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Title:
FUSED MORPHLINOPYRIMIDINES AND METHODS OF USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2015/066696
Kind Code:
A1
Abstract:
The present invention relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.

Inventors:
BURNETT DUANE A (US)
BURSAVICH MATTHEW GREGORY (US)
MCRINER ANDREW J (US)
Application Number:
PCT/US2014/063878
Publication Date:
May 07, 2015
Filing Date:
November 04, 2014
Export Citation:
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Assignee:
FORUM PHARMACEUTICALS INC (US)
International Classes:
A61K31/5383; A61P25/28; C07D498/04
Foreign References:
US20100298359A12010-11-25
US20110201605A12011-08-18
US20130165462A12013-06-27
US20090069287A12009-03-12
Attorney, Agent or Firm:
BARBIC, Andrej et al. (60 State StreetBoston, MA, US)
Download PDF:
Claims:
We claim:

1. A compound of Formula (I)

(I)

or a pharmaceutically acceptable salt thereof,

wherein:

R is phenyl, -C1-C4 alkylene-phenyl or -Ci-C6 alkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -CN, - NH2, -C1-C4 alkyl, halo-substituted C1-C4 alkyl, amino-substituted C1-C4 alkyl, -NH-C1-C4 alkyl, -NHC(0)-Ci-C4 alkyl, -C(0)N(Ci-C4 alkyl)2, -C(0)NH-Ci-C4 alkyl, -C(0)N(Ci-C4 alkyl)2, hydroxy-substituted C C4 alkyl, -S(0)2-C C4 alkyl, -S(0)2-halo-substituted C C4 alkyl, -S(0)2- NH-Ci-C4 alkyl, -S(0)2-N(Ci-C4 alkyl)2, -NH-S(0)2-Ci-C4 alkyl, -N(Ci-C4 alkyl)-S(0)2-Ci-C4 alkyl, -C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, 3- to 7-membered monocyclic heterocycle, C3-C8 monocyclic cycloalkyl and -C(0)NH2;

Y is 4- to 6- membered nitrogen-containing nonaromatic heterocycle, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of

-halo, oxo, -C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, -C1-C4 alkyl, halo-substituted C1-C4 alkyl, amino-substituted C1-C4 alkoxy, -CN, (C1-C4 alkyl)2N-Ci-C4 alkoxy, -NH-C1-C4 alkyl, - OH and

-NH2; and

Z is 5- to 6-membered nitrogen-containing heterocycle which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -

NH2, -OH,

-C1-C4 alkyl, halo-substituted C1-C4 alkyl, -C1-C4 alkoxy and 3- to 7-membered monocyclic heterocycle.

2. A compound of claim 1 , wherein R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, - CN, -NH2,

-C1-C4 alkyl, halo-substituted C1-C4 alkyl, amino-substituted C1-C4 alkyl, -NH-C1-C4 alkyl, -NHC(0)-Ci-C4 alkyl, -C(0)N(Ci-C4 alkyl)2, -C(0)NH-Ci-C4 alkyl, -C(0)N(Ci-C4 alkyl)2, hydroxy-substituted C1-C4 alkyl, -S(0)2-Ci-C4 alkyl, -S(0)2-halo-substituted C1-C4 alkyl, - S(0)2-NH-Ci-C4 alkyl, -S(0)2-N(Ci-C4 alkyl)2, -NH-S(0)2-Ci-C4 alkyl, -N(Ci-C4 alkyl)- S(0)2-Ci-C4 alkyl, -C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, 3- to 7-membered monocyclic heterocycle, C3-C8 monocyclic cycloalkyl and -C(0)NH2; or a pharmaceutically acceptable salt thereof.

3. The compound of any one of claims 1-2, wherein Z is pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C1-C4 alkyl, -C1-C4 alkoxy and - CF3; or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein Y is azetidinyl or piperidinyl, each of which is unsubstituted or substituted with oxo; or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, wherein R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of

-halo, -C1-C4 alkyl, -CF3 and -OCF3; or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-5, wherein:

R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C1-C4 alkyl, -CF3 and -OCF3;

Y is azetidinyl or piperidinyl, each of which is unsubstituted or substituted with oxo; and

Z is pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C1-C4 alkyl, -C1-C4 alkoxy and -CF3;

or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, wherein:

R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting -halo, -C1-C4 alkyl, -CF3 and -OCF3;

Y is piperidinyl; and

Z is pyridinyl which is unsubstituted or substituted with one or more substituents

independently selected from -halo and -Ci-C4 alkoxy;

or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-6, wherein R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of

-halo, -Ci-C4 alkyl, -CF3 and -OCF3; or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-6, wherein:

R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -Ci-C4 alkyl, -CF3 and -OCF3; and

Z is pyridinyl which is unsubstituted or substituted with one or more -Ci-C4 alkoxy;

or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1-9, wherein R is phenyl substituted with -CI, - CF3 or -F; or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1 -9, wherein R is phenyl substituted with one -F; or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1-9, wherein Ris phenyl substituted with two -F; or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claims 1 -9, wherein Ris phenyl substituted with three -

F;

or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 1-9, wherein Ris phenyl substituted with one -CI; or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1-9, wherein Ris phenyl substituted with one - halo and one -CF3; or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1-9, wherein Ris phenyl substituted with one -F and one -CF3; or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1-9, wherein Ris phenyl substituted with one -CI and one -CF3;

or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 1-9, wherein Ris phenyl substituted with one - OCF3;

or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 1-9, wherein Ris phenyl substituted with one - halo and one -OCF3; or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1-9, wherein Ris phenyl substituted with one -F and one -OCF3; or a pharmaceutically acceptable salt thereof.

21. The compound of any one of claims 1-9, wherein Ris phenyl substituted with one -CI and one -OCF3; or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein Ris -Ci-C6 alkyl substituted with three -F; or a pharmaceutically acceptable salt thereof.

23. The compound of any one of claims 1-9, wherein at least one -C1-C4 alkyl is methyl; or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 1-21 or 23, wherein R is phenyl substituted with one methyl; or a pharmaceutically acceptable salt thereof.

25. The compound of any one of claims 1-24, wherein Y is azetidinyl or piperidinyl, each of which is unsubstituted or substituted with oxo; or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1-25, wherein Y is piperidinyl unsubstituted or substituted with oxo; or a pharmaceutically acceptable salt thereof.

27. The compound of any one of claims 1-26, wherein Y is piperidinyl;

or a pharmaceutically acceptable salt thereof.

28. The compound of any one of claims 1-25, wherein Y is azetidinyl; or a

pharmaceutically acceptable salt thereof.

29. The compound of any one of claims 1-28, wherein Z is pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C1-C4 alkyl, -C1-C4 alkoxy and - CF3;

or a pharmaceutically acceptable salt thereof.

30. The compound of any one of claims 1-29, wherein Z is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C1-C4 alkyl, -C1-C4 alkoxy and -CF3; or a pharmaceutically acceptable salt thereof.

31. The compound of any one of claims 1-30, wherein Z is pyridinyl substituted with one -CI; or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 1-30, wherein Z is pyridinyl substituted with one methoxy; or a pharmaceutically acceptable salt thereof.

33. The compound of any one of claims 1-30, wherein Z is pyridinyl substituted with one methyl; or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1-29, wherein Z is pyrimidinyl which is unsubstituted or substituted with one to three -C1-C4 alkyl or -C1-C4 alkoxy; or a

pharmaceutically acceptable salt thereof.

35. The compound of any one of claims 1-29 and 34, wherein Z is pyrimidinyl substituted with one methyl; or a pharmaceutically acceptable salt thereof.

36. The compound of any one of claims 1-29 and 34, wherein Z is pyrimidinyl substituted with one methoxy; or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 1-29, wherein Z is pyridazinyl; or a

pharmaceutically acceptable salt thereof.

38. A compound selected from the group consisting of:

N-(l-(2-chloropyridin-4-yl)piperidin-4-yl)-8-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4- b][l,4]oxazin-2-amine;

N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4- b][l,4]oxazin-2-amine;

N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrimido[5,4- b][l,4]oxazin-2-amine;

8-(2-chlorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine;

N-(l-(2-chloropyridin-4-yl)piperidin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrimido[5,4- b][l,4]oxazin-2-amine; 8-(3,5-difluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine;

N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-(2-(trifluoromethoxy)phenyl)-7,8-dih 6H-pyrimido [5 ,4-b] [ 1 ,4]oxazin-2-amine;

8-(o-tolyl)-N-(l-(2-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine;

8-(2-chlorophenyl)-N-(l-(2-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine;

8-(3,5-difluorophenyl)-N-(l-(2-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)-7,8-dih pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine;

N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-(2,2,2-trifluoroethyl)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine;

N-(l-(2-methoxypyridin-4-yl)piperidm^

pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine;

8-(2,4-difluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine;

8-(4-chlorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine;

8-(2-chloro-4-fluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine;

8-(4-fluoro-2-(trifluoromethyl)phenyl)-N

dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; 8-(4-chloro-2-(trifluoromethoxy)phenyl)-N-(l-(2-methoxypyridin-4-yl)piperidm dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine;

8-(4-chloro-2-(trifluoromethyl)phenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)- dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine;

8-(4-fluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine;

8-(2,4-dichlorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine; and

8-(4-fluoro-2-(trifluoromethoxy)phenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4- dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; or a pharmaceutically acceptable salt thereof.

39. The compound of claim 28 selected from the group consisting of:

N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrimido[5,4- b][l,4]oxazin-2-amine;

8-(3,5-difluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine;

N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-(2-(trifluoromethoxy)phenyl)-7,8-dihydro- 6H-pyrimido [5 ,4-b] [ 1 ,4]oxazin-2-amine;

N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-(3,4,5-trifluorophenyl)-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine;

8-(2,4-difluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine; 8-(4-chlorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine;

8-(2-chloro-4-fluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine;

8-(4-fluoro-2-(trifluoromethyl)phenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl^ dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine;

8-(4-chloro-2-(trifluoromethoxy)phenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-y dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine;

8-(4-chloro-2-(trifluoromethyl)phenyl)-N-(l-(2-m

dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine;

8-(4-fluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine;

8-(2,4-dichlorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine; and

8-(4-fluoro-2-(trifluoromethoxy)phenyl)-N^

dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of any one of claims 1-39.

41. A method for treating a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of any one of claims 1-39.

42. The method of claim 41, wherein the neurodegenerative disease is panic disorder, obsessive compulsive disorder, delusional disorder, drug-induced psychosis, post-traumatic stress disorder, age-related cognitive decline, attention deficit/hyperactivity disorder, personality disorder of the paranoid type, personality disorder of the schizoid type, dyskinesia, choreiform condition, psychosis associated with Parkinson's disease, psychotic symptoms associated with Alzheimer's disease, mood disorder, or dementia.

43. A method for treating Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of any one of claims 1-39.

44. A method for improving an impaired cognitive function, comprising administering to a subject having impaired cognitive function an effective amount of a compound or a pharmaceutically acceptable salt of a compound of any one of claims 1-39.

45. A method for ameliorating a symptom of Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of any one of claims 1-39.

46. The method of any one of claims 44-45, wherein Alzheimer's disease is early onset Alzheimer's disease.

47. The method of any one of claims 41-46, wherein the subject is a human.

48. The method of claim 45, wherein the symptom is progressive loss of memory, progressive loss of cognition, progressive loss of reasoning and/or progressive loss of judgment.

49. The method of claim 44, wherein the cognitive function impaired is one or more of attention, learning, delayed memory, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.

Description:
FUSED MORPHOLINOP YRIMIDINE S AND METHODS OF USE THEREOF

RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Serial No. 62/047,215, filed September 8, 2014 and to U.S. Provisional

Application Serial No. 61/899,616, filed November 4, 2013, the entire disclosures of which are incorporated by reference herein in their entirety.

1. FIELD

[0002] This application relates generally to fused morpholinopyrimidine compounds. More specifically, the application relates to the use of the fused morpholinopyrimidine compounds for the treatment of neurological disease.

2. BACKGROUND

[0003] Alzheimer's disease (AD) is the most prevalent form of dementia. It is a neurodegenerative disease that is associated (though not exclusively) with aging. The disease is clinically characterized by a progressive loss of memory, cognition, reasoning and judgment that leads to an extreme mental deterioration and ultimately death. The disease is pathologically characterized by the deposition of extracellular plaques and the presence of neurofibrillary tangles. The plaques are considered to play an important role in the pathogenesis of the disease. They mainly consist of fibrillar aggregates of β-amyloid peptide (Αβ), which are products of the amyloid precursor protein (APP). APP is initially processed by β-secretase forming a secreted peptide and a membrane bound C99 fragment. The C99 fragment is subsequently processed by the proteolytic activity of γ -secretase. Multiple sites of proteolysis on the C99 fragment lead to the production of a range of smaller peptides (Αβ 37-42 amino acids). N-terminal truncations can also be found e.g., Αβ (4-42). For convenience, notations Αβ40 and Αβ42, as used herein, include these N-terminal truncated peptides. Upon secretion, the Αβ peptides initially form soluble aggregates which ultimately lead to the formation of insoluble deposits and plaques. Αβ42 is believed to be the most neurotoxic; the shorter peptides have less propensity to aggregate and form plaques. Αβ plaques in the brain are also associated with cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, multi infarct dementia, dementia pugilistisca and Down's Syndrome.

[0004] γ-secretase is an association of four proteins: Aphl, nicastrin, presenilin and Pen- 2 (review De Strooper, Neuron 38:9-12 (2003)). Subjects carrying particular mutations in one of these components, presenilin, show increased Αβ42/Αβ40 ratio. These mutations are correlated with early onset familial AD. Inhibition of γ-secretase resulting in the lowering of Αβ42 has been investigated by the pharmaceutical community, and numerous inhibitors have been found. See, e.g., Thompson et al. {Bioorg. Med. Chem. Lett. 2006, 16, 2357-63), Shaw et al. {Bioorg. Med. Chem. Lett. 2006, 17, 511-16) and Asberom et al. {Bioorg. Med. Chem. Lett. 2007, 15, 2219-2223). Inhibition of γ-secretase, though, is not without side-effects, some of which are due to the γ-secretase complex processing substrates other than C99, e.g., Notch. A more desirable approach is to modulate the proteolytic activity of the γ-secretase complex in a manner that lowers Αβ42 in favor of shorter peptides without significantly affecting the activity of γ-secretase on substrates such as Notch.

[0005] Compounds that have shown modulation of γ-secretase include certain nonsteroidal, anti-inflammatory drugs (NSAIDs), for example Flurbiprofen, (Stock et al, Bioorg. Med. Chem. Lett. 2006, 16, 2219-2223). Other publications that disclose agents said to reduce Αβ42 through the modulation of γ-secretase include: WO 2004/074232, WO

2005/054193, Perreto et al, Journal of Medicinal Chemistry 2005, 48:5705-20, WO

2005/108362, WO 2006/008558, WO 2006/021441, WO 2006/041874, WO 2006/045554, WO 2004/110350, WO 2006/043964, WO 2005/115990, EP 1847524, WO 2007/116228, WO 2007/110667, WO 2007/124394, EP 184752, EP 1849762, WO 2007/125364, WO 2009/086277.

3. SUMMARY

[0006] It is understood that any of the embodiments described below can be combined in any desired way, and that any embodiment or combination of embodiments can be applied to each of the aspects described below, unless the context indicates otherwise.

[0007] A compound of Formula (I), Formula (Γ) or a pharmaceutically acceptable salt thereof (also referred to herein as a "Fused Morpholinopyrimidine") is useful for treating, preventing or ameliorating symptoms of a neurodegenerative disease.

[0008] In one aspect, the invention provides a compound of Formula (I)

(I)

or a pharmaceutically acceptable salt thereof, wherein: R is phenyl, -C 1 -C 4 alkylene-phenyl or -Ci-C 6 alkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of

-halo, -CN, -NH 2 , -C 1 -C 4 alkyl, halo-substituted C 1 -C 4 alkyl, amino-substituted C 1 -C 4 alkyl, - NH-C1-C4 alkyl, -NHC(0)-Ci-C 4 alkyl, -C(0)N(Ci-C 4 alkyl) 2 , -C(0)NH-Ci-C 4 alkyl, - C(0)N(Ci-C 4 alkyl) 2 , hydroxy-substituted C1-C4 alkyl, -S(0) 2 -Ci-C 4 alkyl, -S(0) 2 -halo- substituted C r C 4 alkyl, -S(0) 2 - H-Ci-C 4 alkyl, -S(0) 2 -N(d-C 4 alkyl) 2 , -NH-S(0) 2 -Ci-C 4 alkyl, -N(Ci-C 4 alkyl)-S(0) 2 -Ci-C 4 alkyl, -C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, 3- to 7-membered monocyclic heterocycle, C 3 -C 8 monocyclic cycloalkyl and -C(0)NH 2 ; Y is 4- to 6- membered nitrogen-containing nonaromatic heterocycle, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, oxo, -C 1 -C 4 alkoxy, halo-substituted C 1 -C 4 alkoxy, -C 1 -C 4 alkyl, halo-substituted Ci- C 4 alkyl, amino-substituted C1-C4 alkoxy, -CN, (C1-C4 alkyl) 2 N-Ci-C 4 alkoxy, -NH-C1-C4 alkyl, -OH and -NH 2 ; and Z is 5- to 6-membered nitrogen-containing heterocycle which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -NH 2 , -OH, -C 1 -C 4 alkyl, halo-substituted C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and 3- to 7-membered monocyclic heterocycle.

[0009] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -CN, -NH 2 , - C 1 -C 4 alkyl, halo-substituted C 1 -C 4 alkyl, amino-substituted C 1 -C 4 alkyl, -NH-C 1 -C 4 alkyl, - NHC(0)-Ci-C 4 alkyl, -C(0)N(Ci-C 4 alkyl) 2 , -C(0)NH-Ci-C 4 alkyl, -C(0)N(Ci-C 4 alkyl) 2 , hydroxy-substituted C1-C4 alkyl, -S(0) 2 -Ci-C4 alkyl, -S(0) 2 -halo-substituted C1-C4 alkyl, - S(0) 2 -NH-Ci-C 4 alkyl, -S(0) 2 -N(Ci-C 4 alkyl) 2 , -NH-S(0) 2 -Ci-C 4 alkyl, -N(Ci-C 4 alkyl)- S(0) 2 -Ci-C 4 alkyl, -C 1 -C 4 alkoxy, halo-substituted C 1 -C 4 alkoxy, 3- to 7-membered monocyclic heterocycle, C 3 -C 8 monocyclic cycloalkyl and -C(0)NH 2 ; or a pharmaceutically acceptable salt thereof. [0010] In some embodiments, Z is pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C4 alkyl, -C 1 -C4 alkoxy and -CF 3 .

[0011] In some embodiments, Y is azetidinyl or piperidinyl, each of which is

unsubstituted or substituted with oxo.

[0012] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C4 alkyl, -CF 3 and -OCF 3 .

[0013] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C4 alkyl, -CF 3 and -OCF 3 ; Y is azetidinyl or piperidinyl, each of which is unsubstituted or substituted with oxo; and Z is pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C4 alkyl, -C 1 -C4 alkoxy and -CF 3 .

[0014] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting -halo, -C 1 -C4 alkyl, - CF 3 and -OCF 3 ; Y is piperidinyl; and Z is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from -halo and -C 1 -C4 alkoxy.

[0015] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C4 alkyl, -CF 3 and -OCF 3 .

[0016] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C4 alkyl, -CF 3 and -OCF 3 ; and Z is pyridinyl which is unsubstituted or substituted with one or more - C 1 -C4 alkoxy.

[0017] In some embodiments, R is phenyl substituted with -CI, -CF 3 or -F.

[0018] In some embodiments, R is phenyl substituted with one -F.

[0019] In some embodiments, Ris phenyl substituted with two -F.

[0020] In some embodiments, Ris phenyl substituted with three -F.

[0021] In some embodiments, Ris phenyl substituted with one -CI.

[0022] In some embodiments, Ris phenyl substituted with one -halo and one -CF 3 .

[0023] In some embodiments, Ris phenyl substituted with one -F and one -CF 3 .

[0024] In some embodiments, Ris phenyl substituted with one -CI and one -CF 3 . [0025] In some embodiments, Ris phenyl substituted with one -OCF 3 .

[0026] In some embodiments, R is phenyl substituted with one -halo and one -OCF 3

[0027] In some embodiments, Ris phenyl substituted with one -F and one -OCF 3 .

[0028] In some embodiments, Ris phenyl substituted with one -CI and one -OCF 3 .

[0029] In some embodiments, Ris -Ci-C 6 alkyl substituted with three -F.

[0030] In some embodiments, at least one -C 1 -C 4 alkyl is methyl.

[0031] In some embodiments, Ris phenyl substituted with one methyl.

[0032] In some embodiments, Y is azetidinyl or piperidinyl, each of which is

unsubstituted or substituted with oxo.

[0033] In some embodiments, Y is piperidinyl unsubstituted or substituted with oxo.

[0034] In some embodiments, Y is piperidinyl.

[0035] In some embodiments, Y is azetidinyl.

[0036] In some embodiments, Z is pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 .

[0037] In some embodiments, Z is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 .

[0038] In some embodiments, Z is pyridinyl substituted with one -CI.

[0039] In some embodiments, Z is pyridinyl substituted with one methoxy.

[0040] In some embodiments, Z is pyridinyl substituted with one methyl.

[0041] In some embodiments, Z is pyrimidinyl which is unsubstituted or substituted with one to three -C 1 -C 4 alkyl or -C 1 -C 4 alkoxy.

[0042] In some embodiments, Z is pyrimidinyl substituted with one methyl.

[0043] In some embodiments, Z is pyrimidinyl substituted with one methoxy.

[0044] In some embodiments, Z is pyridazinyl.

[0045] In one aspect, the compound of Formula (I) is selected from the group consisting of:

N-(l-(2-chloropyridin-4-yl)piperidin-4-yl)-8-(o-tolyl)-7,8-d ihydro-6H-pyrimido[5,4- b][l,4]oxazin-2-amine; N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-(o-tolyl)-7,8- dihydro- 6H-pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine; N-( 1 -(2-methoxypyridin-4-yl)piperidin-4-yl)-8- phenyl-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; 8-(2-chlorophenyl)-N-(l-(2- methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[ 5,4-b][l,4]oxazin-2-amine; N-(l-(2-chloropyridin-4-yl)piperidin-4-yl)-8-phenyl-7,8-dihy dro-6H-pyrimi b][l,4]oxazin-2-amine; 8-(3,5-difluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin -4-yl)- 7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; N-(l-(2-methoxypyridin-4- yl)piperidin-4-yl)-8-(2-(trifluoromethoxy)phenyl)-7,8-dihydr o-6H-pyrimido[5,4- b][l,4]oxazin-2-amine; 8-(o-tolyl)-N-(l-(2-(trifluoromethyl)pyridin-4-yl)piperidin- 4-yl)-7,8- dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; 8-(2-chlorophenyl)-N-(l-(2- (trifluoromethyl)pyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H -pyrimido[5,4-b][l,^

amine; 8-(3,5-difluorophenyl)-N-(l-(2-(trifluoromethyl)pyridin-4-yl )piperidin-4-yl)-7,8- dihydro-6H-pyrimido [5 ,4-b] [ 1 ,4]oxazin-2-amine; N-( 1 -(2-methoxypyridin-4-yl)piperidin-4- yl)-8-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-pyrimido[5,4-b][ l,4]oxazin-2-amine; N-(l-(2- methoxypyridin-4-yl)piperidin-4-yl)-8-(3,4,5-trifluorophenyl )-7,8-dihydro-6H-pyrimid b][l,4]oxazin-2-amine; 8-(2,4-difluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin -4-yl)- 7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; 8-(4-chlorophenyl)-N-(l-(2- methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[ 5,4-b][l,4]oxazin-2-am 8- (2-chloro-4-fluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperi din-4-yl)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine; 8-(4-fluoro-2-(trifluoromethyl)phenyl)-N-( 1 -(2- methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[ 5,4-b][l,4]oxazin-2-ami^^ 8- (4-chloro-2-(trifluoromethoxy)phenyl)-N-(l-(2-methoxypyridin -4-yl)piperidin-4-yl)-7,8- dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; 8-(4-chloro-2-(trifluoromethyl)phenyl)-N- (l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyr imido[5,4-b][l,4]oxazin-2- amine; 8-(4-fluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-y l)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine; 8-(2,4-dichlorophenyl)-N-( 1 -(2-methoxypyridin-4- yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin -2-amine; and 8-(4-fluoro-2- (trifluoromethoxy)phenyl)-N-(l-(2-methoxypyridin-4-yl)piperi din-4-yl)-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine; or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the compound of Formula (I) is selected from the group consisting of: N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-phenyl-7,8-dih ydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine; 8-(3,5-difluorophenyl)-N-(l-(2-methoxypyridin-4- yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin -2-amine; N-(l-(2- methoxypyridin-4-yl)piperidin-4-yl)-8-(2-(trifluoromethoxy)p henyl)-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine; N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-(3,4,5- trifluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2 -amine; 8-(2,4- difluorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)- 7,8-dihydro-6H-pyrimido[5,4- b][l,4]oxazin-2-amine; 8-(4-chlorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-y l)-7,8- dihydro-6H-pyrimido [5 ,4-b] [ 1 ,4]oxazin-2-amine; 8-(2-chloro-4-fluorophenyl)-N-( 1 -(2- methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[ 5,4-b][l,4]oxazin-2-a 8- (4-fluoro-2-(trifluoromethyl)phenyl)-N-(l-(2-methoxypyridin- 4-yl)piperidin-4-yl^ dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; 8-(4-chloro-2-(trifluoromethoxy)phenyl)- N-(l-(2-methoxypyridin-4-yl)piperidm^

amine; 8-(4-chloro-2-(trifluoromethyl)phenyl)-N-( 1 -(2-methoxypyridin-4-yl)piperidin-4-yl)- 7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; 8-(4-fluorophenyl)-N-(l-(2- methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[ 5,4-b][l,4]oxazin-2-amine; 8- (2,4-dichlorophenyl)-N-(l-(2-methoxypyridin-4-yl)piperidin-4 -yl)-7,8-dihydro-6H- pyrimido[5 ,4-b] [ 1 ,4]oxazin-2-amine; and 8-(4-fluoro-2-(trifluoromethoxy)phenyl)-N-( 1 -(2- methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[ 5,4-b][l,4]oxazin-2-amine; or a pharmaceutically acceptable salt thereof.

[0047] In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or vehicle and an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0048] In one aspect, the invention provides a method for treating a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula (I).

[0049] In one aspect, the invention provides a method for treating Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula (I).

[0050] In one aspect, the invention provides a method for improving an impaired cognitive function, comprising administering to a subject having impaired cognitive function an effective amount of a compound or a pharmaceutically acceptable salt of a compound of

Formula (I). In one embodiment, the subject has impaired cognitive function relative to a healthy subject, for example a healthy subject of the same age.

[0051] In one aspect, the invention provides a method for ameliorating a symptom of Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula (I).

[0052] In some embodiments, the symptom of Alzheimer's disease is progressive loss of memory, progressive loss of cognition, progressive loss of reasoning and/or progressive loss of judgment. [0053] In some embodiments, Alzheimer's disease is early onset Alzheimer's disease. In some embodiments, the subject is a human.

[0054] Exemplary neurodegenerative disease include Alzheimer's disease, early onset Alzheimer's disease, panic disorder, obsessive compulsive disorder, delusional disorder, drug-induced psychosis, post-traumatic stress disorder, age-related cognitive decline, attention deficit/hyperactivity disorder, personality disorder of the paranoid type, personality disorder of the schizoid type, dyskinesia, choreiform condition, psychosis associated with Parkinson's disease, psychotic symptoms associated with Alzheimer's disease, mood disorder, dementia, cognitive impairment, myclonus, seizures, Parkinsonism, extrapyramidal signs (EPS), apraxia, dystonia, dementia with Lewy bodies (DLB), aphasia, visual agnosia, and ataxia.

[0055] In some embodiments, the cognitive function impaired is one or more of attention, learning, delayed memory, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.

[0056] In some embodiments, the subject is 65 years old or older. In other embodiments, the subject is 55 years old or older. In still other embodiments, the subject is 55 years old or younger, or 50 years old or younger.

[0057] A pharmaceutical composition comprising an effective amount of a Fused

Morpholinopyrimidine of Formula (I) and a pharmaceutically acceptable carrier or vehicle is useful for treating or preventing a neurodegenerative disease.

[0058] In another aspect, the invention provides a compound of Formula (Γ)

( )

or a pharmaceutically acceptable salt thereof, wherein: R is phenyl, -C 1 -C4 alkylene-phenyl or -Ci-C 6 alkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of

-halo, -CN, -NH 2 , -Ci-C 4 alkyl, halo-substituted Ci-C 4 alkyl, amino-substituted Ci-C 4 alkyl, - NH-Ci-C 4 alkyl, -NHC(0)-C C 4 alkyl, -C(0)N(C C 4 alkyl) 2 , -C(0)NH-C C 4 alkyl, - C(0)N(Ci-C 4 alkyl) 2 , hydroxy-substituted C1-C4 alkyl, -S(0) 2 -Ci-C 4 alkyl, -S(0) 2 -halo- substituted Ci-C 4 alkyl, -S(0) 2 - H-Ci-C 4 alkyl, -S(0) 2 -N(Ci-C 4 alkyl) 2 , - H-S(0) 2 -Ci-C 4 alkyl, -N(Ci-C 4 alkyl)-S(0) 2 -Ci-C 4 alkyl, -C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, 3- to 7-membered monocyclic heterocycle, C 3 -C 8 monocyclic cycloalkyl and -C(0)NH 2 ; Y is 4- to 6- membered nitrogen-containing nonaromatic heterocycle, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, oxo, -C 1 -C 4 alkoxy, halo-substituted C 1 -C 4 alkoxy, -C 1 -C 4 alkyl, halo-substituted Ci- C 4 alkyl, amino-substituted C C 4 alkoxy, -CN, (C 1 -C 4 alkyl) 2 N-Ci-C 4 alkoxy, -NH-C 1 -C 4 alkyl, -OH and -NH 2 ; Z is 5- to 6-membered nitrogen-containing heterocycle which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -NH 2 , -OH, -C 1 -C 4 alkyl, halo-substituted C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and 3- to 7-membered monocyclic heterocycle; each R 1 is independendently -H or -Ci-C 6 alkyl; and each R 2 is independendently -H or -Ci-C 6 alkyl, provided that at least one of R 1 and R 2 groups is -Ci-C 6 alkyl.

[0059] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -CN, -NH 2i - C 1 -C 4 alkyl, halo-substituted C 1 -C 4 alkyl, amino-substituted C 1 -C 4 alkyl, -NH-C 1 -C 4 alkyl, - NHC(0)-Ci-C 4 alkyl, -C(0)N(Ci-C 4 alkyl) 2 , -C(0)NH-Ci-C 4 alkyl, -C(0)N(Ci-C 4 alkyl) 2 , hydroxy-substituted C1-C4 alkyl, -S(0) 2 -Ci-C4 alkyl, -S(0) 2 -halo-substituted C1-C4 alkyl, - S(0) 2 -NH-Ci-C 4 alkyl, -S(0) 2 -N(Ci-C 4 alkyl) 2 , -NH-S(0) 2 -Ci-C 4 alkyl, -N(Ci-C 4 alkyl)- S(0) 2 -Ci-C 4 alkyl, -C 1 -C 4 alkoxy, halo-substituted C 1 -C 4 alkoxy, 3- to 7-membered monocyclic heterocycle, C 3 -Cs monocyclic cycloalkyl and -C(0)NH 2 ; or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, Z is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 .

[0061] In some embodiments, Y is piperidinyl which is unsubstituted.

[0062] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl and

-OCF 3 .

[0063] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -CF 3 and -OCF 3 ; Y is piperidinyl which is unsubstituted; Z is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of

-halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 ; and each R 1 is independendently -H or -Ci-C 6 alkyl; and each R 2 is independendently -H or -Ci-C 6 alkyl.

[0064] In some embodiments, R is phenyl which is unsubstituted; Y is piperidinyl; and Z is pyridinyl which is substituted with one -C 1 -C 4 alkoxy.

[0065] In some embodiments, R is phenyl substituted with -CI, -CF 3 or -F.

[0066] In some embodiments, R is phenyl unsubstituted.

[0067] In some embodiments, at least one -C 1 -C 4 alkyl is methyl.

[0068] In some embodiments, Y is piperidinyl which is unsubstituted.

[0069] In some embodiments, Z is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 .

[0070] In some embodiments, Z is pyridinyl which is substituted with one -C 1 -C 4 alkoxy.

[0071] In some embodiments, each R 1 is -H. In some embodiments, one R 1 is -H.

[0072] In some embodiments, each R 2 is -H. In some embodiments, one R 2 is -H.

[0073] In some embodiments, each of R 1 and R 2 is independendently -Ci-C 6 alkyl.

[0074] In some embodiments, each R 1 is independendently -Ci-C 6 alkyl and each R 2 is - H.

[0075] In some embodiments, each R 2 is independendently -Ci-C 6 alkyl and each R 1 is - H.

[0076] In some embodiments, one R 1 is -H and the other R 1 is -Ci-C 6 alkyl and each R 2 is

-H.

[0077] In some embodiments, one R 2 is -H and the other R 2 is -Ci-C 6 alkyl alkyl and each R 1 is -H.

[0078] In some embodiments, each R 1 is methyl. In some embodiments, each R 2 is methyl.

[0079] In one aspect, the compound of Formula (Γ) is selected from the group consisting of:

N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-6,6-dimethyl-8-p henyl-7,8-dihydro-6H- pyrimido [5 ,4-b] [ 1 ,4]oxazin-2-amine; (+)-N-( 1 -(2-methoxypyridin-4-yl)piperidin-4-yl)-6- methyl-8-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2- amine; (-)-N-(l-(2- methoxypyridin-4-yl)piperidin-4-yl)-6-methyl-8-phenyl-7,8-di hydro-6H-pyrimido[5,4- b] [ 1 ,4]oxazin-2-amine; (-)-N-( 1 -(2-methoxypyridin-4-yl)piperidin-4-yl)-7-methyl-8-phenyl-

7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; (+)-N-(l-(2-methoxypyridin-4- yl)piperidin-4-yl)-7-methyl-8-phenyl-7,8-dihydro-6H-pyrimido [5,4-b][l,4]oxazin-2-am and N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,7-dimethyl-8-p henyl-7,8-dihydro-6H- pyrimido[5,4-b][l,4]oxazin-2-amine; or a pharmaceutically acceptable salt thereof.

[0080] In one aspect, the compound of Formula (Γ) is selected from the group consisting of:

(+)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-6-methyl-8-p henyl-7,8-dihydro-6H- pyrimido [5 ,4-b] [ 1 ,4]oxazin-2-amine; (-)-N-( 1 -(2-methoxypyridin-4-yl)piperidin-4-yl)-6- methyl-8-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2- amine; (-)-N-(l-(2- methoxypyridin-4-yl)piperidin-4-yl)-7-methyl-8-phenyl-7,8-di hydro-6H-pyrimido[5,4- b][l,4]oxazin-2-amine; (+)-N-(l-(2-methoxypyridin-4-yl)piperidin-4-yl)-7-methyl-8-p henyl- 7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine; and N-(l-(2-methoxypyridin-4- yl)piperidin-4-yl)-7,7-dimethyl-8-phenyl-7,8-dihydro-6H-pyri mido[5,4-b][l,4]oxazin-2- amine; or a pharmaceutically acceptable salt thereof.

[0081] In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or vehicle and an effective amount of a compound of Formula (Γ) or a pharmaceutically acceptable salt thereof.

[0082] In one aspect, the invention provides a method for treating a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula (Γ).

[0083] In one aspect, the invention provides a method for treating Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula (Γ).

[0084] In one aspect, the invention provides a method for improving an impaired cognitive function, comprising administering to a subject having impaired cognitive function an effective amount of a compound or a pharmaceutically acceptable salt of a compound of

Formula (Γ). In one embodiment, the subject has impaired cognitive function relative to a healthy subject, for example a healthy subject of the same age. [0085] In one aspect, the invention provides a method for ameliorating a symptom of Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula (Γ).

[0086] In some embodiments, the symptom of Alzheimer's disease is progressive loss of memory, progressive loss of cognition, progressive loss of reasoning and/or progressive loss of judgment.

[0087] In some embodiments, Alzheimer's disease is early onset Alzheimer's disease. In some embodiments, the subject is a human.

[0088] Exemplary neurodegenerative disease include Alzheimer's disease, early onset Alzheimer's disease, panic disorder, obsessive compulsive disorder, delusional disorder, drug-induced psychosis, post-traumatic stress disorder, age-related cognitive decline, attention deficit/hyperactivity disorder, personality disorder of the paranoid type, personality disorder of the schizoid type, dyskinesia, choreiform condition, psychosis associated with Parkinson's disease, psychotic symptoms associated with Alzheimer's disease, mood disorder, dementia, cognitive impairment, myclonus, seizures, Parkinsonism, extrapyramidal signs (EPS), apraxia, dystonia, dementia with Lewy bodies (DLB), aphasia, visual agnosia, and ataxia.

[0089] In some embodiments, the cognitive function impaired is one or more of attention, learning, delayed memory, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.

[0090] In some embodiments, the subject is 65 years old or older. In other embodiments, the subject is 55 years old or older. In still other embodiments, the subject is 55 years old or younger, or 50 years old or younger.

[0091] A pharmaceutical composition comprising an effective amount of a Fused

Morpholinopyrimidine of Formula (Γ) and a pharmaceutically acceptable carrier or vehicle is useful for treating or preventing a neurodegenerative disease.

[0092] The details of the invention are set forth in the accompanying description below.

[0093] All patents and publications cited in this specification are hereby incorporated by reference in their entirety. 1. DETAILED DESCRIPTION

4.1 Definitions and Abbreviations

[0094] The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0095] The term "-C 1 -C 4 alkyl" as used herein, refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond. Representative straight chain -C 1 -C 4 alkyls include -methyl, -ethyl, -n-propyl and -n-butyl. Representative branched -C 1 -C 4 alkyls include

-isopropyl, -sec-butyl, -isobutyl and -tert-butyl. In one embodiment, the -C 1 -C 4 alkyl is substituted.

[0096] The term "-Ci-C 6 alkyl" as used herein, refers to a straight chain or branched non- cyclic hydrocarbon having from 1 to 6 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond. Representative straight chain -Ci-C 6 alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl. Representative branched

-Ci-C 6 alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, -1-methylbutyl, -isohexyl, -neohexyl, -2-methylbutyl, -3-methylbutyl, -1,1-dimethylpropyl and

-1,2-dimethylpropyl. In one embodiment, the -Ci-C 6 alkyl is substituted. The term "-C3-C8 monocyclic cycloalkyl" as used herein, refers to a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms. Representative -C 3 -C 8 monocyclic cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and -cyclooctyl. In one embodiment, the -C 3 -Cg monocyclic cycloalkyl is substituted.

[0097] A "C 1 -C 4 alkylene" refers to a straight or branched chain saturated hydrocarbon containing 1-4 carbon atoms, wherein two of the hydrocarbon's hydrogen atoms have been replaced by a single a bond. Representative C 1 -C 4 alkylene groups include, methylene, ethylene, n-propylene, isopropylene, n-butylene and isobutylene. [0098] The term "C 1 -C 4 alkoxy" is a C 1 -C 4 alkyl-O- group wherein the C 1 -C 4 alkyl is as defined above. Examples of C 1 -C 4 alkoxy include, but are not limited to, methoxy, trifluoromethoxy, ethoxy, propoxy or butoxy.

[0099] "Halo-substituted C 1 -C 4 alkoxy" refers to a C 1 -C 4 alkoxy group, as defined above, wherein one or more of the C 1 -C 4 alkoxy group's hydrogen atoms have been replaced with - F,

-CI, -Br or -I. Examples of a halo-substituted C 1 -C 4 alkoxy include, but are not limited to, -0-CH 2 F, -O-CCI 3 , -O-CF 3 , -0-CH 2 Cl, -0-CH 2 CH 2 Br, -0-CH 2 CH 2 I, -0-CF 2 CF 3 , -O- CH 2 CH 2 CH 2 F, -0-CH 2 CH 2 CH 2 Cl, -0-CH 2 CH 2 CH 2 CH 2 Br, -0-CH 2 CH 2 CH 2 CH 2 I, -O- CH 2 CH(Br)CH 3 , -0-CH 2 CH(Cl)CH 2 CH 3 , -0-CH(F)CH 2 CH 3 and -0-C(CH 3 ) 2 (CH 2 Cl).

[0100] "Amino-substituted C 1 -C 4 alkoxy" refers to a C 1 -C 4 alkoxy group, as defined above, wherein one or more of the C 1 -C 4 alkoxy group's hydrogen atoms have been replaced with -NH 2 . Examples of amino-substituted C 1 -C 4 alkoxy include, but are not limited to, -O- CH 2 NH 2 , -0-CH 2 CH 2 NH 2 , -0-CH(NH 2 )CH 3 , -0-CH 2 CH 2 CH 2 NH 2 , -O- CH 2 CH 2 CH 2 CH 2 NH 2 , -0-CH 2 CH(NH 2 )CH 3 , -0-CH(NH 2 )CH 2 CH 3 and -O- C(CH 3 ) 2 (CH 2 NH 2 ).

[0101] A "nitrogen containing 3- to 7-membered monocyclic heterocycle" refers to a monocyclic 3- to 7-membered aromatic or non-aromatic monocyclic cycloalkyl group in which one of the cycloalkyl group's ring carbon atoms has been replaced with a nitrogen atom and 0-4 of the cycloalkyl group's remaining ring carbon atoms are independently replaced with a N, O or S atom. The nitrogen-containing 3- to 7-membered monocyclic heterocycles can be attached via a nitrogen or carbon atom. Representative examples of nitrogen-containing 3- to 7-membered monocyclic heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, piperidonyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrimidinyl, morpholinyl, furuzanyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, pyrazolidinyl and thiomorpholinyl.

[0102] In one embodiment, the nitrogen-containing 3- to 7-membered monocyclic heterocycle is fully saturated or partially saturated.

[0103] In another embodiment, the nitrogen-containing 3- to 7-membered monocyclic heterocycle is substituted with one or more of -halo, -CF 3 , -CN, -OH, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy or -OCF 3 . Unless otherwise indicated, the nitrogen-containing 3- to 7-membered monocyclic heterocycle is unsubstituted.

[0104] A "nitrogen containing 4- to 6-membered nonaromatic heterocycle" refers to a monocyclic 4- to 6-membered nonaromatic monocyclic cycloalkyl group in which one of the cycloalkyl group's ring carbon atoms has been replaced with a nitrogen atom and 0-3 of the cycloalkyl group's remaining ring carbon atoms are independently replaced with a N, O or S atom. The nitrogen-containing 4- to 6-membered nonaromatic heterocycles can be attached via a nitrogen or carbon atom. Representative examples of nitrogen-containing 4- to 6- membered nonaromatic heterocycles include, but are not limited to, azetidinyl, piperidinyl, oxazinyl, morpholinyl, imidazolidinyl, pyrazolidinyl and thiomorpholinyl.

[0105] A "3- to 7-membered monocyclic heterocycle" refers to a monocyclic 3- to 7- membered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom. The 3- to 7- membered monocyclic heterocycles can be attached via a nitrogen or carbon atom. Representative examples of a 3- to 7-membered monocyclic heterocycle group include, but are not limited to, nitrogen-containing 3- to 7-membered monocyclic heterocycles discussed above, tetrahydrofuranyl, dihydrofuranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, dioxanyl, dithianyl, trithianyl, dioxolanyl, furanyl and thiophenyl. In one embodiment, the 3- to 7-membered monocyclic heterocycle is a nitrogen-containing 3- to 7-membered monocyclic heterocycle. In another embodiment, the 3- to 7-membered monocyclic heterocycle is saturated or partially saturated.

[0106] The terms "halogen" or "halo" refer to chlorine, bromine, fluorine or iodine.

[0107] "Halo-substituted C 1 -C 4 alkyl" refers to a C 1 -C 4 alkyl group, as defined above, wherein one or more of the C 1 -C 4 alkyl group's hydrogen atoms have been replaced with -F, - CI, -Br or -I. Examples of a halo-substituted C 1 -C 4 alkyl include, but are not limited to, -CH 2 F, -CCI 3 , -CF 3 , -CH 2 CI, -CH 2 CH 2 Br, -CH 2 CH 2 I, -CF 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 C1, -CH 2 CH 2 CH 2 CH 2 Br, -CH 2 CH 2 CH 2 CH 2 I, -CH 2 CH(Br)CH 3 , -CH 2 CH(C1)CH 2 CH 3 , - CH(F)CH 2 CH 3 and -C(CH 3 ) 2 (CH 2 C1).

[0108] "Amino-substituted C 1 -C 4 alkyl" refers to a C 1 -C 4 alkyl group, as defined above, wherein one or more of the C 1 -C 4 alkyl group's hydrogen atoms have been replaced with - NH 2 . Examples of amino-substituted C 1 -C 4 alkyl include, but are not

limited to, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH(NH 2 )CH 3 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH(NH 2 )CH 3 , -CH 2 CH(NH 2 )CH 2 CH 3 , -CH(NH 2 )CH 2 CH 3 and -C(CH 3 ) 2 (CH 2 NH 2 ). [0109] "Halo-substituted phenyl" refers to a phenyl group, wherein one or more of the phenyl group's hydrogen atoms have been replaced with -F, -Cl,-Br or -I. The one or more - F,

-Cl,-Br or -I can be in ortho, meta and/or para position. Representative examples of halo- substituted phenyl include, but are not limited to, -C 6 H 4 F, -C 6 H 3 CIF, -CH 3 CI 2 , -C 6 H 2 F 3 , -C 6 HC1 4 , -C 6 H 2 FC1I and -C 6 F 5 .

[0110] A "C 1 -C 4 alkylene -phenyl" refers to a C 1 -C 4 alkyl group, as defined above, wherein one of the C 1 -C 4 alkyl group's hydrogen atoms has been replaced with phenyl.

[0111] "Hydroxy-substituted C 1 -C 4 alkyl" refers to a C 1 -C 4 alkyl group, as defined above, wherein one or more of the C 1 -C 4 alkyl group's hydrogen atoms have been replaced with - OH. Representative examples of a hydroxy-substituted C 1 -C 4 alkyl include, but are not limited to,

-CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH(OH)CH 3 ,

-CH 2 CH(OH)CH 2 CH 3 , -CH(OH)CH 2 CH 3 and -C(CH 3 ) 2 (CH 2 OH).

[0112] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0113] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the Fused Morpholinopyrimidine from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being comingled with the compounds described herein, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0114] The compounds described herein may form salts which are also within the scope of this invention. Reference to a compound described herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound described herein contains both a basic moiety, such as, but not limited to, amine, pyridine or imidazole and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compounds described herein may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium, such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0115] The compounds described herein which contain a basic moiety, such as, but not limited to, an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2- hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates,

phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates, such as tosylates, undecanoates and the like.

[0116] The compounds described herein which contain an acidic moiety, such as, but not limited to, a carboxylic acid, may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts, such as sodium, lithium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases (for example, organic amines), such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D- glucamines, N-methyl-D-glycamides, t-butyl amines and salts with amino acids, such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents, such as lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0117] Prodrugs and solvates of the compounds described herein are also contemplated herein. The term "prodrug" as employed herein denotes a compound that, upon

administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound described herein, or a salt and/or solvate thereof. Solvates of the compounds described herein include, for example, hydrates.

[0118] Compounds described herein are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 97%, equal to or greater than 98%, or equal to or greater than 99% of the compounds

("substantially pure" compounds), which is then used or formulated as described herein. Such "substantially pure" compounds described herein are also contemplated herein as part of the present invention.

[0119] All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected,

stereoisomers. The chiral centers of the compounds described herein may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0120] If, for instance, a particular enantiomer of a compound described herein is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0121] All configurational isomers of the compounds described herein are contemplated, either in admixture or in pure or substantially pure form. Certain compounds described herein may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, cis (Z) and trans (E) alkene isomers R- and ^-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0122] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[0123] Throughout the specifications, groups and substituents thereof may be chosen to provide stable moieties and compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example, of infectious diseases or proliferative disorders. The term "stable", as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein. [0124] Definitions of specific functional groups and chemical terms are described in more detail above. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999, the entire contents of which are incorporated herein by reference.

[0125] In some embodiments, the present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, U C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F and 36 C1, respectively. Compounds described herein, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, which contain the aforementioned isotopes and/or other isotopes of other atoms, are within the scope of this invention. Certain isotopically labeled compounds described herein, for example those into which radioactive isotopes, such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes, such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence, may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0126] When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.

[0127] As used herein, "effective amount" refers to any amount that is necessary or sufficient for achieving or promoting a desired outcome, e.g., for treating, preventing, or ameliorating a symptom of a neurodegenerative disease. In some instances an effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount that is necessary or sufficient for promoting or achieving a desired biological response in a subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition.

[0128] As used herein, "treat" or "treating" includes reducing a symptom of a

neurodegenerative disease, for example, improving cognitive function.

[0129] As used herein, the term "subject" refers to a vertebrate animal. In one embodiment the subject is a mammal. In one embodiment the subject is a human. In other embodiments the subject is a non-human vertebrate animal, including, without limitation, non-human primates, laboratory animals, livestock, domesticated animals and non- domesticated animals. Non-limiting examples of subject include a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, and non-human primate, such as a monkey, chimpanzee, baboon or rhesus. In one embodiment, the subject is a human.

[0130] Practitioners of the art will recognize that certain chemical groups may exist in multiple tautomeric forms (for example, as an amide or imino ether). The scope of this disclosure is meant to include all such tautomeric forms. For example, a tetrazole may exist in two tautomeric forms, 1-H tetrazole and a 2-H tetrazole. This is depicted in the figure below. This example is not meant to be limiting in the scope of tautomeric forms.

N ' n

H

[0131] Practitioners of the art will recognize that certain electrophilic ketones, may exist in a hydrated form. The scope of this disclosure is to include all such hydrated forms. For example, a trifluoromethyl ketone may exist in a hydrated form via addition of water to the carbonyl group. This is depicted in the figure below. This example is not meant to be limiting in the scope of hydrated forms.

R CF.. . HsO R CF-:,

Abbreviations

[0132] Abbreviations used in the following examples and preparations include: Αβ Amyloid-beta

Ac Acyl (Me-C(O)-)

ACN Acetonitrile

AD Alzheimer's Disease

APP Amyloid Precursor Protein

Aq Aqueous

BINAP 2,2'-Bis(diphenylphosphino)-l,r-bmaphthy

Boc tert-Butoxycarbonyl

Bn Benzyl

BSA Bovine Serum Albumin

Bu Butyl

c Cyclo

cBu Cylcobutyl

Cone. Concentrated

cPr Cyclopropyl

CSF Cerebrospinal Fluid

dba Dibenzylideneacetone

DCE 1 , 2-Dichloroethane

DCM Dichloromethane

DEA Di-ethylamine

DIAD Diisopropyl Azodicarboxylate

DIPEA N, N-Diisopropylethylamine

DME 1 ,2-Dimethoxyethane

DMF D imethy lformamide

DMP Dess-Martin Periodinane

DMSO Dimethyl Sulfoxide

DPPA Diphenoxyphosphoryl Azide

dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene

ELISA Enzyme -Linked Immuno Sorbent Assay

Et Ethyl

Et 3 N Triethylamine

Eq. Equivalent

ESI Eiectrospray Ionization g Grams(s)

HPLC High Pressure Liquid Chromatography

h Hour(s)

IPA Isopropyl Alcohol

iPr Isopropyl

i.v or IV. Intravenous

LAH Lithium Aluminum Hydride

LC-MS Liquid Chromatography-Mass Spectrometry

LG Leaving Group

m Multiplet

MeOH Methyl Alcohol or Methanol

min Minute(s)

mmol Millimoles

μΐ Microliter

ul Microliter

μηι Micrometer

Ms Mesylate

MS Mass Spectrometry

MW Molecular Weight (all values are ±0.05)

n Normal

N Normal

NBS N-Bromosuccinimide

NMP 1 -Methylpyrrolidin-2-one

NMR Nuclear Magnetic Resonance

NSAIDS Non-Steroidal Anti-Inflammatory Drugs

o/n Overnight

PBS Phosphate Buffered Saline

PMB Para-Methoxybenzyi

RT (or rt) Room Temperature (about 20-25°C) or Retention Time s Singlet

sat. Saturated

t Triplet

tert Tertiary TEA Triethylamine

t-Bu Tertiary Butyl

TFA Trifluoro acetic Acid

Tf Triflate

THF Tetrahydrofuran

TLC Thin Layer Chromatography

TMS Trimethylsilyl

TPP Triphenylphosphine

Ts Tosylate

UPLC Ultra Performance Liquid Chromatography

v/v Volume/volume

wt/v Weight/volume

4.2 Fused Morpholinopyrimidines

[0133] Described below are Fused Morpholinopyrimidines, i.e., compounds according to Formula (I) and Formula (Γ) and pharmaceutically acceptable salts thereof, as well as methods for preparing the compounds and using the compounds to treat one or more neurodegenerative diseases, e.g., reducing a symptom of Alzheimer's disease (such as improving cognitive function). The compounds of the disclosure are believed to be gamma secretase modulators (GSMs), i.e., compounds that act to shift the relative levels of Αβ peptides produced by γ-secretase. In some embodiments, the compounds alter the relative levels of Αβ peptides produced by γ-secretase, for example the level of Αβ42 peptide, without significantly changing the total level of Αβ peptides produced.

[0134] In one aspect, described herein are compounds according to Formula (I), below:

(I) and pharmaceutically acceptable salts thereof,

wherein R, Y and Z are as defined above for the compounds of Formula (I). [0135] In some embodiments, Z is pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 .

[0136] In some embodiments, Y is azetidinyl or piperidinyl, each of which is

unsubstituted or substituted with oxo.

[0137] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -CF 3 and -OCF 3 .

[0138] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -CF 3 and -OCF 3 ; Y is azetidinyl or piperidinyl, each of which is unsubstituted or substituted with oxo; and Z is pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 .

[0139] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting -halo, -C 1 -C 4 alkyl, - CF 3 and -OCF 3 ;

Y is piperidinyl; and Z is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from -halo and -C 1 -C 4 alkoxy.

[0140] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -CF 3 and -OCF 3 .

[0141] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -CF 3 and -OCF 3 ; and Z is pyridinyl which is unsubstituted or substituted with one or more - C 1 -C 4 alkoxy.

[0142] In some embodiments, R is phenyl substituted with -CI, -CF 3 or -F.

[0143] In some embodiments, R is phenyl substituted with one -F.

[0144] In some embodiments, R is phenyl substituted with two -F.

[0145] In some embodiments, R is phenyl substituted with three -F.

[0146] In some embodiments, R is phenyl substituted with one -CI.

[0147] In some embodiments, R is phenyl substituted with one -halo and one -CF 3 .

[0148] In some embodiments, R is phenyl substituted with one -F and one -CF 3 . [0149] In some embodiments, R is phenyl substituted with one -CI and one -CF 3 .

[0150] In some embodiments, R is phenyl substituted with one -OCF 3 .

[0151] In some embodiments, R is phenyl substituted with one -halo and one -OCF 3

[0152] In some embodiments, R is phenyl substituted with one -F and one - OCF 3 .

[0153] In some embodiments, R is phenyl substituted with one -CI and one -OCF 3 .

[0154] In some embodiments, R is -Ci-C 6 alkyl substituted with three -F.

[0155] In some embodiments, at least one -C 1 -C 4 alkyl is methyl.

[0156] In some embodiments, R is phenyl substituted with one methyl.

[0157] In some embodiments, Y is azetidinyl or piperidinyl, each of which is

unsubstituted or substituted with oxo.

[0158] In some embodiments, Y is piperidinyl unsubstituted or substituted with oxo.

[0159] In some embodiments, Y is piperidinyl.

[0160] In some embodiments, Y is azetidinyl.

[0161] In some embodiments, Z is pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 .

[0162] In some embodiments, Z is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 .

[0163] In some embodiments, Z is pyridinyl substituted with one CI.

[0164] In some embodiments, Z is pyridinyl substituted with one methoxy.

[0165] In some embodiments, Z is pyridinyl substituted with one methyl.

[0166] In some embodiments, Z is pyrimidinyl which is unsubstituted or substituted with one to three -C 1 -C 4 alkyl or -C 1 -C 4 alkoxy.

[0167] In some embodiments, Z is pyrimidinyl substituted with one methyl.

[0168] In some embodiments, Z is pyrimidinyl substituted with one methoxy.

[0169] In some embodiments, Z is pyridazinyl.

[0170] In some embodiments, Z is attached to Y at the 4 position of Y. In some embodiments, Z is attached to Y at the 4 position of Z. In some embodiments, Z is attached to Y at the 1 position of Z.

[0171] In some embodiments, the compound of Formula (I) is a compound selected from the compounds in Table I. Table I. Exemplary Fused Morpholinopyrimidines

[0172] In one aspect, the invention provides a compound of Formula (Γ)

( )

or a pharmaceutically acceptable salt thereof, wherein: R is phenyl, -C 1 -C 4 alkylene-phenyl or -Ci-C 6 alkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -CN, -NH 2 , -C 1 -C 4 alkyl, halo- substituted C 1 -C4 alkyl, amino-substituted C r C 4 alkyl, -NH-C C 4 alkyl, -NHC(0)-C C 4 alkyl,

-C(0)N(Ci-C 4 alkyl) 2 , -C(0)NH-Ci-C 4 alkyl, -C(0)N(Ci-C 4 alkyl) 2 , hydroxy-substituted Ci- C 4 alkyl, -S(0) 2 -Ci-C 4 alkyl, -S(0) 2 -halo-substituted C1-C4 alkyl, -S(0) 2 - H-Ci-C 4 alkyl, - S(0) 2 -N(Ci-C 4 alkyl) 2 , - H-S(0) 2 -Ci-C 4 alkyl, -N(C C 4 alkyl)-S(0) 2 -Ci-C 4 alkyl, -C C 4 alkoxy, halo-substituted C 1 -C 4 alkoxy, 3- to 7-membered monocyclic heterocycle, C 3 -C 8 monocyclic cycloalkyl and -C(0)NH 2 ; Y is 4- to 6- membered nitrogen-containing nonaromatic heterocycle, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, oxo, -C 1 -C 4 alkoxy, halo-substituted C 1 -C 4 alkoxy, -C 1 -C 4 alkyl, halo-substituted C 1 -C 4 alkyl, amino-substituted C1-C4 alkoxy, -CN, (C1-C4 alkyl) 2 N-Ci-C 4 alkoxy, -NH-C1-C4 alkyl, -OH and -NH 2 ; Z is 5- to 6-membered nitrogen-containing heterocycle which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -NH 2 , -OH, - C 1 -C 4 alkyl, halo-substituted C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and 3- to 7-membered monocyclic heterocycle; each R 1 is mdependendently -H or -Ci-C 6 alkyl; and each R 2 is mdependendently -H or -Ci-C 6 alkyl, provided that at least one of R 1 and R 2 groups is -Ci-C 6 alkyl.

[0173] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -CN, -NH 2 , - C 1 -C 4 alkyl, halo-substituted C 1 -C 4 alkyl, amino-substituted C 1 -C 4 alkyl, -NH-C 1 -C 4 alkyl, - NHC(0)-Ci-C 4 alkyl, -C(0)N(Ci-C 4 alkyl) 2 , -C(0)NH-Ci-C 4 alkyl, -C(0)N(Ci-C 4 alkyl) 2 , hydroxy-substituted C1-C4 alkyl, -S(0) 2 -Ci-C 4 alkyl, -S(0) 2 -halo-substituted C1-C4 alkyl, - S(0) 2 -NH-Ci-C 4 alkyl, -S(0) 2 -N(d-C 4 alkyl) 2 , -NH-S(0) 2 -C C 4 alkyl, -N(C C 4 alkyl)- S(0) 2 -Ci-C4 alkyl, -C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, 3- to 7-membered monocyclic heterocycle, C 3 -C 8 monocyclic cycloalkyl and -C(0)NH 2 ; or a pharmaceutically acceptable salt thereof. [0174] In some embodiments, Z is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 .

[0175] In some embodiments, Y is piperidinyl which is unsubstituted.

[0176] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl and

-OCF 3 .

[0177] In some embodiments, R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -CF 3 and -OCF 3 ; Y is piperidinyl which is unsubstituted; Z is pyridinyl which is

unsubstituted or substituted with one or more substituents independently selected from the group consisting of

-halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 ; and each R 1 is independendently -H or -Ci-C 6 alkyl; and each R 2 is independendently -H or -Ci-C 6 alkyl.

[0178] In some embodiments, R is phenyl which is unsubstituted; Y is piperidinyl; and Z is pyridinyl which is substituted with one -C 1 -C 4 alkoxy.

[0179] In some embodiments, R is phenyl substituted with -CI, -CF 3 or -F.

[0180] In some embodiments, R is phenyl unsubstituted.

[0181] In some embodiments, at least one -C 1 -C 4 alkyl is methyl.

[0182] In some embodiments, Y is piperidinyl which is unsubstituted.

[0183] In some embodiments, Z is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy and -CF 3 .

[0184] In some embodiments, Z is pyridinyl which is substituted with one -C 1 -C 4 alkoxy.

[0185] In some embodiments, each R 1 is -H. In some embodiments, one R 1 is -H.

[0186] In some embodiments, each R 2 is -H. In some embodiments, one R 2 is -H.

[0187] In some embodiments, each of R 1 and R 2 is independendently -Ci-C 6 alkyl.

[0188] In some embodiments, each R 1 is independendently -Ci-C 6 alkyl and each R 2 is - H.

[0189] In some embodiments, each R 2 is independendently -Ci-C 6 alkyl and each R 1 is - H. [0190] In some embodiments, one R 1 is -H and the other R 1 is -Ci-C 6 alkyl and each R 2 is

-H.

[0191] In some embodiments, one R 2 is -H and the other R 2 is -Ci-C 6 alkyl alkyl and each R 1 is -H.

[0192] In some embodiments, each R 1 is methyl. In some embodiments, each R 2 is methyl.

[0193] In some embodiments, Z is attached to Y at the 4 position of Y. In some embodiments, Z is attached to Y at the 4 position of Z. In some embodiments, Z is attached to Y at the 1 position of Z.

[0194] In some embodiments, the compound of Formula (Γ) is a compound selected from the compounds in Table II.

Table II. Exemplary Fused Morpholinopyrimidines

4.3 Methods for Making Fused Morpholinopyrimidines

[0195] Methods useful for making the Fused Morpholinopyrimidines are set forth in the Examples below and generalized in Schemes 1-4.

[0196] Schemes 1-4 are general synthetic schemes for manufacturing Fused

Morpholinopyrimidines. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture compounds disclosed herein. Different methods will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound(s). All documents cited herein are incorporated herein by reference in their entirety. For example, the following reactions are illustrations but not limitations of the preparation of some of the starting materials and examples used herein. Throughout the schemes, R, R 1 , R 2 , Y and Z are as defined above for the compounds of Formula (I) and Formula (Γ).

[0197] Schemes 1-4 describe various methods for the synthesis of intermediates that may be used to prepare compounds described herein. Various modifications to these methods may be envisioned by those skilled in the art to achieve similar results to that of the inventors given below. For example, optional protecting groups can be used as described, for example, in Greene et al., Protective Groups in Organic Synthesis (3 rd ed. 1999).

Scheme 1 heteroc

[0198] As shown in Scheme 1, a compound of formula 1 can be coupled to the compound of formula 2 under standard coupling conditions to provide a compound of formula 3. The compound of formula 3 was deprotected to provide a compound of formula 4.

Scheme 2

sealed tube

[0199] As shown in Scheme 2, a compound of formula 5 can be reacted with a compound of formula 6 under basic conditions to provide a compound of formula 7. The compound of formula 7 can then be reacted with BBr 3 to provide a compound of formula 8. The compound of formula 8 can be reacted using, for example, l-bromo-2-chloroethane, to provide a compound of formula 9. The compound of formula 9 can then be reacted with compound of formula 4 to provide a Fused Morpholinopyrimidine of Formula (I).

Scheme 3 15 sealed tube 17

[0200] As shown in Scheme 3, a compound of formula 5 can be reacted with a compound of formula 10 under basic conditions to provide a compound of formula 11. The compound of formula 11 can then be reacted with BBr 3 to provide a compound of formula 12. The compound of formula 12 can then be reacted using, for example, di-tert-butyl dicarbonate, to provide a compound of formula 13. The compound of formula 13 can then be reacted using, for example, triphenylphosphine and diisopropyl azodicarboxylate, to provide a compound of formula 14. The compound of formula 14 can then be reacted with hydrochloric acid to provide a compound of formula 15. The compound of formula 15 can then be reacted with a compound of formula 16 to provide a compound of formula 17. The compound of formula 17 can then be reacted with compound of formula 4 to provide a Fused Morpholinopyrimidine of

Formula (Γ), wherein both R are -H.

Scheme 4

[0201] As shown in Scheme 4, a compound of formula 8 can be reacted with a compound of formula 18 under basic conditions to provide a compound of formula 19. The compound of formula 19 can then be reacted with BBr 3 to provide a compound of formula 17. The compound of formula 17 can then be reacted with compound of formula 4 to provide a Fused Morpholinopyrimidine of Formula (Γ), wherein both R 1 are -H.

4.4 Pharmaceutical Compositions Comprising a Fused Morpholinopyrimidine

[0202] In another aspect, the present disclosure provides pharmaceutical compositions for treating, preventing, or ameliorating a symptom of a neurodegenerative disease in a subject having a neurodegenerative disease, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Fused Morpholinopyrimidine, and a pharmaceutically acceptable carrier or vehicle. In some embodiments, a Fused Morpholinopyrimidine is in the form of a hydrate or a pharmaceutically acceptable salt.

[0203] As set out above, in some embodiments, Fused Morpholinopyrimidines are provided in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt," in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds described herein. These salts can be prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound described herein in its free base or acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate, ammonium, amine salts and the like. (See, for example, Berge, et ah, (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.)

[0204] The pharmaceutically acceptable salts of Fused Morpholinopyrimidines include the conventional nontoxic salts or acid salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids, such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids, such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric,

toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic and the like. [0205] In other cases, Fused Morpholinopyrimidines may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds described herein. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et ah, supra.)

[0206] In general a suitable dose of a Fused Morpholinopyrimidine will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.2 to 10 mg per kilogram body weight per day. The desired dose is preferably presented once daily, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.

[0207] The concentration of compounds included in compositions used in the methods described herein can range from about 1 nM to about 100 μΜ. Effective doses are believed to range from about 10 picomole/kg to about 100 micromole/kg.

[0208] A Fused Morpholinopyrimidine can be administered as the sole active agent, or in combination with other known therapeutics to be beneficial in the treatment of

neurodegenerative diseases. In any event, the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of drug administration on the basis of observations of one or more symptoms (e.g., motor or cognitive function as measured by standard clinical scales or assessments) of the disease being treated.

[0209] Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. ("Remington's"). After a pharmaceutical composition has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of a Fused Morpholinopyrimidine, such labeling would include, e.g., instructions concerning the amount, frequency and method of administration.

[0210] The pharmaceutical compositions described herein may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers, such as polyethylene glycols.

[0211] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymer, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the pharmaceutical compositions.

[0212] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

[0213] Methods of preparing these formulations or compositions include the step of bringing into association a compound described herein with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound described herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0214] When a Fused Morpholinopyrimidines is administered as pharmaceuticals to humans and animals, it can be given per se or as a pharmaceutical composition containing, for example, 0.1 % to 99.5% (more preferably, 0.5%> to 90%>) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0215] The compounds and pharmaceutical compositions described herein can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.

[0216] The pharmaceutical compositions described herein can be administered in a variety of dosage forms including, but not limited to, a solid dosage form, a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, a buccal dosage form, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof.

Oral Formulations and Administration

[0217] Pharmaceutical formulations described herein suitable for oral administration can be in the form of capsules, cachets, pills, tablets, caplet, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes and the like, each containing a predetermined amount of a compound described herein as an active ingredient. The dosage can be an oral dosage form that is a controlled release dosage form. A Fused Morpholinopyrimidine may also be administered as a bolus, electuary or paste.

[0218] In solid dosage forms described herein for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymer; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0219] A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0220] The tablets, and other solid dosage forms of the pharmaceutical compositions described herein, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0221] Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules, wherein the active ingredients is mixed with water or an oil, such as peanut oil, liquid paraffin or olive oil.

[0222] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0223] Liquid dosage forms for oral administration of the compounds described herein include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins, e.g., hydroxybutyl- -cyclodextrin, may be used to solubilize compounds.

[0224] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0225] Besides inert diluents, the oral compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0226] Pharmaceutical preparations for oral use can be obtained through combination of a Fused Morpholinopyrimidine with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose, such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins, such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0227] Pharmaceutical preparations for oral use can be presented as aqueous or liposome formulations. Aqueous suspensions can contain a Fused Morpholinopyrimidine in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose,

hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents, such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.

[0228] Oil suspensions can be formulated by suspending a Fused Morpholinopyrimidine in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant, such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997. The pharmaceutical formulations can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum

tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and

condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

Formulations for Parenteral Formulations and Administration

[0229] In another embodiment, a Fused Morpholinopyrimidine can be administered parenterally, such as intravenous (IV) or intramuscular (IM) administration. The

formulations for administration will commonly comprise a solution of a Fused

Morpholinopyrimidine dissolved in a pharmaceutically acceptable carrier. Administration of a Fused Morpholinopyrimidine to any of the above mentioned sites can be achieved by direct injection of the pharmaceutical composition comprising the Fused Morpholinopyrimidine or by the use of infusion pumps. The pharmaceutical compositions may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms are also included. The injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.

[0230] Pharmaceutical compositions of this invention suitable for parenteral

administration comprise one or more compounds described herein in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0231] Among the acceptable vehicles and solvents that can be employed for formulation and/or reconstitution are water (e.g., water for injection) and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques such as gamma-radiation or electron beam sterilization. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of a Fused Morpholinopyrimidine in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of

administration selected and the subject's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0232] In some embodiments, a Fused Morpholinopyrimidine can be administered by introduction into the central nervous system of the subject, e.g., into the cerebrospinal fluid of the subject. The formulations for administration will commonly comprise a solution of the Fused Morpholinopyrimidine dissolved in a pharmaceutically acceptable carrier. In certain aspects, the Fused Morpholinopyrimidine is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar region, or the cisterna magna.

[0233] In some embodiments, the pharmaceutical composition comprising a Fused Morpholinopyrimidine is administered into a subject intrathecally. As used herein, the term "intrathecal administration" is intended to include delivering a pharmaceutical composition comprising a Fused Morpholinopyrimidine directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebroventricular injection through a borehole or cisternal or lumbar puncture or the like (described in Lazorthes et al. Advances in Drug Delivery

Systems and Applications in Neurosurgery, 1991, 18:143-192 and Omaya et al., Cancer Drug Delivery, 1984, 1 : 169-179, the contents of which are incorporated herein by reference). The term "lumbar region" is intended to include the area between the third and fourth lumbar (lower back) vertebrae. The term "cisterna magna" is intended to include the area where the skull ends and the spinal cord begins at the back of the head. The term "cerebral ventricle" is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord. In some embodiments, the pharmaceutical composition is administered by injection into the cisterna magna, or lumbar area of a subject.

Depot Formulations and Administration

[0234] A Fused Morpholinopyrimidine can also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0235] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. One strategy for depot injections includes the use of polyethylene oxide-polybutylene oxide copolymers, wherein the vehicle is fluid at room temperature and solidifies at body temperature.

[0236] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers, such as polylactide-polyglycolide.

Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.

Intranasal Formulations and Administration

[0237] For administration by inhalation, the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,

dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

Other Formulations and Modes of Administration

[0238] For transmucosal administration (e.g., buccal, rectal, nasal, ocular, etc.), penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0239] Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the

compounds, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid and polyanhydrides.

Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075,109. Delivery systems also include non-polymer systems that are: lipids including sterols, such as cholesterol, cholesterol esters and fatty acids or neutral fats, such as mono-, di- and tri-glycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like. Specific examples include, but are not limited to: (a) erosional systems in which an agent described herein is contained in a form within a matrix, such as those described in U.S. Pat. Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer, such as described in U.S. Pat. Nos. 3,854,480, 5,133,974 and 5,407,686. In addition, pump-based hardware delivery systems can be used, some of which are adapted for implantation.

4.5 Treatment, Prevention or Amelioration of Symptoms of a

Neurodegenerative Disease

[0240] In another aspect, a method for treating a neurodegenerative disease is described, comprising administering to a subject an effective amount of the compound or

pharmaceutical composition or formulation thereof as described herein.

[0241] In some embodiments, the method for treating a neurodegenerative disease is a method for reducing or ameliorating a symptom of the neurodegenerative disease.

[0242] In some embodiments, a method for reducing or ameliorating a symptom of a neurological disease is described, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine. Ameliorating or reducing the symptoms can be manifested in a variety of ways, for example by improvement in cognitive function.

[0243] Exemplary symptoms of neurological disease that can be reduced or ameliorated by administration of a Fused Morpholinopyrimidine are loss of memory, loss of cognition, loss of reasoning and/or loss of judgment. The loss of each of memory, cognition, reasoning and/or judgment can be progressive or sudden. Dementia is an exemplary symptom of neurodegenerative disease. Administration of a Fused Morpholinopyrimidine can reduce or improve one or more of these symptoms.

[0244] Exemplary cognitive functions that can be improved by administration of a Fused Morpholinopyrimidine are attention, learning, delayed memory, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.

[0245] In one embodiment, the neurodegenerative disease is Alzheimer's disease. In some embodiments, the neurodegenerative disease is early onset Alzheimer's disease. In some embodiments, the early onset Alzheimer's disease is autosomal dominant early onset Alzheimer's disease. [0246] In some embodiments, the subject is 65 years or older. In some embodiments, the subject is 55 years old or younger, or 50 years old or younger. In some embodiments, the subject us older than 55 years and younger than 65 years. In some embodiments, the subject is older than 55 years.

[0247] In some embodiments, the neurodegenerative disease is panic disorder, obsessive compulsive disorder, delusional disorder, drug-induced psychosis, post-traumatic stress disorder, age-related cognitive decline, attention deficit/hyperactivity disorder, personality disorder of the paranoid type, personality disorder of the schizoid type, dyskinesia, choreiform condition, psychosis associated with Parkinson's disease, psychotic symptoms associated with Alzheimer's disease, mood disorder, or dementia.

[0248] In some embodiments, the neurodegenerative disease is cognitive impairment, myclonus, seizures, Parkinsonism, extrapyramidal signs (EPS), apraxia, dystonia, dementia with Lewy bodies (DLB), aphasia, visual agnosia, or ataxia.

[0249] In some embodiments, the subject has impaired cognitive function including one or more of attention, learning, delayed memory, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.

[0250] In some embodiments, the subject has a mutation in at least one gene selected from PSEN1, PSEN2 and APP. In some embodiments, the mutation in PSEN1, PSEN2 or APP is a missense mutation.

[0251] In some embodiments, the invention provides a method for treating or

ameliorating a symptom of neurodegenerative disease (e.g., Alzheimer's disease) in a subject with an increased level of Αβ42 in cerebrospinal fluid, the method comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine. In such subject, the increased level of Αβ42 in cerebrospinal fluid can be detected relative to the level of Αβ42 in cerebrospinal fluid of a healthy subject.

[0252] In some embodiments, the invention provides a method for lowering Αβ42 concentration in a subject, the method comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine. In some embodiments, the subject has an elevated Αβ42 concentration relative to a healthy subject.

[0253] In some embodiments, the invention provides a method for preventing increase of Αβ42 concentration in a subject, the method comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine. 4.6 Kits

[0254] Described herein are kits that can simplify the administration of an Fused

Morpholinopyrimidine to a subject. The kit can comprise one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein.

Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0255] A typical kit comprises a unit dosage form of a Fused Morpholinopyrimidine. In one embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of a Fused Morpholinopyrimidine and a pharmaceutically acceptable carrier or vehicle. The kit can further comprise a label or printed instructions instructing the use of the Fused Morpholinopyrimidine to treat or prevent a neurodegenerative disease. The kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of the other prophylactic or therapeutic agent. In one embodiment, the kit comprises a container containing an effective amount of a Fused Morpholinopyrimidine and an effective amount of another prophylactic or therapeutic agent. Examples of other prophylactic or therapeutic agents include, but are not limited to, those listed above.

[0256] The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art.

[0257] The following examples contain additional information, exemplification and guidance which can be adapted to the practice of this invention in its various embodiments and equivalents thereof. The examples do not limit the scope of the invention described in the claims. 5. EXAMPLES

Example 1

Synthesis of l-(pyridazin-4-yl) piperidin-4-amine hydrochloride

Synthesis of tert-Butyl (l-(6-chloropyridazin-4-yl) piperidin-4-yl) carbamate

[0258] To a stirred solution of 3, 5-dichloropyridazine (1.2 g, 8.05 mmol) in NMP (12 mL) under argon atmosphere were added tert-butyl piperidin-4-yl-carbamate (1.6 g, 8.05 mmol), and DIPEA (1.4 mL, 8.05 mmol). The mixture was purged under argon for 20 min at RT then stirred at 80 °C for 4 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-Butyl (l-(6-chloropyridazin-4-yl) piperidin- 4-yl) carbamate (2.3 g) as a thick black liquid was used without further purification. 1H-NMR (CDCls, 400 MHz): δ 8.72 (s, 1H), 6.67 (s, 1H), 4.59 (br s, 1H), 3.91-3.82 (m, 2H), 3.80-3.71 (m, 1H), 3.09-3.05 (m, 2H), 2.35-2.39 (m, 2H), 2.13-2.11 (m, 2H), 1.45 (s, 9H); LC-MS: 313.4 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μ); RT 3.58 min. 5 mM NH 4 OAc: ACN; 0.80 mL/min); TLC: 60% EtOAc:hexanes (R/. 0.3).

Synthesis of tert-Butyl (1 -(pyridazin-4-yl) piperidin-4-yl) carbamate

[0259] To a stirred solution of tert-Butyl (l-(6-chloropyridazin-4-yl) piperidin-4-yl) carbamate (1.1 g, 3.52 mmol) in EtOH (80 mL) under argon atmosphere, were added 10% Pd/C (250 mg) and triethyl amine (0.5 mL, 3.52 mmol) at RT. The reaction was stirred under a Hydrogen atmosphere (balloon pressure) for 1 h. After consumption of the starting material (monitored by TLC), the reaction was filtered through celite and the filtrate was concentrated in vacuo. The crude material was triturated with ether (2 x 20 mL) to afford tert-Butyl (1- (pyridazin-4-yl) piperidin-4-yl) carbamate (480 mg, 49%) as an off-white solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 8.94-8.93 (m, 1H), 8.60-8.59 (m, 1H), 6.97-6.95 (m, 1H), 6.90-6.85 (m, 1H), 3.98-3.95 (m, 2H), 3.55-3.53 (m, 1H), 3.08-3.01 (m, 2H), 1.80-1.75 (m, 2H), 1.40- 1.37 (m, 11H); LC-MS: 279.1 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μ); RT 2.29 min. 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 60% EtOAc:hexanes (R 0.3).

Synthesis of 1 -(pyridazin-4-yl) piperidin-4-amine hydrochloride

[0260] To a stirred solution of tert-Butyl (l-(pyridazin-4-yl) piperidin-4-yl) carbamate (450 mg, 1.61 mmol) in EtOAc (7 mL) under argon atmosphere was added 4M HC1 in EtOAc (1 mL) at 0 °C and stirred at RT for 1 h. After consumption of the starting material

(monitored by TLC), the volatile components were removed in vacuo. The crude material was washed with ether (2 x 10 mL) to afford l-(pyridazin-4-yl) piperidin-4-amine

hydrochloride (320 mg, HC1 salt) as an off-white solid. 1H-NMR (DMSO-<¾, 500 MHz): δ 8.98 (s, 1H), 8.82 (d, 1H,), 8.40 (br s, 2H), 7.41-7.39 (m, 1H), 4.40-4.38 (m, 2H), 3.45-3.30 (m, 3H), 2.10-2.08 (m, 2H), 1.65-1.62 (m, 2H); TLC: 60% EtOAc:hexanes (R 0.1).

Example 2 -(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride

Synthesis of tert-Butyl (l-(2-methoxypyridin-4-yl) piperidin-4-yl) carbamate

[0261] To a stirred solution of tert-Butyl piperidin-4-ylcarbamate (1.2 g, 6.38 mmol) in toluene (80 mL) under argon atmosphere were added 4-bromo-2-methoxypyridine (1.3 g, 6.38 mmol), sodium tert-Butoxide (1.8 g, 19.14 mmol) and Xantphos (220 mg, 0.06 mmol)l. The mixture was purged under argon for 20 min, then Pd 2 (dba) 3 (73 mg, 0.12 mmol) added. The reaction mixture was stirred at 90 °C for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified through silica gel column chromatography using 30% EtOAc:hexanes to afford tert-Butyl (l-(2-methoxypyridin-4-yl) piperidin-4-yl) carbamate (1 g, 53%) as an off-white solid. 1H-NMR (DMSO-<¾, 500 MHz): δ 7.77-7.75 (m, 1H), 6.83-6.82 (m, 1H), 6.52 (d, 1H), 6.08 (s, 1H), 3.80-3.75 (m, 5H), 3.47 (s, 1H), 2.86 (t, 2H), 1.75-1.73 (m, 2H), 1.38-1.30 (m, 11H); LC-MS: 308.3 (M+1); (column; X- Bridge C-18 (50 3.0 mm, 3.5 μ); RT 3.14 min. 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 45% EtOAc:hexanes (R 0.3).

Synthesis of l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride

[0262] To a stirred solution of tert-Butyl (l-(2-methoxypyridin-4-yl) piperidin-4-yl) carbamate (1 g, 3.25 mmol) in EtOAc (15 mL) under argon atmosphere was added 4M HC1- EtOAc (2 mL) at 0 °C. The reaction mixture was warmed to RT and stirred for 2 h. After consumption of the starting material (monitored by TLC), the volatile components were removed in vacuo. The crude material was washed with ether (2 x 20 mL) to afford l-(2- methoxypyridin-4-yl) piperidin-4-amine hydrochloride (950 mg) as an off-white solid which was used without further purification. 1H-NMR (DMSO-< 5 , 500 MHz): δ 8.34 (bs, 2H), 7.90- 7.89 (m, 1H), 6.88-6.87 (m, 1H), 6.50 (s, 1H), 4.26 (d, 2H), 4.02 (s, 3H), 3.40-3.39 (m, 1H), 3.24-3.19 (m, 2H), 2.06-2.04 (m, 2H), 1.60-1.54 (m, 2H); LC-MS: 208.1 (M+1); (column; X- Bridge C-18 (50 3.0 mm, 3.5 μ); RT 0.52 min. 0.05% aq TFA: ACN; 0.80 mL/min) TLC: 5% MeOH:CH 2 Cl 2 (R 0.1).

Example 3 -(2-chloropyridin-4-yl) piperidin-4-amine hydrochloride

Synthesis of tert-Butyl (4-(2-chloropyridin-4-yl) piperidine-4-yl) carbamate

[0263] To a stirred solution of 2-chloro-4-fluoropyridine (1.5 g, 11.40 mmol) in NMP (15 mL) under argon atmosphere were added tert-Butyl piperidin-4-ylcarbamate (2.7 g, 13.68 mmol) and DIPEA (1.9 ml, 14.82 mmol). The mixture was purged under argon for 15 min at

RT, then stirred at 150 °C for 2 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 50% EtOAc:hexanes to afford tert-Butyl (4-(2-chloropyridin-4-yl) piperidine-4-yl) carbamate (2.3 g, 65%) as a brown solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 7.90-7.89 (m, 1H), 6.83-6.79 (m, 2H), 3.85 (d, 2H), 3.49 (br s, 1H), 2.94 (t, 2H), 1.76-1.73 (m, 2H), 1.37 (s, 9H), 1.33-1.30 (m, 3H); LC-MS: 312 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 2.55 min. 0.05% aq TFA in water: ACN; 0.80 mL/min); TLC: 30% EtOAc:hexanes (R 0.2).

Synthesis of l-(2-chloropyridin-4-yl) piperidin-4-amine hydrochloride

[0264] To a stirred solution of tert- utyl (4-(2-chloropyridin-4-yl) piperidine-4-yl) carbamate (2.1 g, 3.20 mmol) in EtOAc (25 mL) under argon atmosphere was added 4M HCl-EtOAc (4 mL) at 0 °C. The reaction was warmed to RT and stirred for 2 h. After consumption of the starting material (monitored by TLC), the reaction was neutralized with a saturated NaHC0 3 solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford l-(2-chloropyridin-4-yl) piperidin-4-amine hydrochloride (950 mg, 67%) as an off- white solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 7.99-7.97 (m, 2H), 7.95-7.94 (m, 1H), 6.88 (s, 1H), 6.86-6.85 (m, 1H), 3.99 (d, 2H), 3.31-3.29 (m, 1H), 2.96 (t, 2H), 1.91 (d, 2H), 1.47-1.45 (m, 2H); LC-MS: 212.2 (M+l); (column; Eclipse XDB C18 (150 4.6 mm, 5 μπι); RT 7.92 min. 0.05% aq TFA: ACN; 1.00 mL/min); TLC: 50% EtOAc:hexanes (R 0.1).

Example 4

Synthesis of l-(pyrimidin-4-yl) piperidin-4-amine hydrochloride

NH 2 HCI

Synthesis of tert-butyl (l-(2-chloropyrimidin-4-yl) piperidin-4-yl) carbamate

[0265] To a stirred solution of 2, 4-dichloropyrimidine (2 g, 13.42 mmol) in DMF (20 mL) under argon atmosphere were added triethyl amine (2.03 g, 20.13 mmol) and tert-butyl piperidin-4-ylcarbamate (2.9 g, 14.76 mmol) at RT. The reaction was stirred for 18 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified through silica gel column chromatography using 50% EtOAc:hexanes to afford tert-butyl (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) carbamate (2.2 g, 53%) as an off-white solid. 1H- NMR (CDCls, 400 MHz): δ 8.03-8.02 (m, 1H), 6.40-6.39 (m, 1H), 4.49-4.29 (m, 3H), 3.74 (br s, 1H), 3.09-3.02 (m, 2H), 2.07-2.04 (m, 2H), 1.50 (s, 9H), 1.38-1.25 (m, 2H); LC-MS: 313.2 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 3.21 min. 5 mM

NH 4 OAc: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (R 0.6).

Synthesis of tert-butyl (1 -(pyrimidin-4-yl) piperidin-4-yl) carbamate

[0266] To a stirred solution of tert-butyl (l-(2-chloropyrimidin-4-yl) piperidin-4-yl) carbamate (2 g, 6.39 mmol) in EtOH (300 mL) were added 10% Pd/C (300 mg) and triethylamine (646 mg, 6.39 mmol) at RT. The mixture was stirred for 5 h under ¾ atmosphere (balloon pressure). After consumption of the starting material (monitored by TLC), the reaction was filtered through celite and concentrated in vacuo. The crude material was purified through silica gel column chromatography using 50% EtOAc:hexanes to afford tert-butyl (l-(pyrimidin-4-yl) piperidin-4-yl) carbamate (1 g, 56%) as an off-white solid. 1H- NMR (DMSO-< 5 , 400 MHz): δ 8.45 (s, 1H), 8.14-8.12 (m, 1H), 6.85-6.80 (m, 2H), 4.28-4.25 (m, 2H), 3.54 (br s, 1H), 3.02-2.95 (m, 2H), 1.79-1.76 (m, 2H), 1.35 (s, 9H), 1.32-1.23 (m, 2H); LC-MS: 279 (M+l); (column; X-Bridge C18 (50 3.0 mm, 3.5 μπι); RT 2.83 min. 5 mM NH 4 OAc: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (R 0.2).

Synthesis of 1 -(pyrimidin-4-yl) piperidin-4-amine hydrochloride

[0267] To a stirred solution of tert-butyl (l-(pyrimidin-4-yl) piperidin-4-yl) carbamate (1 g, 3.59 mmol) in EtOAc (10 mL) under argon atmosphere was added 4M HC1 in EtOAc (2 mL) at 0 °C. The mixture was warmed to RT and stirred for 2 h. After consumption of the starting material (monitored by TLC), the reaction was filtered through celite and

concentrated in vacuo to afford l-(pyrimidin-4-yl) piperidin-4-amine hydrochloride (700 mg, 94%) as a brown solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 8.8 (s, 1H), 8.35-8.33 (m, 2H), 7.24-7.22 (m, 1H), 4.14-4.12 (m, 2H), 3.40-3.30 (m, 3H), 2.11-2.06 (m, 2H), 1.62-1.54 (m, 2H); LC-MS: 179.2 (M+l); (column; Deltapak C-4 (150 x 3.9 mm, 5 μπι); RT 2.02 min. 0.05% aq TFA: ACN; 1.00 mL/min). TLC: 10% MeOH/ DCM (R 0.1). Example 5

Synthesis of l-(6-methylpyrimidin-4-yl) piperidin-4-amine hydrochloride HCI

Synthesis of tert-butyl (l-(6-methylpyrimidin-4-yl) piperidin-4-yl) carbamate

[0268] To a stirred solution of 4-chloro-6-methylpyrimidine (1 g, 7.77 mmol) in 1, 4- dioxane (30 mL) under argon atmosphere were added diisopropyl ethyl amine (1.35 g, 10.50 mmol) and tert-butyl piperidin-4-ylcarbamate (1.7 g, 8.55 mmol) at RT. The reaction mixture was stirred at 150 °C for 3 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified through silica gel column chromatography using 5% MeOH: DCM to afford tert-butyl (l-(6-methylpyrimidin-4-yl) piperidin-4-yl) carbamate (1.75 g, 77%) as an off-white solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 8.34 (s, 1H), 6.69 (s, 1H), 4.28-4.24 (m, 2H), 3.54-3.52 (m, 1H), 3.00-2.93 (m, 2H), 2.23 (s, 3H), 1.77-1.75 (m, 2H), 1.38 (s, 9H), 1.30-1.22 (m, 3H); LC-MS: 293.3 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 3.32 min. 5 mM NH 4 OAc: ACN; 0.80 mL/min); TLC: 50%

EtOAc:hexanes (R/. 0.2).

Synthesis of l-(6-methylpyrimidin-4-yl) piperidin-4-amine hydrochloride

[0269] To a stirred solution of tert-butyl (l-(6-methylpyrimidin-4-yl) piperidin-4-yl) carbamate (1.75 g, 5.13 mmol) in EtOAc (5 mL) under argon atmosphere was added 4M

HCI in EtOAc (4.5 mL) at 0 °C. The reaction was warmed to RT and stirred for 6 h. After consumption of the starting material (monitored by TLC), the reaction was filtered through celite and concentrated in vacuo to afford l-(6-methylpyrimidin-4-yl) piperidin-4-amine hydrochloride (1.1 g, 84%) as a brown solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 8.76 (s, 1H),

8.42 (bs, 2H), 7.19 (br s, 1H), 4.86-4.36 (m, 2H), 3.4-3.25 (m, 3H), 2.40 (s, 3H), 2.11-2.09

(m, 2H), 1.59-1.56 (m, 2H); LC-MS: 193.2 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μηι); RT 2.13 min. 5 mM NH 4 OAc: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (R/. 0.1).

Example 6

Synthesis of l-(2-methylpyrimidin-4-yl) piperidin-4-amine hydrochloride

150 °C, 3 h

Synthesis of tert-butyl (l-(2-methylpyrimidin-4-yl) piperidin-4-yl) carbamate

[0270] To a stirred solution of 4-chloro-2-methylpyrimidine (1 g, 7.77 mmol) in 1, 4- dioxane (30 mL) under a argon atmosphere were added diisopropyl ethyl amine (1.35 g, 10.50 mmol) and tert-butyl piperidin-4-ylcarbamate (1.7 g, 8.55 mmol) at RT. The reaction mixture was stirred at 150 °C for 3 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified through silica gel column chromatography using 5% MeOH: DCM to afford tert-butyl (l-(2-methylpyrimidin-4-yl) piperidin-4-yl) carbamate (1.5 g, 66%) as an off-white solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 8.04-8.02 (m, 1H), 6.83- 6.82 (m, 1H), 6.61-6.60 (m, 1H), 4.27-4.25 (m, 2H), 3.51 (s, 1H), 2.96-2.91 (m, 2H), 2.33 (s, 3H), 1.77-1.74 (m, 2H), 1.37 (s, 9H), 1.28-1.22 (m, 2H); LC-MS: 293.3 (M+1); (column; X- Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 2.90 min. 5 mM NH 4 OAc: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (R 0.2).

Synthesis of l-(2-methylpyrimidin-4-yl) piperidin-4-amine hydrochloride

[0271] To a stirred solution of tert-butyl (l-(2-methylpyrimidin-4-yl) piperidin-4-yl) carbamate (2.1 g, 7.18 mmol) in EtOAc (5 mL) under argon atmosphere was added 4M HCI in EtOAc (5 mL) at 0 °C. The reaction was warmed to RT and stirred for 6 h. After consumption of the starting material (monitored by TLC), the reaction was filtered through celite and concentrated in vacuo to afford l-(2-methylpyrimidin-4-yl) piperidin-4-amine hydrochloride (1 g, 61%) as a brown solid. 1H-NMR (DMSO-<¾, 500 MHz): δ 8.37 (bs, 2H), 8.29 -7.96 (d, 1H), 7.13-7.12 (d, 1H), 4.91-4.89 (m, 1H), 4.30-4.28m (m, 1H), 3.41-3.34 (m, 2H), 3.16-3.14 (m, 1H), 2.52 (s, 3H), 2.10-2.07 (m, 2H), 1.58-1.56 (m, 2H); LC-MS: 193.2 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 2.06 min. 5 mM NH 4 OAC: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (R/. 0.1).

Example 7 -(2-methylpyridin-4-yl) piperidin-4-amine hydrochloride

Synthesis of tert-butyl (l-(2-methylpyridin-4-yl) piperidin-4-yl) carbamate

[0272] To a stirred solution of 4-bromo-2-methylpyridine (2 g, 11.62 mmol) in toluene (200 mL) under argon atmosphere were added tert-butyl piperidin-4-ylcarbamate (2.56 g, 12.79 mmol), sodium tertiary butoxide (3.35 mg, 34.86 mmol) and Xantphos (403 mg, 0.69 mmol) at 0 °C. The reaction mixture was stirred while purging under argon for 20 min, then added Pd 2 (dba) 3 (212 mg, 0.23 mmol) and again purged under argon for 20 min. The reaction mixture was stirred at 50 °C for 5 h. After consumption of the starting material (monitored by TLC), the reaction was filtered through celite and the filtrate was concentrated in vacuo. The crude material was washed with hexane:ether: EtOAc (1 : 1 : 1, 2 x 30 mL) to afford tert-butyl (l-(2-methylpyridin-4-yl) piperidin-4-yl) carbamate (1.4 g, 41%) as a brown solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 8.01-7.99 (m, 1H), 6.83-6.80 (m, 1H), 6.67 (s, 1Η),6.64-6.60 (m, 1H), 3.87-3.79 (m, 2H), 3.53-3.48 (m, 1H), 2.88-2.83 (m, 2H), 2.30 (s, 3H), 1.79-1.73 (m, 2H), 1.40 (s, 9H), 1.29-1.26 (m, 2H); LC-MS: 292.1 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 2.49 min. 5 mM NH 4 OAc: ACN; 0.80 mL/min); TLC: 40%

EtOAc:hexanes (R 0.1).

Synthesis of l-(2-methylpyridin-4-yl) piperidin-4-amine hydrochloride [0273] To a stirred solution of tert-butyl (l-(2-methylpyridin-4-yl) piperidin-4-yl) carbamate (800 mg, 2.74 mmol) in EtOAc (8 mL) under argon atmosphere was added 4M HC1 in EtOAc (2 mL) at 0 °C. The reaction was stirred for 1 h, then warmed to RT and stirred for 2 h. After consumption of the starting material (monitored by TLC), the volatile components were removed in vacuo. The crude material was washed with ether (2 x 20 mL) to afford l-(2-methylpyridin-4-yl) piperidin-4-amine hydrochloride (600 mg, 96%) as an off- white solid. 1H-NMR (DMSO-<¾, 500 MHz): δ 8.22-8.16 (m, 3H), 7.10-7.07 (m, 2H), 4.21- 4.20 (m, 2H), 3.23-2.19 (m, 3H), 2.43 (s, 3H), 2.07-2.02 (m, 2H), 1.57-1.50 (m, 2H); LC-MS: 192.3 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 0.38 min. 5 mM

NH 4 OAc: ACN; 0.80 mL/min); TLC: 10% MeOH:CH 2 Cl 2 (R 0.1).

Example 8

Synthesis of 3-(2-methoxypyridin-4-yl) cyclobutanamine hydrochloride

90 °C, 12 h

Synthesis of tert-butyl (l-(2-methoxypyridin-4-yl) azetidin-3-yl) carbamate

[0274] To a stirred solution of tert-butyl azetidin-3-ylcarbamate (50 mg, 0.29 mmol) in 1, 4-dioxane (5 mL) under argon atmosphere were added 4-bromo-2-methoxypyridine (50 mg, 0.29 mmol), Xantphos (11.7 mg, 0.02 mmol), and cesium carbonate (236 mg, 0.72 mmol). The mixture was purged under argon for 15 min, then Pd(OAc) 2 (1.95 mg, 0.08 mmol) was added and stirred at 90 °C for 12 h. After consumption of the starting material (monitored by TLC), the volatile components were removed in vacuo. The crude material was purified by silica gel column chromatography using 40% EtOAc:hexanes to afford tert-butyl (l-(2- methoxypyridin-4-yl) azetidin-3-yl) carbamate (40 mg, 50%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.69-7.67 (m, 1H), 6.09-6.05 (m, 1H), 5.70 (s, 1H), 4.50 (br s, 1H), 4.21-4.19 (m, 2H), 3.80 (s, 3H), 3.75-3.69 (m, 2H), 1.43 (s, 9H); LC-MS: 280.3 (M+l);

(column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 3.88 min. 5 mM NH 4 OAc: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (R/. 0.4). Synthesis of 3-(2-methoxypyridin-4-yl) cyclobutanamine hydrochloride

[0275] To a stirred solution of tert-butyl (l-(2-methoxypyridin-4-yl) azetidin-3-yl) carbamate 210 mg, 0.75 mmol) in EtOAc (3 mL) under argon atmosphere was added 4M HC1 in EtOAc (0.2 mL) at 0 °C. The reaction was warmed to RT and stirred for 3 h. After consumption of the starting material (monitored by TLC), the volatile components were removed in vacuo to afford 3-(2-methoxypyridin-4-yl) cyclobutanamine hydrochloride (200 mg) as an off-white solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 8.99-8.97 (m, 2H), 7.84 (d, 1H), 6.42-6.40 (d, 1H), 6.18 (s, 1H), 4.46-4.40 (m, 2H), 4.29-4.24 (m, 2H), 4.20 (br s, 1H), 4.03 (s, 3H); LC-MS: 180 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 0.49 min. 0.05% TFA in water: ACN; 0.80 mL/min); TLC: 5% MeOH:CH 2 Cl 2 (R 0.1).

Example 9

Synthesis of l-(2-methylpyridin-4-yl) azetidin-3-amine

Synthesis of benzyl (l-(2-methylpyridin-4-yl) azetidin-3-yl) carbamate

[0276] To a solution of 4-bromo-2-methylpyridine 1 (598 mg, 2.90 mmol) in 1, 4- dioxane (15 mL) under argon atmosphere were added benzyl azetidin-3-ylcarbamate (500 mg, 2.90 mmol), Xantphos (132 mg, 0.22 mmol), Pd(OAc) 2 (25.3 mg, 0.11 mmol) and Cs 2 C0 3 (2.3 g, 7.26 mmol) at RT. The reaction mixture was stirred at 100 °C for 16 h. After consumption of the starting material (monitored by TLC), the reaction mixture was cooled to RT and volatile components were removed in vacuo. The residue was quenched with water and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford benzyl (l-(2-methylpyridin-4-yl) azetidin-3-yl) carbamate (0.35 g, 40%) as a white solid. 1 H-NMR (DMSO d 6 , 400 MHz): δ 7.96 (d, 2H), 7.38-7.31 (m, 5H), 6.21 (s, 1H), 6.14 (d, 1H), 5.04 (s, 2H), 4.44-4.41 (m, 1H), 4.14 (t, 2H), 3.64 (m, 2H), 2.26 (s, 3H); Mass (ESI): 298 [M+l];

TLC: 30% MeOH/DCM (R/. 0.3).

Synthesis of l-(2-methylpyridin-4-yl) azetidin-3 -amine

[0277] To a stirred solution of benzyl (l-(2-methylpyridin-4-yl) azetidin-3 -yl) carbamate (0.35 g, 1.17 mmol) in MeOH (20 mL) was added 10% Pd-C (75 mg). The suspension was stirred at RT for 3 h under H 2 atmosphere (balloon pressure). After consumption of the starting material (monitored by TLC), the reaction was filtered through celite and washed with MeOH (10 mL). The filtrate was concentrated in vacuo to afford l-(2-methylpyridin-4- yl) azetidin-3 -amine (200 mg) as a white solid which was used without further purification. 1H-NMR (DMSO d 6 , 400 MHz): δ 7.96 (d, 1H), 6.19 (s, 1H), 6.12 (d, 1H), 4.12-4.04 (m, 2H), 3.84-3.81 (m, 1H), 3.48-3.42 (m, 2H), 2.31 (s, 3H); Mass (ESI): 164 [M+l]; TLC: 30% MeOH/DCM (R f . 0.2).

Example 10

Synthesis of 2-chloro-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

CI X NT) sea e u e

Synthesis of 2-chloro-5-methoxy-N-phenylpyrimidin-4-amine

[0278] To a stirred solution of 2,4-dichloro-5-methoxypyrimidine (5 g, 28.0 mmol) in isopropyl alcohol (37.5 mL) under argon atmosphere were added aniline (2.61 g, 28.0 mmol) and DIPEA (37.5 mL, 210.6 mmol) at RT. The reaction mixture was heated to 120 °C for 17 h in a sealed tube. After completion of the reaction (monitored by TLC), the volatile components were removed in vacuo. The crude material was purified by silica gel column chromatography (30-100% EtOAc:hexane) to afford 2-chloro-5-methoxy-N- phenylpyrimidin-4-amine (4.5 g, 68%) as a yellow solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 9.26 (s, 1H), 7.93 (s, 1H), 7.74 (d, 2H), 7.34 (t, 2H), 7.08 (t, 1H), 3.94 (s, 3H). LC-MS: 236 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μιη); RT 3.37 min. 0.05% Aq TFA: ACN; 0.80 ml/min); UPLC (column; Acquity BEH C-18, 50 2.1mm, 1.7 μπι); RT 2.25 min. ACN: 0.025% TFA (Aq); 0.50 ml/min; TLC: 70% EtOAc:hexanes (R/. 0.3).

Synthesis of 2-chloro-4-(phenyl amino) pyrimidin-5-ol

[0279] To a stirred solution of 2-chloro-5-methoxy-N-phenylpyrimidin-4-amine (1 g, 4.23 mmol) in DCM (17.5mL) under argon atmosphere at 0 °C was added 1 M BBr 3 in DCM (8.9 mL, 93.6 mmol). The reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction was diluted with a saturated sodium bicarbonate solution (30 mL) and extracted with DCM (2 x 30 mL). The combined organic extracts were washed with water (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-4-(phenyl amino) pyrimidin-5-ol (760 mg, 81%) as a brown solid used without further purification. 1 H-NMR (DMSO- 6 , 500 MHz): δ 10.72 (br s, 1H), 9.08 (s, 1H), 7.78-7.77 (m, 2H), 7.71 (s, 1H), 7.33 (t, 2H), 7.06 (t, 1H). LC-MS: 222 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μιη); RT 3.11 min. 0.05% Aq TFA: ACN; 0.80 ml/min); UPLC (column; Acquity BEH C-18, 50 x 2.1mm, 1.7 μιη); RT 2.07 min. ACN: 0.025% TFA (Aq); 0.50 ml/min; TLC: 10% MeOH:DCM (R/. 0.3).

Synthesis of 2-chloro-8-phenyl-7 , 8-dihydro-6H-pyrimido [5, 4-bJ [I, 4] oxazine

[0280] To a stirred solution of 2-chloro-4-(phenyl amino) pyrimidin-5-ol (600 mg, 2.71 mmol) in DMF (6 mL) under argon atmosphere were added potassium carbonate (1.12 g, 8.14 mmol) and l-bromo-2-chloroethane (582 mg, 4.07 mmol) at RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2- chloro-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (550 mg, 82%) as a brown solid used without further purification. 1H-NMR (DMSO-< 5 , 500 MHz): δ 7.87 (s, 1H), 7.44 (s, 4H), 7.29-7.28 (m, 1H), 4.36-4.35 (m, 2H), 3.95-3.93 (m, 2H). LC-MS: 248 (M+l);

(column; X-Bridge C-18 (50 x 3.0 mm, 3.5 μιη); RT 3.23 min. 0.05% TFA in water: ACN; 0.80 ml/min); UPLC (column; Acquity BEH C-18, 50 x 2.1mm, 1.7 μιη); RT 2.17 min. ACN: 0.025% TFA (Aq); 0.50 ml/min; TLC: 10% MeOH: DCM (R/. 0.6).

Example 11 Synthesis of 2-chloro-8-(3,5-difluorophenyl)-7,8-dihydro-6H-pyrimido [5,4- b] [l,4]oxazine

Synthesis of 2-chloro-N-(3, 5-difluorophenyl)-5-methoxypyrimidin-4-amine

[0281] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (2 g, 11.23 mmol) in isopropyl alcohol (15 mL) under argon atmosphere were added 3, 5-difluoroaniline (1.4 g, 11.23 mmol) and N, N-diisopropylethylamine (15 mL) at RT. The reaction mixture was heated to 130 °C and stirred for 32 h in a sealed tube. After completion of the reaction (monitored by TLC), the volatile components were removed in vacuo. Water (200 mL) was added to the residue and extracted with CH 2 CI 2 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 30% EtOAc:hexanes to afford 2-chloro- N-(3,5-difluorophenyl)-5-methoxypyrimidin-4-amine (1.1 g, 36%>) as an off-white solid. 1H- NMR (OMSO-d 6 , 500 MHz): δ 9.60 (s, 1H), 8.01 (s, 1H), 7 ' .62-7 ' .56 (m, 2H), 6.83 (t, 1H), 3.81 (s, 3H); TLC: 50% EtOAc:hexanes (R/. 0.5).

Synthesis of 2-chloro-4-((3 , 5-difluorophenyl) amino) pyrimidin-5-ol

[0282] To a stirred solution of 2-chloro-N-(3,5-difluorophenyl)-5-methoxypyrimidin-4- amine (1.2 g, 4.42 mmol) in DCM (150 mL) under argon atmosphere at 0 °C was added 1 M BBr 3 in CH 2 CI 2 (1.2 mL). The reaction mixture was warmed to RT and stirred for 48 h. After completion of the reaction (monitored by TLC), the volatile components were removed in vacuo. A saturated sodium bicarbonate solution (20 mL) was added to the residue and extracted with CH 2 CI 2 (2 x 50 mL). The combined organic extracts were washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-4- ((3, 5-difluorophenyl) amino) pyrimidin-5-ol (900 mg, 80%>) as an off white solid used without further purification. 1H-NMR (DMSO-< 5 , 400 MHz): δ 11.00 (s, 1H), 9.51 (s, 1H), 7.80 (s, 1H), 7.69-7.60 (m, 2H), 6.87 (t, 1H); TLC: 50% EtOAc:hexanes (R/. 0.3).

Synthesis of 2-chloro-8-(3, 5-difluorophenyl) -7, 8-dihydro-6H-pyrimido [5, 4-bJ [I, 4] oxazine [0283] To a stirred solution of 2-chloro-4-((3, 5-difluorophenyl) amino) pyrimidin-5-ol (1.5 g, 5.83 mmol) in DMF (15 mL) under argon atmosphere were added potassium carbonate (2.4 g, 17.5 mmol) and l-bromo-2-chloroethane (1.25 g, 8.75 mmol) at RT and stirred for 8 h. After completion of the reaction (monitored by TLC), the reaction was diluted with water (200 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-8-(3,5- difluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazine (1.5 g, 90%) as an off white solid used without further purification. 1H-NMR (DMSO-< 5 , 400 MHz): δ 7.93 (s, 1H), 7.30 (d, 2H), 7.13 (t, 1H), 4.36-4.31 (m, 2H), 3.96-3.92 (m, 2H); TLC: 50% EtOAc:hexanes (Rf. 0.6).

Example 12

Synthesis of 2-chloro-8-(3,4,5-trifluorophenyl)-7,8-dihydro-6H-pyrimido [5,4- b] [l,4]oxazine

Synthesis of 2-chloro-5-methoxy-N-(3, 4, 5-trifluorophenyl) pyrimidin-4-amine

[0284] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (2 g, 11.20 mmol) in IPA (15 mL) under argon atmosphere were added 3, 4, 5-trifluoroaniline (1.65 g, 11.20 mmol) and diisopropyl ethyl amine (15 mL). The reaction was stirred at 120 °C for 48 h in a sealed tube. After completion of the reaction (monitored by TLC), the volatile components were removed in vacuo. The crude material was purified by silica gel column

chromatography using 45% EtOAc:hexanes to afford 2-chloro-5-methoxy-N-(3, 4, 5- trifluorophenyl) pyrimidin-4-amine (1.5 g, 41%) as a white solid. 1H-NMR (OMSO-d 6 , 500 MHz): δ 9.63-9.60 (m, 1H), 8.01 (s, 1H), 7.82-7.77 (m, 2H), 3.97 (s, 3H); LC-MS: 289.9 (M+l); (column; Eclipse XDB C-18 (150 4.6 mm, 5 μπι); RT 9.01 min. 0.05% Aq TFA: ACN; 1.0 mL/min); TLC: 50% EtOAc:hexanes (R/ 0.2). Synthesis of2-chloro-4-((3, 4, 5-trifluorophenyl) amino) pyrimidin-5-ol

[0285] To a stirred solution of 2-chloro-5-methoxy-N-(3, 4, 5-trifluorophenyl) pyrimidin-

4- amine (1.4 g, 4.84 mmol) in CH 2 CI 2 (245 mL) under argon atmosphere at 0 °C was added BBr 3 (6.7 mL, 72.6 mmol). The reaction was allowed to warm to RT and stirred for 48 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0 °C, quenched with methanol and the volatile components were removed in vacuo. The crude material was triturated with ether (2 x 20 mL) to afford 2-chloro-4-((3, 4, 5-trifluorophenyl) amino) pyrimidin-5-ol (1.5 g) as a white solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 10.98 (brs, 1H), 9.52 (s, 1H), 7.86-7.81 (m, 3H); LC-MS: 275.9 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 3.59 min. 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 80%

EtOAc:hexanes (R 0.2).

Synthesis of2-chloro-8-(3, 4, 5-trifluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-bJ [I, 4] oxazine

[0286] To a stirred solution of 2-chloro-4-((3, 4, 5-trifluorophenyl) amino) pyrimidin-5-ol (1.5 g) in DMF (20 mL) under argon atmosphere were added potassium carbonate (2.3 g, 16.35 mmol) and l-bromo-2-chloroethane (0.68 mL, 8.17 mmol) at RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was triturated with EtOAc (2 x 20 mL) to afford 2-chloro-8-(3, 4,

5- trif uorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (1 g, 63%>) as an off- white solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 7.94 (s, 1H), 7.54-7.51 (m, 2H), 4.33-4.32 (m, 2H), 3.95-3.90 (m, 2H); LC-MS: 302 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 3.65 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.39 min. ACN: 0.025% TFA (Aq); 0.50 mL/min; TLC: 50% EtOAc :hexanes (R 0.5).

Example 13

Synthesis of Intermediate 2-chloro-8-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4- b] [1,4] oxazine

Synthesis of 2-chloro-5-methoxy-N-(o-tolyl) pyrimidin-4-amine

[0287] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (2 g, 11.2 mmol) in isopropyl alcohol (15 mL) under argon atmosphere were added o-toluidine (1.2 g, 11.2 mmol) and DIPEA (15 mL, 84.3 mmol) at RT. The reaction mixture was heated to 120 °C for 17 h in a sealed tube. After completion of the reaction (monitored by TLC), the volatile components were removed in vacuo. The crude residue was purified by silica gel column chromatography (30-100% EtOAc:hexanes) to afford 2-chloro-5-methoxy-N-(o-tolyl) pyrimidin-4-amine (1.5 g, 54%) as an off-white solid. 1H-NMR (CDC1 3 , 500 MHz): δ 8.07 (d, 1H), 7.71 (s, 1H), 7.29-7.25 (m, 1H), 7.22 (d, 1H), 7.12-7.07 (m, 2H), 3.98 (s, 3H), 2.31 (s, 3H). LC-MS: 250 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 3.39 min. 0.05% Aq TFA: ACN; 0.80 ml/min); UPLC (column; Acquity BEH C-18, 50 2.1mm, 1.7 μπι); RT 2.27 min. ACN: 0.025% TFA (Aq); 0.50 ml/min; TLC: 70% EtOAc:hexanes (R/. 0.3).

Synthesis of 2-chloro-4-(o-tolylamino) pyrimidin-5-ol

[0288] To a stirred solution of 2-chloro-5-methoxy-N-(o-tolyl) pyrimidin-4-amine (100 mg, 0.40 mmol) in DCM (2 mL) under argon atmosphere at 0 °C was added 1M BBr 3 in DCM (4 mL, 4.01 mmol). The reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction was diluted with a sodium bicarbonate solution (10 mL) and extracted with DCM (2 x 10 mL). The combined organic extracts were washed with water (10 mL), dried over sodium sulfate, filtered and

concentrated in vacuo to afford 2-chloro-4-(o-tolylamino) pyrimidin-5-ol (70 mg, 74%) as a brown solid used without further purification.1H-NMR (DMSO-<¾, 500 MHz): δ 10.55 (s, 1H), 8.62 (s, 1H), 7.64 (s, 1H), 7.37 (d, 1H), 7.26-7.24 (m, 1H), 7.22-7.18 (m, 1H), 7.14-7.12 (m, 1H), 2.16 (s, 3H). LC-MS: 236 (M+l); (column; X-Bridge C-18 (50 x 3.0 mm, 3.5 μιη); RT 3.09 min. 0.05% Aq TFA: ACN; 0.80 ml/min); UPLC (column; Acquity BEH C-18, 50 x 2.1mm, 1.7 μιη); RT 2.09 min. ACN: 0.025% TFA (Aq); 0.50 ml/min; TLC: 10%

MeOH:DCM (R/. 0.3). Synthesis of 2-chloro-8-(o-tolyl)-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0289] To a stirred solution of 2-chloro-4-(o-tolylamino) pyrimidin-5-ol (45 mg, 0.19 mmol) in DMF (1 mL) under argon atmosphere were added K 2 CO 3 (79.2 mg, 0.57 mmol) and l-bromo-2-chloroethane (41 mg, 0.28 mmol) at RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-8- (o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (35 mg, 70%) as a brown solid used without further purification. 1H-NMR (DMSO-<¾, 400 MHz): δ 7.83 (s, 1H), 7.36-7.28 (m, 4H), 4.43-4.35 (m, 1H), 4.35-4.30 (m, 1H), 3.94-3.89 (m, 1H), 3.73-3.68 (m, 1H), 2.13 (s, 3H). LC-MS: 262 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μιη); RT 3.36 min. 0.05% Aq TFA: ACN; 0.80 ml/min); UPLC (column; Acquity BEH C-18, 50 2.1mm, 1.7 μιη); RT 2.25 min. ACN: 0.025% TFA (Aq); 0.50 ml/min; TLC: 10% MeOH:DCM (R/. 0.7).

Example 14

Synthesis of 2-chloro-8-(2-(trifluor omethoxy)phenyl)-7,8-dihydro-6H-pyrimido [5,4- b] [1,4] oxazine

Synthesis of2-chloro-5-methoxy-N-(2-(trifluoromethoxy) phenyl) pyrimidin-4-amine [0290] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (5 g, 28.08 mmol) in tertiary butyl alcohol (35 mL) under argon atmosphere were added 2-(trifluoromethoxy) aniline (4 g, 22.47 mmol) and diisopropylethylamine (35 mL) at RT. The reaction mixture was stirred at 160 °C for 48 h in a sealed tube. After completion of the reaction (monitored by TLC), the volatile components were removed in vacuo. The crude material was purified by silica gel column chromatography using 10% EtOAc:hexanes to afford 2-chloro-5-methoxy- N-(2-(trifluoromethoxy) phenyl) pyrimidin-4-amine (2 g, 22%) as a colorless syrup. 1H-NMR (CDC1 3 , 400 MHz): δ 8.64 (d, 1H), 7.79 (s, 1H), 7.72 (br s, 1H), 7.38 (t, 1H), 7.30-7.27 (m, 1H), 7.10-7.07 (m, 1H), 4.00 (s, 3H); LC-MS: 320.3 (M+l); (column; X Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 4.63 min. 0.05% Aq TFA: ACN; 0.80 ml/min); TLC: 15% EtOAc:hexanes {Rf. 0.3).

Synthesis of2-chloro-4-((2-(trifluoromethoxy) phenyl) amino) pyrimidin-5-ol

[0291] To a stirred solution of 2-chloro-5-methoxy-N-(2-(trifluoromethoxy) phenyl) pyrimidin-4-amine (800 mg, 2.50 mmol) in CH 2 CI 2 (80 mL) under argon atmosphere at 0 °C was added 1 M BBr 3 in CH 2 CI 2 (3.5 mL, 37.50 mmol). The reaction mixture was warmed to RT and stirred for 48 h. After completion of the reaction (monitored by TLC), the volatile components were removed in vacuo. The crude material was concentrated in vacuo with toluene (2 x 20 mL) to afford 2-chloro-4-((2-(trifluoromethoxy) phenyl) amino) pyrimidin-5- ol (1 g) as a brown solid used without further purification. 1H-NMR (CDC1 3 , 400 MHz): δ 10.8 (bs, 1H), 8.67 (s, 1H), 7.80 (t, 1H), 7.70 (s, 1H), 7.35-7.32 (m, 2H), 7.30-7.28 (m, 1H); LC-MS: 306.2 (M+l); (column; X select C-18 (50 3.0 mm, 3.5 μιη); RT 4.32 min. 0.05% Aq TFA: ACN; 0.80 ml/min); TLC: 40% EtOAc:hexanes (Rf. 0.3).

Synthesis of2-chloro-8-(2-(trifluoromethoxy) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-bJ [I, 4] oxazine

[0292] To a stirred solution of 2-chloro-4-((2-(trifluoromethoxy) phenyl) amino) pyrimidin-5-ol (1.8 g, 5.90 mmol) in DMF (4 mL) under argon atmosphere were added potassium carbonate (2.4 g, 17.70 mmol) and l-bromo-2-chloroethane (1 g, 7.03 mmol) at RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 5% EtOAc:hexanes to afford 2-chloro-8-(2-(trifluoromethoxy) phenyl)-7, 8-dihydro- 6H-pyrimido [5, 4-b] [1, 4] oxazine (700 mg, 36%) as an off-white solid. 1H-NMR (CDC1 3 , 400 MHz): δ 7.85 (s, 1H), 7.40-7.38 (m, 4H), 4.35-4.33 (m, 2H), 3.86-3.83 (m, 2H); LC-MS: 332.3 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 4.27 min. 0.05% Aq TFA: ACN; 0.80 ml/min); TLC: 30% EtOAc:hexanes (R/. 0.5).

Example 15

Synthesis of 2-chloro-8-(2-chlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of2-chloro-N-(2-chlorophenyl)-5-methoxypyrimidin-4-amine

[0293] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (5 g, 28.08 mmol) in isopropyl alcohol (45 mL) under argon atmosphere were added 2-chloroaniline (3.5 g, 28.08 mmol) and N, N-diisopropylethylamine (45 mL) at RT. The reaction mixture was heated to 130 °C and stirred for 32 h in a sealed tube. After complete consumption of the starting material (monitored by TLC), the volatile components were removed in vacuo. The residue was diluted with water (200 mL) and extracted with CH 2 CI 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography using 10% EtOAc:hexanes to afford 2-chloro-N-(2-chlorophenyl)-5-methoxypyrimidin-4-amine (3.5 g, 46%) as an off-white solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 9.00 (s, 1H), 7.91 (s, 1H), 7.69 (d, 1H), 7.53 (d, 1H), 7.40 (t, 1H), 7.28 (t, 1H), 3.98 (s, 3H); LC-MS: 271 (M+l); (column; X-Select CSH C- 18 (50 3.0 mm, 3.5 μιη); RT 4.44 min. 0.05% Aq TFA: ACN; 0.80 ml/min); TLC: 20% EtOAc:hexanes (R/. 0.5).

Synthesis of 2-chloro-4-((2-chlorophenyl) amino) pyrimidin-5-ol

[0294] To a stirred solution of 2-chloro-N-(2-chlorophenyl)-5-methoxypyrimidin-4- amine (1 g, 3.71 mmol) in DCM (100 mL) under argon atmosphere at 0 °C was added 1M BBr 3 in CH 2 CI 2 (1 mL). The reaction mixture was warmed to RT and stirred for 48 h. After completion of the reaction (monitored by TLC), the volatile components were removed in vacuo. To the residue, a saturated sodium bicarbonate solution (20 mL) was added and extracted with CH 2 CI 2 (2 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-4- ((2-chlorophenyl) amino) pyrimidin-5-ol (800 mg, 84%) as an off white solid used without further purification. 1H-NMR (DMSO-< 5 , 500 MHz): δ 10.95 (brs, 1H), 8.61 (s, 1H), 7.90 (d, 1H), 7.79 (s, 1H), 7.58 (d, 1H), 7.37 (t, 1H), 7.21 (t, 1H); LC-MS: 257 (M+l); (column; X- Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.15 min. 0.05% Aq TFA: ACN; 0.80 ml/min); TLC: 30% EtOAc:hexanes (R/. 0.2).

Synthesis of 2-chloro-8-(2-chlorophenyl)-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0295] To a stirred solution of 2-chloro-4-((2-chlorophenyl) amino) pyrimidin-5-ol (1 g, 3.90 mmol) in DMF (10 mL) under argon atmosphere were added potassium carbonate (1.6 g, 11.71 mmol) and l-bromo-2-chloroethane (837 mg, 5.85 mmol) at RT and stirred for 8 h. After completion of the reaction (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-8-(2- chlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (850 mg, 77%>) as an off white solid used without further purification. 1H-NMR (DMSO-<¾, 400 MHz): δ 7.89 (s, 1H), 7.62 (d, 1H), 7.59 (d, 1H), 7.49-7.39 (m, 2H), 4.42-4.38 (m, 1H), 4.37-4.29 (m, 1H), 3.93- 3.89 (m, 1H), 3.79-3.75 (m, 1H); LC-MS: 283 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 4.04 min. 0.05% Aq TFA: ACN; 0.80 ml/min); TLC: 30%

EtOAc:hexanes (R/. 0.6).

Example 16

Synthesis of 8-(3, 5-difluorophenyl)- V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

F F

Synthesis of 8-(3, 5-dtfluorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0296] A dry vial charged with Pd 2 (dba) 3 (16 mg, 0.01 mmol) and BINAP (33 mg, 0.05 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(3, 5-difluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.35 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride (94 mg, 0.38 mmol) and sodium tertiary butoxide (101 mg, 1.05 mmol) in 1, 4-dioxane (0.5 mL) was degassed with argon and the catalyst premixture added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After completion of the reaction (monitored by TLC and LCMS), reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and

concentrated in vacuo. The crude material was purified by silica gel column chromatography using 5% MeOH:CH 2 Cl 2 to afford 8-(3, 5-difluorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (40 mg, 25%) as an off-white solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 7.80 (d, 1H), 7.70 (s, 1H), 7.34-7.30 (m, 2H), 6.99 (t, 1H), 6.51-6.50 (m, 1H), 6.41-6.39 (m, 1H), 6.09 (s, 1H), 4.20-4.18 (m, 2H), 3.92-3.80 (m, 4H), 3.71 (s, 3H), 3.70-3.68 (m, 1H), 2.80 (t, 2H), 1.85-1.79 (m, 2H), 1.41-1.38 (m, 2H); Mass (ESI): 455.6 [M+1]; LC-MS: 455.4 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.71 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column;

Acquity BEH C-18 50 X 2.1 mm, 1.7 μιη); RT 1.51 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 50% EtOAc:hexanes (R 0.2).

Example 17

Synthesis of 8-(3, 5-difluorophenyl)- V-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

F F

Synthesis of 8-(3, 5-difluorophenyl)-N-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0297] A dry vial charged with Pd 2 (dba) 3 (16 mg, 0.01 mmol) and BINAP (33 mg, 0.05 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(3, 5-difluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.35 mmol), l-(6-methylpyrimidin-4-yl) piperidin-4-amine hydrochloride (89 mg, 0.38 mmol) and sodium tertiary butoxide (101 mg, 1.05 mmol) in 1, 4-dioxane (0.5 mL) was degassed with argon and the catalyst premixture added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After completion of the reaction (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 5% MeOH:CH 2 Cl 2 to afford 8 -(3, 5-difluorophenyl)-N-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (56 mg, 36%) as an off-white solid. 1H-NMR (OMSO-d 6 , 500 MHz): δ 8.38 (s, 1H), 7.68 (s, 1H), 7.33 (d, 2H), 7.00 (t, 1H), 6.71 (s, 1H), 6.42 (br s, 1H), 4.35-4.29 (m, 2H), 4.20-4.18 (m, 2H), 3.94-3.90 (m, 2H), 3.74 (br s, 1H), 2.88 (t, 2H), 2.21 (s, 3H), 1.84-1.82 (m, 2H), 1.32-1.29 (m, 2H);

Mass (ESI): 440.5 [M+l]; LC-MS: 440.6 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.65 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 μιη); RT 1.49 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 7% MeOH:CH 2 Cl 2 (R 0.2).

Example 18

Synthesis of V-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-8-phenyl-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-8-phenyl-7 , 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0298] A dry vial charged with Pd 2 (dba) 3 (18 mg, 0.02 mmol) and BINAP (38 mg, 0.06 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.40 mmol), l-(6-methylpyrimidin-4-yl) piperidin-4-amine hydrochloride (101 mg, 0.44 mmol) and sodium tertiary butoxide (117 mg, 1.21 mmol) in 1 , 4-dioxane (0.5 mL) was degassed with argon and the catalyst premixture added. The resultant mixture was stirred at 120 °C for 24 h in a sealed tube. After completion of the reaction (monitored by TLC and LCMS), the reaction was diluted with water (30 mL) and extracted with CH 2 C1 2 (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using

5%MeOH:CH 2 Cl 2 and further purified by preparative HPLC [Kromasil C18 (250 x 21.2mm 10 μιη) (60 mg loading; CH 3 CN;0.05% TFA Aq; (0.1/90, 15/70, 25/10, 35/10) as mobile phase with a Flow rate=15 mL/min] to afford N-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)- 8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (44 mg, 27%) as an off- white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 8.30 (s, 1H), 7.51 (s, 1H), 7.44-7.38 (m, 4H), 7.24-7.20 (m, 1H), 6.63 (s, 1H), 4.34-4.25 (m, 4H), 3.92-3.89 (m, 2H), 3.71-3.63 (m, 1H), 2.98-2.91 (m, 2H), 2.30 (s, 3H), 1.97-1.93 (m, 2H), 1.38-1.29 (m, 2H); LC-MS: 404.6 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.44 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 μιη); RT 1.42 min. ACN: 0.025% TFA (Aq); 0.50 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (R 0.1).

Example 19

Synthesis of 7V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-phenyl-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-phenyl- 7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2- amine

[0299] To a stirred solution of 2-chloro-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1 , 4] oxazine (200 mg, 0.80 mmol) in 1 , 4-dioxane (2.5 mL) under argon atmosphere were added l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride (393 mg, 0.16 mmol) and cesium carbonate (1.18 g, 3.64 mmol) at RT. The mixture was purged with argon for 30 min, then Pd(PPh 3 )4 (140 mg, 0.12 mmol) was added. The reaction mixture was stirred at 130 °C for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with CH2CI2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 2% MeOLLCfLCb to afford N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1 , 4] oxazin-2-amine (35 mg, 20%) as an off-white solid. 1H-NMR (DMSO-<¾, 400 MHz): δ

7.73 (d, 1H), 7.60 (s, 1H), 7.47-7.40 (m, 2H), 7.39-7.30 (m, 2H), 7.18-7.1 1 (m, 1H), 6.51- 6.49 (m, 1H), 6.20-6.17 (m, 1H), 6.12 (s, 1H), 4.21-4.19 (m, 2H), 3.90-3.70 (m, 7H), 3.60 (br s, 1H), 2.79 (t, 2H), 1.83-1.79 (m, 2H), 1.32-1.28 (m, 2H); Mass (ESI): 419.5 [M+1]; LC- MS: 419 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 2.14 min 0.05% TFA in water: ACN; 0.80 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.46 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (Rf. 0.4).

Example 20

Synthesis of V-(l-(2-methoxypyridin-4-yl) azetidin-3-yl)-8-phenyl-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of N-(l-(2-methoxypyridin-4-yl) azetidin-3-yl)-8-phenyl- 7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine)

[0300] To a stirred solution of 2-chloro-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.40 mmol) in 1, 4-dioxane (1 mL) under argon atmosphere were added l-(2-methoxypyridin-4-yl) azetidin-3 -amine (80 mg, 0.44 mmol) and cesium carbonate (593 mg, 0.18 mmol) at RT. The mixture was purged with argon for 30 min, then Pd(PPh 3 )4 (70 mg, 0.06 mmol) was added. The reaction mixture was stirred at 130 °C for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (10 mL) and extracted with CH 2 CI 2 (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 2% MeOH:CH 2 Cl 2 to afford N-(l -(2- methoxypyridin-4-yl) azetidin-3-yl)-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine) (30 mg, 19%) as an off-white solid. 1H-NMR (DMSO-d 6 , 400 MHz): δ 7.71

(d, 1H), 7.61 (s, 1H), 7.47-7.39 (m, 4H), 7.20-7.18 (m, 1H), 6.93-6.89 (m, 1H), 6.02-5.99 (d, 1H), 5.59 (s, 1H), 4.41-4.39 (m, 1H), 4.21-4.19 (m, 2H), 4.01 (t, 2H), 3.88-3.85 (m, 2H), 3.71 (s, 3H), 3.61-3.59 (m, 2H); Mass (ESI): 391.3 [M+l] LC-MS: 391.3 (M+l); (column; X- Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.53 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.39 min. ACN: water; 0.50 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (R 0.5).

Example 21

Synthesis of l-(2-methoxypyridin-4-yl)-4-((8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b]

[1, 4] oxazin-2-yl) amino) piperidin-2-one

Synthesis of l-(2-methoxypyridin-4-yl)-4-((8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-yl) amino) piperidin-2-one

[0301] A dry vial charged with Pd 2 (dba) 3 (22 mg, 0.024 mmol) and BINAP (30 mg, 0.048 mmol). in 1, 4-dioxane (0.3 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (70 mg, 0.24 mmol), 4-amino-l-(2-methoxypyridin-4-yl) piperidin-2-one hydrochloride (68 mg, 0.26 mmol) and cesium carbonate (237 mg, 0.72 mmol) in 1, 4-dioxane (0.3 mL) was degassed with argon and the catalyst premixture added. The resultant mixture was stirred at 95°C for 18 h in a sealed tube. After completion of the reaction (monitored by TLC and LCMS), the volatile components were removed in vacuo. The residue was diluted with water (10 mL) and extracted with CH 2 C1 2 (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 2% MeOH:CH 2 Cl 2 to afford l-(2-methoxypyridin-4- yl)-4-((8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-yl) amino) piperidin-2- one (25 mg, 20%) as a pale yellow solid. 1H-NMR (CD 3 OD, 500 MHz): δ 8.13-8.11 (d, 1H), 7.56 (s, 1H), 7.44-7.41 (m, 4H), 7.26-7.24 (m, 1H), 6.97-6.96 (d, 1H), 6.78 (s, 1H), 4.29-4.28 (m, 2H), 3.99-3.96 (m, 3H), 3.93 (s, 3H), 3.69-3.67 (m, 2H), 2.82-2.77 (m, 1H), 2.55-2.49 (m, 1H), 2.17-2.16 (m, 1H), 1.92-1.90 (m, 1H); Mass (ESI): 433.4 [M+1]; LC-MS: 433.4 (M+1); (column; X-Select C-18 (50 3.0 mm, 3.5 μιη); RT 3.11 min 5 mM NH40Ac: ACN; 0.80 mL/min); HPLC (column; Eclipse XDB C-18 150 X 4.6 mm, 5 μιη); RT 9.27 min. ACN: 5 mM Aq NH 4 OAc; 1.0 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (R 0.3).

Example 22

Synthesis of V-(l-(2-methylpyridin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-methylpyridin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2- amine

[0302] To a stirred solution of 2-chloro-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.38 mmol) in 1, 4-dioxane (1 mL) were added l-(2-methylpyridin-4-yl) piperidin-4-amine hydrochloride (173 mg, 0.76 mmol) and cesium carbonate (561 mg, 1.72 mmol). The solution was purged with argon for 30 min, then Pd(Ph 3 ) 4 (65 mg, 0.05 mmol) was added. The reaction mixture was stirred at 160 °C for 12 h. After consumption of the starting material (monitored by TLC), the reaction was filtered. The filtrate was diluted with water (20 mL) and extracted with CH 2 CI 2 (2 x 10 mL). The combined organic extracts were washed with brine (20 m), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 3% MeOH:CH 2 Cl 2 to afford N-(l -(2 -methylpyridin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (7.4 mg, 5%) as an off white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.95 (d, 1H), 7.50 (s, 1H), 7.39-7.25 (m, 4H), 6.94-6.90 (m, 2H), 4.43-4.39 (m, 2H), 4.10- 4.03 (m, 3H), 3.91-3.89 (m, 1H), 3.54-3.50 (m, 1H), 3.03-2.95 (m, 2H), 2.50 (s, 3H), 2.22 (s, 3H), 1.92-1.88 (m, 2H), 1.52-1.47 (m, 2H); LC-MS: 417.4 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.01 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.53 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (R 0.4).

Example 23

Synthesis of l-(2-methoxypyridin-4-yl)-4-((8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b]

[1, 4] oxazin-2-yl) amino) piperidin-2-one

Synthesis of l-(2-methoxypyridin-4-yl)-4-((8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-yl) amino) piperidin-2-one

[0303] A dry vial charged with Pd 2 (dba) 3 (24 mg, 0.02 mmol) and BINAP (33 mg, 0.05 mmol) in 1, 4-dioxane (0.4 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (70 mg, 0.26 mmol), 4-amino-l-(2-methoxypyridin-4-yl) piperidin-2-one hydrochloride (82 mg, 0.32 mmol) and cesium carbonate (262 mg, 0.80 mmol) in 1, 4-dioxane (0.4 mL) was degassed with argon and the catalyst premixture added. The resultant mixture was stirred at 95 °C for 18 h in a sealed tube. After completion of the reaction (monitored by TLC and LCMS), the volatile components were removed in vacuo. The residue was diluted with water (10 mL) and extracted with CH 2 C1 2 (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 2% MeOH:CH 2 Cl 2 to afford l-(2-methoxypyridin-4- yl)-4-((8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-yl) amino) piperidin-2- one (25 mg, 21%) as an off-white solid. 1H-NMR (CD 3 OD, 500 MHz): δ 8.12-8.11 (d, 1H), 7.53 (s, 1H), 7.35-7.25 (m, 4H), 6.95-6.94 (d, 1H), 6.76 (s, 1H), 4.33-4.27 (m, 2H), 3.94-3.93 (s, 3H), 3.92-3.83 (m, 2H), 3.73-3.71 (m, 1H), 3.64-3.52 (m, 2H), 2.74-2.68 (m, 1H), 2.50- 2.45 (m, 1H), 2.24 (s, 3H), 2.11-2.09 (m, 1H), 1.87-1.81 (m, 1H); Mass (ESI): 447.6 [M+l]; LC-MS: 447.7 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 3.01 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 1.73 min. ACN: 0.025% TFA (Aq); 0.50 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (R

0.3).

Example 24 Synthesis of 7V-(l-(2-chloropyridin-4-yl) piperidin-4-yl)-8-phenyl-7, 8-dihydi

pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-chloropyridin-4-yl) piperidin-4-yl)-8-phenyl-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2- amine

[0304] To a stirred solution of 2-chloro-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (200 mg, 0.80 mmol) in tertiary butanol (2 mL) under argon atmosphere were added diisopropyl ethyl amine (0.4 mL) and l-(2-chloropyridin-4-yl) piperidin-4-amine (343 mg, 1.61 mmol) at RT. The reaction mixture was stirred at 130 °C for 48 h in a sealed tube. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with CH 2 CI 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 3% MeOH:CH 2 Cl 2 to afford N-(l-(2- chloropyridin-4-yl) piperidin-4-yl)-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-

2-amine (15 mg, 4%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.88 (br s, 1H), 7.41 (s, 4H), 7.29-7.27 (m, 1H), 6.80-6.77 (m, 3H), 4.30-4.28 (m, 2H), 3.99-3.97 (m, 2H), 3.90-3.87 (m, 2H), 3.65-3.59 (m, 1H), 3.89 (t, 2H), 1.94-1.90 (m, 2H), 1.42-1.30 (m, 2H); Mass (ESI): 423.4 [M+1]; LC-MS: 423.3 (M+1); (column; X-Selected CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.67 minO.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 μιη); RT 1.55 min. ACN: 0.025% TFA (Aq); 0.50 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (R 0.3).

Example 25 Synthesis of 7V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H- -b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7 , 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0305] To a stirred solution of 2-chloro-8-(o-tolyl)-7, 8-dihydro-6H-pyrano [3, 2-d] pyrimidine (200 mg, 0.76 mmol) in 1, 4-dioxane (3 mL) under argon atmosphere were added l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride (372 mg, 1.53 mmol) and cesium carbonate (1.12g, 3.44 mmol). The solution was degassed under argon atmosphere for 30 min at RT, then Pd(PPh 3 )4 (132 mg, 0.11 mmol) was added. The reaction mixture was stirred at 130 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with CH2CI2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 2-3% MeOH:CH 2 Cl 2 and further purified by preparative HPLC [Ascentis CI 8 (25 Ox 21.2 mm 10 μιη) (25 mg loading; CH 3 CN;0.05% TFA Aq (0.01/90, 15/65, 30/30, 35/0) as mobile phase with a Flow rate=15 mL/min] to afford N-(l -(2 -methoxypyridin-4-yl) piperidin-4-yl)-8-(o- tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (60 mg, 18%) as an off-white solid. 1H-NMR (DMSO- d 6 , 400 MHz): δ 7.78 (d, 1H), 7.55 (s, 1H), 7.30-7.20 (m, 4H), 6.52 (d, 1H), 6.08-6.07 (m, 2H), 4.29-4.18 (m, 2H), 3.84-3.70 (m, 6H), 3.60-3.50 (m, 2H), 2.78- 2.62 (m, 2H), 2.19 (s, 3H), 1.80-1.73 (m, 2H), 1.38-1.25 (m, 2H); Mass (ESI): 433.5 [M+2]; LC-MS: 433.3 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μιη); RT 2.78 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 1.52 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (Rf. 0.4).

Example 26 Synthesis of V-(l-(2-methoxypyridin-4-yl) azetidin-3-yl)-8-(o-tolyl)-7, 8-dihydi

-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-methoxypyridin-4-yl) azetidin-3-yl)-8-(o-tolyl)-7 , 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0306] To a stirred solution of 2-chloro-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.38 mmol) in 1, 4-dioxane (1 mL) under argon atmosphere were added cesium carbonate (561 mg, 1.72 mmol) and l-(2-methoxypyridin-4-yl) azetidin-3 -amine (75 mg, 0.42 mmol). The solution was degassed under argon atmosphere for 30 min at RT, then Pd(PPh 3 ) 4 (66 mg, 0.05 mmol) was added. The reaction mixture was stirred at 130 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with CH 2 CI 2 (2 x 20 mL). The combined organic extracts were washed with a brine solution (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 5% MeOH:CH 2 Cl 2 to afford N-(l-(2-methoxypyridin-4-yl) azetidin-3 - yl)-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (20 mg, 13%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.67 (d, 1H), 7.50 (s, 1H), 7.32-7.21 (m, 4H), 5.96-5.94 (m, 1H), 5.56-5.55 (m, 1H), 4.30-4.26 (m, 3H), 3.95-3.85 (m, 3H), 3.80 (s, 3H), 3.72-3.67 (m, 1H), 3.60-3.30 (m, 2H), 2.21 (s, 3H); Mass (ESI): 405.4 [M+1]; LC-MS: 405.4 (M+1); (column; X-Bridge C-18 (50 3 mm, 3.5 μπι); RT 2.74 min. 0.05% TFA in water: ACN; 0.8 mL/min); HPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.44 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (Rf. 0.5).

Example 27

Synthesis of V-(l-(2-methylpyridin-4-yl) piperidin-4-yl)-8-phenyl-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-methylpyridin-4-yl) piperidin-4-yl)-8-phenyl-7 , 8-dihydro-6H-pyrimido [5, 4-bJ [I, 4] oxazin-2- amine

[0307] To a stirred solution of 2-chloro-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.40 mmol) in 1, 4-dioxane (1 mL) under argon atmosphere were added l-(2-methylpyridin-4-yl) piperidin-4-amine hydrochloride (183 mg, 0.80 mmol), cesium carbonate (592 mg, 1.81 mmol). The solution was degassed under argon atmosphere for 15 min, then Pd(PPh 3 )4 (70 mg, 0.06 mmol) was added. The reaction mixture was stirred at 160 °C for 12 h in a sealed tube. After consumption of the starting material (monitored by TLC), the reaction was filtered and concentrated in vacuo. The crude material was purified by preparative HPLC [Kromasil C 18, 250 x 21.2 mm, 5 μιη (60 mg loading; CH 3 CN; 0.05% TFA Aq (0.01/90, 15/25, 30/10, 35/10) as mobile phase with a Flow rate=15 rnL/min] to afford N-(l -(2 -methylpyridin-4-yl) piperidin-4-yl)-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4- b] [1, 4] oxazin-2-amine (8 mg, 5%) as an off-white solid. 1H-NMR (CD 3 OD-<¾, 400 MHz): δ 7.94 (d, 1H), 7.53 (s, 1H), 7.43-7.42 (m, 4H), 7.25-7.23 (m, 1H), 6.99-6.98 (m, 2H), 4.29- 4.27 (m, 2H), 4.13-4.10 (m, 2H), 3.94-3.92 (m, 2H), 3.80-3.72 (m, 1H), 3.21-3.13 (m, 2H), 2.49 (s, 3H), 2.05-2.01 (m, 2H), 1.49-1.37 (m, 2H); LC-MS: 403.4 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.92 min. 0.05% Aq TFA: ACN; 0.80 mL/min);

UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 1.45 min. ACN: 0.025% Aq TFA; 0.50 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (R 0.3).

Example 28

Synthesis of 8-(2-chlorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8-(2-chlorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7 , 8-dihydro- 6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0308] A dry vial charged with Pd 2 (dba) 3 (16 mg, 0.017 mmol) and BINAP (33 mg, 0.53 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2-chlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.35 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride 2 (95 mg, 0.38 mmol) and sodium tertiary butoxide (102 mg, 1.06 mmol) in 1, 4-dioxane (0.5 mL) was degassed with argon and the catalyst premixture added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube, after completion of the reaction (monitored by TLC and LCMS), the volatile components were removed in vacuo. The residue was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 7% MeOH:CH 2 Cl 2 to afford 120 mg further purified by preparative HPLC [Kromasil CI 8 (250 x 21.2mm 10 μιη ) (60 mg loading;

CH 3 CN;5mM NH40Ac (0.1/60, 15/30, 25/10, 35/10) as mobile phase with a Flow rate=15 mL/min] to afford 8-(2-chlorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (52 mg, 32%) as an off-white solid. 1 H- NMR (OMSO-d 6 , 400 MHz): δ 7.75-7.73 (m, 1H), 7.58-7.56 (m, 2H), 7.50 (d, 1H), 7.42 (t, 1H), 7.37-7.33 (m, 1H), 6.51-6.49 (m, 1H), 6.13-6.11 (m, 1H), 6.05-6.04 (m, 1H), 4.25-4.20 (m, 2H), 3.77-3.75 (m, 7H), 3.57-3.55 (m, 1H), 2.70-2.64 (m, 2H), 1.77-1.71 (m, 2H), 1.30- 1.23 (m, 2H); Mass (ESI): 453.7 [M+1]; LC-MS: 453.5 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μιη); RT 3.06 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 μιη); RT 1.57 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 50% EtOAc:hexanes (R 0.2).

Example 29 Synthesis of 8-(2-chlorophenyl)- V-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-7, 8- -6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8-(2-chlorophenyl)-N-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-7 , 8-dihydro- 6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0309] A dry vial charged with Pd 2 (dba) 3 (16.3 mg, 0.017 mmol) and BINAP (33.2 mg, 0.053 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2-chlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.35 mmol), l-(6-methylpyrimidin-4-yl) piperidin-4-amine (89.2 mg, 0.39 mmol) and sodium tertiary butoxide (102 mg, 1.06 mmol) in 1 , 4-dioxane (0.5 mL) was degassed with argon and the catalyst premixture added. The resultant mixture was stirred at 120 °C for 24 h in a sealed tube. After completion of the reaction (monitored by TLC and LCMS), the volatile components were removed in vacuo. The residue was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 5% MeOH:CH 2 Cl 2 and further purified by preparative HPLC [Kromasil CI 8 (250 x 21.2mm 10 μιη) (50 mg loading; CH 3 CN;5mM NH40Ac (0.1/70, 15/40, 25/10, 35/10) as mobile phase with a Flow rate=15 mL/min] to afford S-(2-chlorophenyl)-N-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine (50 mg, 32%) as a pale yellow solid. 1H-NMR (DMSO-<¾, 500 MHz): δ 8.33 (s, 1H), 7.59-7.50 (m, 3H), 7.42-7.20 (m, 2H), 6.64 (s, 1H), 6.10-6.09 (d, 1H), 4.32-4.20 (m, 4H), 3.76-3.70 (m, 2H), 3.58-3.50 (m, 1H), 2.79-2.70 (m, 2H), 2.20 (s, 3H), 1.78-1.70 (m, 2H), 1.24-1.20 (m, 2H); LC-MS: 438.3 (M+1); (column; X- Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.70 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 μιη); RT 1.46 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 5% MeOH:CH 2 Cl 2 (R/. 0.1). Example 30

Synthesis of V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-(2-(trifluoromethoxy) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-(2-(trifluoromethoxy) phenyl)-!, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0310] A dry vial charged with Pd 2 (dba) 3 (41 mg, 0.04 mmol) and BINAP (37 mg, 0.06 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2-(trifluoromethoxy)phenyl)-7,8-dihydro-6H-pyrim ido [5, 4-b] [1, 4] oxazine (100 mg, 0.36 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine

hydrochloride (81 mg, 0.33 mmol) and sodium tertiary butoxide (116 mg, 1.20 mmol) in 1, 4- dioxane (0.5 mL) was degassed with argon and the catalyst premixture added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After completion of the reaction (monitored by TLC and LCMS), the volatile components were removed in vacuo. The residue was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC [Kromasil CI 8 (250 x 21.2mm 10 μιη) (45 mg loading; CH 3 CN;0.05% TFA Aq (0.1/90, 15/70, 25/50, 35/10) as mobile phase with a Flow rate=15 mL/min] to afford N-(l -(2 -methoxypyridin-4-yl) piperidin-4-yl)-8-(2- (trifluoromethoxy) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (35 mg, 23%) as a pale yellow solid. 1H-NMR (DMSO-d 6 , 400 MHz): δ 7.75-7.73 (m, 1H), 7.60-7.56 (m, 2H), 7.48-7.42 (m, 3H), 6.51-6.49 (m, 1H), 6.11-6.06 (m, 1H), 6.05 (s, 1H), 4.20-4.18 (m, 2H), 3.81-3.70 (m, 7H), 3.52-3.45 (m, 1H), 2.69-2.63 (m, 2H), 1.75-1.72 (m, 2H), 1.33- 1.23 (m, 2H); Mass (ESI): 503.6 [M+1]; LC-MS: 503.6 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.88 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 μιη); RT 1.67 min. ACN: 0.025% Aq TFA; 0.5 mL/min.; TLC: 70% EtOAc:hexane (R 0.3).

Example 31 Synthesis of V-(l-(pyrimidin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido

-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(pyrimidin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7 , 8-dihydro-6H-pyrimido [5, 4- b] [1, 4] oxazin-2-amine

[0311] To a stirred solution of 2-chloro-8-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4- ¾][l,4]oxazine (100 mg, 0.38 mmol) in tert-butanol (0.5 mL) under argon atmosphere were added l-(pyrimidin-4-yl)piperidin-4-amine hydrochloride (136 mg, 0.76 mmol) and N,N- diisopropylethylamine (0.33 mL, 1.90 mmol) at RT. The reaction mixture was stirred at 170 °C for 32 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with 5% MeOH:EtOAc (4 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 1% MeOH: EtOAc to afford N-(l-(pyrimidin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine (38 mg, 25%) as an off-white solid. 1H-NMR (CD 3 OD, 500 MHz): δ 8.40 (s, 1H), 8.08-8.05 (m, 1H), 7.49 (s, 1H), 7.33-7.23 (m, 4H), 6.74- 6.73 (m, 1H), 4.32-4.26 (m, 4H), 3.91-3.86 (m, 1H), 3.73-3.69 (m, 1H), 3.60-3.58 (m, 1H), 2.96-2.88 (m, 2H), 2.23 (s, 3H), 1.92-1.90 (m, 2H), 1.36-1.26 (m, 2H); Mass (ESI): 404.3 [M+l]; LC-MS: 404.2 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μπι); RT 2.36 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.41 min. ACN: 0.025% TFA (Aq); 0.50 mL/min.; TLC: 5% MeOH/ EtOAc (Rf. 0.1).

Example 32 Synthesis of V-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7 , 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0312] To a stirred solution of 2-chloro-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.38 mmol) in tert-butanol (0.5 mL) under argon atmosphere were added l-(6-methylpyrimidin-4-yl)piperidin-4-amine hydrochloride (147 mg, 0.76 mmol) and N,N- diisopropylethylamine (0.33 mL, 1.90 mmol) at RT. The reaction mixture was stirred at 130 °C for 96 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (4 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 2% MeOH: EtOAc to afford N-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (26 mg, 16%) as an off-white solid.1H-NMR (CD 3 OD, 500 MHz): δ 8.30 (s, 1H), 7.49 (s, 1H), 7.33-7.23 (m, 4H), 6.62 (s, 1H), 4.31-4.26 (m, 4H), 3.91- 3.86 (m, 1H), 3.73-3.69 (m, 1H), 3.59-3.57 (m, 1H), 2.94-2.87 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 1.99-1.90 (m, 2H), 1.35-1.26 (m, 2H); Mass (ESI): 418.3 [M+1]; LC-MS: 418.3 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μ); RT 2.42 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.45 min. ACN: 0.025% TFA (Aq); 0.50 mL/min.; TLC: 10% MeOH/ EtOAc (R 0.2).

Example 33

Synthesis of V-(l-(2-methylpyrimidin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-methylpyrimidin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7 , 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0313] To a stirred solution of 2-chloro-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.38 mmol) in tert-butanol (0.5 mL) under argon atmosphere were l-(2- methylpyrimidin-4-yl)piperidin-4-amine hydrochloride (147 mg, 0.76 mmol) and N,N- diisopropylethylamine (0.33 mL, 1.90 mmol) at RT. The reaction mixture was stirred at 130 °C for 36 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC [acentis-C18 (250 X 21.2 mm X 10 μιη ) (40 mg loading; CH 3 CN;0.05% Aq TFA (0.01/95, 2/95,3/80, 15/65, 15.1/0, 25/ 0, 35/95) as mobile phase with a Flow rate=15 mL/min] and further purified by trituration with CH 3 CN:Ether (1 : 1, 2 x 10 mL) to afford N-(l -(2 -methylpyrimidin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (30 mg, 19%) as an off-white solid. 1 H- NMR (DMSO-< 5 , 500 MHz): δ 8.03-8.02 (m, 1H), 7.55 (s, 1H), 7.29-7.21 (m, 4H), 6.60-6.59 (m, 1H), 6.04-6.03 (m, 1H), 4.24-4.19 (m, 4H), 3.81-3.79 (m, 1H), 3.61-3.59 (m, 2H), 2.81- 2.79 (m, 2H), 2.33 (s, 3H), 2.15 (s, 3H), 1.76-1.74 (m, 2H), 1.24-1.22 (m, 2H); Mass (ESI): 418.5 [M+1]; LC-MS: 418.4 (M+1); (column; Eclipse XDB C-18 (150 4.6 mm, 5 μπι); RT 6.99 min. 0.05% TFA: ACN; 0.80 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.48 min. ACN: 0.025% TFA (Aq); 0.50 mL/min.; TLC: 5% MeOH/ EtOAc (Rf. 0.2).

Example 34

Synthesis of 7V-(l-(2-chloropyridin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydi

pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-chloropyridin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2- amine

[0314] To a stirred solution of 2-chloro-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.38 mmol) in tert-butanol (0.5 mL) under argon atmosphere were added l-(2-chloropyridin-4-yl) piperidin-4-amine (162 mg, 0.76 mmol) and diisopropylethylamine (0.33 mL, 1.90 mmol) at RT. The reaction mixture was stirred at reflux for 48 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with 2% MeOH: EtOAc (3 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 2% MeOH: EtOAc and further purified by trituration with CH 3 CN: Ether (1 : 1, 2 x 10 mL) to afford N-(l-(2-chloropyridin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (23 mg, 14%) as a white solid. 1H-NMR (DMSO-< 5 , 500 Mz): δ 7.87-7.86 (m, 1H), 7.53 (s, 1H), 7.28-7.20 (m, 4H), 6.77 (s, 2H), 6.02-6.01 (m, 1H), 4.23-4.18 (m, 2H), 3.82-3.80 (m, 3H), 3.60-3.58 (m, 1H), 2.80-2.78 (m, 2H), 2.14 (s, 3H), 1.75-1.73 (m, 2H), 1.29-1.23 (m, 2H); Mass (ESI): 437.4 [M+1]; LC-MS: 437.2 (M+1); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μ); RT 3.60 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 1.60 min. ACN: 0.025% TFA (Aq); 0.50 mL/min.; TLC: 10% MeOH/ EtOAc (R 0.2).

Example 35

Synthesis of V-(l-(pyridazin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido

[5, 4-b] [1, 4] oxazin-2-amine

Synthesis of ' N-(l -(pyridazin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7 , 8-dihydro-6H-pyrimido [5, 4- b] [I, 4] oxazin-2-amine

[0315] To a stirred solution of 2-chloro-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.38 mmol) in tert-butanol (0.5 mL) under argon atmosphere were added l-(pyridazin-4-yl) piperidin-4-amine (136 mg, 0.76 mmol) and N,N-diisopropylethylamine (0.33 mL, 1.90 mmol) at RT. The reaction mixture was stirred at reflux for 24 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (3 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified preparative HPLC_[Chiralpak-IA (250 X 20 mm X 5 μιη ) (30 mg loading; n-hexane;CH 2 Cl 2 : MeOH (50: 50); (75:25) as mobile phase with a Flow rate=15 mL/min] to afford N-(l- (pyridazin-4-yl) piperidin-4-yl)-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2- amine (18 mg, 12%) as an off-white solid. 1H-NMR (CD 3 OD, 500 Mz): δ 8.46-8.42 (m, 2H), 7.54 (s, 1H), 7.30-7.21 (m, 4H), 6.71-6.69 (m, 1H), 4.32-4.24 (m, 2H), 4.16-4.13 (m, 2H), 3.93-3.87 (m, 1H), 3.71-3.66 (m, 1H), 3.55-3.40 (m, 1H), 2.89-2.81 (m, 2H), 2.20 (s, 3H), 1.85-1.83 (m, 2H), 1.35-1.26 (m, 2H); Mass (ESI): 404.5 [M+l]; LC-MS: 404.4 (M+l); (column; Eclipse XDB C-18 (150 4.6 mm, 5 m); RT 6.93 min. 5.0 mM NH 4 OAc: ACN; 1.0 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 1.40 min. ACN: 0.025% TFA (Aq); 0.50 mL/min.; TLC: 5% MeOH/ EtOAc (R 0.3).

Example 36

Synthesis of 8-phenyl- V-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of8-phenyl-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7 , 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0316] A dry vial charged with Pd 2 (dba) 3 (22 mg, 0.02 mmol) and BINAP (45 mg, 0.07 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (120 mg, 0.48 mmol), l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-amine hydrochloride (130 mg, 0.53 mmol) and sodium tertiary butoxide (140 mg, 1.45 mmol) in 1, 4-dioxane (0.6 mL) was degassed with argon and the catalyst premixture added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After completion of the reaction (monitored by TLC and LCMS), the volatile components were removed in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC [Kromasil C 18, 250 x 21.2 mm, 5 μπι) (50 mg loading; CH 3 CN; 0.05% TFA (0.01/90, 15/70, 25/10, 35/10) as mobile phase with a Flow rate=15 mL/min] to afford 8-phenyl-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (35 mg, 16%) as an off-white solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 8.22 (d, 1H), 7.60 (s, 1H), 7.47 (d, 2H), 7.36 (t, 2H), 7.20-7.12 (m, 2H), 7.00-6.98 (m, 1H), 6.20-6.18 (m, 1H), 4.21-4.18 (m, 2H), 3.97-3.90 (m, 2H), 3.87-3.85 (m, 2H), 3.68 (br s, 1H), 2.90 (t, 2H), 1.84-1.79 (m, 2H), 1.38-1.28 (m, 2H); Mass (ESI): 457.4 [M+l];; LC-MS: 457.4 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.90 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity-BEH-C-18 50 X 2.1 mm, 1.7 μπι); RT 1.72 min. ACN: 0.025% Aq TFA; 1.0 mL/min.; TLC: 5% MeOH:CH 2 Cl 2 (R/. 0.3).

Example 37 Synthesis of V-(l-(6-methoxypyrimidin-4-yl) piperidin-4-yl)-8-phenyl-7, 8-dihydro-6H- -b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(6-methoxypyrimidin-4-yl) piperidin-4-yl)-8-phenyl-7 , 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0317] A dry vial charged with Pd 2 (dba) 3 (22 mg, 0.02 mmol) and BINAP (45 mg, 0.07 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (120 mg, 0.48 mmol), l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-amine hydrochloride (130 mg, 0.53 mmol) and sodium tertiary butoxide (140 mg, 1.45 mmol) in 1, 4-dioxane (0.6 mL) was degassed with argon and the catalyst premixture added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After completion of the reaction (monitored by TLC and LCMS), the volatile components were removed in vacuo. The residue was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 4% MeOH:CH 2 Cl 2 to afford 130 mg was further triturated with acetonitrile (2 x 5 mL) to afford the product (60 mg, 30%) as an off- white solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 8.20 (s, 1H), 7.59 (s, 1H), 7.49-7.43 (m, 2H), 7.38 (t, 2H), 7.18 (t, 1H), 6.17-6.12 (m, 1H), 6.03 (s, 1H), 4.28-4.19 (m, 4H), 3.88-3.86 (m, 2H), 3.79 (s, 3H), 3.67 (br s, 1H), 2.82 (t, 2H), 1.82-1.78 (m, 2H), 1.28-1.20 (m, 2H); Mass (ESI): 420.4 [M+l]; LC-MS: 420.3 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.77 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity-BEH-C-18 50 X 2.1 mm, 1.7 μπι); RT 1.55 min. ACN: 0.025% Aq TFA; 0.5 mL/min.; TLC: 5%

MeOH:CH 2 Cl 2 (Rf. 0.3).

Example 38

Synthesis of l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-amine hydrochloride

Synthesis of tert-butyl (l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl) carbamate

[0318] To a stirred solution of 4-iodo-2-(trifluoromethyl) pyridine (2 g, 7.32 mmol) in NMP (20 mL) under argon atmosphere were added diisopropylethylamine (1.32 g, 10.23 mmol) and tert-butyl piperidin-4-ylcarbamate (1.90 g, 9.50 mmol) and purged with argon for 15 min. The reaction mixture was stirred at 130 °C for 24 h. After the consumption of the starting material (monitored by TLC), the reaction was diluted with ice water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 25% EtOAc: hexanes to afford tert-butyl (l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl) carbamate (1.7 g, 67%) as an off-white solid. 1H-NMR (DMSO- d 6 , 400 MHz): δ 8.23 (d, 1H), 7.18 (s, 1H), 7.02-7.00 (m, 1H), 6.85 (d, 1H), 3.97-3.93 (m, 2H), 3.57-3.50 (m, 1H), 3.00 (t, 2H), 1.80-1.77 (m, 2H), 1.34 (s, 9H), 1.31-1.30 (m, 2H); LCMS: 346.4 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.25 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 30% EtOAc/hexanes (R 0.2).

Synthesis of l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-amine hydrochloride

[0319] To a stirred solution of tert-butyl (l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4- yl) carbamate (1.7 g, 4.92 mmol) in CH 2 C1 2 (20 mL) was added 2M HCI in 1 , 4-dioxane (10 mL) at RT and stirred for 16 h. After consumption of the starting material (monitored by TLC), the volatile components were concentrated in vacuo. The crude material was washed with n-pentane (2 x 10 mL) and ether (2 x 10 mL) to afford l-(2-(trifluoromethyl) pyridin-4- yl) piperidin-4-amine hydrochloride (1 g, 90%) as a yellow solid. 1H-NMR (DMSO-d 6 , 500 MHz): δ 8.32-8.30 (m, 3H), 7.35 (s, 1H), 7.16-7.14 (m, 1H), 4.18-4.15 (m, 2H), 3.36-3.32 (m, 1H), 3.10 (t, 2H), 2.02-2.00 (m, 2H), 1.59-1.51 (m, 2H); LCMS: 246.1 (M+l); (column; Eclipse XDB C-18 (150 4.6 mm, 5 μπι); RT 5.02, 43.20 min 0.05% Aq TFA: ACN; 1.0 mL/min); TLC: 5% MeOH: CH 2 C1 2 (R 0.1).

Example 39 Synthesis of 8-benzyl-2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of 2-chloro-5-methoxypyrimidin-4-amine

[0320] To a stirred solution of 2-chloro-5-methoxypyrimidin-4-amine (5 g, 31.44 mmol) in CH 2 CI 2 (100 mL) under argon atmosphere was added 1M boron tribromide in CH 2 CI 2 (45.5 mL, 471.69 mmol) drop-wise at 0 °C. The reaction mixture was warmed to RT and stirred for 32 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with methanol (22.5 mL) and stirred for 1 h. The obtained solid was filtered and dried in vacuo to afford 4-amino-2-chloropyrimidin-5-ol (4.5 g) as a brown solid. This compound was used without further purification. 1H-NMR (DMSO-<¾, 500 MHz): δ 10.04 (br s, 1H), 7.48 (s, 1H); LCMS: 146.2 (M+l); (column; Eclipse XDB C-18 (150 4.6 mm, 5 μπι); RT 3.37 min. 0.05% Aq TFA: ACN; 1.0 mL/min); TLC: 60% EtOAc/hexanes (R 0.5).

Synthesis of 2-chloro-4-((2-chloroethyl) amino) pyrimidin-5-ol

[0321] To a stirred solution of 4-amino-2-chloropyrimidin-5-ol (4.5 g, 31.03 mmol) in DMF (50 mL) under argon atmosphere were added potassium carbonate (12.8 g, 93.10 mmol) and l-bromo-2-chloroethane (3.86 mL, 46.55 mmol) at RT. The reaction mixture was stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with cold water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-4-((2-chloroethyl) amino) pyrimidin-5-ol (4 g, 62%) as a brown solid. This compound was used without further purification. 1H-NMR (DMSO-<¾, 500 MHz): δ 7.76 (s, 1H), 4.29 (t, 2H), 3.93 (t, 2H); LCMS: 209.2 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 μιη); RT 2.08 min. 0.05% TFA : ACN; 0.80 mL/min); TLC: 60% EtOAc/hexanes {Rf. 0.5). Synthesis of 2-chloro-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0322] To a stirred solution of 2-chloro-4-((2-chloroethyl) amino) pyrimidin-5-ol (4 g, 19.23 mmol) in DMF (70 mL) under argon atmosphere was added potassium carbonate (7.96 g, 57.69 mmol) at RT. The reaction mixture was stirred at 100 °C for 16 h. After

consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 40% EtOAc/hexanes to afford 2-chloro-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazine (2.1 g, 67%) as a brown solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 8.29 (s, 1H), 7.65 (s, 1H), 4.13-4.10 (m, 2H), 3.46-3.43 (m, 2H); LCMS: 172 (M+l); (column; Eclipse XDB C-18 (150 4.6 mm, 5 μπι); RT 5.61 min. 0.05% aq TFA: ACN; 1.0 mL/min); TLC: 60% EtOAc/hexanes (Rf. 0.5).

Synthesis of 8-benzyl-2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0323] To a stirred solution of 2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (50 mg, 0.29 mmol) in DMF (0.25 mL) under argon atmosphere were added sodium hydride (35 mg, 0.87 mmol) at 0 °C. After stirring for 5 mins, benzyl bromide (0.035 mL, 0.29 mmol) was added to the reaction mixture at RT and stirred for 2 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (10 mL) and extracted with 5% MeOH/ CH 2 CI 2 (2 x 5 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 2% MeOH: CH 2 CI 2 to afford 8-benzyl-2-chloro-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazine (75 mg, 98%) as an off-white solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 7.70 (s, 1H), 7.33-7.21 (m, 5H), 4.78 (s, 2H), 4.20-4.17 (m, 2H), 3.50-3.48 (m, 2H); LCMS: 262.3 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.10 min. 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 5% MeOH/ CH 2 C1 2 (Rf 0.7).

Example 40

Synthesis of 2-chloro-8-(2, 2, 2-trifluoroethyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of2-chloro-8-(2, 2, 2-trifluoroethyl)-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0324] To a stirred solution of 2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (500 mg, 2.92 mmol) in DMF (5 mL) under argon atmosphere were added cesium carbonate (1.9 g, 5.84 mmol) and 1, 1, l-trifluoro-2-iodoethane (611 mg, 2.92 mmol) at RT. The reaction mixture was stirred for 32 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 20%

EtOAc:hexanes to afford 2-chloro-8-(2, 2, 2-trifluoroethyl)-7, 8-dihydro-6H-pyrimido [5, 4- b] [1, 4] oxazine (235 mg, 32%) as an off-white solid. 1H-NMR (CDC1 3 , 500 MHz): δ 7.79 (s, 1H), 4.30-4.28 (m, 2H), 4.27-4.23 (m, 2H), 3.70-3.68 (m, 2H); LCMS: 254.4 (M+l);

(column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.76 min. 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 60% EtOAc/hexanes (R/. 0.6).

Example 41

Synthesis of 2-chloro-8-(2, 4-difluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of 2-chloro-N-(2, 4-dtfluorophenyl)-5-methoxypyrimidin-4-amine

[0325] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (5 g, 28.09 mmol) in isopropyl alcohol (45 mL) under argon atmosphere were added diisopropylethylamine (2.8 mL) and 2, 4-difluoroaniline (3.6 g, 28.09 mmol) at RT. The reaction mixture was stirred at 140 °C for 48 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 5% EtOAc:hexanes to afford 2-chloro-N-(2, 4-difluorophenyl)-5-methoxypyrimidin-4-amine (2 g) as a pale brown solid. 1H-NMR (CDC1 3 , 500 MHz): δ 8.50-8.44 (m, 1H), 7.80 (s, 1H), 7.41 (br s, 1H), 6.99-6.90 (m, 2H), 4.00 (s, 3H); TLC: 20% EtOAc/hexane (R 0.4).

Synthesis of 2-chloro-4-((2 , 4-difluorophenyl) amino) pyrimidin-5-ol

[0326] To a stirred solution of 2-chloro-N-(4-chlorophenyl)-5-methoxypyrimidin-4- amine (1.5 g, 5.54 mmol) in CH 2 CI 2 (15 mL) under argon atmosphere was added 1M boron tribromide in CH 2 CI 2 (15 mL) at 0 °C. The reaction mixture was warmed to RT and stirred for 64 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (200 mL) and filtered. The filtrate was concentrated in vacuo to afford 2- chloro-4-((2, 4-difluorophenyl) amino) pyrimidin-5-ol (1 g) as a pale brown solid used without further purification. 1H-NMR (DMSO-<¾, 400 MHz): δ 10.70 (br s, 1H), 8.90 (s, 1H), 7.70 (s, 1H), 7.57-7.50 (m, 1H), 7.36-7.30 (m, 1H), 7.12-7.08 (m, 1H); TLC: 30%

EtOAc/hexane (R 0.5).

Synthesis of 2-chloro-8-(2, 4-difluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-bJ [I, 4] oxazine

[0327] To a stirred solution of 2-chloro-4-((2, 4-difluorophenyl) amino) pyrimidin-5-ol (1 g, 3.89 mmol) in DMF (5 mL) under argon atmosphere were added potassium carbonate (1.6 g, 11.67 mmol) and l-bromo-2-chloroethane (830 mg, 5.84 mmol) at RT. The reaction mixture was stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 20% EtOAc:hexanes to afford 2-chloro-8-(2, 4-difluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (500 mg, 45%) as an off-white solid. 1H-NMR (CDC1 3 , 500 MHz): δ 7.83 (s, 1H), 7.35-7.30 (m, 1H), 7.27 (s, 1H), 6.99-6.90 (m, 1H), 4.39-4.34 (m, 2H), 3.87-3.80 (m, 2H); TLC: 30% EtOAc/hexane (R 0.5).

Example 42 Synthesis of 2-chloro-8-(4-chlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4]

oxazine

Synthesis of2-chloro-N-(4-chlorophenyl)-5-methoxypyrimidin-4-amine

[0328] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (5 g, 27.93 mmol) in 1, 4-dioxane (50 mL) under argon atmosphere were added diisopropylethylamine (7 g, 55.81 mmol) and 4-chloroaniline (3.5 g, 27.95 mmol) at RT. The reaction mixture was stirred at 120 °C for 48 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 20-50% EtOAc:hexanes to afford 2-chloro-N-(4-chlorophenyl)-5-methoxypyrimidin-4-amine (6 g, 79%) as a pale brown solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 9.40 (s, 1H), 7.95 (s, 1H), 7.76 (d, 2H), 7.39 (d, 2H), 3.91 (s, 3H); LCMS: 270.1 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπ ; RT 4.44 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 95.7%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.46 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 50% EtOAc/hexane (R 0.2).

Synthesis of 2-chloro-4-((4-chlorophenyl) amino) pyrimidin-5-ol

[0329] To a stirred solution of 2-chloro-N-(4-chlorophenyl)-5-methoxypyrimidin-4- amine (6 g, 22.22 mmol) in CH 2 CI 2 (350 mL) under argon atmosphere was added 1M boron tribromide in CH 2 CI 2 (31 mL, 332.64 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 64 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (200 mL), neutralized with a sodium bicarbonate solution

(100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-4-((4- chlorophenyl) amino) pyrimidin-5-ol (5.3 g, 93%>) as pale brown solid. 1 H-NMR (DMSO-<¾,

400 MHz): δ 10.80 (s, 1H), 9.23 (s, 1H), 7.81 (d, 2H), 7.72 (s, 1H), 7.39 (d, 2H); LCMS: 256.1 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.13 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 92.1%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.26 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 50%

EtOAc/hexane (R 0.4).

Synthesis of 2-chloro-8-(4-chlorophenyl)-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0330] To a stirred solution of 2-chloro-4-((4-chlorophenyl) amino) pyrimidin-5-ol (4.3 g, 16.79 mmol) in DMF (45 mL) under argon atmosphere were added potassium carbonate (6.9 g, 50.36 mmol) and l-bromo-2-chloroethane (3.6 g, 25.17 mmol) at RT. The reaction mixture was stirred for 16 h at RT. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 20-50%)

EtOAc:hexanes to afford 2-chloro-8-(4-chlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (4.5 g, 77%) as an off-white solid. 1H-NMR (DMSO-<¾, 500 MHz): δ 7.88 (s, 1H), 7.53-7.45 (m, 4H), 4.37-4.32 (m, 2H), 3.97-3.90 (m, 2H); LCMS: 282.3 (M+1); (column; X- Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.28 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 95.2%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.35 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 50% EtOAc/hexane (R/. 0.6).

Example 43

Synthesis of 2-chloro-7-methyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of2-chloro-N-(2-chloro-4-fluorophenyl)-5-methoxypyrimidin-4- amine

[0331] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (5 g, 27.93 mmol) in DMF (50 mL) under argon atmosphere were added sodium hydride (1.3 g, 55.86 mmol) and 2-chloro-4-fluoroaniline (4 g, 27.93 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with ice water (50 mL) to afford the solid which was filtered, washed with water and dried in vacuo to afford 2-chloro-N-(2-chloro-4-fluorophenyl)-5- methoxypyrimidin-4-amine (3.5 g, 44%) as an off-white solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 9.10 (s, 1H), 7.92 (s, 1H), 7.61-7.55 (m, 2H), 7.29 (t, 1H), 3.93 (s, 3H); LCMS: 288.2 (M+); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.76 min. 5 mM Aq NH 4 OAc: ACN; 0.80 mL/min); TLC: 10% EtOAc:hexanes (R/. 0.5).

Synthesis of2-chloro-4-((2-chloro-4-fluorophenyl) amino) pyrimidin-5-ol

[0332] To a stirred solution of 2-chloro-N-(2-chloro-4-fluorophenyl)-5- methoxypyrimidin-4-amine (3.5 g, 12.15 mmol) in CH 2 CI 2 (175 mL) under argon atmosphere were added 1M boron tribromide in CH 2 CI 2 (17.26 mL, 182.20 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 36 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was washed with n-pentane (2 x 20 mL) to afford 2-chloro-4-((2-chloro-4-fluorophenyl) amino) pyrimidin-5-ol (2.9 g, 87%) as a white solid. This compound was used without further purification. 1H-NMR (DMSO-<¾, 400 MHz): δ 10.80 (br s, 1H), 8.74 (s, 1H), 7.79-7.70 (m, 2H), 7.55 (d, 1H), 7.29 (t, 1H); LCMS: 275.9 (M+); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.39 min. 5 mM Aq NH 4 OAc: ACN; 0.80 mL/min); TLC: 40% EtOAc:hexanes (R/. 0.3).

Synthesis of 2-chloro-8-(2-chloro-4-fluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

[0333] To a stirred solution of 2-chloro-N-(2-chloro-4-fluorophenyl)-5- methoxypyrimidin-4-amine (2.7 g, 9.85 mmol) in DMF (20 mL) under argon atmosphere were added potassium carbonate (4 g, 29.56 mmol) and l-bromo-2-chloroethane (2 g, 14.78 mmol) at RT and stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column

chromatography using 5% EtOAc:hexanesto afford 2-chloro-8-(2-chloro-4-fluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (1.2 g, 41%) as an off-white solid. 1H-NMR (DMSO-d 6 , 400 MHz): δ 7.90 (s, 1H), 7.66 (d, 2H), 7.38 (t, 1H), 4.47-4.40 (m, 1H), 4.34- 4.29 (m, 1H), 3.90-3.83 (m, 1H), 3.79-3.70 (m, 1H); LCMS: 300.3 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.20 min. 0.05% Aq TFA: ACN; 0.80 mL/min);

UPLC (purity): 98.7%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.27 min. ACN: 0.025% TFA (Aq); 0.50 mL/min; TLC: 40% EtOAc:hexanes (Rf. 0.7).

Example 44

Synthesis of 2-chloro-8-(4-fluoro-2-(trifluoromethyl) phenyl)-7, 8-dihydro-6H-pyrimido

-b] [1, 4] oxazine

Synthesis of 2-chloro-N-(4-fluoro-2-(trifluoromethyl) phenyl)-5-methoxypyrimidin-4-amine

[0334] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (5 g, 27.93 mmol) in DMF (50 mL) under argon atmosphere were added sodium hydride (1.3 g, 55.86 mmol) and 4-fluoro-2-(trifluoromethyl) aniline (5 g, 27.93 mmol) 0 °C. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 40% EtOAc:hexane to afford 2-chloro-N-(4-fluoro-2-(trifluoromethyl) phenyl)-5-methoxypyrimidin-4-amine (2.6 g, 29%) as a brown solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 9.10 (s, 1H), 7.90 (s, 1H), 7.70 (d, 1H), 7.66-7.59 (m, 2H), 3.91 (s, 3H); LCMS: 322.2 (M+); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.30 min 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 40% EtOAc/hexane (R 0.2).

Synthesis of2-chloro-4-((4-fluoro-2-(trifluoromethyl) phenyl) amino) pyrimidin-5-ol

[0335] To a stirred solution of 2-chloro-N-(4-fluoro-2-(trifluoromethyl) phenyl)-5- methoxypyrimidin-4-amine (2.6 g, 8.08 mmol) in CH 2 CI 2 (100 mL) was added 1M boron tribromide in CH 2 CI 2 (30 g, 121.26 mmol) at 0 °C under argon atmosphere. The reaction mixture was warmed to RT and stirred for 36 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with cold water (20 mL), basified with sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 40% EtOAc :hexane to afford 2-chloro-4-((4-fluoro-2-(trifluoromethyl) phenyl) amino) pyrimidin-5-ol (1.9 g, 76%) as an off-white solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 10.69 (s, 1H), 8.72 (s, 1H), 7.70-7.66 (m, 3H), 7.65-7.58 (m, 1H); LCMS: 308.2 (M+); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.17 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 40% EtOAc/hexane (R 0.2).

Synthesis of 2-chloro-8-(4-fluoro-2-(trtfluoromethyl) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4- b] [I, 4] oxazine

[0336] To a stirred solution of 2-chloro-4-((4-fluoro-2-(trifluoromethyl) phenyl) amino) pyrimidin-5-ol (1.8 g, 5.86 mmol) in DMF (18 mL) under argon atmosphere were added 1- bromo-2-chloroethane (1.2 g, 8.79 mmol) and potassium carbonate (2.4 g, 17.58 mmol) at RT. The reaction mixture was stirred for 16 h at RT. After consumption of the starting material (monitored by TLC), the reaction was quenched with cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 20% EtOAc:hexane to afford 2-chloro-8-(4-fluoro-2-(trifluoromethyl) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (1.3 g, 66%>) as an off-white solid. 1H-NMR (DMSO-<¾, 500 MHz): δ 7.91 (s, 1H), 7.85-7.72 (m, 3H), 4.48 (d, 1H), 4.30-4.21 (m, 1H), 3.99-3.96 (m, 1H), 3.63 (d, 1H); LCMS: 334.3 (M+); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 4.28 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 98.1%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 2.38 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 40% EtOAc/hexane (R 0.7).

Example 45 Synthesis of 2-chloro-8-(4-chloro-2-(trifluoromethoxy) phenyl)-7, 8-dihydi

-b] [1, 4] oxazine

Synthesis of 2-chloro-N-(4-chloro-2-(trifluoromethoxy) phenyl)-5-methoxypyrimidin-4-amine

[0337] To a stirred solution of sodium hydride (1.3 g, 55.84 mmol) in DMF (50 mL) under argon atmosphere were added 2, 4-dichloro-5-methoxypyrimidine (5 g, 27.93 mmol) and 4-chloro-2-(trifluoromethoxy) aniline (5.9 g, 27.93 mmol) at 0 °C. The reaction mixture was warmed to RT for 4 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 10-30% EtOAc:hexanes to afford 2-chloro-N-(4-chloro-2-(trifluoromethoxy) phenyl)-5-methoxypyrimidin-4-amine (4.5 g, 45%) as a pale yellow solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 9.23 (s, 1H), 8.00 (s, 1H), 7.67-7.60 (m, 2H), 7.53 (d, 1H), 3.96 (s, 3H); LCMS: 355 (M+1); (column; X-Select CSH C- 18 (50 3.0 mm, 3.5 μιη); RT 4.90 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC

(purity): 94.2%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 2.86 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc/hexane (R 0.3).

Synthesis of 2-chloro-N-(4-chloro-2-(trifluoromethoxy) phenyl)-5-methoxypyrimidin-4-amine

[0338] To a stirred solution of 2-chloro-N-(4-chloro-2-(trifluoromethoxy) phenyl)-5- methoxypyrimidin-4-amine (4.4 g, 12.42 mmol) in CH 2 CI 2 (250 mL) was added 1M boron tribromide in CH 2 CI 2 (46 g, 186.40 mmol) at 0 °C under argon atmosphere. The reaction mixture was warmed to RT and stirred for 24 h. After consumption of the starting material

(monitored by TLC), the reaction was diluted with water (100 mL), neutralized with sodium bicarbonate solution (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-N-(4-chloro-2-(trifluoromethoxy) phenyl)-5-methoxypyrimidin-4-amine (4 g, 89%) as an off-white solid used without further purification. LCMS: 341.1 (M+l); (column; X- Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.73 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 79.9%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.66 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc/hexane (R/. 0.2).

Synthesis of2-chloro-8-(4-chloro-2-(trifluoromethoxy) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0339] To a stirred solution of 2-chloro-N-(4-chloro-2-(trifluoromethoxy) phenyl)-5- methoxypyrimidin-4-amine (3.9 g, 11.47 mmol) in DMF (40 mL) under argon atmosphere were added potassium carbonate (4.74 g, 34.34 mmol) and l-bromo-2-chloroethane (2.4 g, 17.20 mmol) at RT. The reaction mixture was stirred for 36 h at RT. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 10-25% EtOAc:hexanes to afford 2-chloro-8-(4-chloro-2- (trifluoromethoxy) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (3 g, 71%) as an off-white solid. 1H-NMR (CD 3 OD, 500 MHz): δ 7.83 (s, 1H), 7.59-7.50 (m, 3H), 4.41-4.38 (m, 2H), 3.92-3.89 (m, 2H); LCMS: 367.1 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.59 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 94.2%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.62 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc/hexane (R/. 0.5).

Example 46

Synthesis of 2-chloro-8-(4-chloro-2-(trifluoromethyl) phenyl)-7, 8-dihydro-6H-pyrimido

[5, 4-b] [1, 4] oxazine

Synthesis of 2-chloro-N-(4-chloro-2-(trifluoromethyl) phenyl)-5-methoxypyrimidin-4-amine

[0340] To a stirred solution of sodium hydride (1.3 g, 55.83 mmol) in DMF (50 mL) under argon atmosphere were added 4-chloro-2-(trifluoromethyl) aniline (5.4 g, 27.94 mmol) and 2, 4-dichloro-5-methoxypyrimidine (5 g, 27.93 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 30%

EtOAc:hexanes to afford 2-chloro-N-(4-chloro-2-(trifluoromethyl) phenyl)-5- methoxypyrimidin-4-amine (4.6 g, 49%) as a pale yellow solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 9.10 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.86 (d, 1H), 7.63 (d, 1H), 3.93 (s, 3H); LCMS: 338.2 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.71 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 96.9%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.70 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc/hexane (R 0.3).

Synthesis of2-chloro-4-((4-chloro-2-(trifluoromethyl) phenyl) amino) pyrimidin-5-ol

[0341] To a stirred solution of 2-chloro-N-(4-chloro-2-(trifluoromethyl) phenyl)-5- methoxypyrimidin-4-amine (4.4 g, 13.16 mmol) in CH 2 CI 2 (250 mL) was added 1M boron tribromide in CH 2 CI 2 (18.7 mL, 197.47 mmol) at RT under argon atmosphere. The reaction mixture was stirred for 24 h at RT. After consumption of the starting material (monitored by

TLC), the reaction was diluted with ice water (100 mL), neutralized with a sodium

bicarbonate solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was washed with n-pentane (2 x 10 mL) to afford 2-chloro-4-((4-chloro-2- (trifluoromethyl) phenyl) amino) pyrimidin-5-ol (3.8 g, 90%) as an off-white solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 10.81 (s, 1H), 8.70 (s, 1H), 7.88-7.70 (m, 4H); Mass (ESI): 375.4 [M+1]; LCMS: 324.4 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.56 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 30% EtOAc/hexane (R 0.2).

Synthesis of2-chloro-8-(4-chloro-2-(trifluoromethyl) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0342] To a stirred solution of 2-chloro-4-((4-chloro-2-(trifluoromethyl) phenyl) amino) pyrimidin-5-ol (3.8 g, 11.72 mmol) in DMF (40 mL) under argon atmosphere were added potassium carbonate (4.85 g, 35.14 mmol) and l-bromo-2-chloroethane (2.5 g, 17.55 mmol) at RT. The reaction mixture was stirred for 36 h at RT. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column

chromatography using 10-25% EtOAc:hexanes to afford 2-chloro-8-(4-chloro-2- (trifluoromethyl) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (3.1 g, 76%) as a yellow solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 8.00-7.96 (m, 2H), 7.91 (s, 1H), 7.79 (d, 1H), 4.53 (d, 1H), 4.28-4.21 (m, 1H), 4.00-3.92 (m, 1H), 3.69-3.61 (m, 1H); LCMS: 350.3 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.50 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 96.1%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.56 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc/hexane

Example 47

Synthesis of 2-chloro-8-(4-fluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of 4-fluoroaniline

[0343] To a stirred solution of l-fluoro-4-nitrobenzene (10 g, 70.90 mmol) in MeOH (100 mL) under argon atmosphere was added 10% Pd/C (500 mg) at RT and stirred for 16 h under a hydrogen atmosphere. After consumption of the starting material (monitored by TLC), the reaction was filtered and washed with MeOH (2 x 20 mL). The filtrate was concentrated in vacuo to afford 4-fluoroaniline (7.8 g, 99%) as a brown liquid. 1H-NMR (CDCls, 500 MHz): δ 6.84 (t, 2H), 6.63-6.60 (m, 2H), 3.53 (br s, 2H); LCMS: 112.2 (M+); (column; Eclipse XDB C-18 (150 4.6 mm, 5 μπι); RT 5.34 min 0.05% Aq TFA: ACN; 1.0 mL/min); TLC: 30% EtOAc/hexane (R 0.3).

Synthesis of 2-chloro-N-(4-fluorophenyl)-5-methoxypyrimidin-4-amine

[0344] To a stirred solution of 4-fluoroaniline (3.1 g, 27.93 mmol) in 1, 4-dioxane (50 mL) under argon atmosphere were added diisopropylethylamine (9.8 mL, 55.80 mmol) and 2, 4-dichloro-5-methoxypyrimidine (5 g, 27.90 mmol) at RT. The reaction mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC), the reaction was diluted with a saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was washed with n-hexane (2 x 30 mL) to afford 2-chloro-N-(4-fluorophenyl)-5-methoxypyrimidin-4-amine (6 g, 86%) as a red solid. 1H-NMR (CDC1 3 , 400 MHz): δ 7.72 (s, 1H), 7.64 (t, 2H), 7.25-7.21 (m, 1H), 7.08 (t, 2H), 3.99 (s, 3H); LCMS: 254.1 (M+); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.06 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 30% EtOAc/hexane (R 0.2).

Synthesis of 2-chloro-4-((4-fluorophenyl) amino) pyrimidin-5-ol

[0345] To a stirred solution of 2-chloro-N-(4-fluorophenyl)-5-methoxypyrimidin-4-amine (6 g, 23.62 mmol) in CH 2 CI 2 (100 mL) under argon atmosphere was added 1M boron tribromide in CH 2 CI 2 (4.4 mL, 47.24 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with ice cold water (50 mL), basified with a saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro- 4-((4-fluorophenyl) amino) pyrimidin-5-ol (5.4 g, 96%) as a brown solid. 1H-NMR (DMSO- d 6 , 400 MHz): δ 10.74 (br s, 1H), 9.19 (s, 1H), 7.80 (t, 2H), 7.71 (s, 1H), 7.20 (t, 2H); LCMS: 240.1 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.84 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 60% EtOAc/hexane (R 0.3).

Synthesis of 2-chloro-8-(4-fluorophenyl)-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0346] To a stirred solution of 2-chloro-4-((4-fluorophenyl) amino) pyrimidin-5-ol (5.4 g, 22.50 mmol) in DMF (60 mL) under argon atmosphere were added l-bromo-2-chloroethane (4.8 g, 33.75 mmol) and potassium carbonate (9.3 g, 67.50 mmol) at RT and stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 100% EtOAc to afford 2-chloro-8-(4- fluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (5 g, 84%) as a brown solid.

1H-NMR (CDCls, 500 MHz): δ 7.80 (s, 1H), 7.35-7.31 (m, 2H), 7.12 (t, 2H), 4.35-4.30 (m, 2H), 3.93-3.90 (m, 2H); LCMS: 266.1 (M+); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.91 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 60% EtOAc/hexane (R 0.6).

Example 48

Synthesis of 2-chloro-8-(2, 4-dichlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of 2-chloro-N-(2, 4-dichlorophenyl)-5-methoxypyrimidin-4-amine

[0347] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (5 g, 27.93 mmol) in DMF (50 mL) under argon atmosphere were added sodium hydride (670 mg, 27.93 mmol) and 2, 4-dichloroaniline (3 g, 19.55 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 30% EtOAc:hexane to afford 2-chloro-N-(2, 4-dichlorophenyl)-5-methoxypyrimidin-4-amine (2.5 g, 29%) as an off- white solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 9.05 (s, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 7.70- 7.68 (m, 1H), 7.49 (d, 1H), 3.95 (s, 3H); LCMS: 304.1 (M+); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.87 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 20% EtOAc/hexane (R 0.2).

Synthesis of 2-chloro-4-((2 , 4-dichlorophenyl) amino) pyrimidin-5-ol

[0348] To a stirred solution of 2-chloro-N-(2, 4-dichlorophenyl)-5-methoxypyrimidin-4- amine (2.5 g, 8.22 mmol) in CH 2 CI 2 (250 mL) was added 1M boron tribromide in CH 2 CI 2 (25 mL) at 0 °C under argon atmosphere. The reaction mixture was warmed to RT and stirred for 48 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 40% EtOAc:hexane to afford 2-chloro-4-((2, 4-dichlorophenyl) amino) pyrimidin-5-ol (1.8 g, 75%) as an off-white solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 10.94 (s, 1H), 8.67 (s, 1H), 7.90 (d, 1H), 7.79 (s, 1H), 7.77-7.71 (m, 1H), 7.49 (d, 1H); LCMS: 292.1 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.76 min 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 50%

EtOAc/hexane (R 0.2).

Synthesis of 2-chloro-8-(2, 4-dichlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

[0349] To a stirred solution of 2-chloro-4-((2, 4-dichlorophenyl) amino) pyrimidin-5-ol (1.7 g, 5.86 mmol) in DMF (17 mL) under argon atmosphere were added l-bromo-2- chloroethane (1.2 g, 8.79 mmol) and potassium carbonate (2.4 g, 17.58 mmol) at RT. The reaction mixture was stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and

concentrated in vacuo. The crude material was purified by column chromatography using 20%) EtOAc:hexane to afford 2-chloro-8-(2, 4-dichlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (1.2 g, 65%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.90

- I l l - (s, 1H), 7.81 (s, 1H), 7.62 (d, 1H), 7 ' .59-7 ' .57 (m, 1H), 4.50-4.28 (m, 2H), 3.94-3.74 (m, 2H); LCMS: 318.1 (M+); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.47 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 94.2%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.47 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 40% EtOAc/hexane (R 0.5).

Example 49

Synthesis of 2-chloro-8-(4-fluoro-2-(trifluoromethoxy) phenyl)-7, 8-dihydi

-b] [1, 4] oxazine

Synthesis of 2-chloro-N-(4-fluoro-2-(trifluoromethoxy) phenyl)- 5 -methoxypyrimidin-4 -amine

[0350] To a stirred solution of sodium hydride (804 mg, 33.50 mmol) in DMF (30 mL) under argon atmosphere were added and 2, 4-dichloro-5-methoxypyrimidine (3 g, 16.76 mmol) and 4-fluoro-2-(trifluoromethoxy) aniline (3.2 g, 16.76 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 6 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with ice water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 10% EtOAc:hexanes to afford 2-chloro-N-(4-fluoro-2-(trifluoromethoxy) phenyl)-5- methoxypyrimidin-4-amine (2.5 g, 38%) as an off-white solid. 1H-NMR (DMSO-<¾, 500 MHz): δ 9.20 (s, 1H), 7.93 (s, 1H), 7.59 (t, 1H), 7.44 (d, 1H), 7.30 (t, 1H), 3.93 (s, 3H); LCMS: 337.8 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.88 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 99.5%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 2.59 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc/hexane (R 0.3). Synthesis of2-chloro-4-((4-fluoro-2-(trifluoromethoxy) phenyl) amino) pyrimidin-5-ol

[0351] To a stirred solution of 2-chloro-N-(4-fluoro-2-(trifluoromethoxy) phenyl)-5- methoxypyrimidin-4-amine (2.5 g, 7.41 mmol) in CH 2 CI 2 (130 mL) was added 1M boron tribromide in CH 2 CI 2 (10.5 mL, 110.88 mmol) at 0 °C under argon atmosphere. The reaction mixture was warmed to RT and stirred for 24 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with ice water (100 mL), neutralized with sodium bicarbonate solution (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-4-((4-fluoro-2-(trifluoromethoxy) phenyl) amino) pyrimidin-5-ol (2.1 g, 88%) as an off-white solid used without further purification. 1H-NMR (DMSO-<¾, 500 MHz): δ 10.72 (s, 1H), 8.93 (s, 1H), 7.71-7.69 (m, 2H), 7.42 (d, 1H), 7.33 (t, 1H); LCMS: 323.8 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.73 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 70.8%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 2.39 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc/hexane (R 0.2).

Synthesis of2-chloro-8-(4-fluoro-2-(trifluoromethoxy) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-bJ [I, 4] oxazine

[0352] To a stirred solution of 2-chloro-4-((4-fluoro-2-(trifluoromethoxy) phenyl) amino) pyrimidin-5-ol (2.1 g, 6.50 mmol) in DMF (20 mL) under argon atmosphere were added potassium carbonate (2.7 g, 19.49 mmol) and l-bromo-2-chloroethane (1.4 g, 9.72 mmol) at RT and stirred for 24 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 10-20% EtOAc:hexanes to afford 2-chloro-8-(4-fluoro-2-(trifluoromethoxy) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (1.65 g, 73%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.80 (s, 1H), 7.59-7.57 (m, 1H), 7.30-7.20 (m, 2H), 4.39-4.35 (m, 2H), 3.90-3.80 (m, 2H); LCMS: 349.8 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 3.44 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 93.4%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 2.47 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30%

EtOAc/hexane (R 0.5).

Example 50 Synthesis of 8-(o-tolyl)- V-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin

-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of8-(o-tolyl)-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7 , 8-dihydro- 6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0353] A dry vial charged with Pd 2 (dba) 3 (21 mg, 0.02 mmol) and (±) BINAP (42 mg, 0.06 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(o-tolyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (120 mg, 0.45 mmol), l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-amine hydrochloride (142 mg, 0.50 mmol) and sodium tert-butoxide (132 mg, 1.37 mmol) in 1, 4-dioxane (0.6 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 4% MeOH: CH 2 Cl 2 to afford 8-(o-tolyl)-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (48 mg, 22%) as a pale yellow solid.

1H-NMR (OMSO-d 6 , 400 MHz): δ 8.19 (d, 1H), 7.53 (s, 1H), 7.30-7.19 (m, 4H), 7.13 (s, 1H), 6.98-6.96 (m, 1H), 6.01-5.99 (m, 1H), 4.29-4.14 (m, 2H), 3.98-3.88 (m, 2H), 3.87-3.78 (m, 1H), 3.63-3.57 (m, 2H), 2.87-2.79 (m, 2H), 2.12 (s, 3H), 1.79-1.70 (m, 2H), 1.32-1.20 (m, 2H); Mass (ESI): 471.4 [M+l]; LCMS: 471 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.50 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 95.0%; (column; Acquity BEH C-18, 50 2.1mm, 1.7 μπι); RT 1.77 min. ACN: 0.025% TFA (Aq); 0.50 mL/min; TLC: 10% MeOH/CH 2 Cl 2 (R 0.3).

Example 51 Synthesis of 8-(2-(trifluoromethoxy) phenyl)- V-(l-(2-(trifluoromethyl) pyridin-4-yl) -4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8-(2-(trifluoromethoxy) phenyl)-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0354] A dry vial charged with Pd 2 (dba) 3 (13 mg, 0.01 mmol) and (±) BINAP (28 mg, 0.04 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2-(trifluoromethoxy) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.30 mmol), l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4- amine hydrochloride (93 mg, 0.33 mmol) and sodium tert-butoxide (87 mg, 0.90 mmol) in 1, 4-dioxane (0.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (50 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC ((Kromacil C-18 (250 x 21.2 mm, ΙΟμιη (50 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 15/65, 25/10, 35/10)) to afford 8-(2-(trifluoromethoxy) phenyl)-N-(l-(2-(trifhioromethyl) pyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (55 mg, 34%) as an off-white solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 8.21 (d, 1H), 7.60-7.55 (m, 2H), 7.48-7.39 (m, 3H), 7.14 (s, 1H), 6.99-6.97 (m, 1H), 6.13-6.10 (m, 1H), 4.20-4.18 (m, 2H), 3.93-3.89 (m, 2H), 3.77 (br s, 2H), 3.58-3.50 (m, 1H), 2.83-2.79 (m, 2H), 1.77-1.70 (m, 2H), 1.32-1.20 (m, 2H); Mass (ESI): 541.4 [M+l]; LCMS: 540.9 (M+l); (column; X- Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.67 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 98.0%; (column; Acquity BEH C-18, 50 2.1mm, 1.7 μπι); RT 1.91 min. ACN: 0.025% TFA (Aq); 0.50 mL/min; TLC: 10% MeOH/CH 2 Cl 2 (R 0.3).

Example 52 Synthesis of 8-(2-chlorophenyl)- V-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of8-(2-chlorophenyl)-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7 , 8- dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0355] A dry vial charged with Pd 2 (dba) 3 (16 mg, 0.02 mmol) and (±) BINAP (33 mg, 0.05 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2-chlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.35 mmol), l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-amine hydrochloride (110 mg, 0.39 mmol) and sodium tert-butoxide (102 mg, 1.06 mmol) in 1, 4- dioxane (0.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (100 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column

chromatography using 4% MeOH: CH 2 C1 2 to afford 8-(2-chlorophenyl)-N-(l-(2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (60 mg, 34%) as an off-white solid. 1H-NMR (OMSO-d 6 , 400 MHz): δ 8.20 (d, 1H), 7.57 (s, 2H), 7.48 (d, 1H), 7.40 (t, 1H), 7.35-7.30 (m, 1H), 7.12 (d, 1H), 6.98-6.95 (m, 1H), 6.10-6.08 (m, 1H), 4.29-4.11 (m, 2H), 3.92-3.88 (m, 2H), 3.79-3.67 (m, 2H), 3.60- 3.53 (m, 1H), 2.83-2.79 (m, 2H), 1.81-1.72 (m, 2H), 1.39-1.20 (m, 2H); Mass (ESI): 491.4 [M+l]; LCMS: 491.3 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.05 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 97.4%; (column; Acquity BEH C- 18 50 X 2.1 mm, 1.7 μπι); RT 1.79 min. ACN: 0.025% TFA (Aq); 0.50 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (R 0.2).

Example 53 Synthesis of 7V-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-8-(3, 4, 5- trifluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-8-(3 , 4, 5-trifluorophenyl)- 7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0356] A dry vial charged with Pd 2 (dba) 3 (15 mg, 0.01 mmol) and (±) BINAP (31 mg, 0.04 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(3, 4, 5-trifluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.33 mmol), l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-amine hydrochloride (103 mg, 0.36 mmol) and sodium tert-butoxide (96 mg, 0.99 mmol) in 1 , 4- dioxane (0.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (50 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column

chromatography using 4% MeOH: CH 2 Cl 2 to afford N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-8-(3, 4, 5-trifluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2- amine (50 mg, 29%) as an off-white solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 8.23 (d, 1H), 7.69 (s, 1H), 7.59-7.50 (m, 2H), 7.19-7.17 (m, 1H), 7.01-6.99 (m, 1H), 6.41-6.39 (m, 1H), 4.20-4.18 (m, 2H), 4.00-3.96 (m, 2H), 3.84-3.80 (m, 2H), 3.73-3.69 (m, 1H), 2.93 (t, 2H), 1.89-1.81 (m, 2H), 1.41-1.35 (m, 2H); Mass (ESI): 511.4 [M+l]; LCMS: 511.3 (M+l); (column; X-Select C-18 (50 3.0 mm, 3.5 μπι); RT 3.46 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 99.3%; (column; Acquity BEH C-18, 50 2.1 mm, 1.7 μπι); RT 1.86 min. ACN: 0.025% Aq TFA; 0.50 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (R 0.2).

Example 54 Synthesis of 8-benzyl- V-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H- -b] [1, 4] oxazin-2-amine

Synthesis of8-benzyl-N-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-7 , 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0357] A dry vial charged with Pd 2 (dba) 3 (17 mg, 0.02 mmol) and (±) BINAP (38 mg, 0.06 mmol) in 1, 4-dioxane (2.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 8-benzyl-2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.38 mmol), l-(6-methylpyrimidin-4-yl) piperidin-4-amine (88 mg, 0.45 mmol) and sodium tert-butoxide (147 mg, 1.53 mmol) in 1, 4-dioxane (2.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 12 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (50 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 4% MeOH: CH 2 Cl 2 to afford 8-benzyl-N-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (50 mg, 31%) as a pale yellow solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 8.31 (s, 1H), 7.41 (s, 1H), 7.31-7.12 (m, 5H), 6.58 (s, 1H), 6.21 (d, 1H), 4.73 (s, 2H), 4.30-4.23 (m, 2H), 4.06-4.02 (m, 2H), 3.84-3.80 (m, 1H), 3.41-3.39 (m, 2H), 2.94 (t, 2H), 2.20 (s, 3H), 1.85-1.80 (m, 2H), 1.33-1.23 (m, 2H); Mass (ESI): 418.4 [M+l]; LCMS: 418.5 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.23 min. 5 mM NH 4 OAc: ACN; 0.80 mL/min); HPLC (purity): 98.9%; (column; Eclipse XDB C-18, 150 4.6 mm, 1.7 μπι); RT 10.23 min. ACN: 5 mM Aq NH 4 OAc; 1.0 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (R 0.3).

Example 55

Synthesis of 8-(3, 5-difluorophenyl)- V-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4- yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8- (3, 5-difluorophenyl)-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0358] A dry vial charged with Pd 2 (dba) 3 (16 mg, 0.02 mmol) and (±) BINAP (33 mg, 0.05 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(3, 5-difluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.35 mmol), l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-amine hydrochloride (109 mg, 0.38 mmol) and sodium tert-butoxide (102 mg, 1.06 mmol) in 1, 4- dioxane (0.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (50 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Kromacil C-18 (250 x 21.2 mm, 10 μιη (50 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 15/65, 25/10, 35/10)) to afford 8-(3, 5-difluorophenyl)-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (60 mg, 35%>) as an off-white solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 8.21 (d, 1H), 7.69 (s, 1H), 7.32 (d, 2H), 7.18-7.15 (m, 1H), 7.01-6.93 (m, 2H), 6.42-6.38 (m, 1H), 4.21-4.18 (m, 2H), 4.00-3.92 (m, 2H), 3.89-3.83 (m, 2H), 3.78-3.70 (m, 1H), 2.91 (t, 2H), 1.89-1.81 (m, 2H), 1.42-1.31 (m, 2H); Mass (ESI): 493.4 [M+1]; LCMS: 493.4 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.08 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 98.6%; (column; Acquity BEH C-18, 50 2.1 mm, 1.7 μπι); RT 1.82 min. ACN: 0.025% Aq TFA; 0.50 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (R 0.2).

Example 56

Synthesis of 8-benzyl-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

ea e tu e

Synthesis of8-benzyl-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7 , 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0359] A dry vial charged with Pd 2 (dba) 3 (21 mg, 0.02 mmol) and (±) BINAP (42 mg, 0.06 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 8-benzyl-2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (120 mg, 0.45 mmol), l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-amine hydrochloride (142 mg, 0.50 mmol) and sodium tert-butoxide (132 mg, 1.37 mmol) in 1, 4-dioxane (0.6 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the volatile components were evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC ((Kromacil C-18 (250 x 21.2 mm, 10 μιη (60 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 15/65, 30/10, 35/10)) to afford 8-benzyl-N-(l-(2-(trifhioromethyl) pyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (70 mg, 32%) as an off-white solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 8.23 (d, 1H), 7.41 (s, 1H), 7.38-7.22 (m, 5H), 7.29-7.28 (m, 1H), 7.04-7.02 (m, 1H), 7.16 (d, 1H), 6.76 (s, 2H), 4.07- 4.01 (m, 2H), 4.00-3.92 (m, 2H), 3.87-3.80 (m, 1H), 3.40-3.38 (m, 2H), 3.00 (t, 2H), 1.90- 1.87 (m, 2H), 1.41-1.39 (m, 2H); Mass (ESI): 471.4 [M+l]; LCMS: 471.3 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.02 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 99.5%; (column; Acquity BEH C-18, 50 2.1mm, 1.7 μπι); RT 1.78 min. ACN: 0.025% TFA (Aq); 0.50 mL/min; TLC: 5% MeOH/CH 2 Cl 2 (R 0.3).

Example 57

Synthesis of 8-benzyl-7V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine NH 2 . HCI sealed tube

Synthesis of 8-benzyl-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2- amine

[0360] A dry vial charged with Pd 2 (dba) 3 (17 mg, 0.02 mmol) and (±) BINAP (35 mg, 0.06 mmol) in 1, 4-dioxane (2 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 8-benzyl-2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.38 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride (96 mg, 0.45 mmol) and sodium tert-butoxide (147 mg, 1.53 mmol) in 1, 4-dioxane (2 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the volatile components were concentrated in vacuo. The crude material was purified by silica gel column chromatography using 4% MeOH: CH 2 C1 2 to afford 8-benzyl-N-(l-(2- methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2- amine (35 mg, 21%) as an off-white solid. 1H-NMR (CD 3 OD, 500 MHz): δ 7.75 (d, 1H), 7.39 (s, 1H), 7.38-7.22 (m, 5H), 6.53-6.50 (m, 1H), 6.12 (s, 1H), 4.89 (s, 2H), 4.10-4.08 (m, 2H), 3.90-3.88 (m, 3H), 3.84 (s, 3H), 3.50-3.48 (m, 2H), 2.98 (t, 2H), 2.00-1.97 (m, 2H), 1.52-1.49 (m, 2H); LCMS: 433.4 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.61 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 95.4%; (column; Acquity BEH- C18 50 X 2.1 mm, 1.7 μπι); RT 1.48 min. ACN: 0.025% TFA (Aq); 0.5 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (R 0.2).

Example 58

Synthesis of V-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-8-(2, 2, 2-trifluoroethyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine NH 2. HCI Sealed tube

Synthesis of N-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-8-(2, 2, 2-trifluoroethyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0361] A dry vial charged with Pd 2 (dba) 3 (22 mg, 0.02 mmol) and (±) BINAP (44 mg, 0.07 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2, 2, 2-trifluoroethyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1,4] oxazine (120 mg, 0.47 mmol), l-(6-methylpyrimidin-4-yl) piperidin-4-amine hydrochloride (118 mg, 0.52 mmol) and sodium tert-butoxide (137 mg, 1.42 mmol) in 1, 4- dioxane (0.6 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 50% EtOAc:hexanes to afford N-(l-(6-methylpyrimidin-4-yl) piperidin-4-yl)-8-(2, 2, 2-trifluoroethyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2- amine (60 mg, 31%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 8.31 (s, 1H), 7.45 (s, 1H), 6.68 (s, 1H), 4.41-4.30 (m, 4H), 4.12-4.10 (m, 2H), 3.93-3.89 (m, 1H), 3.65-3.60 (m, 2H), 3.10 (t, 2H), 2.31 (s, 3H), 2.07-2.01 (m, 2H), 1.49-1.39 (m, 2H); Mass (ESI): 410.3

[M+1]; LCMS: 410.4 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.64 min. 5 mM Aq NH 4 OAc: ACN; 0.80 mL/min); HPLC (purity): 95.6%; (column; Eclipse- XDB-C181 50 X 4.6 mm, 5 μπι); RT 9.33 min. ACN: 5 mM Aq NH 4 OAc; 1.0 mL/min; TLC: 70% EtOAc/hexanes (R 0.4).

Example 59

Synthesis of 8-(2, 2, 2-trifluoroethyl)- V-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4- yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine NH 2 HCI Sealed tube

Synthesis of 8- (2, 2, 2-trifluoroethyl)-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)- 7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0362] A dry vial charged with Pd 2 (dba) 3 (18 mg, 0.02 mmol) and (±) BINAP (37 mg, 0.06 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2, 2, 2-trifluoroethyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.40 mmol), l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-amine hydrochloride (122 mg, 0.43 mmol) and sodium tert-butoxide (114 mg, 1.18 mmol) in 1, 4- dioxane (0.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Kromacil C-18 (250 x 21.2 mm, 10 μιη (50 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 15/65, 30/10, 35/10)) to afford 8-(2, 2, 2-trifluoroethyl)-N-(l-(2-(trifluoromethyl) pyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (45 mg, 25%) as an off-white solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 8.21 (d, 1H), 7.51 (s, 1H), 7.20-7.18 (m, 1H), 7.02-7.00 (m, 1H), 6.34 (d, 1H), 4.41-4.37 (m, 2H), 4.10-4.00 (m, 2H), 3.99-3.95 (m, 2H), 3.89-3.81 (m, 1H), 3.60-3.58 (m, 2H), 3.01 (t, 2H), 1.92-1.89 (m, 2H), 1.46-1.38 (m, 2H); Mass (ESI): 463.3 [M+l]; LCMS: 463.3 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.73 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 97.4%; (column; Acquity BEH C18 50 X 2.1 mm, 1.7 μπι); RT 1.58 min. ACN: 0.025% TFA (Aq); 0.5 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (Rf. 0.3).

Example 60

Synthesis of 7V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-(2, 2, 2-trifluoroethyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

NH 2. HCI Sealed tube

Synthesis of N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-(2, 2, 2-trifluoroethyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0363] A dry vial charged with Pd 2 (dba) 3 (18 mg, 0.02 mmol) and (±) BINAP (37 mg, 0.06 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2, 2, 2-trifluoroethyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.39 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride (106 mg, 0.43 mmol) and sodium tert-butoxide (114 mg, 1.18 mmol) in 1, 4-dioxane (0.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (50 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Kromacil-C18 (250 x 21.2 mm, 10 μιη (50 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 15/65, 25/10, 35/10)) to afford N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-(2, 2, 2-trifiuoroethyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (48 mg, 28%) as a brown solid. 1H-NMR (DMSC ¾, 400 MHz): δ 7.76 (d, 1H), 7.51 (s, 1H), 6.51 (d, 1H), 6.31 (d, 1H), 6.10-6.08 (m, 1H), 4.41-4.37 (m, 2H), 4.05-4.01 (m, 2H), 3.82-3.79 (m, 3H), 3.75 (s, 3H), 3.60-3.57 (m, 2H), 2.87 (t, 2H), 1.90-1.83 (m, 2H), 1.43-1.38 (m, 2H); Mass (ESI): 425.4 [M+l]; LCMS: 425.5 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 4.01 min. 5 mM Aq NH 4 OAc: ACN; 0.80 mL/min); UPLC (purity): 98.7%; (column; Acquity BEH C18 50 X 2.1 mm, 1.7 μιη); RT 1.36 min. ACN: 0.025% TFA (Aq); 0.5 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (R 0.2).

Example 61

Synthesis of 7V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-(3, 4, 5-trifluorophenyl)-7,

8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-(3, 4, 5-trifluorophenyl)-7, 8- dihydro-6H-pyrimido [5, 4-bJ [I, 4] oxazin-2-amine

[0364] A dry vial charged with Pd 2 (dba) 3 (18 mg, 0.02 mmol) and (±) BINAP (37 mg, 0.06 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(3, 4, 5-trifluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (120 mg, 0.39 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride (106 mg, 0.43 mmol) and sodium tert-butoxide (114 mg, 0.19 mmol) in 1, 4- dioxane (0.6 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Kromacil C-18 (250 x 21.2 mm, 10 μιη (60 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 15/65, 25/10, 35/10)) to afford N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-8-(3, 4, 5- trifluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (52 mg, 28%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.71 (d, 1H), 7.59 (s, 1H), 7.37-7.30 (m, 2H), 6.51 (d, 1H), 6.11 (s, 1H), 4.24-4.21 (m, 2H), 3.89-3.81 (m, 4H), 3.79 (s, 3H), 3.72-3.68 (m, 1H), 2.90 (t, 2H), 1.99-1.91 (m, 2H), 1.51-1.42 (m, 2H); Mass (ESI): 473.4 [M+l];

LCMS: 473.4 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.87 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 99.1%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.54 min. ACN: 0.025% TFA (Aq); 0.50 mL/min; TLC: 10% MeOH/ CH 2 C1 2 (R 0.4).

Example 62

Synthesis of 8-(2, 4-difluorophenyl)-7V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8-(2, 4-dtfluorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8- dihydro-6H-pyrimido [5, 4-bJ [I, 4] oxazin-2-amine

[0365] A dry vial charged with Pd 2 (dba) 3 (19 mg, 0.02 mmol) and (±) BINAP (39 mg, 0.06 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2, 4-difluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (120 mg, 0.42 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride (113 mg, 0.46 mmol) and sodium tert-butoxide (122 mg, 1.27 mmol) in 1, 4-dioxane (0.6 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with 5% MeOH: CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Kromacil C-18 (250 x 21.2 mm, 10 μιη (45 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 15/65, 25/10, 35/10)) to afford 8-(2, 4-difluorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4- yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (45 mg, 23%) as an off-white solid. 1H-NMR (DMSO-<¾, 500 MHz): δ 7.76 (d, 1H), 7.60 (s, 1H), 7.58-7.51 (m, 1H), 7.37 (t, 1H), 7.15 (t, 1H), 6.51 (d, 1H), 6.15 (br s, 1H), 6.07 (s, 1H), 4.21-4.19 (m, 2H), 3.80-3.71 (m, 7H), 3.50 (br s, 1H), 2.72-2.67 (m, 2H), 1.80-1.72 (m, 2H), 1.37-1.27 (m, 2H); Mass (ESI): 455.4 [M+l]; LCMS: 455.4 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.72 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 97.7%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 1.47 min. ACN: 0.025% TFA (Aq); 0.50 mL/min; TLC: 50% EtOAc/hexane (R/. 0.1).

Example 63 Synthesis of_8-(4-chlorophenyl)- V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8- -6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8-(4-chlorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7 , 8-dihydro- 6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0366] A dry vial charged with Pd 2 (dba) 3 (19 mg, 0.02 mmol) and (±) BINAP (40 mg, 0.06 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(4-chlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (120 mg, 0.42 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride (113 mg, 0.46 mmol) and sodium tert-butoxide (122 mg, 1.27 mmol) in 1, 4-dioxane (0.6 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (YMC polymer C-18 (300 x 20 mm (50 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 15/70, 25/10, 35/10)) to afford 8-(4-chlorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine (80 mg, 42%) as a pale yellow solid. 1H-NMR (OMSO-d 6 , 400 MHz): δ 7.74 (d, 1H), 7.61 (s, 1H), 7.52-7.48 (m, 2H), 7.47-7.40 (m, 2H), 6.51 (d, 1H), 6.21-6.19 (m, 1H), 6.07 (s, 1H), 4.21-4.19 (m, 2H), 3.90-3.81 (m, 2H), 3.80- 3.72 (m, 2H), 3.71 (s, 3H), 3.61 (br s, 1H), 2.83-2.79 (m, 2H), 1.81-1.78 (m, 2H), 1.40-1.30 (m, 2H); Mass (ESI): 453.5 [M+1]; LCMS: 453.6 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.74 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 98.8%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.53 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (R/. 0.2). Example 64

Synthesis of 8-(2-chloro-4-fluorophenyl)- V-(l-(2-methoxypyridin-4-yl) piperidin

8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of8-(2-chloro-4-fluorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7 , 8- dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0367] A dry vial charged with Pd 2 (dba) 3 (18 mg, 0.02 mmol) and (±) BINAP (37 mg, 0.06 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A second vial was charged 2-chloro-8-(2-chloro-4-fluorophenyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazine (120 mg, 0.40 mmol), l-(2-methoxypyridin-4-yl) piperidin- 4-amine hydrochloride (106 mg, 0.44 mmol) and sodium tert-butoxide (115 mg, 1.20 mmol) in 1, 4-dioxane (0.6 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Column YMC polymer C-18 (300 x 20 mm, 10 μιη (55 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 15/70, 20/10, 35/10)) to afford 8-(2-chloro-4-fluorophenyl)-N-(l-(2- methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2- amine (48 mg, 26%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.69 (d, 1H), 7.49 (s, 1H), 7.48-7.40 (m, 1H), 7.38 (d, 1H), 7.19-7.12 (m, 1H), 6.44 (d, 1H), 6.05 (s, 1H), 4.28- 4.21 (m, 2H), 3.80 (s, 3H), 3.79-3.74 (m, 4H), 3.51-3.47 (m, 1H), 2.79 (t, 2H), 1.90-1.80 (m, 2H), 1.40-1.21 (m, 2H); Mass (ESI): 471.5 [M+1]; LCMS: 471.5 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.72 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 99.6%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 1.51 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (Rf. 0.4). Example 65

Synthesis of 8-(4-fluoro-2-(trifluoromethyl) phenyl)- V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8-(4-fluoro-2-(trifluoromethyl) phenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin- 4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0368] A dry vial charged with Pd 2 (dba) 3 (13 mg, 0.01 mmol) and (±) BINAP (28 mg,

0.04 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(4-fluoro-2-(trifluoromethyl) phenyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.30 mmol), l-(2-methoxypyridin-4-yl) piperidin- 4-amine hydrochloride (87 mg, 0.36 mmol) and sodium tert-butoxide (86 mg, 0.90 mmol) in

1, 4-dioxane (0.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative

HPLC (Kromacil C-18 (250 x 21.2 mm, 10 μιη (50 mg loading; CH 3 CN: 0.05% TFA (0.1/90,

2/80, 15/75, 25/10, 35/10)) to afford 8-(4-fluoro-2-(trifluoromethyl) phenyl)-N-(l-(2- methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2- amine (40 mg, 26%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.72 (d, 1H),

7.60-7.58 (m, 1H), 7.57-7.50 (m, 3H), 6.49 (d, 1H), 6.08 (s, 1H), 4.34-4.30 (m, 1H), 4.29-

4.20 (m, 1H), 3.90-3.83 (m, 1H), 3.80 (s, 3H), 3.79-3.71 (m, 2H), 3.69-3.62 (m, 1H), 3.49-

3.40 (m, 1H), 2.81-2.70 (m, 2H), 1.89-1.79 (m, 2H), 1.40-1.30 (m, 2H); Mass (ESI): 505.5

[M+l]; LCMS: 505 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.33 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 98.2%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 1.57 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 10% MeOH/ CH 2 C1 2 (R 0.3).

Example 66

Synthesis of 8-(4-chloro-2-(trifluoromethoxy) phenyl)- V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8-(4-chloro-2-(trifluoromethoxy) phenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2- amine

[0369] A dry vial charged with Pd 2 (dba) 3 (12 mg, 0.01 mmol) and (±) BINAP (25 mg,

0.04 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for

3 min. A mixture of 2-chloro-8-(4-chloro-2-(trifluoromethoxy) phenyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1,4] oxazine (100 mg, 0.27 mmol), l-(2-methoxypyridin-4-yl) piperidin-4- amine hydrochloride (73 mg, 0.30 mmol) and sodium tert-butoxide (79 mg, 0.82 mmol) in 1,

4-dioxane (0.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (50 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative

HPLC (YMC pack polymer C-18 (300 x 20 mm (60 mg loading; CH 3 CN: 0.05% TFA

(0.1/90, 2/80, 18/70, 30/10, 35/10)) to afford 8-(4-chloro-2-(trifiuoromethoxy) phenyl)-N-(l-

(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2- amine (46 mg, 31%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.71 (d, 1H),

7.57-7.47 (m, 4H), 6.50 (d, 1H), 6.10 (s, 1H), 4.26-4.23 (m, 2H), 3.82 (s, 3H), 3.81-3.79 (m,

4H), 3.54-3.46 (m, 1H), 2.81-2.78 (m, 2H), 1.90-1.87 (m, 2H), 1.41-1.30 (m, 2H); Mass

(ESI): 537.7 [M+1]; LCMS: 537.7 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μηι); RT 2.97 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 96.9%; (column; Acquity UPLC BEH C- 18 2.1 X 50 mm, 1.7 μιη); RT 1.73 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (Rf. 0.2).

Example 67

Synthesis of 8-(4-chloro-2-(trifluoromethyl) phenyl)- V-(l-(2-methoxypyridin-4-yl)

-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8-(4-chloro-2-(trifluoromethyl) phenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin- 4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0370] A dry vial charged with Pd 2 (dba) 3 (13 mg, 0.01 mmol) and (±) BINAP (26 mg,

0.04 mmol) in 1 , 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(4-chloro-2-(trifluoromethoxy) phenyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1 , 4] oxazine (100 mg, 0.28 mmol), l-(2-methoxypyridin-4-yl) piperidin- 4-amine hydrochloride (76 mg, 0.31 mmol) and sodium tert-butoxide (82 mg, 0.86 mmol) in

1 , 4-dioxane (0.6 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (50 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (YMC pack polymer C-18 (300 x 20 mm (60 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 18/70, 25/10, 35/10)) to afford 8-(4-chloro-2-(trifiuoromethyl) phenyl)-N-(l-(2- methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1 , 4] oxazin-2- amine (40 mg, 27%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.81 (s, 1H), 7.76 (d, 1H), 7.70 (d, 1H), 7.51-7.49 (m, 2H), 6.48 (d, 1H), 6.08 (s, 1H), 4.30-4.20 (m, 2H), 3.89- 3.83 (m, 1H), 3.80 (s, 3H), 3.79-3.73 (m, 2H), 3.70-3.65 (m, 1H), 3.47-3.38 (m, 1H), 2.80- 2.69 (m, 2H), 1.89-1.80 (m, 2H), 1.40-1.29 (m, 2H); Mass (ESI): 521.6 [M+1]; LCMS: 521.7 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.97 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 97.6%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.67 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (R 0.2).

Example 68

Synthesis of 8-(4-fluorophenyl)- V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8- -6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of8-(4-fluorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7 , 8-dihydro- 6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0371] A dry vial charged with Pd 2 (dba) 3 (17 mg, 0.01 mmol) and (±) BINAP (34 mg,

0.05 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for

3 min. A mixture of 2-chloro-8-(4-fluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.37 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine (109 mg, 0.45 mmol) and sodium tert-butoxide (108 mg, 1.13 mmol) in 1, 4-dioxane (0.5 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo.

The crude material was purified by preparative HPLC (YMC pack polymer C-18 (300 x 20 mm, 10 μιη (60 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 20/70, 30/10, 35/10)) to afford 8-(4-fluorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine (55 mg, 33%) as an off-white solid. 1H-NMR

(CD 3 OD, 400 MHz): δ 7.72 (d, 1H), 7.50 (s, 1H), 7.42 (d, 2H), 7.13 (t, 2H), 6.51 (d, 1H), 6.12 (s, 1H), 4.28-4.25 (m, 2H), 3.90-3.82 (m, 4H), 3.80 (s, 3H), 3.69-3.60 (m, 1H), 2.88 (t, 2H), 1.94-1.90 (m, 2H), 1.48-1.38 (m, 2H); Mass (ESI): 437.5 [M+1]; LCMS: 437.4 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.52 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 98.8%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.47 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 10% MeOH/ CH 2 C1 2 (R 0.5)

Example 69

Synthesis of 8-(2, 4-dichlorophenyl)- V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8- -6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8- (2, 4-dichlorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0372] A dry vial charged Pd 2 (dba) 3 (17 mg, 0.01 mmol) and (±) BINAP (35 mg, 0.05 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2, 4-dichlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (120 mg, 0.37 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine (86 mg, 0.41 mmol) and sodium tert-butoxide (109 mg, 1.13 mmol) in 1, 4-dioxane (0.7 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the volatile components were evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with 5% MeOH/ CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 3%> MeOH: CH 2 C1 2 to afford 8-(2, 4- dichlorophenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (25 mg, 14%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.70 (d, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 7.44 (s, 2H), 6.49 (d, 1H), 6.10 (s, 1H), 4.30- 4.28 (m, 2H), 3.82 (s, 3H), 3.81-3.78 (m, 4H), 3.51-3.48 (m, 1H), 2.78 (t, 2H), 1.90-1.80 (m, 2H), 1.40-1.35 (m, 2H); Mass (ESI): 487 [M+]; LCMS: 487 (M+1); (column; X-select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.62 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 97.9%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μιη); RT 1.65 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (Rf. 0.3).

Example 70

Synthesis of 8-(4-fluoro-2-(trifluoromethoxy) phenyl)-N-(l-(2-methoxypyridin-4-yl)

-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of 8-(4-fluoro-2-(trifluoromethoxy) phenyl)-N-(l-(2-methoxypyridin-4-yl) piperidin- 4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0373] A dry vial charged with Pd 2 (dba) 3 (16 mg, 0.02 mmol) and (±) BINAP (32 mg,

0.05 mmol) in 1 , 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(4-fluoro-2-(trifluoromethoxy) phenyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1 , 4] oxazine (120 mg, 0.34 mmol), l-(2-methoxypyridin-4-yl) piperidin- 4-amine hydrochloride (92 mg, 0.37 mmol) and sodium tert-butoxide (99 mg, 1.03 mmol) in

1 , 4-dioxane (0.6 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Ascentis C-18 (250 x 21.2 mm X 10 μιη (50 mg loading; CH 3 CN: 0.05% TFA (0.01/90, 15/70, 25/50, 35/10)) to afford 8-(4-fluoro-2-(trifhioromethoxy) phenyl)-N-(l-(2- methoxypyridin-4-yl) piperidin-4-yl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1 , 4] oxazin-2- amine (40 mg, 22%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.70 (d, 1H), 7.57-7.51 (m, 2H), 7.30-7.20 (m, 2H), 6.50 (d, 1H), 6.10 (s, 1H), 4.30-4.22 (m, 2H), 3.85 (s, 3H), 3.84-3.80 (m, 4H), 3.53-3.48 (m, 1H), 2.80 (t, 2H), 1.90-1.83 (m, 2H), 1.40-1.30 (m, 2H); Mass (ESI): 521.1 [M+1]; LCMS: 521 (M+1); (column; X-select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.39 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 99.7%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.62 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 10% MeOH/ CH 2 C1 2 (R 0.4).

Example 71

Synthesis of 2-chloro-6-methyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of 2-chloro-5-methoxy-N-phenylpyrimidin-4-amine

[0374] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (2 g, 11.17 mmol) in 1, 4-dioxane (20 mL) under argon atmosphere were added diisopropylethylamine (3.8 mL, 22.34 mmol) and aniline (1.03 g, 11.17 mmol) at RT. The reaction mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo. The crude material was purified by column chromatography using 30-50% EtOAc:hexanes to afford 2-chloro-5-methoxy-N- phenylpyrimidin-4-amine (2.1 g, 80%>) as a brown solid used without further purification. LCMS: 236.1 [M+1]; (column; X-select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 3.96 min. 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 50% EtOAc/hexanes (Rf. 0.5).

Synthesis of 2-chloro-4-(phenylamino) pyrimidin-5-ol [0375] To a stirred solution of 2-chloro-5-methoxy-N-phenylpyrimidin-4-amine (4.5 g, 19.14 mmol) in CH 2 CI 2 (50 mL) under argon atmosphere was added 1M boron tribromide in CH 2 CI 2 (25 mL) drop-wise at 0 °C. The reaction mixture was stirred at 20-25 °C for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with cold water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-4- (phenylamino) pyrimidin-5-ol (3 g, 71%) as a pale brown solid used without further purification. 1H-NMR (DMSO-<¾, 400 MHz): δ 10.73 (br s, 1H), 9.09 (s, 1H), 7.79 (d, 2H), 7.70 (s, 1H), 7.77 (t, 2H), 7.07 (t, 1H); LCMS: 222.1 [M+1]; (column; X-select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.99 min. 5mM Aq NH 4 OAc: ACN; 0.80 mL/min); TLC: 10%

Synthesis of ethyl 2-((2-chloro-4-(phenylamino) pyrimidin-5-yl) oxy) propanoate

[0376] To a stirred solution of 2-chloro-4-(phenylamino) pyrimidin-5-ol (100 mg, 0.45 mmol) in CH3CN (2 mL) under argon atmosphere were added potassium carbonate (186 mg, 1.35 mmol) and ethyl 2-bromopropanoate (0.07 mL, 0.54 mmol) at RT and stirred for 5 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 2-((2- chloro-4-(phenylamino) pyrimidin-5-yl) oxy) propanoate (120 mg, 82%) as a pale brown solid without further purification. 1H-NMR (DMSO-<¾, 400 MHz): δ 9.12 (s, 1H), 7.89 (s, 1H), 7.70 (d, 2H), 7.39 (t, 2H), 7.12 (t, 1H), 5.20-5.13 (m, 1H), 4.20-4.11 (m, 2H), 1.62 (d, 3H), 1.20 (t, 3H); LCMS: 322.3 [M+1]; (column; X-select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 4.50 min. 0.05% TFA : ACN; 0.80 mL/min); TLC: 5% MeOH/ CH 2 C1 2 (Rf. 0.7).

Synthesis of 2-((2-chloro-4-(phenylamino) pyrimidin-5-yl) oxy) propan-l-ol

[0377] To a stirred solution of ethyl 2-((2-chloro-4-(phenylamino) pyrimidin-5-yl) oxy) propanoate (100 mg, 0.31 mmol) in THF (2 mL) under argon atmosphere was added sodium borohydride (17 mg, 0.46 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-((2-chloro-4-(phenylamino) pyrimidin-5-yl) oxy) propan-l-ol (70 mg, 87%) as a pale yellow solid used without further purification. 1H-NMR (OMSO-d 6 , 400 MHz): δ 9.15 (s, 1H), 8.00 (s, 1H), 7.69 (d, 2H), 7.39 (t, 2H), 7.12 (t, 1H), 5.27 (t, 1H), 4.42-4.38 (m, 1H), 3.67-3.52 (m, 2H), 1.29 (d, 3H); LCMS: 280.3 [M+1]; (column; X-select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 3.84 min. 0.05% TFA : ACN; 0.80 mL/min); TLC: 50% EtOAc/hexane (Rf. 0.2).

Synthesis of 2-((2-chloro-4-(phenylamino) pyrimidin-5-yl) oxy) propyl methanesulfonate

[0378] To a stirred solution of 2-((2-chloro-4-(phenylamino) pyrimidin-5-yl) oxy) propan-l-ol (60 mg, 0.21 mmol) in CH 2 CI 2 (2 mL) under argon atmosphere were added triethylamine (0.08 mL, 0.63 mmol) followed by mesyl chloride (0.2 mL, 0.25 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 1 h. After consumption of the starting material (monitored by TLC), the reaction was neutralized with a saturated sodium bicarbonate solution (20 mL) and extracted with CH 2 CI 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-((2- chloro-4-(phenylamino) pyrimidin-5-yl) oxy) propyl methanesulfonate (100 mg) as colorless thick syrup. LCMS: 358.3 [M+1]; (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 4.27 min. 0.05% Aq TFA: ACN; 0.8 mL/min); TLC: 5% MeOH/ CH 2 C1 2 (Rf. 0.7).

Synthesis of 2-chloro-6-methyl-7, 8-dihydro-6H-pyrimido [5, 4-bJ [I, 4] oxazine

[0379] To a stirred solution of 2-((2-chloro-4-(phenylamino) pyrimidin-5-yl) oxy) propyl methanesulfonate (100 mg, 0.26 mmol) in DMF (1 mL) under argon atmosphere was added potassium carbonate (54 mg, 0.39 mmol) at RT. The reaction mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-6-methyl-7, 8-dihydro- 6H-pyrimido [5, 4-b] [1, 4] oxazine (40 mg) as an off-white solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 7.88 (s, 1H), 7.47-7.40 (m, 4H), 7.30-7.25 (m, 1H), 4.45-4.40 (m, 1H), 3.91-3.89 (m, 1H), 3.78-3.70 (m, 1H), 1.38 (d, 3H); LCMS: 262.2 [M+1]; (column; X-Select CSH C-18 (50 x 3.0 mm, 3.5 μιη); RT 4.11 min. 0.05% Aq TFA: ACN; 0.8 mL/min); TLC: 50%

EtOAc/hexanes (Rf. 0.6).

Example 72 Synthesis of 2-chloro-6, 6-dimethyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of 2-chloro-6, 6-dimethyl-8-phenyl-6H-pyrimido [5, 4-b] [I, 4] oxazin-7 (8H)-one

[0380] To a stirred solution of 2-chloro-4-(phenylamino) pyrimidin-5-ol (500 mg, 2.26 mmol) in CH3CN (10 mL) under argon atmosphere were added potassium carbonate (936 mg, 6.78 mmol) and ethyl 2-bromo-2-methylpropanoate (529 mg, 2.71 mmol) at RT. The reaction mixture was stirred at RT for 36 h in a sealed tube. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-6, 6-dimethyl-8-phenyl-6H-pyrimido [5, 4-b] [1, 4] oxazin-7 (8H)-one (560 mg, 86%) as a pale brown solid used without further purification. LCMS: 290.3 [M+l]; (column; X-select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.23 min. 0.05% TFA : ACN; 0.80 mL/min); TLC: 50% EtOAc/ CH 2 C1 2 (Rf. 0.7).

Synthesis of 2-chloro-6, 6-dimethyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

[0381] To a stirred solution of 2-chloro-6, 6-dimethyl-8-phenyl-6H-pyrimido [5, 4-b] [1, 4] oxazin-7 (8H)-one (560 mg, 1.93 mmol) in DME (30 mL) under argon atmosphere were added sodium borohydride (439 mg, 11.62 mmol) and boron trifluoride etherate (2.80 g, 19.37 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 32 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with cold water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 20% EtOAc:hexanes to afford 2-chloro-6, 6-dimethyl-8- phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (170 mg, 32%) as an off-white solid, 1H-NMR (DMSO-< 5 , 500 MHz): δ 7.87 (s, 1H), 7.46-7.41 (m, 4H), 7.30-7.27 (m, 1H), 3.78 (s, 2H), 1.40 (s, 6H); LCMS: 276.3 [M+1]; (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.35 min. 0.05% Aq TFA: ACN; 0.8 mL/min); TLC: 50% EtOAc/hexane (R 0.5).

Example 73

Synthesis of 7V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-6, 6-dimethyl-8-ph

-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-6, 6-dimethyl-8-phenyl-7 , 8- dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0382] A dry vial charged with Pd 2 (dba) 3 (20 mg, 0.02 mmol) and (±) BINAP (40 mg, 0.06 mmol) in 1, 4-dioxane (0.6 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-6, 6-dimethyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (120 mg, 0.43 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride (116 mg, 0.43 mmol) and sodium tert-butoxide (125 mg, 1.30 mmol) in 1, 4-dioxane (0.6 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Column YMC polymer C-18 (300 x 20 mm, 10 μιη (55 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 16/70, 20/10, 35/10)) to afford N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-6, 6-dimethyl- 8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (30 mg, 15%>) as an off- white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.70 (d, 1H), 7.49 (s, 1H), 7.44-7.38 (m, 4H), 7.21-7.19 (m, 1H), 6.48 (d, 1H), 6.09 (s, 1H), 3.85-3.80 (m, 2H), 3.79 (s, 3H), 3.69 (s, 2H), 3.67-3.60 (m, 1H), 2.83 (t, 2H), 1.97-1.91 (m, 2H), 1.42-1.39 (m, 2H), 1.38 (s, 6H); Mass (ESI): 447.5 [M+l]; LCMS: 447.1 [M+l]; (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.39 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 98.1%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.62 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (R 0.3).

Example 74

Synthesis of V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-6-methyl-8-phi

-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-6-methyl-8-phenyl-7, 8-dihydro- 6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine

[0383] A dry vial charged with Pd 2 (dba) 3 (35 mg, 0.03 mmol) and (±) BINAP (70 mg, 0.11 mmol) in 1, 4-dioxane (1 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-6-methyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (200 mg, 0.76 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine hydrochloride (223 mg, 0.91 mmol) and sodium tert-butoxide (220 mg, 2.29 mmol) in 1, 4-dioxane (1 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CFi 2 Cl 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and

concentrated in vacuo. The crude material was purified by column chromatography using 5% MeOH: CH 2 C1 2 to afford N-(l -(2 -methoxypyridin-4-yl) piperidin-4-yl)-6-methyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (80 mg, 24%>) as a pale yellow solid. Racemic compound of Example 74 was separated using a Chiralcel ODH (250 x 20 mm, 5μιη (40 mg loading; 0.1 % DEA in n-hexane: EtOH: MeOH (50: 50); (85: 15) as mobile phase) to provide the compound of Example 74A Fraction I (+) and the compound of Example 74B Fraction II (-). Example 74A

Synthesis of (+)- V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-6-methyl-8-phi

dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

[0384] The compound of Example 74A was produced as described in Example 74.

Analytical data for Fraction I (+): 1H-NMR (CD 3 OD, 500 MHz): δ 7.73 (d, 1H), 7.51 (s, 1H), 7.47-7.40 (m, 4H), 7.08-7.01 (m, 1H), 6.52 (d, 1H), 6.11 (s, 1H), 4.30-4.26 (m, 1H), 3.88- 3.84 (m, 3H), 3.80 (s, 3H), 3.73-3.60 (m, 2H), 2.93-2.81 (m, 2H), 2.00-1.90 (m, 2H), 1.44- 1.41 (m, 2H), 1.40 (s, 3H); Mass (ESI): 433.5 [M+1]; LC-MS: 98.5%; 433 [M+1]; (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.32 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 99.8%; (column; Acquity UPLC-BEH-C18 2.1 X 50 mm, 1.7 μπι); RT 1.57 min. ACN: 0.025% Aq TFA; 0.5 mL/min; Chiral HPLC: 100% RT = 14.61 min (chiralcel-ODH (250 x 4.6 mm, 5 μιη; mobile phase (A) 0.1 % DEA in n-hexane (B) EtOH: MeOH (50: 50) (A: B: 75 : 25); flow Rate: 1.0 mL/min); Optical rotation [a] D 20 05 : +12.04 (c = 0. 25, CH 2 C1 2 ).

Example 74B

Synthesis of (-)- V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-6-methyl-8-phenyl-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

[0385] The compound of Example 74B was produced as described in Example 74.

Analytical data for Fraction II (-): 1H-NMR (CD 3 OD, 500 MHz): δ 7.73 (d, 1H), 7.51 (s, 1H), 7.47-7.40 (m, 4H), 7.08-7.01 (m, 1H), 6.52 (d, 1H), 6.11 (s, 1H), 4.30-4.26 (m, 1H), 3.88- 3.84 (m, 3H), 3.80 (s, 3H), 3.73-3.60 (m, 2H), 2.93-2.81 (m, 2H), 2.00-1.90 (m, 2H), 1.44- 1.41 (m, 2H), 1.40 (s, 3H); Mass (ESI): 433.5 [M+1]; LCMS: 433.1 [M+1]; (column; X- Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.32 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 99.2%; (column; Acquity UPLC-BEH-C18 2.1 X 50 mm, 1.7 μπι); RT 1.57 min. ACN: 0.025% Aq TFA; 0.5 mL/min; Chiral HPLC: 99.0% RT = 16.54 min (chiralcel- ODH (250 x 4.6 mm, 5μιη; mobile phase (A) 0.1 % DEA in n-hexane (B) EtOH: MeOH (50: 50) (A: B: 75: 25); flow Rate: 1.0 mL/min); Optical rotation [a] D 20 02 : -8.30 (c = 0.25, CH 2 C1 2 ).

Example 75

Synthesis of 2-chloro-7-methyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of l-((4-amino-2-chloropyrimidin-5-yl) oxy) propan-2-one [0386] To a stirred solution of 4-amino-2-chloropyrimidin-5-ol (3 g, 20.68 mmol) in CH 3 CN (50 mL) under argon atmosphere were added cesium carbonate (13.4 g, 41.37 mmol) and l-chloropropan-2-one (2.3 g, 24.82 mmol) at RT. The reaction mixture was stirred at RT for 12 h. After consumption of the starting materials (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1 -((4- amino-2-chloropyrimidin-5-yl) oxy) propan-2-one (3.2 g, 78%) as an off-white solid was used without further purification. 1H-NMR (DMSO-< 5 , 500 MHz): δ 8.89 (s, 1H), 7.75 (s, 1H), 6.00 (s, 1H), 4.00 (d, 1H), 3.74 (d, 1H), 1.38 (s, 3H); LCMS: 202.1 (M+l); (column; X- Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 1.64 min. 5 mM Aq NH 4 OAc: ACN; 0.80 mL/min; TLC: 50% EtOAc:hexanes (R/. 0.7).

Synthesis of 2-chloro-7 -methyl-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0387] To a stirred solution of l-((4-amino-2-chloropyrimidin-5-yl) oxy) propan-2-one (3.2 g, 15.92 mmol) in CH 2 CI 2 (150 mL) under argon atmosphere were added sodium triacetoxy borohydride (6.7 g, 31.80 mmol) and trifluoroacetic acid (3.2 mL) at RT. The reaction mixture was stirred at RT for 16 h. After consumption of the starting materials (monitored by TLC), the reaction was diluted with a sodium bicarbonate solution (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-7-methyl-7, 8-dihydro- 6H-pyrimido [5, 4-b] [1, 4] oxazine (2.1 g, 72%>) as an off- white solid was used without further purification. 1H-NMR (DMSO-<¾, 400 MHz): δ 8.40-8.38 (m, 1H), 7.68 (s, 1H), 4.18 (d, 1H), 3.71-3.60 (m, 2H), 1.11 (d, 3H); LCMS: 186 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.22 min. 5 mM Aq NH 4 OAc: ACN; 0.80 mL/min; TLC: 50% EtOAc:hexanes (R f : 0.7).

Synthesis of 2-chloro-7-methyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0388] To a stirred solution of 2-chloro-7-methyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (2 g, 10.81 mmol) in toluene (100 mL) under argon atmosphere were added bromobenzene (1.7 g, 10.81 mmol), cesium carbonate (7 g, 21.62 mmol), Xantphos (374 mg, 0.64 mmol) and Pd 2 (dba) 3 (495 mg, 0.54 mmol) at RT. The reaction mixture was stirred at 100 °C for 20 h. After consumption of the starting materials (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 10% EtOAc:hexanes to afford 2-chloro-7-methyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (1 g, 35%>) as an off-white solid. 1H-NMR (OMSO-d 6 , 400 MHz): δ 7.83 (s, 1H), 7.45 (d, 2H), 7.39-7.30 (m, 3H), 4.30-4.10 (m, 3H), 1.13 (d, 3H); LCMS: 262.1 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 3.44 min. 5 mM Aq NH 4 OAc: ACN; 0.80 mL/min); TLC: 30% EtOAc:hexanes {Rf. 0.7).

Example 76

Synthesis of 2-chloro-7, 7-dimethyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

Synthesis of 2-((2-chloro-5-methoxypyrimidin-4-yl) amino)-2-methylpropan-l-ol

[0389] To a stirred solution of 2, 4-dichloro-5-methoxypyrimidine (5 g, 27.93 mmol) in 1, 4-dioxane (50 mL) under argon atmosphere were added diisopropylethylamine (7.2 g, 55.86 mmol) and 2-amino-2-methylpropan-l-ol (2.4 g, 27.93 mmol) at RT. The reaction mixture was stirred at 130 °C for 48 h. After consumption of the starting materials (monitored by TLC), the volatile components were evaporated in vacuo. The residue was diluted with a saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 10% EtOAc:hexanes to afford 2-((2-chloro-5-methoxypyrimidin-4-yl) amino)-2-methylpropan-l-ol (5.5 g, 84%) as a white solid. 1H-NMR (OMSO-d 6 , 500 MHz): δ 7.69 (s, 1H), 6.19 (s, 1H), 6.11 (t, 1H), 3.82 (s, 3H), 3.45 (d, 2H), 1.33 (s, 6H); TLC: 50% EtOAc:hexanes (R 0.3).

Synthesis of2-chloro-4-((l-hydroxy-2-methylpropan-2-yl) amino) pyrimidin-5-ol

[0390] To a stirred solution of 2-((2-chloro-5-methoxypyrimidin-4-yl) amino)-2- methylpropan-l-ol (5.5 g, 23.80 mmol) in CH 2 CI 2 (100 mL) were added boron tribromide (34 mL, 357.14 mmol) at 0 °C under argon atmosphere. The reaction mixture was warmed to RT and stirred for 24 h. After consumption of the starting materials (monitored by TLC), the reaction was quenched with methanol (50 mL) at 0 °C and concentrated in vacuo. The residue was dissolved in EtOAc (2 x 100 mL) and washed with a sodium bicarbonate solution (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-4-((l-hydroxy-2-methylpropan-2-yl) amino) pyrimidin-5-ol (4 g, 81%) as a white solid used without further purification. 1H-NMR (DMSO-< 5 , 500 MHz): δ 10.38 (br s, 1H), 7.48 (s, 1H), 6.03 (s, 1H), 5.11 (br s, 1H), 3.45 (s, 2H), 1.37 (s, 6H); TLC: 80% EtOAc:hexanes (R/. 0.3).

Synthesis of tert-butyl (2-chloro-5-hydroxypyrimidin-4-yl) (l-hydroxy-2-methylpropan-2-yl) carbamate

[0391] To a stirred solution of 2-chloro-4-((l-hydroxy-2-methylpropan-2-yl) amino) pyrimidin-5-ol (4.3 g, 19.90 mmol) in CH 2 CI 2 (50 mL) under argon atmosphere were added triethylamine (4.3 mL, 29.80 mmol) and Boc anhydride (4.3 g, 19.90 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting materials (monitored by TLC), the volatile components were evaporated in vacuo. The crude material was purified by column chromatography using 40% EtOAc:hexanes to afford tert- butyl (2-chloro-5-hydroxypyrimidin-4-yl) (l-hydroxy-2-methylpropan-2-yl) carbamate (3 g, 48%) as a white solid. 1H-NMR (DMSO-< 5 , 500 MHz): δ 8.00 (s, 1H), 6.61 (s, 1H), 5.07 (t, 1H), 3.49 (d, 2H), 1.50 (s, 9H), 1.37 (s, 6H); TLC: 50% EtOAc:hexanes (R 0.5).

Synthesis of tert-butyl 2 -chloro-7 , 7-dimethyl-6, 7-dihydro-8H-pyrimido [5, 4-b] [1, 4] oxazine-8-carboxylate

[0392] To a stirred solution of tert-butyl (2-chloro-5-hydroxypyrimidin-4-yl) (1-hydroxy- 2-methylpropan-2-yl) carbamate (3 g, 9.46 mmol) in THF (30 mL) under argon atmosphere were added triphenylphosphine (2.9 g, 11.36 mmol) and DIAD (2.3 g, 11.35 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After consumption of the starting materials (monitored by TLC), the volatile components were evaporated in vacuo. The crude material was purified by column chromatography using 20% EtOAc:hexanes to afford tert-butyl 2- chloro-7, 7-dimethyl-6, 7-dihydro-8H-pyrimido [5, 4-b] [1, 4] oxazine-8-carboxylate (1.5 g, 53%) as a white solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 8.11 (s, 1H), 4.01 (s, 2H), 1.52 (s, 9H), 1.38 (s, 6H); LCMS: 300.3 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 4.69 min. 5 mM Aq NH 4 OAc: ACN; 0.80 mL/min); TLC: 30% EtOAc:hexanes (R 0.3).

Synthesis of 2-chloro-7 , / 1 -dimethyl- ' / ', 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine

[0393] To a stirred solution of tert-butyl 2-chloro-7, 7-dimethyl-6, 7-dihydro-8H- pyrimido [5, 4-b] [1, 4] oxazine-8-carboxylate (500 mg, 1.67 mmol) in CH 2 C1 2 (5 mL) under argon atmosphere was added 4M HC1 in 1, 4-dioxane (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 16 h. After consumption of the starting materials (monitored by TLC), the volatile components were evaporated in vacuo. The residue was diluted with a saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-7, 7-dimethyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (260 mg, 78%>) as a white solid. 1H-NMR (DMSO-<¾, 400 MHz): δ 8.50 (s, 1H), 7.71 (s, 2H), 1.20 (s, 6H); TLC: 50% EtOAc:hexanes (R/. 0.3).

Synthesis of 2 -chloro-7 , 7-dimethyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine

[0394] To a stirred solution of 2-chloro-7, 7-dimethyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (500 mg, 2.51 mmol) in DMSO (5 mL) under argon atmosphere were added potassium carbonate (698 mg, 5.02 mmol), iodo benzene (717 mg, 3.51 mmol). After purging the solution with argon for 10 min, L-proline (115 mg, 1.00 mmol) and copper iodide (95 mg, 0.50 mmol) were added. The reaction was then stirred at 120 °C for 48 h in a sealed tube. After consumption of the starting materials (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 15% EtOAc:hexanes to afford 2-chloro-7, 7- dimethyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (50 mg, 7%>) as a white solid. 1H-NMR (DMSO-< 5 , 400 MHz): δ 7.80 (s, 1H), 7.50-7.40 (m, 3H), 7.12 (d, 2H), 4.00 (s, 2H), 1.25 (s, 6H); LCMS: 276.3 (M+1); (column; Eclipse XDB C-18 (150 4.6 mm, 5 μπι); RT 9.55 min. 0.05% Aq TFA: ACN; 1.0 mL/min); TLC: 50% EtOAc:hexanes (R/. 0.3).

Example 77

Synthesis of 7V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7-methyl-8-phi

-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis ofN-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7-methyl-8-phenyl-7, 8-dihydro- 6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine

[0395] A dry vial charged with Pd 2 (dba) 3 (8.7 mg, 0.09 mmol) and (±) BINAP (18 mg, 0.28 mmol) in 1, 4-dioxane (0.25 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-7-methyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (50 mg, 0.19 mmol), 3-methoxy-4-(4-methyl-lH-imidazol-l-yl) aniline (51 mg, 0.21 mmol) and sodium tert-butoxide (55 mg, 0.57 mmol) in 1, 4-dioxane (0.25 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 12 h in a sealed tube. After consumption of the starting materials (monitored by TLC and LCMS), the reaction was diluted with water (20 mL) and extracted with CH 2 C1 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to afford N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7-methyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (30 mg, 36%) as an off-white solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.77-7.69 (m, 1H), 7.51 (s, 1H), 7.48-7.40 (m, 2H), 7.39-7.27 (m, 3H), 6.50-6.47 (m, 1H), 6.09 (s, 1H), 4.20-4.06 (m, 3H), 3.83 (s, 3H), 3.82-3.71 (m, 2H), 3.60-3.50 (m, 1H), 2.87-2.73 (m, 2H), 1.98-1.81 (m, 2H), 1.40-1.30 (m, 2H), 1.23 (d, 3H); LCMS: 433.5 (M+1); (column; X-Select CSH C-18 (50 x 3.0 mm, 3.5 μιη); RT 2.73 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 98.4%; (column; Acquity UPLC-BEH-C18 2.1 X 50 mm, 1.7 μπι); RT 1.52 min. ACN:

0.025% Aq TFA; 0.5 niL/min; TLC: 5% MeOH/ CH 2 C1 2 (R 0.3).

[0396] Racemic compound of Example 77 was separated using a Chiralpak IA (250 x 20 mm, 5μιη (15 mg loading; 0.1 % DEA in rc-hexane: DCM: MeOH (50: 50); (A:B: 85: 15) as mobile phase) to provide the compound of Example 77A Fraction I (-) and the compound of Example 77B Fraction II (+).

Example 77A

Synthesis of (-)- V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7-methyl-8-phenyl-7, 8- dihydro- -pyrimido [5, 4-b] [1, 4] oxazin-2-amine

[0397] The compound of Example 77A was produced as described in Example 77.

Analytical data for Fraction I (-): 1H-NMR (CD 3 OD, 400 MHz): δ 7.77-7.69 (m, 1H), 7.50 (s, 1H), 7.47-7.40 (m, 2H), 7.37-7.27 (m, 3H), 6.50-6.47 (m, 1H), 6.09 (s, 1H), 4.19-4.08 (m, 3H), 3.80 (s, 3H), 3.79-3.77 (m, 2H), 3.59-3.50 (m, 1H), 2.80-2.70 (m, 2H), 1.95-1.80 (m, 2H), 1.40-1.30 (m, 2H), 1.21 (d, 3H); Mass (ESI): 433.4 [M+1]; LCMS: 433.4 (M+1);

(column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.67 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 99.1%; (column; Acquity UPLC-BEH-C 18 2.1 X 50 mm, 1.7 μπι); RT 1.53 min. ACN: 0.025% Aq TFA; 0.5 mL/min; Chiral HPLC: 99.6% RT = 12.58 min (CHIRALPAK-IA (250 x 4.6 mm, 5 μιη; mobile phase (A) 0.1 % DEA in n-hexane (B) CH 2 C1 2 : MeOH (50: 50) (A: B: 85: 15); flow Rate: 1.0 mL/min); Optical rotation [a] D 20 0 °: - 41.98 (c = 0. 25, CH 2 C1 2 ).

Example 77B

Synthesis of (+)- V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7-methyl-8-phenyl-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

[0398] The compound of Example 77B was produced as described in Example 77.

Analytical data for Fraction II (+): 1H-NMR (CD 3 OD, 400 MHz): δ 7.77-7.69 (m, 1H), 7.50 (s, 1H), 7.47-7.40 (m, 2H), 7.37-7.27 (m, 3H), 6.50-6.47 (m, 1H), 6.09 (s, 1H), 4.19-4.08 (m, 3H), 3.80 (s, 3H), 3.79-3.77 (m, 2H), 3.59-3.50 (m, 1H), 2.80-2.70 (m, 2H), 1.95-1.80 (m, 2H), 1.40-1.30 (m, 2H), 1.21 (d, 3H); Mass (ESI): 433.4 [M+1]; LCMS: 433.4 (M+1);

(column; X-Select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.68 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 98.8%; (column; Acquity UPLC-BEH-C 18 2.1 X 50 mm, 1.7 μπι); RT 1.53 min. ACN: 0.025% Aq TFA; 0.5 mL/min; Chiral HPLC: 99.1% RT = 14.54 min (CHIRALPAK-IA (250 x 4.6 mm, 5 μιη; mobile phase (A) 0.1 % DEA in n-hexane (B) CH 2 C1 2 : MeOH (50: 50) (A: B: 85: 15); flow Rate: 1.0 mL/min); Optical rotation [a] D 19 ": +33.50 (c = 0. 25, CH 2 C1 2 ).

Example 78

Synthesis of V-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 7-dimethyl-8-ph

dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine

Synthesis of N-(l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 7-dimethyl-8-phenyl-7, 8- dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazin-2-amine [0399] A dry vial charged with Pd 2 (dba) 3 (28 mg, 0.03 mmol) and (±) BINAP (25 mg, 0.04 mmol) in 1, 4-dioxane (0.25 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-7, 7-dimethyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (60 mg, 0.21 mmol), l-(2-methoxypyridin-4-yl) piperidin-4-amine (58 mg, 0.24 mmol) and sodium tert-butoxide (80 mg, 0.84 mmol) in 1, 4-dioxane (0.25 mL) was degassed and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Ascentis C-18 (250 x 21.2 mm, 10 μιη (45 mg loading; CH 3 CN: 0.05% TFA (0.1/90, 2/80, 15/70, 25/20, 30/10, 35/10)) to afford N- (l-(2-methoxypyridin-4-yl) piperidin-4-yl)-7, 7-dimethyl-8-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (20 mg, 20%) as a solid. 1H-NMR (CD 3 OD, 400 MHz): δ 7.70 (d, 1H), 7.45-7.40 (m, 3H), 7.38 (d, 1H), 7.18-7.16 (m, 2H), 6.46 (d, 1H), 6.05 (s, 1H), 3.98 (s, 2H), 3.80 (s, 3H), 3.75-3.70 (m, 2H), 3.40-3.35 (m, 1H), 2.70 (t, 2H), 1.80 (d, 2H), 1.30- 1.27 (m, 2H), 1.25 (s, 6H); LCMS: 447.5 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.84 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 98.3%; (column; Acquity BEH C-18, 50 2.1 mm, 1.7 μιη); RT 1.64 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 5% MeOH/ CH 2 C1 2 (Rf. 0.5).

Example 79

In Vitro Cell screening Assay and Quantification of Αβ ( ι -χ) and Αβ(ΐ -42 ) Peptides

[0400] Human neuroglioma H4 cells were transfected with a pcDNA3.1 plasmid expressing human wild type APP751 cDNA and a stable cell line was generated using G418 selection. Cells are plated at 15,000 cells/well in Costar 96-well plates and placed at 37°C and 5% C0 2 . Six hours after plating, cells are washed three times with Pro293™ chemically defined medium, followed by addition of compounds (0.003-10 μΜ, final DMSO

concentration of 0.33%). Plates were incubated overnight (16-18 h) and supernatant was removed for quantification of Αβ peptides by sandwich ELISA. Cytotoxicity was evaluated using Cell-Titer 96W Aqueous One Solution Cell Proliferation Assay according to the manufacturer's protocol. ELISA measurements of Αβ peptides

[0401] Αβ peptide levels were quantified by sandwich ELISA. 96-well plates are coated with C-terminal specific Αβ antibodies recognizing either Αβ37, Αβ38, Αβ40, Αβ42, Αβ43 or a N-terminal specific Αβ antibody to detect Αβ 1-x. Plates are then blocked overnight at 4°C with 1% bovine serum albumin (BSA) in PBS-T. Plates are washed and 100 μΐ of cultured cell supernatant or synthetic Αβ peptide standards and a detection antibody (4G8-HRP) are applied to the blocked plate and incubated overnight at 4°C. The next day, wells are washed before the addition the addition of detection substrate (TMB peroxidase). Plates are then read for absorbance at 450 nm on a Molecular Devices SpectraMax M5e Microplate Reader.

[0402] Compound-treated samples were normalized to samples treated with DMSO alone (no inhibition) and to samples treated with DAPT. IC50 and EC50 values were calculated from values reported as percent of DMSO controls using nonlinear regression, based on a sigmoidal dose-response (variable slope) model. GraphPAD software from Prism used for calculation.

Table III. Biological Assay

b] [ 1 ,4]oxazin-2-amine