yl)indolin-2-yl)methanol Example 71c 35 (14.80 mg, 26.2%) and (S)-(1-(6-methyl-2-(4-(2-methyl-1H imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido4.3- dpyrimidin-4-yl)indolin-2-yl)methanol (4.60 mg, 8.07%) tert-Butyl 4-oxo-3-(2-phenylpropanoyl)piperidine-1- carboxylate were obtained as acetate salt. 40 MS (ES+) m/z 482.2 (M+H)+ 1H NMR (600 MHz, CHLOROFORM-d) 8 ppm 2.38 (s.3 H) 2.50 (s.3 H)2.78 (d. 2 H) 2.85-2.92 (m, 6 H)3.26 (dd. 1 H)3.33 (s.2H)3.82-3.90 (m, 1 H)4.56-4.62 (m.2 H)6.48 (d. 1H) 6.70 (t, 1H)6.99 (s, 1 H) 7.05 (d. 1 H) 7.08 (d. 1 H) 7.11 45 (t, 1 H) 722 (m, 2H) 7.75 (m, 2 H) Example 72a

50 (S)-(1-(2-(4-(2-Methyl-1H-imidazol-1-yl)pheny lamino)-5,6,7,8-tetrahydropyrido4.3-dpyrimidin-4- yl)indolin-2-yl)methanol

55 tert-Butyl 4-oxopiperidine-1-carboxylate (2.363 g, 11.86 mmol) was dissolved in toluene (7 mL) and cooled to 0°C.

LHMDS (12.45 mL, 12.45 mmol) in THF was added. After 2 min 2-phenylpropanoyl chloride (0.855 mL, 5.93 mmol) was added. After 2 min the cooling bath was removed and after 5 60 min 1:1 acetic acid:water (3 ml) was added. The water phase was separated after hard stirring and the organic phase was dried with MgSO and the solvent was evaporated. Purifica tion by flash column chromatography (0-25% EtOAc in hep tane) yielded tert-butyl 4-oxo-3-(2-phenylpropanoyl)piperi 65 dine-1-carboxylate (1.319 g, 67.1%). MS (ES-) m/z 330.1 (M-H)-

US 8,188,101 B2 131 132 1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (953 Example 88a mg, 4.43 mmol, example9e), 5-phenylhexane-2,4-dione (842 mg, 4.43 mmol) and Sodium ethoxide (301 mg, 4.43 mmol) in 6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8- ethanol (5 mL) were heated in a microwave reactor at 100° C. tetrahydropyrido4.3-dpyrimidin-4-yl trifluo for 15 minutes. The mixture was allowed to reach room 5 romethanesulfonate temperature and the crude was purified by HPLC yielding 4-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-6-(1- phenylethyl)pyrimidin-2-amine (23.00 mg, 1.313%). MS

(ES+) m/z. 370.2 (M+H)+ 10 1H NMR (400 MHz, CHLOROFORM-d) & ppm 1.64 (d. 3 H)2.30 (s.3 H) 2.32 (s.3 H)4.04 (q, 1 H) 6.45 (s, 1 H) 6.96 (dd, 2 H) 7.09-7.24 (m, 4H) 728-7.32 (m.2 H) 7.70-7.78 (m, 2 H) 7.85 (s, 1 H) General Procedure for Amine Substitution of Tosylate on 15 Pyrimidines An amine (1 eq) was added to 6-acetyl-2-(4-(oxazol-5-yl) phenylamino)-5,6,7,8-tetrahydropyrido4,3-dipyrimidin-4- yl trifluoromethanesulfonate (1 eq) in DMSO (1 mL) and stirred overnight at 80°C., filtered and purified by preparative 1-(4-Hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihy HPLC. dropyrido4,3-dipyrimidin-6(5H)-yl)ethanone (1.4 g, 3.98 mmol) was dissolved in dichloromethane (40 mL) and 1.8- diazabicyclo5.4.0]undec-7-ene (0.595 mL, 3.98 mmol). 1.1, Example 88 1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methane 25 sulfonamide (1.566 g. 4.38 mmol) was added in small portions followed by 4-dimethylaminopyridine (0.487 mg, 1-(4-(Cyclohexyl(methyl)amino)-2-(4-(oxazol-5-yl) 3.98 umol). The reaction mixture was stirred at room tem phenylamino)-7,8-dihydropyrido4.3-dpyrimidin-6 perature for 4 h. The crude was impregnated in silica gel and (5H)-yl)ethanone purified by flash column chromatography using dichlo 30 romethane and methanol (0-10%) as eluent yielding 6-acetyl 2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido 4.3-dpyrimidin-4-yl trifluoromethanesulfonate (1.340 g, 69.6%). MS (ES+) m/z 484.2 (M+H)+ 35 1H NMR (500 MHz, DMSO-d) d ppm 2.13 (br. s.3 H) 3.34 (br. S., 2 H)3.79 (br. S., 2 H)4.52 (br. S., 2 H) 7.61 (br. s. 1H) 7.67 (br. s.3 H) 7.79 (br. s. 2 H)8.40 (br. s. 1 H) 10.37 (br. S. 1 H)

40 Example 88b

1-(4-Hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8- dihydropyrido4,3-dipyrimidin-6(5H)-yl)ethanone 45

/S O le 50

1-(4-(Cyclohexyl(methyl)amino)-2-(4-(oxazol-5-yl)phe nylamino)-7,8-dihydropyrido4.3-dpyrimidin-6(5H)-yl) ethanone (12.6 mg, 17%) was prepared from N-methylcyclo hexanamine and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)- 55 1-(4-(Oxazol-5-yl)phenyl)guanidine (2 g, 9.89 mmol. 5,6,7,8-tetrahydropyrido4.3-dpyrimidin-4-yl example le), methyl 1-acetyl-4-oxopiperidine-3-carboxylate trifluoromethanesulfonate according to the general procedure (1,970 g., 9.89 mmol) and sodium ethoxide (0.673 g, 9.89 for amine Substitution of tosylate on pyrimidines. mmol) in ethanol were charged in a thick wall glass which Mixture of Rotamers: 60 was sealed and heated at 100° C. under microwave irradia tion. The reaction mixture was allowed to reach room tem 1H NMR (500 MHz, DMSO-d) 8 ppm 1.09-1.22 (m) perature and water was added until a solid was obtained. The 1.31-146 (m) 1.56-1.70 (m) 1.70- 1.87 (m) 2.02-2.10 (m) solid was filtered and dried in a vacuum oven at 40° C. 2.78 (t) 2.83-2.95 (m)3.66-3.76 (m) 4.42-4.54 (m) 7.46-7.55 overnight yielding 1-(4-hydroxy-2-(4-(oxazol-5-yl)pheny (m) 7.58 (m) 7.86 (m) 8.36 (s) 9.36 (br. s.) 65 lamino)-7,8-dihydropyrido4,3-dipyrimidin-6(5H)-yl)etha Total no of protons in spectrum: 29 none (1.400 g, 40.3%). Ratio major:minor 3:1.4 MS (ES+) m/z. 352.2 (M+H)+

US 8,188,101 B2 141 142 Example 98c 2-(2-(4-Fluorophenyl)acetyl)-4-(trifluoromethyl)cyclo hexanone (75 mg, 0.25 mmol), 1-(4-(2-methyl-1H-imidazol tert-Butyl 3-(2-(2-fluorophenyl)acetyl)-4-oxopiperi 1-yl)phenyl)guanidine (53.4 mg., 0.25 mmol) and potassium dine-1-carboxylate carbonate (68.6 mg, 0.50 mmol) were added to a microwave vial. EtOH (3 mL) was added and the reaction was heated to 130° C. for 2 h. DCM (3 mL) and water (3 mL) were added. The organic phase was separated and the solvent was evapo rated. The product was purified by preparative HPLC yielding 4-(4-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phe 10 nyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroquinazolin-2- amine (30.0 mg, 25.1%). 1H NMR (500 MHz, CHLOROFORM-d) 8 ppm 1.72 15 1.84 (m, 1 H)2.22-2.30 (m, 1 H)2.43 (br. S., 3 H)2.47-2.54 (m. 1 H)2.61 (dd. 1 H)2.80-2.89 (m, 1 H)2.92-3.00 (m.2 H) 4.01 (s, 2 H) 7.04 (t, 3 H) 7.14-7.19 (m, 3 H) 7.23 (dd, 2 H) 7.67 (d. 2 H) Example 99a tert-Butyl 3-(2-(2-fluorophenyl)acetyl)-4-oxopiperidine 1-carboxylate (295 mg, 52%) was prepared from 2-(2-fluo 2-(2-(4-Fluorophenyl)acetyl)-4-(trifluoromethyl) rophenyl)acetyl chloride according to the general procedure cyclohexanone for the preparation of diketones. MS (ES-) m/z 334.1 (M-H)- 25 F Example 98d F O F 2-(2-Fluorophenyl)acetyl chloride 30 F

O 2-(2-(4-Fluorophenyl)acetyl)-4-(trifluoromethyl)cyclo C 35 hexanone (75 mg, 50%) was prepared from 4-fluoropheny lacetyl chloride according to the general procedure for the preparation of diketones. MS (ES+) m/z. 303.1 (M+H)+ Example 100 40 N-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phe 2-(2-Fluorophenyl)acetic acid, (1.7 mmol) was dissolved nyl)-4-(3-methoxybenzyl)-7,8-dihydro-5H-pyrano.4. in thionyl chloride (0.372 ml, 5.10 mmol) and heated to reflux 3-dipyrimidin-2-amine for 1 h. The reaction was cooled and the excess thionyl chlo ride was evaporated. The residue was instantly dissolved in 45 dry THF and refridgerated until used. No purity analysis or weighing were performed. Example 99 O 50 4-(4-Fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1- yl)phenyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydro quinazolin-2-amine S. 55 \l - - toN N 60 1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl) guanidine (85 mg, 0.35 mmol), 3-(2-(3-methoxyphenyl) acetyl)dihydro-2H-pyran-4(3H)-one (86 mg, 0.35 mmol) and potassium carbonate (47.9 mg, 0.35 mmol) in ethanol (2 mL) N 65 were heated to 60°C. over night. DCM and water were added and the organic phase was separated and the solvent was removed under reduced pressure. The crude product was puri US 8,188,101 B2 143 144 fied by preparative HPLC yielding N-(3-methoxy-4-(4-me thyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phe thyl-1H-imidazol-1-yl)phenyl)-4-(3-methoxybenzyl)-7,8- nyl)-7,8-dihydro-5H-pyrano.4.3-dpyrimidin-2-amine (8.00 dihydro-5H-pyrano.4.3-dpyrimidin-2-amine (10.00 mg. mg, 2%). 6%). 1H NMR (500 MHz, DMSO-d) 8 ppm 9.86 (s, 1 H) 8.11 MS (ES+) m/z 458.2 (M+H)+ 1H NMR (500 MHz, CHLOROFORM-d) 8 ppm 2.33 (s.3 (d. 1 H) 7.65 (d. 1 H) 7.40-7.45 (m.2 H) 7.37 (t, 3 H) 7.31 (d. H)2.88 (t, 2 H)3.80 (s.3 H)3.81 (s.3 H)3.89 (s. 2 H)4.02 1 H) 7.24-7.30 (m, 2 H) 7.18 (d. 1 H) 7.03 (s, 1 H) 5.36 (s, 1 (t, 2 H)4.68 (s, 2 H) 6.79-6.82 (m.2 H) 6.84 (d. 2 H) 6.89 (s. H)4.67-4.73 (m, 1 H)4.57 (d. 1 H)3.95 (dt, 5.62 Hz, 1 H) 1H) 7.06 (dd, 1 H) 7.16 (d. 1 H) 7.23 (s, 1 H) 7.66 (br. s. 1 H) 3.82-3.90 (m, 1 H)3.79 (s.3 H)3.35 (s, 4H)2.80-2.89 (m. 1 7.80 (d. 1 H) 10 H)2.72-2.79 (m, 1 H) 2.12-2.17 (m, 3 H) Example 100a 3-(2-(3-Methoxyphenyl)acetyl)dihydro-2H-pyran-4 Example 101 a (3H)-one 15 1-(1H-imidazol-1-yl)-2-methoxy-2-phenylethanone

O 25 Tetrahydro-4H-pyran-4-one (0.138 mL, 1.50 mmol) was N/ dissolved in toluene (1 mL) and cooled to 0° C. LHMDS (1.573 mL, 1.57 mmol) was added. 3-Methoxyphenylacetyl Di-(1H-imidazol-1-yl)methanone (1.073 g. 6.62 mmol) chloride (0.117 mL, 0.75 mmol) was added after 2 minutes. After 5 minutes, acetic acid (0.129 mL, 2.25 mmol) and water 30 was added in Small portions to a stirred solution of 2-meth was added. The organic phase was separated and the crude oxy-2-phenylacetic acid (1.047 g. 6.30 mmol) in dichlo product was purified by flash column chromatography romethane (3 mL) at room temperature under argon. The (EtOAc 0-40% in heptane) yielding 3-(2-(3-methoxyphenyl) reaction mixture was stirred at room temperature overnight. acetyl)dihydro-2H-pyran-4(3H)-one (86 mg, 46%). The mixture was washed twice with water, dried over MgSO MS (ES-) m/z, 247 (M-H)- 35 and concentrated yielding 1-(1H-imidazol-1-yl)-2-methoxy 2-phenylethanone (1.118 g. 82%). Example 101 1H NMR (400MHz, DMSO-d) 8 ppm 8.52-8.56 (m. 1 H), 4-(Methoxy(phenyl)methyl)-N-(3-methoxy-4-(4- 7.76 (t, 1H), 747-7.53 (m.2 H), 7.36-7.44 (m, 3 H), 7.06 (dd, methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H 40 1 H), 5.86 (s, 1 H), 3.38 (s, 3 H); (No correct MS was pyrano 4.3-dipyrimidin-2-amine obtained) Example 101b 45 3-(2-Methoxy-2-phenylacetyl) dihydro-2H-pyran-4 (3H)-one

50 -ClCIOC N1 N O 55 A reaction mixture of 1-(3-methoxy-4-(4-methyl-1H-imi dazol-1-yl)phenyl)guanidine (0.300 g, 0.81 mmol) and potas sium carbonate (0.337 g, 2.44 mmol) in ethanol (5 mL) was stirred at 50° C. for 5 minutes. 3-(2-methoxy-2-phenylacetyl) Lithium bis(trimethylsilyl)amide (2.024 mL, 10.78 mmol) dihydro-2H-pyran-4(3H)-one (0.161 g, 0.65 mmol) in etha 60 was added to a stirred solution of tetrahydro-4H-pyran-4-one nol (0.5 mL) was added dropwise to the reaction mixture and (0.948 mL, 10.27 mmol) in toluene (3 mL) at 0°C. After 2 the resulting mixture was stirred at 50° C. overnight. The minutes 1-(1H-imidazol-1-yl)-2-methoxy-2-phenylethanone Solvent was evaporated and the residue was partitioned (1.110 g, 5.13 mmol) was added and the mixture was stirred between water and dichloromethane. The water phase was at 0°C. for 5 minutes. The reaction was quenched with acetic extracted twice with dichloromethane. The combined organic 65 acid (0.882 mL, 15.40 mmol) in 5 mL water. The organic layer was dried over MgSO filtered, concentrated and puri layer was separated and concentrated. The crude product was fied by preparative HPLC yielding 4-(methoxy(phenyl)me purified by Silica flash chromatography using ethyl acetate (0 US 8,188,101 B2 145 146 to 40%) in heptane giving 3-(2-methoxy-2-phenylacetyl)di H)3.58 (td, 6.38 Hz, 1 H)3.06 (td, 3.78 Hz, 2 H) 1.95 (dddd, hydro-2H-pyran-4(3H)-one (0.245 g, 19%). MS (ES-) m/z. 8.45, 6.50, 5.28 Hz, 1 H) 1.75-1.89 (m, 4H) 1.41-1.51 (m. 1 247 (M-H)- H) MS (ES-) m/z 194 (M-H)- Example 102 Example 102b N-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phe nyl)-4-(2-(tetrahydrofuran-2-yl)ethyl)-7,8-dihydro 3-(3-(Tetrahydrofuran-2-yl)propanoyl)dihydro-2H 5H-pyrano 4.3-dipyrimidin-2-amine pyran-4(3H)-one 10

15

O

-Cl N1 N O Lithium bis(trimethylsilyl)amide (1.283 ml, 6.83 mmol) was added to a stirred solution of tetrahydro-4H-pyran-4-one CIOC (0.601 ml, 6.51 mmol) in toluene (3 mL) at 0° C. and the resulting mixture was stirred for 2 minutes. 1-(1H-imidazol 1-yl)-3-(tetrahydrofuran-2-yl)propan-1-one (0.632 g, 3.25 A reaction mixture of 1-(3-methoxy-4-(4-methyl-1H-imi 25 mmol) toluene (1 mL) was added and the reaction mixture dazol-1-yl)phenyl)guanidine (0.305 g, 0.83 mmol, example was stirred for 5 minutes before it was quenched with acetic 7c) and potassium carbonate (0.343 g, 2.48 mmol) in ethanol acid (0.559 ml, 9.76 mmol) in water (4 mL). The organic layer (3 mL) was stirred at 50° C. for 20 minutes under argon. was separated and purified by flash column chromatography 3-(3-(tetrahydrofuran-2-yl)propanoyl)dihydro-2H-pyran-4 (ethyl acetate in heptane, 0 to 40%) yielding 3-(3-(tetrahy (3H)-one (0.187 g. 0.83 mmol) was added dropwise (neat) 30 drofuran-2-yl)propanoyl)dihydro-2H-pyran-4(3H)-one (117 over 2 hours and stirred at 50° C. overnight. The solvent was mg, 16%). evporated and the residue was partitioned between water and 1H NMR (500 MHz, DMSO-d) 8 ppm 4.31-438 (m, 1 H) dichloromethane. The water phase was extracted twice with 3.94-4.06 (m, 1 H)3.74-3.78 (m.2 H)3.68-3.74 (m.2 H)3.56 dichloromethane. The combined organic layer was dried over (td, 6.31 Hz, 1 H) 2.54-2.62 (m, 1 H) 2.34–2.45 (m, 3 H) MgSO filtered and concentrated. 4 of the crude was puri 35 1.85-196 (m, 1 H) 1.73-1.85 (m, 2 H) 1.58-1.71 (m, 2 H) fied by preparative HPLC and concentrated. The residue was 1.33-1.45 (m, 1 H) partitioned between NaHCO (aq) and dichloromethane and MS (ES-) m/z 225 (M-H)- the the water phase was extracted twice with dichlo romethane, dried (MgSO4) and concentrated giving 4 mg of Example 103 the product. 40 2-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl) MS (ES+) m/z 436 (M+H)+ phenylamino)-7,8-dihydro-5H-pyrano 4.3-dpyrimi Example 102a din-4-yl)propan-2-ol 1-(1H-Imidazol-1-yl)-3-(tetrahydrofuran-2-yl)pro 45 pan-1-one

O 50

55 Methylmagnesium bromide (0.769 mL, 0.77 mmol) was Di-(1H-imidazol-1-yl)methanone (0.554 g, 3.42 mmol) added at 0° C. to a solution of ethyl 2-(3-methoxy-4-(4- was added in small portions to a stirred solution of 3-(tetrahy methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydro-5H drofuran-2-yl)propanoic acid (0.469 g, 3.25 mmol) in dichlo pyrano.4.3-dpyrimidine-4-carboxylate (150 mg, 0.37 romethane (3 mL) at room temperature under argon. The 60 mmol) in dry THF (5 mL). 4 eq extra equivalents of methyl reaction mixture is stirred at room temperature for 2 hours. magnesium bromide were added over 2 h. The crude product The mixture was washed twice with water, dried over MgSO was partitioned between DCM and water. The organic phase and concentrated resulting a quantitative yield of 1-(1H-imi was separated and the solvent was evaporated. The crude dazol-1-yl)-3-(tetrahydrofuran-2-yl)propan-1-one (632 mg, product was purification on a prepHPLC affording 2-(2-(3- 100%). 65 methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8- 1H NMR (500 MHz, DMSO-d) & ppm 8.43 (s, 1 H) 7.71 dihydro-5H-pyrano 4.3-dipyrimidin-4-yl)propan-2-ol (t, 1 H) 7.06 (d. 1 H)3.76-3.85 (m, 1 H)3.72 (td, 6.15 Hz, 1 (11.00 mg, 7.59%). MS (ES+) m/z 396.2 (M+H)+;

US 8,188,101 B2 149 150 Example 104b Example 106 2-(3,5-Dimethyl-1H-pyrazol-1-1)propanoyl chloride 4-Benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol 5 1-yl)phenyl)-5,6,7,8-tetrahydropyrido4,3-dipyrimi din-2-amine

10

C

15

tert-Butyl 4-benzyl-2-(3-methoxy-4-(4-methyl-1H-imida Zol-1-yl)phenylamino)-7,8-dihydropyrido4.3-dpyrimi 2-(3,5-Dimethyl-1H-pyrazol-1-yl)propanoyl chloride was dine-6(5H)-carboxylate (1.0 g, 1.90 mmol) was dissolved in synthesised from 243,5-dimethyl-1H-pyrazol-1-yl)pro methanol (10 mL). Hydrochloric acid (0.156 mL, 1.90 mmol) panoic acid (0.5 g, 2.97 mmol) using reaction conditions 25 was added and the reaction mixture was stirred at 80°C. for 1 similar to the procedure described in example 98a. h. The solvent was evaporated under reduced pressure and the Example 105 crude was used in the subsequent step as such. MS (ES+) m/z. 2-(4-Benzyl-2-(3-methoxy-4-(4-methyl-1H-imida 427.0 (M+H)+ Zol-1-yl)phenylamino)-7,8-dihydropyrido4.3-d 1H NMR (500 MHz, MeOD) 8 ppm 2.42 (s.3 H)3.10 (t, 2 pyrimidin-6(5H)-yl)acetonitrile 30 H) 3.56 (t, 2 H) 3.85 (s, 3 H) 4.09 (s. 2 H)4.27 (s, 2 H) 723-7.38 (m, 6H) 742-746 (m. 1 H) 7.50 (s, 1 H) 7.92 (d. 1 H) 9.04 (d. 1 H)

35 Example 106a

tert-Butyl 4-benzyl-2-(3-methoxy-4-(4-methyl-1H imidazol-1-yl)phenylamino)-7,8-dihydropyrido4.3- 40 dpyrimidine-6(5H)-carboxylate

45

50

Bromoacetonitrile (0.031 mL, 0.45 mmol) was added to a solution of 4-benzyl-N-(3-methoxy-4-(4-methyl-1H-imida Zol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido4.3-dpyrimidin 55 1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl) 2-amine (175 mg, 0.41 mmol. Example 106) and TEA (0.063 mL, 0.45 mmol) in THF (3 mL). The solution was stirred at guanidine (300 mg, 1.22 mmol, example 43a), tert-butyl RT for 2 hours. Solvent was evaporated and the crude product 4-oxo-3-(2-phenylacetyl)piperidine-1-carboxylate (466 mg, was purified on a prepHPLC yielding 2-(4-benzyl-2-(3-meth 1.47 mmol, example 41 d) and sodium ethoxide (83 mg, 1.22 oxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihy 60 mmol) in ethanol (4 mL) were heated at 100°C. in a micro dropyrido4,3-dipyrimidin-6(5H)-yl)acetonitrile (72.0 mg. wave reactor for 20 minutes. The reaction mixture was 37.7%). MS (ES+) m/z. 466.3 (M+H)+ allowed to reach room temperature and the solvent was 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 2.30 (s.3 evaporated under reduced pressure. The crude was dissolved H)2.89-2.98 (m, 4H)3.68 (s, 2 H)3.73 (s, 2 H)3.76 (s.3 H) in ethylacetate and washed with water. The organic phase was 3.97 (s, 2 H) 6.86 (s, 1 H) 7.00-7.05 (m, 1 H) 7.09-7.13 (m. 1 65 dried under MgSO and the solvent was evaporated under H) 722-7.26 (m, 3 H) 7.29-7.38 (m, 3 H) 7.63 (d. 1 H) 7.72 (d. reduced pressure yielding tert-butyl 4-benzyl-2-(3-methoxy 1H) 4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydro

US 8,188,101 B2 153 154 (196 mg, 1.42 mmol) in EtOH (7 mL) were heated to 50° C. purification on prepHPLC was performed to afford the title and tert-butyl 3-(2-(3,5-dimethyl-1H-pyrazol-1-yl)pro compound (83 mg, 16% yield). panoyl)-4-oxopiperidine-1-carboxylate (248 mg, 0.71 mmol) added. The reaction mixture was stirred overnight. The sol 1H NMR (500 MHz, CHLOROFORM-d) 8 ppm 1.53-1.62 vent was evaporated and DCM added. The organic phase was (m.2 H) 1.70-1.80 (m, 6H)2.32 (s.3 H)2.91 (t, 2 H)3.87 (s, washed with water and concentrated. The crude product was 3 H)4.01 (dt, 1H)4.05 (t, 2H)4.41 (s, 2 H)4.80 (s. 2H)6.88 used as such in next step (450 mg, 113%). (s, 1 H) 7.06 (dd, 1 H) 7.14 (s, 1 H) 7.17 (d. 1 H) 7.68 (s, 1 H) MS (ES+) m/z 559.2 (M+H)+ 7.80 (d. 1 H) Example 108c 10 Example 109a tert-Butyl 3-(2-(3,5-dimethyl-1H-pyrazol-1-yl)pro 3-(2-(Cyclopentyloxy)acetyl) dihydro-2H-pyran-4 panoyl)-4-oxopiperidine-1-carboxylate (3H)-one 15

( 1s.N 1. 25 2-(Cyclopentyloxy)acetic acid (476mg, 3.3 mmol) was tert-Butyl 3-(2-(3,5-dimethyl-1H-pyrazol-1-yl)pro 30 heated to reflux in thionyl chloride (0.365 ml, 5.00 mmol). panoyl)-4-oxopiperidine-1-carboxylate (0.248 g, 23.87% After 30 min the excess of thionyl chloride was evaporated to yield) was synthesised from 2-(3,5-dimethyl-1H-pyrazol-1- afford (2-(cyclopentyloxy)acetyl chloride (3.3 mmol) that yl)propanoyl chloride (0.5g, 2.97 mmol, example 104b) and was used directly in the next step. tert-butyl 4-oxopiperidine-1-carboxylate (1.185 g, 5.95 3-(2-(cyclopentyloxy)acetyl)dihydro-2H-pyran-4(3H)- mmo) by the general procedure for the preparation of dike 35 one (280 mg, 21.5%) was synthesised from dihydro-2H-py tOneS. ran-4(3H)-one (0.462 ml, 5.00 mmol) and (2-(cyclopenty MS (ES-) m/z 348.7 (M-H)- loxy)acetylchloride (3.3 mmol) by the general procedure for Example 109 the preparation of diketones. 40 MS (ES-) m/z 225.1 (M-H)- 4-(Cyclopentyloxymethyl)-N-(3-methoxy-4-(4-me Example 110 thyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H pyrano 4.3-dipyrimidin-2-amine 1-(2-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl) phenylamino)-7,8-dihydro-5H-pyrano 4.3-dpyrimi 45 din-4-yl)ethyl)pyrrolidin-2-one

O s O --> N N S. Yu- So N N - N - Yu-N N1 N O H

N - N - 3-(2-(Cyclopentyloxy)acetyl)dihydro-2H-pyran-4(3H)- 60 H one (280 mg, 1.24 mmol), 1-(3-methoxy-4-(4-methyl-1H imidazol-1-yl)phenyl)guanidine (1 equiv.) and potassium 1-(3-oxo-3-(4-oxotetrahydro-2H-pyran-3-yl)propyl)pyr carbonate (2 equiv.) were heated to 50° C. over night in EtOH rolidin-2-one (202 mg 0.84 mmol), 1-(3-methoxy-4-(4-me (5 mL). The crude product was extracted into DCM, the thyl-1H-imidazol-1-yl)phenyl)guanidine (1 equiv.) and organic phase collected and solvent evaporated. The crude 65 potassium carbonate (2 equiv.) were heated to 50° C. over product was purified by flash chromatography (0-100% night in EtOH (5 mL). The crude product was extracted into EtOAc in Heptane). The purity was not satisfactory so further DCM and solvent was evaporated. The crude product was

US 8,188,101 B2 157 158 Example 111b Lithium bis(trimethylsilyl)amide (2.231 ml, 11.88 mmol) was added to a stirred solution of tert-butyl 4-oxopiperidine tert-Butyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1- 1-carboxylate (1.127 g. 5.66 mmol) in toluene (3 mL) at 0°C. yl)phenylamino)-4-(2-(tetrahydrofuran-2-yl)ethyl)-7, and the resulting mixture was stirred for 2 minutes. 1-(1H 8-dihydropyrido4.3-dpyrimidine-6(5H)-carboxy 5 Imidazol-1-yl)-3-(tetrahydrofuran-2-yl)propan-1-one (1.099 g, 5.66 mmol) in toluene (1 mL) was added and the reaction late mixture was stirred for 5 minutes before it was quenched with acetic acid (0.972 ml, 16.97 mmol) in water (4 mL). The organic layer was separated and purified by silica flash chro matography using a gradient of ethyl acetate in heptane (0 to 10 40%) giving tert-butyl 4-oxo-3-(3-(tetrahydrofuran-2-yl)pro panoyl)piperidine-1-carboxylate (0.717 g. 38.9%) as the product. 1H NMR (400 MHz, DMSO-d) 8 ppm 4.12 (s, 1 H)3.81 (br. s. 1 H)3.68-3.77 (m, 2 H)3.56-3.64 (m, 5 H)3.44-3.51 15 (m. 1 H)2.37-2.43 (m, 1 H)2.33-2.36 (m, 4H) 1.85-1.98 (m, / 2H) 1.74-1.85 (m, 3 H) 1.59-1.74 (m.2 H) 1.47-159 (m, 1 H) o / 1.42 (s, 9 H) 1.41 (s, 7 H) 1.40 (s, 2 H) 1.20-1.28 (m, 2 H) 0.81-0.90 (m, 2 H); MS (ES-) m/z 324 (M-H)-. N-N >ss Example 111d N H 1-(1H-Imidazol-1-yl)-3-(tetrahydrofuran-2-yl)pro pan-1-one A reaction mixture of 1-(3-methoxy-4-(4-methyl-1H-imi dazol-1-yl)phenyl)guanidine (0.800g, 2.17 mmol), tert-butyl 4-oxo-3-(3-(tetrahydrofuran-2-yl)propanoyl)piperidine-1- 25 carboxylate (0.705 g, 2.17 mmol) and potassium carbonate O (0.599 g, 4.33 mmol) in ethanol (6 mL) was stirred at 60° C. overnight. The reaction mixture was transferred to a micro wave vial (20 mL) and run in the microwave at 120°C. for 45 30 minutes. The reaction mixture was filtered and washed with dichloromethane. The filtrate was concentrated and the resi due was dissolved in dichloromethane and washed with Di(1H-imidazol-1-yl)methanone (1.196 g, 7.38 mmol) water, dried (MgSO) and concentrated. The crude product was added in small portions to a stirred solution of 3-(tetrahy was purified by silica flash chromatography using a gradient 35 drofuran-2-yl)propanoic acid (1.013 g, 7.03 mmol) in dichlo of methanol in dichloromethane (0 to 4%) giving tert-butyl romethane (3 mL) at room temperature under argon. The 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny reaction mixture was stirred at room temperature for 2 hours. lamino)-4-(2-(tetrahydrofuran-2-yl)ethyl)-7,8-dihydropy The mixture was washed twice with water, dried over MgSO rido4.3-dpyrimidine-6(5H)-carboxylate (0.335 g, 28.9%) and concentrated giving 1-(1H-imidazol-1-yl)-3-(tetrahydro as the product. 40 furan-2-yl)propan-1-one (1.099 g, 81%) as the product. 1H NMR (500 MHz, DMSO-d) 8 ppm 8.34-8.51 (m. 1 H), 1H NMR (500 MHz, DMSO-d) & ppm 9.68 (s, 1 H) 8.03 7.64-7.79 (m, 1 H), 6.98-7.17 (m, 1 H), 3.76-3.85 (m, 1 H), (s, 1 H) 7.64 (s, 1 H) 7.27-7.29 (m, 1 H) 7.19-7.21 (m, 1 H) 3.66-3.76 (m, 1 H), 3.55-3.60 (m, 1 H), 3.03-3.10 (m, 2 H), 7.02 (s, 1 H)4.44 (br.s.,2H)4.05-4.01 (m, 1 H)3.81-3.84 (m, 1.90-2.00 (m, 1 H), 1.73-1.90 (m, 4H), 1.39-1.53 (m, 1 H): 1 H) 3.80 (s, 3 H) 3.74-3.79 (m, 1 H) 3.59-3.65 (m, 3 H) MS (ES-) m/z 194 (M-H)-. 2.75-2.77 (m.2 H)2.66-2.72 (m. 1 H)2.58-2.62 (m, 1 H)2.14 45 (s, 3 H), 1.86-1.92 (m, 2 H) 1.78-1.86 (m, 2 H) 1.44 (s, 9 H) Example 112 1.16-1.19 (m, 1 H); MS (ES+) m/z 535 (M+H)+. N-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phe Example 111c nyl)-6-methyl-4-(2-(tetrahydrofuran-2-yl)ethyl)-5.6, 50 7,8-tetrahydropyrido4.3-dpyrimidin-2-amine tert-Butyl 4-oxo-3-(3-(tetrahydrofuran-2-yl)pro panoyl)piperidine-1-carboxylate

55

60

65 US 8,188,101 B2 159 160 N-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4- Example 113a (2-(tetrahydrofuran-2-yl)ethyl)-5,6,7,8-tetrahydropyrido4. 3-dipyrimidin-2-amine (0.133 g, 0.31 mmol. Example 114a). formaldehyde (8.43 uL, 0.31 mmol) and acetic acid (8.76 uL. 3-(2-(1,3-Difluoropropan-2-yloxy)acetyl) dihydro 0.15 mmol) in methanol (4 mL) was stirred at room tempera 2H-pyran-4(3H)-one ture for 20 minutes. Polymer supported cyanoborohydride (0.46g, 0.92 mmol) was added and the reaction mixture was stirred at room temperature overnight. The polymer Sup ported cyanoborohyride was filtered off and the filtrated was purified by preparative chromatography. The product con 10 taining fractions were pooled and the solvent was evaporated. The residue was dissolved in waterfacetonitrile-mixture (50: 50) and freezedried giving N-(3-methoxy-4-(4-methyl-1H imidazol-1-yl)phenyl)-6-methyl-4-(2-(tetrahydrofuran-2-yl) ethyl)-5,6,7,8-tetrahydropyrido4.3-dpyrimidin-2-amine 15 (0.055 g, 40.1%). 1H NMR (400 MHz, DMSO-d) & ppm 9.60 (s, 1 H) 8.06 (s, 1 H) 7.64 (s, 1 H) 722-7.30 (m, 1 H) 7.14-7.22 (m, 1 H) 2-(1,3-Difluoropropan-2-yloxy)acetic acid (0.382 g, 2.48 7.02 (s, 1 H)3.72-3.82 (m, 5 H)3.57-3.63 (m, 1 H)3.41-3.43 mmol) in 1,2-dichloroethane (8 mL) was treated with thionyl (m.2 H)2.77-2.80 (m.2 H)2.63-2.67 (m, 3 H)2.62-2.57 (m, chloride (0.542 mL, 7.44 mmol) and set under N atmo 1 H) 2.39 (s.3 H) 2.10-2.16 (m, 3 H) 1.92-2.01 (m, 2 H) sphere. The mixture was stirred for 1 hour at 45° C. then 1.74-1.89 (m, 3 H) 1.34-1.52 (m, 1 H); MS (ES+) m/z 449 concentrated in vacuo. The crude oil was used in the next step without further purification. (M+H)+. 25 At 0°C., the toluene (5 mL) solution of tetrahydro-4H Example 113 pyran-4-one (0.344 mL, 3.72 mmol) was treated with LiH MDS, 1M solution in THF (3.97 mL, 3.97 mmol) under N atmosphere. After 2 minutes 2-(1,3-difluoropropan-2-yloxy) 4-((1,3-Difluoropropan-2-yloxy)methyl)-N-(3-meth 30 acetyl chloride (428 mg, 2.48 mmol) in toluene (1 mL) was oxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihy added. After 5 minutes, acetic acid (0.270 mL, 4.71 mmol) dro-5H-pyrano.4.3-dipyrimidin-2-amine and 10 ml water were added. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, fil 35 tered and concentrated. The solvent was removed in vacuo and the residual oil was purified by silica flash chromatogra phy (EtOAc/Heptane gradient) to afford the title product (0.095 g, 16% yield).

40 MS (ES") m/z 237 M+1). Example 113b

45 2-(1,3-Difluoropropan-2-yloxy)acetic acid

Potassium carbonate (222 mg, 1.61 mmol) was added to 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guani 50 dine (149 mg, 0.40 mmol) in DMF (1 mL) and set under N atmosphere. The DMF (1 mL) solution of 3-(2-(1,3-difluoro propan-2-yloxy)acetyl)dihydro-2H-pyran-4(3H)-one (95 mg, 0.40 mmol) was added dropwise to the reaction mixture and stirred for 16 hours at 50° C. The reaction mixture was 55 cooled to room temperature and filtered. The filtrate was concentrated and the crude product was purified by silica Benzyl 2-(1,3-difluoropropan-2-yloxy)acetate (0.91 g, flash chromatography using a gradient of methanol indichlo romethane (0 to 4%) affording the title compound (120 mg. 3.73 mmol) was dissolved in THF (14 mL)/water (7 mL) 60 mixture and treated with lithium hydroxide monohydrate 67% yield). (0.469 g, 11.18 mmol) and allowed to stirfor 16 hours at room MS (ES") m/z 446 M+1). temperature. The mixture was concentrated, redissolved in "H NMR (400 MHz, CDC1,) 8 (8 ppm) 7.81 (d. 2 H) water and extracted with ethyl acetate. The aqueous phase 7.14-7.23 (m, 2 H) 7.09 (dd. 1 H) 6.91 (s, 1 H)4.82 (s, 2 H) was treated with 2M HCl and NaCl then extracted with ethyl 4.66 (s, 2 H)4.58-4.65 (m, 2 H)4.45-4.57 (m.2 H)4.06 (t, 2 65 acetate (3x). The organic layer was dried over anhydrous H)3.90-4.05 (m, 1 H)3.88 (s.3 H)2.84-3.01 (m.2 H)2.36 (s, sodium sulfate, filtered and concentrated to afford the title 3 H). product (0.388 g. 67% yield). US 8,188,101 B2 161 162 H NMR (400 MHz, CDC1) & (ppm) 4.63-4.70 (m, 2 H) Total no of protons in spectrum: 23 4.50-4.59 (m, 2 H)4.38 (s, 2 H)3.90-4.06 (m, 1 H). Ratio major:minor: 1:1 Example 113c Example 114a Benzyl 2-(1,3-difluoropropan-2-yloxy)acetate 4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)- 7,8-dihydro-5H-thiopyrano 4.3-dpyrimidin-2-amine luoO 10 Crs rF 15 CC, C Sodium tert-butoxide (0.923 g, 9.60 mmol) in DMF (20 mL)/THF (12 mL) mixture was cooled down to 0°C. and set under N atmosphere. 1,3-Difluoropropan-2-ol (0.717 mL, --- 9.25 mmol) was added via syringe and stirred for 40 min then benzyl 2-bromoacetate (1.373 mL, 8.73 mmol) was added 4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8- dropwise via syringe and the mixture was stirred at rt for 16 dihydro-5H-thiopyrano 4.3-dipyrimidin-2-amine (74 mg. hours. Ethylacetate and sat NaHCO, solution were added and 28%) was synthesised from 3-(2-phenylacetyl)dihydro-2H the phases were separated. The aqueous layer was extracted thiopyran-4(3H)-one and 1-(4-(2-methyl-1H-imidazol-1-yl) with ethyl acetate and the combined organic layer was dried 25 phenyl)guanidine (Example 41c) according to the general over anhydrous sodium sulfate, filtered and concentrated. The procedure for the synthesis of pyrimidines. MS (ES+) m/z. crude oil was purified by silica gel chromatography (heptane/ 414.2 (M--H)+ EtOAc gradient) to afford the title compound (0.91 g, 43% yield). Example 114b MS (ES") m/z 245 M+1). 30 "H NMR (400 MHz, CDC1) & (ppm) 7.30-7.46 (m, 5 H) 3-(2-Phenylacetyl)dihydro-2H-thiopyran-4(3H)-one 5.21 (s, 2 H)4.66 (d. 2H)4.54 (d. 2H)4.35 (s.2H)3.84-4.07 (m. 1 H). Example 114 35 4-Benzyl-N-4-(2-methyl-1H-imidazol-1-yl)phenyl 7,8-dihydro-5H-thiopyrano.4.3-dpyrimidin-2-amine 6-oxide 40 O 3-(2-Phenylacetyl)dihydro-2H-thiopyran-4(3H)-one (291 mg, 83%) was synthesised from 2-phenylacetyl chloride and 45 dihydro-2H-thiopyran-4(3H)-one according to the general N procedure for the preparation of diketones. MS (ES-) m/z. 233 (M-H)- Assays C. C. The level of activity of the compounds on AB release was tested using the following method: OC Compounds were diluted in 100% DMSO and stored at 20° C. prior to use. Human Embryonic Kidney (HEK) or Human Neuroblastoma (SH-SY5Y) cell lines stably expressing APP 4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8- with the Swedish mutation (APPswe) were cultured using dihydro-5H-thiopyrano.4.3-dpyrimidin-2-amine (90 mg. 55 Dulbecco's Modified Eagles medium (DMEM) supplied 0.22 mmol) and mOPBA (56.3 mg, 0.33 mmol) was dissolved with 4500 g/lglucose, Na-pyruvate and GlutaMAX with 10% in DCM (4 mL). The reaction was completed after 2 h. The FBS, 100 U/ml penicillin-streptomycin (PEST) respectively, Solvent was evaporated and the crude product was purified on 1x non-essential amino acids (NEAA), 10 uM Hepes, 100 preparative HPLC yielding 4-benzyl-N-4-(2-methyl-1H ug/ml Zeocine. Cells at about 80% confluence were washed imidazol-1-yl)phenyl-7,8-dihydro-5H-thiopyrano.4.3-d 60 with PBS, detached from culture flasks using 1x Trypsin/ pyrimidin-2-amine 6-oxide (13.0 mg, 13.0%). MS (ES+) m/z. EDTA diluted in PBS, re-suspended in cell media and plated 430.0 (M+H)+ in 384-well poly-d-lysine coated cell culture plates at about Mixture of Rotamers: 10000-15000 cells/well, in 25 uL cell media. Optionally, 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 2.38 (s), cryo-preserved cells (frozen and stored at -140°C. in 90% 2.92-3.01 (m), 3.04 (t), 3.09 (t), 3.25-3.33 (m), 3.58 (ddd), 65 cell media and 10% DMSO) were thawed, washed and plated 3.72-3.81 (m), 3.91-3.98 (m), 4.02-4.13 (m), 7.00 (s), 7.06 as above. Next the cells were incubated for 15-24 h at 37° C. (s), 7.17-7.41 (m), 7.69-7.75 (m), 7.83 (s) and 5% CO, after which cell medium was changed. Fresh US 8,188,101 B2 medium containing test compound diluted X200 from pre- TABLE 1-continued pared compound plate was added to the cells before further incubation for 4-6 hours at 37° C. and 5% CO. After incu- Example number pIC50 bation with test compound the amount of AB peptides, includ- 59 6.4 ing AB42, AB40, AB39, AB38 and AB37, secreted to the cell 5 60 6.3 medium was analyzed using the electrochemiluminescence 61 S.O assay technology from Meso Scale Discovery Technology, in g i g combination with specific antibodies raised against the dif- 64 6.0 ferent A? peptides. Potential cytotoxic effects of the com- 65 6.5 pounds were usually assayed by measuring the ATP content 10 66 5.9 (ViaLight) from cell lysate. 3. 59 Results 69 64 Typical ICs values of AB42 release for the compounds of 70 6.2 the present invention are in the range of about 1 to about 71 6.6 16000 nM. Biological data on final compounds are given 15 7. below in Table 1. 74 6.O 75 7.6 TABLE 1. 76 6.3 77 6.2 Example number IC50 78 6.O p p 2O 79 5.9 1 6.O 8O 6.8 2 6.4 81 6.6 3 6.O 82 6.5 4 6.5 83 6.8 5 6.O 84 6.8 6 5.9 25 85 6.6 7 7.0 86 6.3 8 7.1 87 6.5 9 5.8 88 6.4 10 6.3 89 6.2 11 6.4 90 6.2 12 5.4 30 91 S.6 13 5.5 92 5.3 14 6.9 93 5.2 15 6.4 94 5.3 16 6.2 95 7.4 17 5.8 96 7.2 18 S.6 35 97 6.2 19 6.1 98 6.1 2O 6.O 99 6.5 21 5.9 1OO 7.0 22 6.4 101 7.3 23 5.2 102 6.9 24 6.6 40 103 7.0 25 6.1 104 6.7 26 6.9 105 7.8 27 6.5 106 7.2 28 6.1 107 7.6 29 6.2 108 6.3 30 6.O 109 7.7 31 6.1 45 110 S.6 32 6.1 111 6.6 33 5.9 112 6.9 34 5.5 113 35 5.5 114 5.8 36 5.3 37 S.O 50 38 6.4 39 6.8 The invention claimed is: 3. 2. 1. A compound orpharmaceutically acceptable Salt thereof 43 72 of formula (Ia) 44 7.1 55 45 6.2

46 5.8 (Ia) 47 7.1 48 6.7 49 6.6 50 6.6 51 6.6 60 52 6.5 53 6.5 S4 6.5 55 6.5 56 6.4 57 6.4 65 wherein: 58 6.7 R" is selected from phenyl substituted in the para position by a heteroaryl group and wherein the phenyl group and US 8,188,101 B2 165 166 the heteroaryl group are optionally and independently Calkoxy Substituted C-alkanoyl, C-carbocyclyl substituted by one to three R' groups; carbonyl, (Calkyl)carbamoyl, Calkylsulfonyl, R’ is Y R7; and C-alkoxycarbonyl. Y is C(R')(R') , N(R) - O - C(R) 3. A compound or salt thereof of formula (Ia) (R') N(R) , N(R) C(R'2)(R') , C(R) (R') O , or O C(R')(R') : R" is selected from halogen, Calkyl, halogenated (Ia) Calkyl, Calkoxy, halogenated Calkoxy. R is selected from hydrogen, C-calkyl, halogenated Calkyl and C-carbocyclyl, wherein said Calkyl, 10 is optionally and independently substituted with one to three substituents selected from cyano, hydroxy or het erocyclyl, R’ is selected from hydrogen, aryl, heteroaryl, Calky 15 laryl, Calkylheteroaryl, C-alkylheterocyclyl, halo wherein: genated C1-alkyl, C-alkyl and C3-carbocyclyl, R" is selected from 3-methoxy-4-(4-methylimidazol-1-yl) wherein said aryl, heteroaryl, C-alkyl or carbocyclyl is phenyl, 4-(1-methylpyrazol-4-yl)phenyl, 4-(2-meth optionally and independently substituted with one to ylimidazol-1-yl)phenyl, or 4-oxazol-5-ylphenyl: three hydroxy, alkoxy, cyano, hydroxyalkyl, C(O)Cl. R’ is selected from the group consisting of 2-fluoro-1- alkyl or R' groups, wherein said C(O)C-alkyl is (fluoromethyl)ethoxymethyl, (2-fluorophenyl)methyl, optionally substituted with hydroxy; or (2-hydroxy-2-phenyl-ethyl)-methyl-amino, (2R)-2- Rand R may, when Y is NR, optionally form together (hydroxymethyl)indolin-1-yl, (2S)-2-(hydroxymeth with the nitrogenatom a saturated, partially Saturated or ylindolin-1-yl, (3-acetylphenyl)amino, (3-methoxyphe unsaturated ring system containing one nitrogenatomas 25 nyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenyl)- a heteroatom, wherein said ring system is optionally and methyl-amino.(2R)-norbornan-2-yl)amino, (2R)- independently substituted by one to three R' groups tetrahydrofuran-2-yl)methylamino, (2S)- R'' and R' are independently selected from Calkyl, tetrahydrofuran-2-yl)methylamino. 1-(hydroxymethyl) halogenated Calkyl, Calkoxy, halogenated cyclopentyl)amino. 2-(hydroxymethyl)phenylmethyl Calkoxy. 30 methyl-amino.3-(hydroxymethyl)phenylamino. 1-(3. Z is N (R): 5-dimethylpyrazol-1-yl)ethyl, 1-hydroxy-1-methyl R is selected from hydrogen, Calkyl, cyano substituted ethyl, 1-phenylethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, Coalkyl, halogenated C-alkyl, C-alkanoyl, 2-(3-fluorophenyl)ethyl, 2-(hydroxymethyl)-1-pip hydroxy Substituted Calkanoyl, dialkylamino Substi eridyl, 2-cyanoethyl-cyclopropyl-amino, 2-cyclohexyl tuted Calkanoyl, Calkoxy substituted Cal 35 ethyl, 2-hydroxyethyl-phenyl-amino, 2-tetrahydrofu kanoyl, C-carbocyclyl-carbonyl, (Calkyl)carbam ran-2-ylethyl, 3-(hydroxymethyl)-1-piperidyl, 4.4- oyl, Calkylsulfonyl, and Calkoxycarbonyl: difluoro-1-piperidyl, benzyl, benzyl-(2-hydroxyethyl) provided that compounds according to formula (Ia), amino, benzylamino, benzyloxy, cyclohexylamino, wherein Y is NR, Z is N-(R), R is hydrogen, alkyl 40 cyclohexyl-methyl-amino, cyclopentoxymethyl, cyclo or cycloalkyl, and R is arylalkyl are excluded. pentylmethyl, ethyl-(tetrahydrofuran-2-ylmethyl) 2. A compound or salt thereof according to claim 1 wherein amino, indolin-1-yl, methoxy-phenyl-methyl, methyl R"is selected from phenyl substituted in the para position by (2-pyridylmethyl)amino, methyl-(3-pyridylmethyl) a heteroaryl group and wherein the phenyl group is further amino, p-tolylmethyl, tetrahydropyran-4-ylmethyl, and optionally Substituted with a Calkoxy group or a haloge 45 tetrahydropyran-4-ylmethylamino; nated C-alkoxy group and the heteroaryl group is optionally Z is N-(R); and Substituted by a Calkyl group or a halogenated Calkyl R is selected from the group consisting of hydrogen, group; (2S)-2-hydroxypropanoyl, 2-dimethylaminoacetyl, R’ is Y R7; 2-hydroxyacetyl, 2-hydroxyethyl, 2-methoxyacetyl, Y is C(R')(R') or C(R)(R') O : 50 acetyl, cyanomethyl, cyclopropanecarbonyl, dimethyl R’ is selected from hydrogen, aryl, heteroaryl, Calky carbamoyl, ethoxycarbonyl, ethylsulfonyl, methoxycar laryl, Calkylheteroaryl, Calkylheterocyclyl, bonyl, methyl, methylsulfonyl, propanoyl, and propyl. Calkyl, halogenatedC-alkyl and C-carbocyclyl, 4. A compound selected from the group consisting of wherein said aryl, heteroaryl, Calkylaryl, Calkyl, 2-((2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydro halogenatedCalkyl or carbocyclyl is optionally Sub 55 pyrido4.3-dpyrimidin-4-yl)(phenyl)amino)ethanol: stituted with one substituent selected from hydroxy, 2-((6-methyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tet alkoxy, cyano, Calkyl, halogenated Calkyl and rahydropyrido4.3-dipyrimidin-4-yl)(phenyl)amino) C(O)Calkyl, wherein said C(O)Calkyl is option ethanol: ally substituted with hydroxy: N2-(4-(oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahy R'' and R' independently independently selected from 60 dropyrido4.3-dpyrimidine-2,4-diamine; Calkyl, halogenated Calkyl, Calkoxy, haloge 6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8- nated Calkoxy: tetrahydropyrido4.3-dpyrimidine-2,4-diamine; Z is N (R): N4-benzyl-N2-(4-(oxazol-5-yl)phenyl)-5,6,7,8-tetrahy and dropyrido4.3-dpyrimidine-2,4-diamine; R’ is selected from hydrogen, Calkyl, cyano substituted 65 N2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)- Calkyl, Calkanoyl, hydroxy Substituted Cal N4-phenyl-5,6,7,8-tetrahydropyrido4.3-dpyrimidine kanoyl, dialkylamino Substituted Calkanoyl, 2,4-diamine;