PKC-theta inhibitors, compositions, and methods of use

Abstract

The present invention provides a compound of Formula (I): (I) or a pharmaceutically acceptable salt thereof. Also disclosed are methods of using such compounds and pharmaceutical compositions comprising such compounds. These compounds are useful in treating disorders and diseases including inflammatory diseases, autoimmune disorders, cancer / oncologic disorders, or autoimmune disorders.

Description

[0001] PKC-THETA INHIBITORS, COMPOSITIONS, AND METHODS OF USE

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 656,814 filed June 6, 2024 which is incorporated herein in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention discloses compounds capable of modulating the biological activity of Protein kinase C-Theta (PKC-theta), a serine / threonine-specific protein kinase that phosphorylates various proteins involved in diverse cellular signaling pathways. Further provided herein are pharmaceutical compositions comprising such compounds, and methods for their use including methods for treating disorders susceptible to PKC modulation.

[0006] BACKGROUND

[0007] Members of the protein kinase C (PKC) family of serine / threonine kinases play critical roles in regulating cellular differentiation and proliferation of diverse cell types. They are activated by specific binding to various lipid messengers including calcium ions, phospholipids, fatty acids, phorbol ester, and diacylglycerol. At present, there are at least ten known isozymes of PKC that differ in their tissue distribution, enzymatic selectivity, requirement for Ca2+, and regulation. For example, the classical PKC enzymes (cPKC), alpha, betal, beta2, and gamma, require diacylglycerol (DAG), phosphatidylserine (PS), and calcium for activation. The novel PKCs (nPKC), delta, epsilon, eta, and theta, require DAG and PS but are calcium-independent. The atypical PKCs (aPKC), iota, lambda, and zeta, do not require calcium or DAG. The aforementioned isoforms, except for, PKC gamma and beta2, are expressed in T cells. (Newton, A. (2003) Biochem. J. 370;36L). The role of the PKC isoforms in T cell activation has been described. The data suggest that PKC theta, in particular, plays a central role in T cell activation / proliferation. Moreover, PKC-theta has a unique role in immune responses by modulating multiple molecules such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein 1 (AP-1), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinases (JNK). PKC- theta is the only member of the PKC family known to translocate to the immunological synapse of an antigen-stimulated T cell upon T cell receptor (TCR) -peptide MHC recognition [4, 5], PKC-theta acts to integrate T-cell receptor (TCR) and cluster of differentiation 28 (CD28) costimulatory signals, which is essential for productive T-cell priming. PKC- theta interacts physically and functionally with downstream effectors to mediate T cell activation, differentiation, and migration that can lead to the development of inflammation. As a result of its critical function in T cells, PKC-theta is implicated in certain disorders ranging from autoimmunity, neuroinflammatory diseases, muscular dystrophy, cancer, and diabetes. (Hage-Sleiman, Rouba, et al. “The Novel PKC- theta from Benchtop to Clinic.” Journal of immunology research vol. 2015 (2015): 348798. doi: 10.1155 / 2015 / 348798).

[0008] While PKC inhibitors have been developed and tested, achieving selectivity and efficacy remains a challenge, particularly for PKC-theta inhibitors, which could significantly advance the treatment of various T-cell-mediated diseases. This invention provides compounds that are effective in modulating PKC-theta, fulfilling the need for selective PKC modulators that are highly selective over other protein kinases and certain specific isozymes of PKC.

[0009] SUMMARY

[0010] The present disclosure is directed to compounds, pharmaceutically acceptable salts, pharmaceutical compositions, and combinations thereof that are effective modulators of protein kinase C (PKC); in particular, protein kinase C-theta (PKC-theta). The invention further provides methods of treating, preventing, or managing a disease or disorder mediated by protein PKC-theta (or mutant); the methods comprising of administering a therapeutically or prophylactically effective amount of the compound of formula I to a subject in need thereof. In one embodiment the disease or disorder mediated by PKC-theta is selected from: an inflammatory disease, a cancer / oncologic disease, an autoimmune infection, rheumatoid arthritis, multiple sclerosis, psoriasis, or atopic dermatitis, inflammatory disease, or an autoimmune disorder.

[0011] These, and other features of the invention will be set forth in expanded form in this disclosure.

[0012] The first aspect of the present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0013] X is N(R1), S, or O;

[0014] Y is O or S, wherein X is O or N(R1) when Y is S;

[0015] A is C(R11) or N;

[0016] B is C(R6) or N;

[0017] Z is C(R12) or N;

[0018] R1is H or C1-C4alkyl;

[0019] R2is C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl, wherein the alkyl, haloalkyl, and cycloalkyl of R2is each independently optionally substituted with one or more R5; each R3is independently H or C1-C4alkyl;

[0020] R4= H Ring D is aryl optionally substituted with one or more R10; each R5is independently OH, halogen, C1-C4alkyl, C1-C4haloalkyl, C3-C8cycloalkyl; or aryl; or two geminal R5, together with the intervening geminal carbon atom form a C3-C6cycloalkyl;

[0021] R6is H, C1-C6alkyl, C1-C4alkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, 3- to 9- membered heterocyclyl, C1-C6, haloalkyl, -C(O)OR9, cyano, or halogen, wherein the alkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and haloalkyl of R6are each independently optionally substituted with one or more halogen, phenyl, benzyl, C3-C6cycloalkyl, hydroxy, C1-C3alkoxy, or C1-C3haloalkyl;

[0022] W is H, halogen, N(R7)2, 3- to 10-membered heterocyclyl, C3-C8cycloalkyl, C1-C3alkyl, wherein the heterocyclyl, cycloalkyl, and alkyl of W are each independently optionally substituted with one or more R8; each instance of R7is independently H, C1-C4alkyl, C3-C6cycloalkyl, wherein the alkyl and the cycloalkyl of R7are each independently optionally substituted with one or more R8, or two R7, together with the intervening N atom form: a 3- to 12-membered heterocyclyl optionally substituted with one or more R8; each R8is independently deuterium, C1-C4alkyl, C1-C4haloalkyl, C1-C6hydroxyalkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl, hydroxy, -(CH2)n-C(O)O(R9), N(R9)2, -NHC(O)R9, -COOH, oxo, thio, -SO3H, halogen, cyano, or C1-C3 alkoxy, or two geminal R8, together with the intervening carbon atom form a C3-C6cycloalkyl; each R9is independently H, or C1-C3alkyl; each R10is independently H, or C1-C3alkoxy; each R11is H, C1-C6alkyl, or halogen; n is an integer from 0 to 6;

[0023] R12is H, NO2, or when B is CR6, R12is H NO2, or R12and R6when taken together form a 6- membered aryl.

[0024] Further disclosed is a compound selected from a group consisting of: (4R)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0025] (4S)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0026] (4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0027] (4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0028] (4S)-4-methyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0029] (4R)-4-methyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0030] 6-{4-methyl-2-oxo-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl}-4-(trifluoromethyl)- 1',2'- dihydro-[2,4'-bipyridine]-2'-one;

[0031] 4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0032] (4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0033] (4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0034] (4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0035] (4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0036] (4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0037] (4R)-4-methyl-5-{6-[(3R)-3-methyl-1,4-diazepan-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0038] (4S)-4-methyl-5-{6-[(3R)-3-methyl-1,4-diazepan-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0039] 4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0040] 5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(2-methylpropyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0041] 4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0042] 4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0043] (4S)-4-ethyl-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0044] (4R)-4-ethyl-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0045] (4R)-4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0046] (4S)-4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; 4-cyclobutyl-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0047] (4S)-4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0048] (4R)-4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0049] (4S)-4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0050] (4R)-4-cyclobutyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0051] (4S)-4-cyclobutyl-5-[6-(piperazin-l -yl)-4-(trifluoromethyl)pyri din-2 -yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0052] (4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0053] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0054] (4S)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0055] (4R)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0056] (4S)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0057] (4R)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0058] (4S)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0059] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0060] (4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0061] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0062] (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(1,1,2,2,2- pentafluoroethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0063] (4R)-5- {6- [(3 S)-3 -methylpiperazin- 1 -yl]-4-(trifluoromethyl)pyridin-2-yl }-4-( 1 , 1 ,2,2,2- pentafluoroethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0064] (4S)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0065] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0066] (4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0067] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0068] 5- { 6- [(3 S)-3 -methylpiperazin- 1 -yl]-4-(trifluoromethyl)pyridin-2-yl } -4-( 1 , 1 ,2,2,2- pentafluoroethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0069] (4S)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0070] (4R)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0071] (4S)-5-[4-(1,1-difluoroethyl)-6-[(2R)-2-ethylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0072] (4R)-5-[4-(1,1-difluoroethyl)-6-[(2R)-2-ethylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0073] 5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(1,1,2,2,2- pentafluoroethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0074] (4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0075] (4R)-5-{6-[(2R)-2-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0076] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0077] (4S)-5-{6-[(2R)-2-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0078] 5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0079] 5-(6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0080] (4R)-5-[4-fluoro-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0081] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0082] (4R)-5 - { 6- [(3 S)-3 -cy clopropylpiperazin- 1 -yl ] -4-methylpyridin-2-yl } -4-(difluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0083] (4R)-4-(1,1-difluoroethyl)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2- yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0084] (4R)-4-(difluoromethyl)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0085] (4R)-4-(difluoromethyl)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-(1,1-difluoroethyl)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0086] (4R)-4-(1,1-difluoroethyl)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0087] (4R)-4-(1,1-difluoroethyl)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0088] (4R)-5 - { 6- [(3 S)-3 -cy clopropylpiperazin- 1 -yl ] -4-methylpyridin-2-yl } -4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0089] (4S)-4-(1,1-difluoropropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0090] (4R)-4-(1,1-difluoropropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0091] (4S)-4-(cyclopropyldifluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0092] (4R)-4-(cyclopropyldifluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0093] (4R)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0094] (4R)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4-yl]pyridin-2-yl]-4-

[0095] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0096] (4R)-5-{6-[4-(difluoromethyl)piperidin-4-yl]-4-(1,1-difluoropropyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0097] (4S)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0098] (4S)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0099] (4R)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0100] (4R)-4-(1,1-difluoroethyl)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0101] (4S)-4-( 1 , 1 -difluoroethyl)-5-[4-(1,1 -difluoroethyl)-6-(piperazin- 1 -yl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0102] (4R)-4-(1,1-difluoroethyl)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0103] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0104] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0105] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0106] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0107] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0108] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4-yl]pyridin- 2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0109] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4-yl]pyridin- 2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0110] (4R)-4-(difluoromethyl)-5-{6-[4-(difluoromethyl)piperidin-4-yl]-4-(1,1- difluoropropyl)pyridin-2-yl } - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;

[0111] (4R)-4-(difluoromethyl)-5-{6-[4-(difluoromethyl)piperidin-4-yl]-4-(1,1- difluoropropyl)pyridin-2-yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0112] (4R)-5-[4-( 1 , 1 -difluoro-2-methoxyethyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl] py ri din-2-yl ] -4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0113] (4R)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0114] (4R)-4-(difluoromethyl)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0115] (4R)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0116] (4R)-4-(difluoromethyl)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0117] (4R)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0118] (4S)-5-{6-[(3R)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0119] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0120] (4R)-5 - {6- [(3R)-3 -methylpiperazin- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl } -4-

[0121] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one; 5-{6-[(3R)-3-aminopyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0122] (4R)-5-{6-[(2R)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0123] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0124] (4R)-5-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0125] (4S)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0126] (4S)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0127] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0128] (4R)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0129] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0130] (4R)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0131] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0132] (4R)-5-{6-[(2S)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0133] 5-[6-(6-methyl-1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0134] (4R)-5-{6-[(3S)-3-(methylamino)pyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0135] (4R)-5-{6-[(3S)-3-aminopiperidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0136] (4R)-5-[6-(6-hydroxy-1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-

[0137] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one; (4R)-5-[6-(6-hydroxy-1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-

[0138] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0139] (4R)-5-{6-[(3R)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0140] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0141] (4R)-5-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0142] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0143] (4R)-5-[6-(3-aminoazetidin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; l-{6-[(4R)-2-oxo-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2, 3-d] [1, 3 ]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}pyrrolidine-3 -carbonitrile; l-{6-[(4R)-2-oxo-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1, 3 ]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}pyrrolidine-3-carbonitrile;

[0144] (4R)-5-[l-(piperazin-1-yl)isoquinolin-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0145] (4R)-5-{6-[(lS,6R)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0146] (4R)-5-{6-[(lS,6S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0147] (4R)-5-{6-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0148] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0149] (4R)-5-{6-[(3 S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-4-(trifluoromethyl)pyri din-2 -yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0150] 5-{6-[(2-aminoethyl)amino]-4-(trifluoromethyl)pyri din-2 -yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one; 5-{6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0151] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0152] (4R)-5-(6-{[l-(aminomethyl)cyclopropyl]amino}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0153] (4R)-5-{6-[(4aS,8aR)-decahydroquinoxalin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0154] (4R)-5-{6-[(4aS,8aR)-decahydroquinoxalin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0155] (4R)-5-[6-(3,3-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0156] (4R)-5 - { 6- [(3 S, 5 S)-3 , 5 -dimethylpiperazin- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl }-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0157] (4R)-5-{6-[(4aS,7aR)-octahydro-1H-cyclopenta[b]piperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0158] (4R)-5-{6-[(4aS,7aR)-octahydro-1H-cyclopenta[b]piperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0159] (4R)-5-{6-[(4aR,7aS)-octahydropyrrolo[3,4-b]morpholin-6-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0160] (4R)-5-{6-[(4aS,7aR)-octahydropyrrolo[3,4-b]morpholin-6-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0161] (4R)-5-{6-[(3S)-3-methyl-1,4-diazepan-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0162] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0163] (4R)-5-(6-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one; (4R)-5-{6-[(2R)-2-(hydroxymethyl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0164] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0165] (4R)-5-{6-[(2S)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0166] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0167] (4R)-5-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0168] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0169] (4R)-5-[6-(4-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0170] (4R)-5-{6-[(3S)-3-aminopyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0171] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0172] N-[(3S)-1-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4-

[0173] (trifluoromethyl)pyridin-2-yl}pyrrolidin-3-yl]acetamide

[0174] (4R)-4-(difluoromethyl)-5-{6-[(2R)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyri din-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0175] (4R)-4-(difluoromethyl)-5-{6-[(3R)-3-(hydroxymethyl)piperazin-1-yl]-4-

[0176] (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0177] (4R)-5-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0178] (4R)-4-(difluoromethyl)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0179] (4R)-4-(difluoromethyl)-5-(6- {octahydro- 1H-cy cl openta[b]piperazin- 1 -yl } -4-

[0180] (trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0181] (4R)-4-(difluoromethyl)-5-(6- {octahydro- 1H-cy cl openta[b]piperazin- 1 -yl } -4-

[0182] (trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0183] (4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0184] 4-(difluoromethyl)-5-[6-(piperazin-l -yl)-4-(trifluoromethyl)pyri din-2 -yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0185] (4R)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0186] (4S)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- methyl-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0187] (4S)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- methyl-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0188] (4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0189] (4S)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0190] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0191] (4S)-4-(difluoromethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0192] (4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0193] (4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0194] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-4-(difluoromethyl)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0195] (4R)-4-(difluoromethyl)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0196] (4R)-5-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0197] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0198] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-

[0199] (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0200] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-

[0201] (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0202] (4R)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0203] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0204] (4R)-5-(6-{2,6-diazabicyclo[3.2.1]octan-6-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0205] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0206] (4R)-5-(6-{2,6-diazabicyclo[3.2.1]octan-6-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0207] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0208] (4R)-5-{6-[(3aR,6aS)-octahydropyrrolo[3,4-c]pyrrol-2-yl]-4-(trifluoromethyl)pyridin-2-yl}- 4-(difluorom ethyl)- 1H,2H,4H-pyrimido[4, 5 -d] [1,3] oxazin-2-one;

[0209] (4R)-4-(difluoromethyl)-5-(6-{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4-

[0210] (trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0211] (4R)-4-(difluoromethyl)-5-(6-{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4-

[0212] (trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0213] (4R)-5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0214] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(propan-2-yl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0215] (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(propan-2-yl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0216] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0217] (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0218] (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0219] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0220] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0221] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0222] (4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0223] (4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0224] (4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0225] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0226] (4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0227] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0228] (4R)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0229] (4R)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0230] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2- yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0231] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2- yl ] - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;

[0232] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0233] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0234] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-ethylpiperazin-1-yl]pyridin-2- yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0235] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-ethylpiperazin-1-yl]pyridin-2- yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0236] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0237] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0238] (4R)-4-(difluoromethyl)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0239] (4R)-4-(difluoromethyl)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0240] (4R)-5-[4-(cyclopropyldifluoromethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-[4-(cyclopropyldifluoromethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0241] (4R)-5-[4-(1,1-difluoro-2,2-dimethylpropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0242] (4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0243] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0244] (4R)-5-[4-(cyclopropyldifluoromethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0245] (4R)-5-[4-(1,1-difluoro-2,2-dimethylpropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0246] (4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0247] 5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0248] 5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0249] 5-(6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0250] 5-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-ethyl-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one;

[0251] 5-{6-[(4aS,7aR)-octahydrofuro[3,4-b]piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0252] 5 - { 6- [(3 S)-3 -aminopiperi din- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl } -4-ethyl - 1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; 5-{6-[(lR,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}- 4-ethyl-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0253] 4-ethyl-5-{6-[(3 S,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl]-4-(trifluoromethyl)pyri din-2 -yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0254] 5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0255] 5-{6-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0256] 4-ethyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethoxy)pyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0257] 4-ethyl-5-{6-[3-(2-hydroxypropan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0258] 4-ethyl-5-[4-(2-hydroxypropan-2-yl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0259] 5-{6-[(2R)-2-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0260] 5-{6-[(lR,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-

[0261] 4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0262] 5-[4-(1,1-difluoroethyl)-6-[(2R)-2-ethylpiperazin-1-yl]pyridin-2-yl]-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0263] 4-(1,1-difluoroethyl)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0264] (4S)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one; (4R)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one;

[0265] (4S)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0266] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0267] (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0268] (4R)-4-cyclopropyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0269] (4S)-4-cyclopropyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0270] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0271] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0272] (4S)-5- { 6-[(3 S)-3 -methyl pi perazi n-1 -yl ]-4-(trifl uoromethyl )pyri di n-2-yl } -4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0273] (4R)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0274] 5-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-ethyl-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0275] (4R)-4-cyclopropyl-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0276] (4S)-4-cyclopropyl-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-cyclopropyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0277] (4S)-4-cyclopropyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0278] (4R)-4-(difluoromethyl)-5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrido[2, 3 - d] [ 1 , 3 ]oxazin-2-one;

[0279] (4R)-4-(difluoromethyl)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0280] (4R)-4-(difluoromethyl)-5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyri din-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0281] (4R)-4-(difluoromethyl)-5-[6-(3-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0282] (4R)-4-(difluoromethyl)-5-[6-(3-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0283] (4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(difluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0284] (4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0285] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-methylpyridin-2-yl}-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0286] (4R)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-methylpyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0287] (4R)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-methylpyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-methylpyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0288] (4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one; methyl 2-[(4R)-4-(difluoromethyl)-2-oxo-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-6-

[0289] (piperazin- l-yl)pyridine-4-carboxylate

[0290] (4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0291] (4R)-4-(difluoromethyl)-5-[5-nitro-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one;

[0292] (4S)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0293] (4R)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0294] 5-{6-[(2S,3S)-2,3-dimethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0295] (4R)-5-[6-(4-methylpiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0296] (4R)-5-[6-(piperidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0297] (4R)-5-[6-(piperidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0298] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,3H,4H-pyrimido[4,5-d] [1,3 ]diazin-2-one; (4R)-5-(6-{2-azabicyclo[3.1.1]heptan-5-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0299] (4R)-4-methyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0300] 3-{4-[(3-chloro-5-{[(2-chloro-4-fluoro-3-hydroxyphenyl)methyl]amino}phenyl)methoxy]-1- oxo- 1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl}piperidine-2, 6-dione;

[0301] (4R)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0302] (4S)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0303] (4S)-4-ethyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0304] (4R)-4-ethyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0305] (4S)-4-methyl-5-{6-[(2,2,3,3,5,5,6,6-2H8)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0306] (4S)-4-methyl-5-{6-[(2,2,3,3,5,5,6,6-2H8)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0307] 5-[4-(cyclopentyldifluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0308] (4R)-5-[4-(1,1-difluoro-2-methylpropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0309] (trifluoromethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0310] (4R)-5-[4-(cyclopropyldifluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0311] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one; (4R)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0312] (4R)-5-[6-( 1 ,4-diazepan- 1 -y l)-4-( 1 , 1 -difluoropropyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0313] (4R)-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoroethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0314] (4R)-4-cyclopropyl-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0315] (4S)-4-cy clopropyl-5-[4-( 1 , 1 -difluoropropyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl] py ri din-2-yl] - 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0316] (4R)-5-[4-(cyclopropyldifluoromethyl)-6-(1,4-diazepan-1-yl)pyridin-2-yl]-4-

[0317] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0318] (4R)-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoro-2-methylpropyl)pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0319] 4-cyclopropyl-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoro-2-methylpropyl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0320] 4-cyclopropyl-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoro-2-methylpropyl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0321] (4R)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0322] (4R)-5-{4-[difluoro(phenyl)methyl]-6-(piperazin-1-yl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0323] (4R)-5-{4-[difluoro(phenyl)methyl]-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-

[0324] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0325] 5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,3H,4H- pyrido[2,3-d]pyrimidin-2-one;

[0326] 4-{6-[2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}piperidin-2-one;

[0327] (4R)-5-(6-{octahydropyrrolo[3,4-b]morpholin-4-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0328] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0329] 5-(6-{octahydropyrrolo[3,4-b]morpholin-6-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0330] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0331] (4R)-5-[6-(piperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0332] (4R)-4-(trifluoromethyl)-5-[4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0333] (4R)-5-[6-(pyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0334] (4R)-5-[6-(pyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0335] (4R)-5-[6-(2,5-dihydro-1H-pyrrol-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0336] (4R)-4-(trifluoromethyl)-5-[4-(trifluoromethyl)- 1',2',5',6'-tetrahydro-[2,3'-bipyridine]-6-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0337] (4R)-5-[5'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluoromethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one; (4R)-5-[3'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)-1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0338] (4R)-5-[3'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluoromethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0339] (4R)-5-[3'-ethyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0340] (4R)-5-[3'-ethyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0341] (4R)-5-[2'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0342] (4R)-5-[2'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0343] (4S)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0344] (4R)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0345] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0346] (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0347] (4S)-5-{6-[(2R)-2-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0348] (4R)-5-{6-[(2R)-2-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one; (4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0349] (4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0350] 4-(l-fluorocyclopropyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;

[0351] (4S)-4-(l-fluorocyclopropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0352] 4-(l-fluorocyclopropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0353] (4S)-4-(fluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0354] (4R)-4-(fluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0355] 5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0356] 5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0357] (4S)-4-( 1 -fluoroethyl)-5 - { 6- [(3 S)-3 -methylpiperazin- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl } - 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0358] (4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0359] (4S)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0360] (4S)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0361] (4S)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0362] (4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0363] (4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0364] (4R)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one;

[0365] 4-{6-[(4R)-4-(1,1-difluoroethyl)-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-5-yl]-4-

[0366] (trifluoromethyl)pyridin-2-yl}piperazin-2-one;

[0367] 5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2 -yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0368] 5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2 -yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; methyl 3-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}pyrrolidine-3 -carboxylate methyl 3-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}pyrrolidine-3 -carboxylate

[0369] (4R)-5-{6-[3-(hydroxymethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0370] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-[3-(hydroxymethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0371] (4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(difluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0372] (4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0373] (4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0374] (4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0375] 5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0376] 5-{6-[3-(difluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0377] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0378] 5-{6-[3-(difluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0379] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0380] (4R)-5-[4-cyclopropyl-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0381] 2-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-6-(piperazin-1- yl)pyridine-4-carbonitrile

[0382] (4R)-5-[4-ethyl-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0383] (4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one; (4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0384] (4R)-4-(difluoromethyl)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0385] (4S)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrido[2, 3 - d] [ 1 , 3 ]oxazin-2-one;

[0386] (4R)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrido[2, 3 - d] [ 1 , 3 ]oxazin-2-one;

[0387] (4R)-4-(difluoromethyl)-5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0388] (4R)-4-(1,1 -difluoroethyl)-5-[4-( 1 , 1 -difluoroethyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl]pyridin-2- yl ] - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;

[0389] (4S)-4-( 1 , 1 -difluoroethyl)-5-[4-(1,1 -difluoroethyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl]pyridin-2- yl ] - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;

[0390] (4R)-4-(difluoromethyl)-5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2- yl } - 1H,2H,4H-pyrido[2, 3 -d] [ 1 , 3 ]oxazin-2-one;

[0391] (4R)-4-(difluoromethyl)-5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2- yl } - 1H,2H,4H-pyrido[2, 3 -d] [ 1 , 3 ]oxazin-2-one;

[0392] (4R)-5-[6-(3-fluoropiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0393] (4R)-5-[6-(3-fluoropiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0394] (4R)-4-(1,1-difluoroethyl)-5-[2-(piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; or a pharmaceutically acceptable salt thereof. In one embodiment, the invention comprises a pharmaceutical composition comprising the compound of Formula I, and a pharmaceutically acceptable carrier.

[0395] In another embodiment, the invention comprises a method of treating, preventing, or managing a disease or disorder mediated by a protein kinase C theta (PKC-theta) or mutant of PCK-theta, in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutical composition thereof to a subject.

[0396] In one embodiment, the disease or disorder is an inflammatory disease, an autoimmune disorder, a cancer, an oncologic disease, or an autoimmune infection.

[0397] In another embodiment, the disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis or atopic dermatitis.

[0398] DETAILED DESCRIPTION

[0399] The present disclosure is directed to compounds pharmaceutically acceptable salts, pharmaceutical compositions, and combinations thereof that are effective modulators of protein kinase C (PKC); in particular, protein kinase C-theta (PKC-theta). The invention further provides methods of treating, preventing, or managing a disease or disorder mediated by protein PKC-theta (or mutant); the methods comprising of administering a therapeutically or prophylactically effective amount of the compound of formula I to a subject in need thereof.

[0400] In one embodiment the disease or disorder mediated by PKC-theta is selected from: an inflammatory disease, a cancer / oncologic disease, an autoimmune infection, rheumatoid arthritis, multiple sclerosis, psoriasis or atopic dermatitis, inflammatory disease, or an autoimmune disorder.

[0401] Definitions Chemical Definitions

[0402] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistiy, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0403] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0404] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, geometric isomer, or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0405] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound.

[0406] The features and advantages of the invention as described in this disclosure may be more readily understood by those of ordinary skill in the art in view of the following definitions. Certain features of the invention described within the context of separate embodiments may also be combined to form a single or extrapolated to include multiple embodiments. Embodiments identified herein as exemplary or preferred are illustrative and not limiting.

[0407] Unless expressly stated otherwise herein, references made in the singular may also include the plural. For example, "a" and "an" may refer to either one or one or more.

[0408] As used herein, the phrase "compounds" refers to at least one compound. For example, a compound of Formula (I) includes a compound of Formula (I) and two or more compounds of Formula (I).

[0409] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0410] The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0411] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.

[0412] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.

[0413] In accordance with a convention used in the art, is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0414] The terms "halo" and "halogen," as used herein, refer to F, Cl, Br, and I.

[0415] The term "cyano" refers to the group -CN.

[0416] The term "amino" refers to the group -NH2.

[0417] The term "oxo" refers to the group =O.

[0418] The term "alkyl" as used herein, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i- butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2- m ethylpentyl, 2-ethylbutyl, 3 -methylpentyl, and 4-methylpentyl. When numbers appear in a subscript after the symbol "C", the subscript defines with more specificity the number of carbon atoms that a particular group may contain. For example, "C1-6alkyl" denotes straight and branched chain alkyl groups with one to six carbon atoms.

[0419] The term "fluoroalkyl" as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C1-4fluoroalkyl" is intended to include C1, C2, C3, and C4alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3and -CH2CF3.

[0420] The term "cyanoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes -CH2CN, -CH2CH2CN, and C1-4cyanoalkyl.

[0421] The term "aminoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more amine groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and C1-4aminoalkyl.

[0422] The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxy alkyl" includes -CH2OH, -CH2CH2OH, and C1-4hydroxy alkyl. The term "hydroxy-fluoroalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms. For example, "hydroxy-fluoroalkyl" includes -CHFCH2OH, -CH2CHFC(CH3)2OH, and C1-4hydroxy-fluoroalkyl .

[0423] The term "cycloalkyl," "carbocyclic" "carbocyclyl" as used herein, refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removal of one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in a subscript after the symbol "C", the subscript defines with more specificity the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C3-C6cycloalkyl" denotes cycloalkyl groups with three to six carbon atoms.

[0424] The term "heterocyclic" as used herein, refers to organic compounds with cyclic structures of both carbon atoms and non-carbon atoms such as oxygen, nitrogen.

[0425] The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, methoxy group (-OCH3). For example, "C1-3alkoxy" denotes alkoxy groups with one to three carbon atoms.

[0426] The term "alkoxyalkyl," as used herein, refers to an alkoxy group attached through its oxygen atom to an alkyl group, which is attached to the parent molecular moiety, for example, methoxymethyl group (-CH2OCH3). For example, "C2-4alkoxyalkyl" denotes alkoxyalkyl groups with two to four carbon atoms, such as -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, and -CH2CH2OCH2CH3.

[0427] The term "amine" or "amines" as used herein refers to compounds in which a nitrogen atom is directly bonded to several carbon atoms. Embodiments are comprised of derivatives of ammonia (-NH3) resulting from a progressive substitution of the three hydrogen atoms by hydrocarbon groups. Amines are classified as primary, secondary, or tertiary by the number of carbons bonded to the nitrogen atom. For example, a primary amine has one carbon bonded to the nitrogen (R-NH2), a secondary amine has two carbons bonded to the nitrogen, amine (R2-NH), and a tertiary amine has three carbons bonded to the nitrogen (R3-N) wherein R is an alkyl group.

[0428] The term "heteroaryl" as used herein, refers to an aromatic heterocycle ring of 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems.

[0429] The term “aryl” as used herein refers to any functional group or substituent derived from an aromatic ring, or an aromatic ring, or substituted aromatic ring, that may optionally comprise or be comprised of, an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization as an aryl group in chemical structures. Solely for example, but not limitation: a simple aryl group is phenyl (C6H5-), a group derived from benzene. Examples of other aryl groups consist of: a tolyl group (CH3C6H4-) which is derived from toluene (methylbenzene), an xylyl group ((CH3)2C6H3-), which is derived from xylene (dimethylbenzene), a naphthyl group (C10H7-), and which is derived from naphthalene.

[0430] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0431] The compounds of Formula (I) can be provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds of Formula (I) as amorphous solids.

[0432] It should further be understood that solvates (e.g., hydrates) of the compounds of Formula (I) are also within the scope of the present invention. The term "solvate" means a physical association of a compound of Formula (I) with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0433] Various forms of prodrugs are well known in the art and are described in: a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113 - 191 (Harwood Academic Publishers, 1991); and d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003).

[0434] In addition, compounds of Formula (I), subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formula (I) ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds of Formula (I) are also contemplated herein as part of the present invention.

[0435] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.

[0436] A person of ordinary skill in the art would also understand that the compounds described and claimed herein as embodiments of the invention also exist in their "tautomeric forms." As used herein, Tautomers that exist in tautomeric form pertain to compounds that are structural isomers that can readily interconvert in rapid equilibrium. As used herein the process of interconversion is called "tautomerization."

[0437] The disclosed structures readily interconvert between left-handed and right-handed structural representations. "Therapeutically effective amount" is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor or effective to treat or ameliorate cancer.

[0438] As used herein, "treating" or "treatment" cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and / or (c) relieving the disease-state, i.e., causing regression of the disease state.

[0439] The compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include13C and14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. For example, methyl (-CH3) also includes deuterated methyl groups such as -CD3.

[0440] The term "pharmaceutically acceptable salts" is meant to include salts of active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compound s with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salt, or a similar salt.

[0441] As defined herein, the term "inhibition", "inhibit", "inhibiting" and the like in reference to a protein-inhibitor (e.g., antagonist) interaction means negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. Thus, inhibition may include, at least in part, partially or totally decreasing stimulation, decreasing or reducing activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity.

[0442] "Patient" or "subject" in need thereof refers to a living organism suffering from or prone to a disease or condition that can be treated by admini stration of a compound or pharmaceutical composition, as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other nonmammalian animals. In some embodiments, a patient is human. In some embodiments, a patient is a domesticated animal. In some embodiments, a patient is a dog. In some embodiments, a patient is a parrot. In some embodiments, a patient is livestock animal. In some embodiments, a patient is a mammal. In some embodiments, a patient is a cat. In some embodiments, a patient is a horse. In some embodiments, a patient is bovine. In some embodiments, a patient is a canine. In some embodiments, a patient is a feline. In some embodiments, a patient is an ape. In some embodiments, a patient is a monkey. In some embodiments, a patient is a mouse. In some embodiments, a patient is an experimental animal. In some embodiments, a patient is a rat. In some embodiments, a patient is a hamster. In some embodiments, a patient is a test animal. In some embodiments, a patient is a newborn animal. In some embodiments, a patient is a newborn human. In some embodiments, a patient is a newborn mammal. In some embodiments, a patient is an elderly animal. In some embodiments, a patient is an elderly human. In some embodiments, a patient is an elderly mammal. In some embodiments, a patient is a geriatric patient.

[0443] "Disease", "disorder" or "condition" refers to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the compounds and methods described herein comprise reduction or elimination of one or more symptoms of the disease, disorder, or condition, e.g., through administration of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0444] The term "signaling pathway" as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components.

[0445] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances, and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0446] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.

[0447] Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "coadminister" it is meant that a compound or composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti-cancer agent, chemotherapeutic, or immunotherapeutic agent). The compounds or compositions described herein can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compound or composition individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0448] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing a disclosed compound (the "active ingredient") into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose unit. Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0449] Methods of Treatment The present disclosure features compounds, compositions, and methods comprising a compound disclosed herein, e.g., a compound of Formula (I). In some embodiments, the compounds, compositions, and methods disclosed herein are used in the prevention or treatment of a disease, disorder, or condition. Exemplary diseases, disorders, or conditions include, but are not limited to cancer, diabetes, metabolic syndrome, obesity, other metabolic diseases, ischaemic heart disease, heart failure autoimmune diseases, Parkinson's disease, Alzheimer's disease bipolar disorder, and psoriasis.

[0450] Cancer

[0451] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), is used to treat cancer. As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinomas), lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), and / or multiple myeloma. In some further instances, "cancer" refers to lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, biliary tract cancer, adrenal gland cancer, salivary gland cancer, bronchus cancer, oral cancer, cancer of the oral cavity or pharynx, laryngeal cancer, renal cancer, gynecologic cancers, brain cancer, central nervous system cancer, peripheral nervous system cancer, cancer of the hematological tissues, small bowel or appendix cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

[0452] Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, B-cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, mu chain disease, Waldenstrom's macroglobulinemia, benign monoclonal gammopathy, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER-positive, ER-negative, chemotherapy-resistant, Herceptin resistant, HER2 positive, doxorubicin-resistant, tamoxifen-resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pinealoma, ependymoma, oligodendroglioma, meningioma, glioma, or melanoma. Additional examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocytic amyloidosis, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, and hepatocellular carcinoma.

[0453] The first aspect of the present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0454] X is N(R1), S, or O;

[0455] Y is O or S, wherein X is O or N(R1) when Y is S;

[0456] A is C(R11) or N;

[0457] B is C(R6) or N;

[0458] Z is C(R12) or N;

[0459] R1is H or C1-C4alkyl;

[0460] R2is C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl, wherein the alkyl, haloalkyl, and cycloalkyl of R2is each independently optionally substituted with one or more R5; each R3is independently H or C1-C4alkyl;

[0461] R4= H

[0462] Ring D is aryl optionally substituted with one or more R10; each R5is independently OH, halogen, C1-C4alkyl, C1-C4haloalkyl, C3-C8cycloalkyl; or aryl; or two geminal R5, together with the intervening geminal carbon atom form a C3-C6cycloalkyl; R6is H, C1-C6alkyl, C1-C4alkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, 3- to 9- membered heterocyclyl, C1-C6, haloalkyl, -C(O)OR9, cyano, or halogen, wherein the alkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and haloalkyl of R6are each independently optionally substituted with one or more halogen, phenyl, benzyl, C3-C6cycloalkyl, hydroxy, C1-C3alkoxy, or C1-C3haloalkyl;

[0463] W is H, halogen, N(R7)2, 3- to 10-membered heterocyclyl, C3-C8cycloalkyl, C1-C3alkyl, wherein the heterocyclyl, cycloalkyl, and alkyl of W are each independently optionally substituted with one or more R8; each instance of R7is independently H, C1-C4alkyl, C3-C6cycloalkyl, wherein the alkyl and the cycloalkyl of R7are each independently optionally substituted with one or more R8, or two R7, together with the intervening N atom form: a 3- to 12-membered heterocyclyl optionally substituted with one or more R8; each R8is independently deuterium, C1-C4alkyl, C1-C4haloalkyl, C1-C6hydroxyalkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl, hydroxy, -(CH2)n-C(O)O(R9), N(R9)2, -NHC(O)R9, -COOH, oxo, thio, -SO3H, halogen, cyano, or C1-C3 alkoxy, or two geminal R8, together with the intervening carbon atom form a C3-C6cycloalkyl; each R9is independently H, or C1-C3alkyl; each R10is independently H, or C1-C3alkoxy; each R11is H, C1-C6alkyl, or halogen; n is an integer from 0 to 6;

[0464] R12is H, NO2, or when B is CR6, R12is H NO2, or R12and R6when taken together form a 6-membered aryl.

[0465] In one embodiment of the compound of formula I, R2is H, -CH2-, -CH3, -CH2CH3, - CH2CH(CH3)2, -CH2CH2CH3, -C(CH3)3, -CF2CH3, -CHFCH3, -CHF2, or -CF3. In one embodiment of the compound of formula I, R2is methyl.

[0466] In one embodiment of the compound of formula I, R6is C1-C6alkyl, C1-C6haloalkyl, C1-C3aminoalkyl, or C1-C3hydroxyalkyl.

[0467] In one embodiment of the compound of formula I, the compound is of Formula la: or a pharmaceutically acceptable salt thereof. In one embodiment of the compound of formula I, W is:

[0468]

[0469] In one embodiment of the compound of formula I, the compound is of formula la-1 : or a pharmaceutically acceptable salt thereof, wherein W is substituted with one or more R8.

[0470] In one embodiment of the compound of formula I, the compound is of formula la-2: or a pharmaceutically acceptable salt thereof, wherein p is 2.

[0471] In one embodiment of the compound of formula I, the compound is of formula la-3:

[0472] or a pharmaceutically acceptable salt thereof.

[0473] In one embodiment of the compound of formula I, the compound is of formula la-4: or a pharmaceutically acceptable salt thereof, wherein W is substituted with one or more R8.

[0474] In one embodiment of the compound of formula I, the compound is of formula la-5: or a pharmaceutically acceptable salt thereof, wherein W is substituted with one or more R8.

[0475] In one embodiment of the compound of formula I, the compound is of formula la-6:

[0476] (Ia-6), or a pharmaceutically acceptable salt thereof, wherein W is substituted with one or more R8.

[0477] In one embodiment of the compound of formula I, the compound is of formula la-7: or a pharmaceutically acceptable salt thereof, wherein W is substituted with one or more R8.

[0478] In one embodiment of the compound of formula I, the compound is of formula la-8: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or

[0479] 3.

[0480] In one embodiment of the compound of formula I, the compound is of formula Ib-1 : or a pharmaceutically acceptable salt thereof.

[0481] In one embodiment of the compound of formula I, the compound is of formula Ib-2:

[0482] or a pharmaceutically acceptable salt thereof.

[0483] In one embodiment of the compound of formula I, the compound is of formula Ib-3 : or a pharmaceutically acceptable salt thereof.

[0484] In one embodiment of the compound of formula I, the compound is of formula Ib-4: or a pharmaceutically acceptable salt thereof.

[0485] In one embodiment of the compound of formula I, the compound is of formula Ib-5 : or a pharmaceutically acceptable salt thereof.

[0486] In one embodiment of the compound of formula I, the compound is of formula Ic-1 : substituted with one or more R8.

[0487] In one embodiment of the compound of formula I, the compound is of formula Ic-2: or a pharmaceutically acceptable salt thereof, wherein W is substituted with one or more R8.

[0488] In one embodiment of the compound of formula I, the compound is of formula Ic-3: or a pharmaceutically acceptable salt thereof, wherein W is substituted with one or more R8. In one embodiment of the compound of formula I, the compound is of formula Ic-4: or a pharmaceutically acceptable salt thereof, wherein W is substituted with one or more R8.

[0489] In one embodiment of the compound of formula I, the compound is of formula Ic-5: or a pharmaceutically acceptable salt thereof.

[0490] In one embodiment of the compound of formula I, the group consisting of:

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507] In another embodiment, the compound is selected from the group consisting of:

[0508] (4R)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0509] 514585313v.1 (4S)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0510] (4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0511] (4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0512] (4S)-4-methyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0513] (4R)-4-methyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0514] 6-{4-methyl-2-oxo-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl}-4-(trifluoromethyl)- 1',2'- dihydro-[2,4'-bipyridine]-2'-one;

[0515] 4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0516] (4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0517] (4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0518] (4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0519] (4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0520] (4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0521] (4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0522] (4R)-4-methyl-5-{6-[(3R)-3-methyl-1,4-diazepan-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-4-methyl-5-{6-[(3R)-3-methyl-1,4-diazepan-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0523] 4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0524] 5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(2-methylpropyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0525] 4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0526] 4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0527] (4S)-4-ethyl-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0528] (4R)-4-ethyl-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0529] (4R)-4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0530] (4S)-4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0531] 4-cyclobutyl-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0532] (4S)-4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0533] (4R)-4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0534] (4S)-4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0535] (4R)-4-cyclobutyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-4-cyclobutyl-5-[6-(piperazin-l -yl)-4-(trifluoromethyl)pyri din-2 -yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0536] (4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0537] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0538] (4S)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0539] (4R)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0540] (4S)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0541] (4R)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0542] (4S)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0543] (4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0544] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0545] (4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0546] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0547] (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(1,1,2,2,2- pentafluoroethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0548] (4R)-5- {6- [(3 S)-3 -methylpiperazin- 1 -yl]-4-(trifluoromethyl)pyridin-2-yl }-4-( 1 , 1 ,2,2,2- pentafluoroethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0549] (4S)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0550] (4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0551] 5- { 6- [(3 S)-3 -methylpiperazin- 1 -yl]-4-(trifluoromethyl)pyridin-2-yl } -4-( 1 , 1 ,2,2,2- pentafluoroethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4S)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0552] (4R)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0553] (4S)-5-[4-(1,1-difluoroethyl)-6-[(2R)-2-ethylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0554] (4R)-5-[4-(1,1-difluoroethyl)-6-[(2R)-2-ethylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0555] 5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(1,1,2,2,2- pentafluoroethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0556] (4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0557] (4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0558] (4R)-5-{6-[(2R)-2-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0559] (4S)-5-{6-[(2R)-2-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0560] 5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0561] 5-(6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0562] (4R)-5-[4-fluoro-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0563] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0564] (4R)-5 - { 6- [(3 S)-3 -cy clopropylpiperazin- 1 -yl ] -4-methylpyridin-2-yl } -4-(difluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-(1,1 -difluoroethyl)-5-[4-( 1 , 1 -difluoroethyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl]pyridin-2- yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0565] (4R)-4-(difluoromethyl)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0566] (4R)-4-(difluoromethyl)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0567] (4R)-4-(1,1-difluoroethyl)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0568] (4R)-4-(1,1-difluoroethyl)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0569] (4R)-4-(1,1-difluoroethyl)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0570] (4R)-5 - { 6- [(3 S)-3 -cy clopropylpiperazin- 1 -yl ] -4-methylpyridin-2-yl } -4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0571] (4S)-4-(1,1-difluoropropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0572] (4R)-4-(1,1-difluoropropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0573] (4S)-4-(cyclopropyldifluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0574] (4R)-4-(cyclopropyldifluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0575] (4R)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4-yl]pyridin-2-yl]-4-

[0576] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0577] (4R)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4-yl]pyridin-2-yl]-4-

[0578] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0579] (4R)-5-{6-[4-(difluoromethyl)piperidin-4-yl]-4-(1,1-difluoropropyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one; (4S)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0580] (4R)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0581] (4S)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0582] (4R)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0583] (4R)-4-(1,1-difluoroethyl)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0584] (4S)-4-( 1 , 1 -difluoroethyl)-5-[4-(1,1 -difluoroethyl)-6-(piperazin- 1 -yl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0585] (4R)-4-(1,1-difluoroethyl)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0586] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0587] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0588] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0589] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0590] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0591] (4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0592] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4-yl]pyridin- 2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4-yl]pyridin- 2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0593] (4R)-4-(difluoromethyl)-5-{6-[4-(difluoromethyl)piperidin-4-yl]-4-(1,1- difluoropropyl)pyridin-2-yl } - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;

[0594] (4R)-4-(difluoromethyl)-5-{6-[4-(difluoromethyl)piperidin-4-yl]-4-(1,1- difluoropropyl)pyridin-2-yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0595] (4R)-5-[4-( 1 , 1 -difluoro-2-methoxyethyl)-6-[(3 S)-3 -methylpiperazin- 1 -y l] py ri din-2-y l ] -4-

[0596] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0597] (4R)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0598] (4R)-4-(difluoromethyl)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0599] (4R)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0600] (4R)-4-(difluoromethyl)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0601] (4R)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0602] (4S)-5-{6-[(3R)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0603] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0604] (4R)-5 - {6- [(3R)-3 -methylpiperazin- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl } -4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0605] 5-{6-[(3R)-3-aminopyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0606] (4R)-5-{6-[(2R)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0607] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0608] (4R)-5-[6-(l, 4-diazepan-1-yl)-4-(trifluoromethyl)pyri din-2 -yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4S)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0609] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0610] (4S)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0611] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0612] (4R)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0613] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0614] (4R)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0615] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0616] (4R)-5-{6-[(2S)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0617] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0618] 5-[6-(6-methyl-1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0619] (4R)-5-{6-[(3S)-3-(methylamino)pyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0620] (4R)-5-{6-[(3S)-3-aminopiperidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0621] (4R)-5-[6-(6-hydroxy-1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-

[0622] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0623] (4R)-5-[6-(6-hydroxy-1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-

[0624] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0625] (4R)-5-{6-[(3R)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0626] (4R)-5-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0627] (4R)-5-[6-(3-aminoazetidin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; l-{6-[(4R)-2-oxo-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1, 3 ]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}pyrrolidine-3-carbonitrile; 1-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}pyrrolidine-3 -carbonitrile;

[0628] (4R)-5-[l-(piperazin-1-yl)isoquinolin-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0629] (4R)-5-{6-[(lS,6R)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0630] (4R)-5-{6-[(lS,6S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0631] (4R)-5-{6-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0632] (4R)-5-{6-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0633] 5-{6-[(2-aminoethyl)amino]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0634] 5-{6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0635] (4R)-5-(6-{[l-(aminomethyl)cyclopropyl]amino}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0636] (4R)-5-{6-[(4aS,8aR)-decahydroquinoxalin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0637] (4R)-5-{6-[(4aS,8aR)-decahydroquinoxalin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0638] (4R)-5-[6-(3,3-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0639] (4R)-5 - { 6- [(3 S, 5 S)-3 , 5 -dimethylpiperazin- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl }-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0640] (4R)-5-{6-[(4aS,7aR)-octahydro-1H-cyclopenta[b]piperazin-1-yl]-4-(trifluoromethyl)pyridin-

[0641] 2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-[(4aS,7aR)-octahydro-1H-cyclopenta[b]piperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0642] (4R)-5-{6-[(4aR,7aS)-octahydropyrrolo[3,4-b]morpholin-6-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0643] (4R)-5-{6-[(4aS,7aR)-octahydropyrrolo[3,4-b]morpholin-6-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0644] (4R)-5-{6-[(3S)-3-methyl-1,4-diazepan-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0645] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0646] (4R)-5-(6-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0647] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0648] (4R)-5-{6-[(2R)-2-(hydroxymethyl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0649] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0650] (4R)-5-{6-[(2S)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0651] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0652] (4R)-5-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0653] (4R)-5-[6-(4-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0654] (4R)-5 - { 6- [(3 S)-3 -aminopyrrolidin- 1 -yl ] -4-(trifluoromethyl)pyridin-2-yl } -4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0655] N-[(3S)-1-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4-

[0656] (trifluoromethyl)pyridin-2-yl}pyrrolidin-3-yl]acetamide

[0657] (4R)-4-(difluoromethyl)-5-{6-[(2R)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyri din-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0658] (4R)-4-(difluoromethyl)-5-{6-[(3R)-3-(hydroxymethyl)piperazin-1-yl]-4-

[0659] (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0660] (4R)-5-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0661] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0662] (4R)-4-(difluoromethyl)-5-(6- {octahydro-1H-cy cl openta[b]piperazin- 1 -yl } -4- (trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0663] (4R)-4-(difluoromethyl)-5-(6- {octahydro- 1H-cy cl openta[b]piperazin- 1 -yl } -4- (trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0664] (4S)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0665] (4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0666] 4-(difluoromethyl)-5-[6-(piperazin-l -yl)-4-(trifluoromethyl)pyri din-2 -yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0667] (4R)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0668] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0669] (4S)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- methyl-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0670] (4S)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- methyl-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0671] (4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0672] (4S)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0673] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0674] (4S)-4-(difluoromethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0675] (4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0676] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0677] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0678] (4S)-4-(difluoromethyl)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0679] (4R)-4-(difluoromethyl)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0680] (4R)-5-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0681] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0682] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-

[0683] (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0684] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-

[0685] (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0686] (4R)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0687] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0688] (4R)-5-(6-{2,6-diazabicyclo[3.2.1]octan-6-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0689] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0690] (4R)-5-(6-{2,6-diazabicyclo[3.2.1]octan-6-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0691] (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0692] (4R)-5-{6-[(3aR,6aS)-octahydropyrrolo[3,4-c]pyrrol-2-yl]-4-(trifluoromethyl)pyridin-2-yl}- 4-(difluorom ethyl)- 1H,2H,4H-pyrimido[4, 5 -d] [1,3] oxazin-2-one;

[0693] (4R)-4-(difluoromethyl)-5-(6-{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4-

[0694] (trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0695] (4R)-4-(difluoromethyl)-5-(6-{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4-

[0696] (trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0697] (4R)-5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0698] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(propan-2-yl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(propan-2-yl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0699] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0700] (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0701] (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0702] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0703] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0704] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0705] (4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0706] (4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0707] (4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0708] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0709] (4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0710] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0711] (4R)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0712] (4R)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0713] (4R)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0714] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2- yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0715] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2- y l ] - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0716] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0717] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-ethylpiperazin-1-yl]pyridin-2- yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0718] (4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-ethylpiperazin-1-yl]pyridin-2- yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0719] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0720] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0721] (4R)-4-(difluoromethyl)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0722] (4R)-4-(difluoromethyl)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0723] (4R)-5-[4-(cyclopropyldifluoromethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0724] (4R)-5-[4-(cyclopropyldifluoromethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0725] (4R)-5-[4-(1,1-difluoro-2,2-dimethylpropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0726] (4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0727] (4R)-5-[4-(cyclopropyldifluoromethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0728] (4R)-5-[4-(1,1-difluoro-2,2-dimethylpropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0729] 5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0730] 5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0731] 5-(6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0732] 5-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-ethyl-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one;

[0733] 5-{6-[(4aS,7aR)-octahydrofuro[3,4-b]piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0734] 5 - { 6- [(3 S)-3 -aminopiperi din- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl } -4-ethyl - 1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0735] 5-{6-[(lR,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}- 4-ethyl-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0736] 4-ethyl-5-{6-[(3 S,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl]-4-(trifluoromethyl)pyri din-2 -yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0737] 5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0738] 5-{6-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0739] 4-ethyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethoxy)pyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0740] 4-ethyl-5-{6-[3-(2-hydroxypropan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0741] 4-ethyl-5-[4-(2-hydroxypropan-2-yl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; 5-{6-[(2R)-2-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0742] 5-{6-[(lR,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-

[0743] 4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0744] 5-[4-(1,1-difluoroethyl)-6-[(2R)-2-ethylpiperazin-1-yl]pyridin-2-yl]-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0745] 4-(1,1-difluoroethyl)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0746] (4S)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one;

[0747] (4R)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one;

[0748] (4S)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0749] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0750] (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0751] (4R)-4-cyclopropyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0752] (4S)-4-cyclopropyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0753] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0754] (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0755] (4S)-5- [ 6-[(3 S)-3 -methyl pi perazi n-1 -yl ]-4-(trifl uoromethyl )pyri di n-2-yl } -4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0756] (4R)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one; 5-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-ethyl-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0757] (4R)-4-cyclopropyl-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0758] (4S)-4-cyclopropyl-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0759] (4R)-4-cy cl opropyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyri din-2 -yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0760] (4S)-4-cyclopropyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0761] (4R)-4-(difluoromethyl)-5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyri din-2- yl } - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;

[0762] (4R)-4-(difluoromethyl)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0763] (4R)-4-(difluoromethyl)-5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyri din-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0764] (4R)-4-(difluoromethyl)-5-[6-(3-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0765] (4R)-4-(difluoromethyl)-5-[6-(3-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0766] (4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(difluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0767] (4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0768] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-methylpyridin-2-yl}-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0769] (4R)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-methylpyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one; (4R)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-methylpyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0770] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-methylpyridin-2-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0771] (4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one; methyl 2-[(4R)-4-(difluoromethyl)-2-oxo-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-6-

[0772] (piperazin- l-yl)pyridine-4-carboxylate

[0773] (4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0774] (4R)-4-(difluoromethyl)-5-[5-nitro-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one;

[0775] (4S)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0776] (4R)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0777] 5-{6-[(2S,3S)-2,3-dimethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0778] (4R)-5-[6-(4-methylpiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0779] (4R)-5-[6-(piperidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0780] (4R)-5-[6-(piperidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0781] (4R)-4-(difluoromethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,3H,4H-pyrimido[4,5-d] [1,3 ]diazin-2-one;

[0782] (4R)-5-(6-{2-azabicyclo[3.1.1]heptan-5-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0783] (difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-methyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0784] 3-{4-[(3-chloro-5-{[(2-chloro-4-fluoro-3-hydroxyphenyl)methyl]amino}phenyl)methoxy]-1- oxo- 1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl}piperidine-2, 6-dione;

[0785] (4R)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0786] (4S)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0787] (4S)-4-ethyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0788] (4R)-4-ethyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0789] (4S)-4-methyl-5-{6-[(2,2,3,3,5,5,6,6-2H8)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0790] (4S)-4-methyl-5-{6-[(2,2,3,3,5,5,6,6-2H8)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0791] 5-[4-(cyclopentyldifluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0792] (4R)-5-[4-(1,1-difluoro-2-methylpropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0793] (4R)-5-[4-(cyclopropyldifluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0794] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0795] (4R)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-

[0796] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0797] (4R)-5-[6-( 1 ,4-diazepan- 1 -y l)-4-( 1 , 1 -difluoropropyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0798] (4R)-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoroethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-cyclopropyl-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0799] (4S)-4-cy clopropyl-5-[4-( 1 , 1 -difluoropropyl)-6-[(3 S)-3 -methylpiperazin- 1 -y l ]py ri din-2-y l] - 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0800] (4R)-5-[4-(cyclopropyldifluoromethyl)-6-(1,4-diazepan-1-yl)pyridin-2-yl]-4-

[0801] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0802] (4R)-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoro-2-methylpropyl)pyridin-2-yl]-4-

[0803] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0804] 4-cyclopropyl-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoro-2-methylpropyl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0805] 4-cyclopropyl-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoro-2-methylpropyl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0806] (4R)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0807] (4R)-5-{4-[difluoro(phenyl)methyl]-6-(piperazin-1-yl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0808] (4R)-5-{4-[difluoro(phenyl)methyl]-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0809] (4R)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0810] 5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,3H,4H- pyrido[2,3-d]pyrimidin-2-one;

[0811] 4-{6-[2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}piperidin-2-one;

[0812] (4R)-5-(6-{octahydropyrrolo[3,4-b]morpholin-4-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0813] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0814] 5-(6-{octahydropyrrolo[3,4-b]morpholin-6-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-

[0815] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one; (4R)-5-[6-(piperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0816] (4R)-4-(trifluoromethyl)-5-[4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0817] (4R)-5-[6-(pyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0818] (4R)-5-[6-(pyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0819] (4R)-5-[6-(2,5-dihydro-1H-pyrrol-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0820] (4R)-4-(trifluoromethyl)-5-[4-(trifluoromethyl)- 1',2',5',6'-tetrahydro-[2,3'-bipyridine]-6-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0821] (4R)-5-[5'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluoromethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0822] (4R)-5-[3'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0823] (4R)-5-[3'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4-

[0824] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0825] (4R)-5-[3'-ethyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4-

[0826] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0827] (4R)-5-[3'-ethyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0828] (4R)-5-[2'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4-

[0829] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0830] (4R)-5-[2'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0831] (4S)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one; (4R)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0832] (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0833] (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0834] (4S)-5- { 6-[(3 S)-3 -methyl pi perazi n-1 -yl ]-4-(trifl uoromethyl )pyri di n-2-yl } -4- (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0835] (4S)-5-{6-[(2R)-2-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0836] (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0837] (4R)-5-{6-[(2R)-2-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0838] (4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0839] (4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;

[0840] 4-(l-fluorocyclopropyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;

[0841] (4S)-4-(l-fluorocyclopropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0842] 4-(l-fluorocyclopropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0843] (4S)-4-(fluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0844] (4R)-4-(fluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0845] 5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0846] 5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0847] (4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0848] (4S)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0849] (4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0850] (4S)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0851] (4S)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0852] (4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0853] (4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0854] (4R)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one;

[0855] 4-{6-[(4R)-4-(1,1-difluoroethyl)-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-5-yl]-4-

[0856] (trifluoromethyl)pyridin-2-yl}piperazin-2-one;

[0857] 5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2 -yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0858] 5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2 -yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; methyl 3-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}pyrrolidine-3 -carboxylate methyl 3-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4-

[0859] (trifluoromethyl)pyridin-2-yl}pyrrolidine-3 -carboxylate (4R)-5-{6-[3-(hydroxymethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0860] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0861] (4R)-5-{6-[3-(hydroxymethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0862] (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;

[0863] (4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(difluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0864] (4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0865] (4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;

[0866] (4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;

[0867] 5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0868] 5-{6-[3-(difluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0869] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0870] 5-{6-[3-(difluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-

[0871] (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0872] (4R)-5-[4-cyclopropyl-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;

[0873] 2-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-6-(piperazin-1- yl)pyridine-4-carbonitrile

[0874] (4R)-5-[4-ethyl-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0875] (4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;

[0876] (4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one; (4R)-4-(difluoromethyl)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0877] (4S)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrido[2, 3 - d] [ 1 , 3 ]oxazin-2-one;

[0878] (4R)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrido[2, 3 - d] [ 1 , 3 ]oxazin-2-one;

[0879] (4R)-4-(difluoromethyl)-5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;

[0880] (4R)-4-(1,1 -difluoroethyl)-5-[4-( 1 , 1 -difluoroethyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl]pyridin-2- yl ] - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;

[0881] (4S)-4-( 1 , 1 -difluoroethyl)-5-[4-(1,1 -difluoroethyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl]pyridin-2- yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0882] (4R)-4-(difluoromethyl)-5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2- yl } - 1H,2H,4H-pyrido[2, 3 -d] [ 1 , 3 ]oxazin-2-one;

[0883] (4R)-4-(difluoromethyl)-5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2- yl } - 1H,2H,4H-pyrido[2, 3 -d] [ 1 , 3 ]oxazin-2-one;

[0884] (4R)-5-[6-(3-fluoropiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;

[0885] (4R)-5-[6-(3-fluoropiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; or

[0886] (4R)-4-(1,1-difluoroethyl)-5-[2-(piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one.

[0887] In one embodiment, the invention provides a pharmaceutical composition comprising the compound of Formula I, and a pharmaceutically acceptable carrier.

[0888] In one embodiment, the invention provides a method of treating, preventing, or managing a disease or disorder mediated by a protein kinase C theta (PKC-theta), or PKC- theta mutant, in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutical composition comprising formula I.

[0889] In one embodiment, the invention provides for a method of treating, preventing, or managing a disease or disorder mediated by a protein kinase C theta (PKC-theta) or PKC theta mutant, in a subject, wherein the disease or disorder is an inflammatory disease, an autoimmune disorder, a cancer, an oncologic disease, or an autoimmune infection.

[0890] In one embodiment, the invention provides for a method of treating, preventing, or managing a disease or disorder mediated by a protein kinase C theta (PKC-theta) or PKC theta mutant, in a subject, wherein the disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, or atopic dermatitis.

[0891] These embodiments are not intended to limit the scope of the invention.

[0892] SYNTHETIC METHODS

[0893] The compounds of the invention may be prepared by the methods and examples presented below and by methods known to those of ordinary skill in the art. In each of the examples below, the R groups are as defined above for each formula unless noted. Optimum reaction conditions and reaction times may vary according to the reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art.

[0894] The intermediates used in the syntheses below are either commercially available or easily prepared by methods known to those skilled in the art. Reaction progress may be monitored by conventional methods such as thin-layer chromatography (TLC) or high- pressure liquid chromatography-mass spec (HPLC-MS). Intermediates and products may be purified by methods known in the art, including column chromatography, HPLC, preparative TLC or Preparatory HPLC Preparation of Intermediates

[0895] INT-1

[0896] 5-chloro-4-(tri fluoromethyl)-1,4-dihydro-2H-pyrido[2, 3-d] [1,3]oxazin-2-one tert-butyl (4-chloro-3-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)carbamate

[0897] To a solution of tert-butyl (4-chl oro-3 -formylpyri din-2 -yl)carbamate (1.0 g, 3.90 mmol) in DMF (10.36 ml) was added Trifluoromethyltrimethylsilane, 98%, 10g (1.152 ml, 7.79 mmol) at 25 °C under nitrogen atmosphere. Next, K2CO3(0.108 g, 0.779 mmol) was added. The reaction was stirred at 25 °C. LCMS after 2h, showed desired product. When completed, water was added and stirred at room temperature. The crude material was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure to give l-(4-amino-6-chloropyrimidin-5-yl)- 2,2,2-trifluoroethan-1-ol. LCMS (ESI, m / z): 326 [M+H]+.

[0898] INT-1

[0899] To a stirred solution of tert-butyl (4-chloro-3 -(2,2, 2-trifluoro-l -hydroxy ethyl)pyridin-2- yl)carbamate (1.273 g, 3.90 mmol) in EtOH (7.79 ml) was added Na2CO3(1.239 g, 11.69 mmol). The reaction was stirred at 60 °C. LCMS after 2h showed some starting material. So the reaction was stirred overnight. When completed, saturated aqueous NH4CI was added and extracted with DCM. The organic layers were dried over sodium sulfate and concentrated. Crude material was columned to (0-50% EtOAc / heptanes) give the title compound. LCMS (ESI, m / z): 253 [M+H]+. INT-2

[0900] (l-(4-methoxybenzyl)-2-oxo-4-(tri fluoromethyl)- 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)boronic acid

[0901] 5-chloro- 1 -(4-methoxybenzyl)-4-(trifluorom ethyl)- 1 ,4-dihydro-2H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-

[0902] 2-one

[0903] To an ice bath cooled solution of racemic 5-chloro-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one (500 mg, 1.980 mmol) in DMF (20 mL) was added sodium hydride (60% in mineral oil, 95 mg, 3.96 mmol) by one portion. The resulted mixture was stirred at this temp for 30 min before addition of 4-methoxybenzyl chloride (0.329 mL, 2.376 mmol). Reaction mixture was stirred at rt for 4 h and poured into ice-water, extracted with EtOAc. The separated organic layer was washed with brined, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by FCC (40 g silica gel cartridge, eluting with gradient 0-20% EtOAc-hexanes) to afford the desired product 5-chloro-1-(4- methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (690 mg) as an off-white viscous oil. RT: 1.06 min, M+H: 373.0.1H NMR (499 MHz, chloroform-d) δ 8.35 (d, J=5.4 Hz, 1H), 7.53 - 7.34 (m, 2H), 7.14 (d, J=5.5 Hz, 1H), 6.94 - 6.77 (m, 2H), 5.88 (q, J=6.2 Hz, 1H), 5.42 - 5.21 (m, 2H), 3.79 (s, 3H).19F NMR (470 MHz, chloroform-d) δ -77.41 (s, 3F).

[0904] INT-2

[0905] A red cap vial containing PdOAc2(12.05 mg, 0.054 mmol), XPhos (51.2 mg, 0.107 mmol), racemic 5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (200 mg, 0.537 mmol) and 1,4-dioxane (2 ml) was evacuated and backfilled with N2. Repeated this process twice. The reaction mixture was stirred at rt for 10 minutes (it became a tan solution) before addition of 1 M potassium trimethylacetate in MeOH (1.610 ml, 1.610 mmol) and hypodiboric acid (74.4 mg, 0.805 mmol) by 2 portions in 10 minutes. The reaction mixture was stirred at rt for additional 30 minutes and then poured into water (10 mL), extracted with EtOAc (5 mL). The separated organic layer was washed with brined, dried over MgSO4, filtered, evaporated in vacuo to afford the desired product racemic (l-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid ( 313 mg) as a tar. This material was taken into DCM (6 mL) and stored as stock solution for the next reaction. RT: 1.01 min, M+H: 382.7.

[0906] INT-3 tert-butyl 2-oxo-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-4H- pyrido[2,3 -d] [1,3 ]oxazine- 1 -carboxylate tert-butyl 5-chloro-2-oxo-4-(trifluoromethyl)-4H-pyrido[2, 3-d] [ 1,3] oxazine- 1 -carboxylate

[0907] To a solution of 5-chloro-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one (165 mg, 0.65 mmol) in dichloromethane (7 mL) were added Boc2O (572 mg, 2.62 mmol), TEA (253 mg, 1.96 mmol) and DMAP (15 mg, 0.13 mmol). The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (4: 1) to afford tert-butyl 5-chloro-2-oxo-4-(trifluoromethyl)-4H-pyrido[2,3 -d] [1 ,3]oxazine- 1 - carboxylate (185 mg, 80%) as a yellow solid. LCMS (ESI, m / z): 353, 355 [M+H]+.

[0908] INT-3 To a solution of tert-butyl 5-chloro-2-oxo-4-(trifluoromethyl)-4H-pyrido[2,3-d][1,3]oxazine- 1-carboxylate (150 mg, 0.43 mmol) in 1,4-dioxane (5 mL) were added B2pin2(162 mg, 0.64 mmol), KOAc (83 mg, 0.85 mmol) and Pd(dppf)Cl2(69 mg, 0.09 mmol). The resulting mixture was stirred at 100 °C for 1 d under nitrogen atmosphere. LCMS showed the reaction was completed. The crude was used in next step without further purification. LCMS (ESI, m / z): 445 [M+H]+.

[0909] INT-4

[0910] (R) -5-chloro-4-(trifluorom ethyl)- 1 ,4-dihydro-2H-pyrido[2,3 -d] [1,3 ]oxazin-2-one tert-butyl (4-chloro-3-(2,2,2-trifluoroacetyl)pyridin-2-yl)carbamate

[0911] To a solution of tert-butyl N-(4-chloro-2-pyridyl)carbamate (50 g, 220 mmol) in THF (1000 mL) was added dropwise n-Buli (2.5M in THF, 180 mL, 450 mmol) at -78 °C under nitrogen atmosphere. After 1 h, a solution of ethyl 2,2,2-trifluoroacetate (93 g, 656 mmol) was added dropwise the resulting mixture. The reaction mixture was stirred for 3 h at -78 °C. LCMS showed the reaction was completed. The reaction was then quenched with aqueous NH4CI (500 mL) and extracted with ethyl acetate (2000 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3 / 1) to give tert-butyl (4-chl oro-3 -(2,2,2- trifluoroacetyl)pyridin-2-yl)carbamate (51 g, 80%) as a light-yellow solid. LCMS (ESI, m / z): 325; 327 [M+H]+. tert-butyl (R)-(4-chloro-3-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)carbamate

[0912] To a solution of tert-butyl (4-chloro-3-(2,2,2-trifluoroacetyl)pyridin-2-yl)carbamate (50 g, 150 mmol) in DCE (1000 mL) was added FA:NEt3(5:2) (66 g, 150 mmol) and (R,R)-Ms- DENEB (880 mg, 1.54 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (2*500 mL) and extracted with DCM (1000 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (5 / 1) to give tertbutyl (R) -(4-chloro-3-(2,2,2-trifluoro-l -hydroxy ethyl)pyridin-2-yl)carbamate (40 g, 90%) as a pink solid. LCMS (ESI, m / z): 327; 329 [M+H]+.

[0913] INT-4

[0914] To a solution of tert-butyl (R)-(4-chloro-3 -(2,2, 2-trifluoro-l -hydroxy ethyl)pyridin-2- yl)carbamate (30 g, 91.83 mmol) in Toluene (600 mL) was added DIEA (48 mL, 275.48 mmol). The resulting mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2 / 1) to give (R) -5-chloro-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (20.719 g, 88%) as a pink solid.

[0915] LCMS (ESI, m / z): 253, 255 [M+H]+. Analytic Conditions: Column: HALO C18, 4.6*100 mm, 2.7 μm; Mobile Phase A: Water / 0.1% FA, Mobile Phase B: Acetonitrile / 0.1% FA; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B in 8.00 min, hold at 95% for 2.00 min; 254 nm; Rt: 3.595 min.1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.37 (d, J = 5.6 Hz, 1H), 6.59 (q, J = 6.8 Hz, 1H).

[0916] INT-5

[0917] (R) -5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d] [ 1 , 3 ]oxazin-2-one

[0918] To an ice bath cooled solution of (R)-5-chloro-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one (2.00 g, 7.92 mmol) in DMF (40 ml) was added NaH ( 60% in mineral oil, 0.443 g, 11.09 mmol) portionwise. After being stirred at this temp for 30 minutes, a premade solution of l-chloromethyl-4-methoxybenzene (1.20 ml, 8.71 mmol) in DMF (10 ml) was added dropwise via an addition funnel. The reaction mixture was stirred at this temp for 5 h and then quenched by iced NH4CI (aq. sat.), and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, then concentrated in vacuo. The residue was purified by FCC (80 g silica gel cartridge, eluted with gradient 0-20% EtOAc-Hexanes) to afford the desired product (R)-5-chl oro-1 -(4-methoxybenzyl)-4- (trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (2.21 g) as a colorless oil. RT: 1.06 min, [M+H]+: 373.0.1H NMR (499 MHz, chloroform-d) δ 8.35 (d, J=5.4 Hz, 1H), 7.53 - 7.34 (m, 2H), 7.14 (d, J=5.5 Hz, 1H), 6.94 - 6.77 (m, 2H), 5.88 (q, J=6.2 Hz, 1H), 5.42 - 5.21 (m, 2H), 3.79 (s, 3H).19F NMR (470 MHz, chloroform-d) δ -77.41 (s, 3F). Chiral purity: 100%. Conditions: Instrument: Agilent SFC1 Column: Chiralcel AS-3 150 X 4.6 mm ID, 3um Temp & Pressure: 400C / 140 Bar Flow rate: 3.0 mL / min Mobile Phase: A: CO2; B: methanol with 0.1% NH4OH. Time / min B 0 2 6 2 Detector Wavelength: 220 nm Injection Volume: 2 μL Sample Preparation: 1.0 mg / mL of the sample in Acetonitrile

[0919] INT-6

[0920] (R) -(l-(4-methoxybenzyl)-2-oxo-4-(tri fluoromethyl)- 1,4-dihydro-2H-pyrido[2, 3- d][1,3]oxazin-5-yl)boronic acid

[0921] To a solution of (R) -5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one (3.0 g, 8.05 mmol) in 1,4-dioxane (30 mL) were added Pd(OAc)2(181 mg, 0.80 mmol) and XPhos (766 mg, 1.61 mmol). The resulting mixture was stirred at room temperature for 15 min under nitrogen atmosphere. Then potassium pivalate (3.43 g, 24.15 mmol) and hypoboric acid (1.44 g, 16.1 mmol) were added. The reaction was stirred at room temperature for another 10 mins before the addition of another portion of hypoboric acid (1.44 g, 16.1 mmol). The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:3) to give (R) -(l-(4-methoxybenzyl)-2- oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)boronic acid (2.0359 g, 65%) as a brown solid.

[0922] LCMS (ESI, m / z): 383 [M+H]+. Analytic Conditions: Column: HALO 90A C18 Column 3.0*30 mm, 2.0 μm; Mobile Phase A: water / 0.05%TFA, Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 0.825 min.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 2H), 8.47 (d, J = 4.8 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.27-7.19 (m, 2H), 6.90-6.81 (m, 2H), 6.72-6.62 (m, 1H), 5.28 (d, J = 14.8 Hz, 1H), 5.13 (d, J = 14.8 Hz, 1H), 3.71 (s, 3H). INT-7

[0923] (R)-5-(6-chloro-4-(trifluoromethyl)pyri din-2 -yl)-4-(tri fluoromethyl)- 1,4-dihydro-214- pyrido[2, 3 -d] [ 1 , 3 ] oxazin-2-one

[0924] To a solution of bis(pinacolato)diboron (1.056 g, 4.16 mmol), (R)-5-chloro-4- (trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (1.0 g, 3.96 mmol) and potassium pivalate (1.666 g, 11.88 mmol) in dioxane (20.0 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (647 mg, 0.792 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 3h. Bronic acid intermediate was observed on LCMS. LCMS (ESI, m / z): 263 [M+H]+. The resulting reaction mixture was allowed to cooled down to rt. To the crude reaction mixture was added [1, 1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (258 mg, 0.396 mmol), cesium carbonate (3.87 g, 11.88 mmol) and 2,6-dichloro-4-(trifluoromethyl)pyridine (1.710 g, 7.92 mmol). The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. The crude reaction was concentrated and purified by column chromatography on silica gel with petroleum ether / ethyl acetate to afford title compound (300 mg). LCMS (ESI, m / z): 398.1 [M+H]+.

[0925] INT-8

[0926] 5-chloro-4-(trifluoromethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one

[0927] 1 -(4-amino-6-chloropyrimidin-5-yl)-2,2,2-trifluoroethan- 1 -ol

[0928] To a solution of 4-amino-6-chloropyrimidine-5-carbaldehyde (1 g, 6.35 mmol) in DMF (10.58 ml) was added Trifluoromethyltrimethylsilane, 98%, 10g (1.876 ml, 12.69 mmol) at 25 °C under nitrogen atmosphere. Next, K2CO3(0.175 g, 1.269 mmol) was added. The reaction was stirred at 25 °C. LCMS after Ih, showed desired product. When completed, water was added and stirred at room temperature. The crude material was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure to give l-(4-amino-6-chloropyrimidin-5-yl)- 2,2,2-trifluoroethan-1-ol. LCMS (ESI, m / z): 302 [M+H (SiMe3)]+.

[0929] INT-8

[0930] To a solution of l-(4-amino-6-chloropyrimidin-5-yl)-2,2,2-trifluoroethan-1-ol (1.444 g, 6.35 mmol)and DIEA (5.54 ml, 31.7 mmol) in THF (21.16 ml) was added triphosgene (5.65 g, 19.04 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C to room tempeature overnight. When completed, sat NaHCO3 was added and extracted with EtOAc. Crude material was column (0-100% ETOAc / heptanes) to 5-chloro-4-(trifluoromethyl)-1,4- dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one. LCMS (ESI, m / z): 253 [M+H]+.

[0931] INT-9

[0932] (R) -5-chloro-4-(tri fluoromethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one tert-butyl (6-chloro-5-(2,2,2-trifluoroacetyl)pyrimidin-4-yl)carbamate To a stirred solution of tert-butyl A-(6-chloropyrimidin-4-yl)carbamate (20 g, 87.09 mmol) in THF (500 mL) was added nBuLi (2.5 M in THF, 70 mL, 174.17 mmol) at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78°C. To the above mixture was added ethyl 2,2,2-trifluoroacetate (62 g, 435.43 mmol) at -78°C. The resulting mixture was stirred overnight at room temperature. The reaction was monitored by LCMS. The reaction was quenched by the addition of NH4Cl(aq.) at -30°C. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate. After filtrate, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc =2: 1) to obtained tert-butyl (6-chloro-5-(2,2,2-trifluoroacetyl)pyrimidin-4-yl)carbamate (11 g, 19.3%) as a light-yellow solid. LCMS (ESI, m / z): 326, 328 [M+H]+. tert-butyl (R) -(6-chloro-5-(2,2,2-trifluoro- 1 -hydroxy ethyl)pyrimidin-4-yl)carbamate

[0933] To a stirred solution of tert-butyl (6-chloro-5-(2,2,2-trifluoroacetyl)pyrimidin-4- yl)carbamate (11 g, 33.78 mmol) in DCE (150 mL) was added (A,R)-Ms-DENEB (192 mg, 0.34 mmol) and FA:NEt3(5:2, 14.59 g, 33.78 mmol) under nitrogen atmosphere. The mixture was stirred at room temperature overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc =1 : 1) to obtain tert-butyl (R)- (6-chloro-5-(2,2,2-trifluoro-l -hydroxy ethyl)pyrimidin-4-yl)carbamate (7 g, 63.2%) as a light-yellow solid. LCMS (ESI, m / z): 328, 330 [M+H]+.

[0934] INT-9

[0935] To a stirred solution of tert-butyl (R) -(6-chloro-5-(2,2,2-trifluoro-l -hydroxy ethyl)pyrimidin- 4-yl)carbamate (14 g, 42.72 mmol) in toluene (150 mL) was added A-ethyl-A- isopropylpropan-2-amine (5.5 g, 42.72 mmol). The mixture was stirred at 100° C for 3 h. LCMS showed the reaction was completed. The mixture was concentrated. The residue was purified by reverse phase flash (MeCN in water (10 mmol / L TFA), 0% to 100% gradient in 15 min; detector, UV 254 nm) to obtain (R) -5-chloro-4-(trifluoromethyl)-1,4-dihydro-2H- pyrimido[4,5-d][1,3]oxazin-2-one (10137 mg, 91.9%) as a yellow solid. LCMS (ESI, m / z): 254, 256 [M+H]+. Analytic Conditions: column: HALO C18, 3*30 mm, 2.0 μm; mobile phase A: water / 0.1%FA, mobile phase B: ACN / 0.1%FA; flow rate: 1.2000 mL / min; gradient: 5% B to 50% B in 1.7 min, 50% B to 100% B in 0.6 min, hold at 100% for 0.5 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.065 min.1H NMR (400 MHz, DMSO- d6) δ 12.23 (s, 1H), 8.79 (s, 1H), 6.68-6.64 (m, 1H).

[0936] INT-10

[0937] (R) -5-bromo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one

[0938] To a solution of (4R) -5-chloro-4-(trifluoromethyl)-1,4-dihydropyrimido[4,5-d][1,3]oxazin-2- one (800 mg, 3.15 mmol) in MeCN (30 mL) was added TMSBr (2.4 g, 15.7 mmol). The resulting solution was stirred at 80 °C for 16h. The reaction was monitored by LCMS. The resulting solution was concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: water (0.5% TFA), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 30% B to 90% B in 25 min; 254 / 210 nm) to afford (R)-5-bromo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (940 mg, 99.9%) as a yellow solid. LCMS (ESI, m / z): 298, 300 [M+H]+.

[0939] INT-11

[0940] 5-chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (4-chloro-3-(2,2-difluoroacetyl)pyridin-2-yl)carbamate

[0941] A mixture of tert-butyl (4-chloropyridin-2-yl)carbamate (250 mg, 1.093 mmol) and THF (5466 μl) was cooled to -78 °C on a dry ice / acetone bath for 5 minutes. A 1.6 M solution of n-butyllithium (1503 μl, 2.405 mmol) in hexanes was added dropwise. After addition was complete, the reaction mixture was stirred at -78 °C for 30 minutes. Methyl 2,2- difluoroacetate (361 mg, 3.28 mmol) was added dropwise. Following complete addition, the reaction was stirred at -78 °C for 1 hour. The reaction was quenched by the slow addition of methanol. The crude reaction mixture was concentrated onto silica gel and purified by flash chromatography (120g silica column, 0-100 % ethyl acetate in heptane gradient). The pure fractions were combined and concentrated under reduced pressure to give tert-butyl (4- chloro-3-(2,2-difluoroacetyl)pyridin-2-yl)carbamate (172 mg, 0.561 mmol, 51.3 % yield) as a white solid. LC / MS(ESI, m / z): 251 [M+H-56]+tert-butyl (4-chl oro-3 -(2, 2-difluoro-1-hydroxyethyl)pyri din-2 -yl)carbamate

[0942] Sodium borohydride (21.22 mg, 0.561 mmol) was added portionwise to a mixture of tertbutyl (4-chloro-3-(2,2-difluoroacetyl)pyridin-2-yl)carbamate (172 mg, 0.561 mmol) and MeOH (2804 μl), sodium borohydride (21.22 mg, 0.561 mmol) at room temperature. The reaction was stirred for 5 minutes. The reaction was concentrated in vacuo and the crude residue was purified by column chromatography (40g silica column, 0-100 % ethyl acetate in heptane) to give tert-butyl (4-chl oro-3 -(2, 2-difluoro-1-hydroxyethyl)pyri din-2 -yl)carbamate (71 mg, 0.230 mmol, 41.0 % yield) as a white powder. LC / MS(ESI, m / z): 309 [M+H]+

[0943] INT-11

[0944] A mixture of tert-butyl (4-chl oro-3 -(2, 2-difluoro-l -hydroxy ethyl)pyridin-2-yl)carbamate (71 mg, 0.230 mmol), ethanol (1150 μl), and sodium carbonate (48.8 mg, 0.460 mmol) was heated to 85 °C overnight. The reaction was filtered to remove excess salts and concentrated directly onto silica gel. The crude product was purified by flash chromatography (12g silica column, 0-100 % ethyl acetate in heptane). The pure fractions were concentrated to give 5- chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (28 mg, 0.119 mmol, 51.9 % yield) as a white solid. LC / MS(ESI, m / z): 235 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.29 (d, J=5.4 Hz, 1H), 7.31 (d, J=5.4 Hz, 1H), 6.47 (br t, J=53.1 Hz, 1H), 6.06 (td, J=13.1 , 1.9 Hz, 1H)

[0945] INT-12

[0946] (R) -5-chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl ( R)-(4-chl oro-3 -(2, 2-difluoro- l -hydroxy ethyl )pyri di n-2-yl)carbamate

[0947] The racemic tert-butyl (4-chloro-3-(2,2-difluoro-l -hydroxy ethyl)pyridin-2-yl)carbamate (1.0 g, 3.24 mmol) was resolved by Achiral-SFC with the following conditions: Column: Column: (R,R)-WHELK-O, 14.6x50mm, 3 μm; Mobile Phase B: MeOH(l%2M NH3- MeOH); Flow rate: 2 mL / min; Gradient: isocratic % B. The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford tert-butyl (R) -(4- chloro-3-(2,2-difluoro-1-hydroxyethyl)pyridin-2-yl)carbamate (the major isomer, 630 mg, 63%) as a brown solid. LCMS (ESI, m / z): 309, 311 [M+H]+.

[0948] INT-12

[0949] To a solution of tert-butyl (R)-(4-chl oro-3 -(2, 2-difluoro-l -hydroxy ethyl)pyridin-2- yl)carbamate (630 mg, 2.04 mmol) and DIPEA (0.35 mL, 2.04 mmol) in toluene (10 mL). The resulting mixture was stirred at 100 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (2x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3: 1) to give (R)-5-chloro-4-(difluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one (272.6 mg, 56%) as an off-white solid.

[0950] LCMS (ESI, m / z): 235 [M+H]+. Analytic Conditions: Column: HALO 90A C18 Column 3.0*30 mm, 2.0 μm; Mobile Phase A: water / 0.05%TFA, Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 10% B to 40% B in 1.70 min, 40% B to 95% B in 0.60 min, hold at 95% for 0.50 min, 95% B to 10% B in 0.03 min; 254 nm; Rt: 0.5057 min.1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.29 (d, J = 5.6 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H), 6.61-6.33 (m, 1H), 6.10-6.03 (m, 1H).

[0951] INT-13

[0952] (R)-(4-(difluoromethyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)boronic acid

[0953] To a solution of tert-butyl (2S)-4-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-2- pyridyl]-2-methyl-piperazine-1-carboxylate (150 mg, 0.64 mmol) in 1,4-dioxane (3 mL) were added B2pin2(649 mg, 2.56 mmol), KO Ac (126 mg, 1.27 mmol) and Pd(dppf)Cl2(51 mg, 0.06 mmol). The resulting mixture was stirred at 90 °C for 6 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was used in next step without further purification. LCMS (ESI, m / z): 245 [M+H]+.

[0954] INT-14

[0955] 5-chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (6-chloropyrimidin-4-yl)carbamate

[0956] N,N-dimethylpyridin-4-amine (0.472 g, 3.86 mmol) was added to a mixture of 6- chloropyrimidin-4-amine (5 g, 38.6 mmol), DCM (154 ml), and di-tert-butyl dicarbonate (9.86 ml, 42.5 mmol). The reaction was stirred for 30 minutes at room temperature. The suspension was filtered and the precipitate was washed with DCM to give tert-butyl (6- chloropyrimidin-4-yl)carbamate (3.546 g, 15.44 mmol, 40.0 % yield) as a white solid. The filtrate was concentrated in vacuo and the orange solid was suspended in DCM. A second precipitate was filtered and washed with DCM to give tert-butyl (6-chloropyrimidin-4- yl)carbamate (1.832 g, 7.98 mmol, 20.67 % yield). The two lots were combined after characterization. LC / MS(ESI, m / z): 230 [M+H]+tert-butyl (6-chloro-5-(2,2-difluoroacetyl)pyrimidin-4-yl)carbamate

[0957] A I M solution of 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex solution (6.10 ml, 6.10 mmol) was added to a mixture of tert-butyl (6- chloropyrimidin-4-yl)carbamate (.56 g, 2.438 mmol) and THF (12.19 ml). After addition, the reaction was stirred for 5 minutes at RT and then quenched with methyl 2,2-difluoroacetate (1.342 g, 12.19 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was acidified with acetic acid (0.363 ml, 6.34 mmol). The reaction was concentrated under reduced pressure and purified by flash chromatography to afford tert-butyl (6-chloro-5-(2,2- difluoroacetyl)pyrimidin-4-yl)carbamate (210 mg, 0.683 mmol, 28.0 % yield).

[0958] LC / MS(ESI, m / z): 308 [M+H]+1H NMR (400 MHz, CHLOROFORM-d) δ 8.71 (s, 1H), 7.77 (br s, 1H), 6.35 (br t, J=53.6 Hz, 1H), 1.53 (s, 9H) tert-butyl (6-chloro-5-(2,2-difluoro-l -hydroxy ethyl)pyrimidin-4-yl)carbamate

[0959] A mixture of tert-butyl (6-chloro-5-(2,2-difluoroacetyl)pyrimidin-4-yl)carbamate (210 mg, 0.683 mmol), (R,R)-Ms-DENEB (2.01 mg, 0.003 mmol), formic acid / triethylamine complex 5:2 (295 mg, 0.683 mmol), and DCE (1.37 ml) were heated to 28 °C for 24 h. The reaction was diluted with DCM and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted twice more with DCM. The combined organic layers were concentrated in vacuo and purified by flash chromatography to give tert-butyl (6- chloro-5-(2,2-difluoro-1-hydroxyethyl)pyrimidin-4-yl)carbamate (180 mg, 0.581 mmol, 85 % yield) as a white solid. LC / MS(ESI, m / z): 307 [M-H]- Chiral analysis of final product showed the material to have ee of 60% (R-isomer is major isomer).

[0960] INT-14

[0961] A mixture of tert-butyl (6-chloro-5-(2,2-difluoro-l -hydroxy ethyl)pyrimidin-4-yl)carbamate (180 mg, 0.581 mmol), toluene (1162 μl), and DIPEA (102 μl, 0.581 mmol) was heated to 80 °C overnight. 145 uL of 4 M HCl in dioxane was added. The reaction mixture was purified directly by flash chromatography (12g silica cartridge, 0-100% ethyl acetate in heptane, 50 ml / min) to afford the title compound (50 mg, 0.212 mmol, 36.5 % yield). LC / MS(ESI, m / z): 238 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) δ 8.72 (s, 1H), 7.75 (br s, 1H), 6.28 - 5.97 (m, 1H), 5.81 (td, J=12.3, 1.6 Hz, 1H)

[0962] INT-15

[0963] (R)-5-chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one

[0964] A red cap vial containing tert-butyl (R)-(6-chloro-5-(2,2-difluoro-l -hydroxy ethyl)pyrimidin- 4-yl)carbamate (100 mg, 0.323 mmol), 4-methylmorpholine (0.039 mL, 0.355 mmol) and DCE (2 mL) was sealed and heated at 80 °C for 8 h. Removed the volatiles with a steady stream of N2. The residue was taken up into EtOAc and washed 5% citric acid and brine, dried over MgSO4, filtered, evaporated in vacuo to afford the desired product (R)-5-chloro-4- (difluoromethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (64 mg) as an off-white solid. LC / MS(ESI, m / z): 236.0 [M+H]+.1H NMR (499 MHz, DMSO-d6) δ 11.91 (br s, 1H), 8.73 (s, 1H), 6.73 - 6.31 (m, 1H), 6.08 (td, J=12.9, 1.7 Hz, 1H).19F NMR (470 MHz, DMSO-d6) δ -128.51 - -132.42 (m, 2F).

[0965] INT-16

[0966] (R) -4-(difluoromethyl)-5-iodo-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one

[0967] To a 40 mL vial with stir bar was added (R)-5-chloro-4-(trifluoromethyl)-1,4-dihydro-2H- pyrimido[4,5-d][1,3]oxazin-2-one (500 mg, 1.972 mmol) and Sodium iodide (1478 mg, 9.86 mmol). Acetonitrile (6 mL) and Chlorotrimethylsilane (1.251 mL, 9.86 mmol) was added. The reaction was allowed to be stirred at room temp for 30 minutes. The reaction mixture was poured into a sodium bisulfate solution and extracted with EtOAc. The separated organic layer was dried over Na2SO4, filtered, and evaporated in vacuo to afford (R)-5-iodo- 4-(trifluoromethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one as the product.

[0968] INT-17

[0969] (R) -5-chloro-4-(difluoromethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one tert-butyl (S)-(6-chloro-5-(2,2-difluoro-l -hydroxy ethyl)pyrimidin-4-yl)carbamate 24 g (77.5 mmol) of tert-butyl (6-chloro-5-(2,2-difluoro-1-hydroxyethyl)pyrimidin-4- yl)carbamate was separated by chrial SFC (Chiral cel OD-H (5 X 25cm, 5 micron) ; CO2 (80%), IPA / ACN 50 :50 w / 0.1% NH4OH (20%), 340mL / min ; Stacked Injection(2.5 ml / 1.8min)) to give 17 g (54.9 mmol) of tert-butyl (R)-(6-chloro-5-(2,2-difluoro-1- hydroxyethyl)pyrimidin-4-yl)carbamate and 4 g (12.9 mmol) of tert-butyl (S)-(6-chloro-5- (2,2-difluoro- 1 -hydroxy ethyl)pyrimidin-4-yl)carbamate. tert-butyl (R) -(5-(l-azido-2,2-difluoroethyl)-6-chloropyrimidin-4-yl)carbamate

[0970] DBU (0.584 mL, 3.87 mmol) was added to a mixture of tert-butyl (S)-(6-chloro-5-(2,2- difluoro-1 -hydroxy ethyl)pyrimidin-4-yl)carbamate (1 g, 3.23 mmol), toluene (8 mL), and diphenyl phosphoryl azide (0.835 mL, 3.87 mmol) and stirred for 10 minutes.. The reaction was diluted in ethyl acetate and water. The layers were separated and the organic layer was concentrated in vacuo to give tert-butyl (R) -(5-(l-azido-2,2-difluoroethyl)-6-chloropyrimidin- 4-yl)carbamate (224 mg, 0.669 mmol, 20.73 % yield). Stereochemical inversion was assumed.

[0971] LC / MS(ESI, m / z): 278.7 [M+H-56]+

[0972] INT-17

[0973] A mixture of tert-butyl (R) -(5-(l-azido-2,2-difluoroethyl)-6-chloropyrimidin-4-yl)carbamate (225 mg, 0.672 mmol), triphenylphosphine (353 mg, 1.344 mmol), THF (5931 μl), and water (791 μl) was stirred ON at room temperature. The reaction was concentrated under reduced pressure. The residue was dissolved in DCM, and DBU (101 μl, 0.672 mmol) was added. The mixture was stirred for 3 hours of stirring at 40 °C. 3 mL of AcOH was added and the reaction was stirred ON at 40 °C. The precipitate was filtered and washed twice with DCM to give (R) -5-chloro-4-(difluoromethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (66 mg, 0.281 mmol, 41.9 % yield.1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.59 (s, 1H), 8.11 (d, J=3.4 Hz, 1H), 6.37 - 6.00 (m, 1H), 4.98 - 4.76 (m, 1H) LC / MS(ESI, m / z): 235 [M+H]+ INT-18

[0974] 5-chloro-4-( 1 , 1 -difluoroethyl)- 1 ,4-dihydropyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one tert-butyl (4-chloro-3-(2,2-difluoropropanoyl)pyridin-2-yl)carbamate

[0975] To a solution of tert-butyl (4-chloro-2-pyridyl)carbamate (2.0 g, 8.75 mmol) in THF (90 mL) was added nBuLi (2.5 M in THF, 7.0 mL, 17.5 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting solution was stirred at -78 °C for 0.5 h under nitrogen atmosphere. Then ethyl 2,2-difluoropropanoate (4.8 g, 34.9 mmol) in THF (10 mL) was added into the mixture at -78 °C. The resulting mixture was stirred at -50 °C for 1 h under nitrogen atmosphere. The reaction was then quenched by aqueous NH4CI (100 mL) at 0 °C and extracted with ethyl acetate (3x100 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated under vacuum at room temperature. The crude product was purified by column chromatography(petroleum ether / ethyl acetate = 3: 1) to afford tert-butyl (4-chloro-3-(2,2-difluoropropanoyl)pyridin-2- yl)carbamate(2 g, 71.3%) as a light-yellow solid. LCMS (ESI, m / z): 321, 323 [M+H]+tert-butyl (4-chl oro-3 -(2, 2-difluoro-1-hydroxypropyl)pyri din-2 -yl)carbamate

[0976] To a solution of tert-butyl N-[4-chloro-3-(2,2-difluoropropanoyl)-2-pyridyl]carbamate (600 mg, 1.871 mmol) sodium borohydride (212 mg, 5.61 mmol) was added slowly. The resulting solution was stirred at room temperature for 0.5 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was successful and confirmed by LCMS. Acetone (100 mL) was added in the reaction. The resulting solution was stirred at room temperature for 0.5 h under nitrogen atmosphere. The solution mixture was concentrated under vacuum. The crude product was used directly for next step without purification. LCMS (ESI, m / z): 323, 325 [M+H]+

[0977] INT-18

[0978] To a solution of tert-butyl (4-chloro-3-(2,2-difluoro-1-hydroxypropyl)pyridin-2-yl)carbamate (2 g, 6.2 mmol) in methanol (60 mL) was added K2CO3(5.1 g, 37.1 mmol) under nitrogen atmosphere. The resulting solution was stirred at 60 °C for 4h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 :2) to afford 5-chloro-4-(1,1-difluoroethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (1 g, 64.9%) as a white solid. LCMS (ESI, m / z): 249, 251 [M+H]+

[0979] INT-19, INT-20, & INT-21

[0980] 5-chloro-4-( 1 , 1 -difluoroethyl)- 1 ,4-dihydro-2H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one tert-butyl (6-chloro-5-(2,2-difluoropropanoyl)pyrimidin-4-yl)carbamate

[0981] To a solution of tert-butyl A-(6-chloropyrimidin-4-yl)carbamate (5.0 g, 21.77 mmol) in THF (500 mL) was added dropwise n-BuLi (2.5 M in THF, 18 mL, 43.54 mmol) at -78 °C under nitrogen atmosphere. After 30 min, a solution of ethyl 2,2-difluoropropanoate (3.0 g, 217.71 mmol) in THF was added dropwise the resulting mixture. The reaction mixture was stirred at -78 °C overnight and was allowed to warm to room temperature. The reaction was then quenched with aqueous NH4CI (700 mL) and extracted with ethyl acetate (3x500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to afford tert-butyl (6-chloro-5-(2,2- difluoropropanoyl)pyrimidin-4-yl)carbamate (3.0 g, 43%) as a yellow solid. LCMS (ESI, m / z): 322, 324 [M+H]+. tert-butyl (6-chloro-5-(2,2-difluoro-1-hydroxypropyl)pyrimidin-4-yl)carbamate

[0982] To a solution of tert-butyl (6-chloro-5-(2,2-difluoropropanoyl)pyrimidin-4-yl)carbamate (3.0 g, 9.34 mmol) in methanol (80 mL) was added NaBH4(710 mg, 18.68 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with acetone (10 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with dichloromethane / methanol (10: 1) to afford tert-butyl (6- chloro-5-(2,2-difluoro-1-hydroxypropyl)pyrimidin-4-yl)carbamate (1.4 g, 46%) as an orange solid. LCMS (ESI, m / z): 324 [M+H]+.

[0983] INT-19

[0984] To a solution of tert-butyl (6-chloro-5-(2,2-difluoro-1-hydroxypropyl)pyrimidin-4- yl)carbamate (1.4 g, 4.32 mmol) in toluene (30 mL) was added DIEA (1.67 g, 12.97 mmol) The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and the residue was quenched with water (300 mL) and extracted with ethyl acetate (3x200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (4: 1) to afford 5-chloro-4- (1,1-difluoroethyl)-1,4-dihydropyrimido[4,5-d][1,3]oxazin-2-one (1.0 g, 92%) (racemate) as a white solid. LCMS (ESI, m / z): 250, 252 [M+H]+.

[0985] INT-20 and INT-21

[0986] The racemate of 5-chloro-4-(1,1-difluoroethyl)-1,4-dihydropyrimido[4,5-d][1,3]oxazin-2-one (1.0 g, 4.00 mmol) was resolved by chiral-SFC (Column: CHIRALPAK IH 3x25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (l%-2M-NH3-MeOH); Flow rate: 90 mL / min; Gradient: isocratic 16% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 3.25; RT2(min): 4.1) to afford the (S)-5-chloro-4-(1,1- difluoroethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (the first eluting peak, 350.0 mg, 35%) and the (R)-5-chloro-4-(1,1-difluoroethyl)-1,4-dihydro-2H-pyrimido[4,5- d][1,3]oxazin-2-one (the second eluting peak, 350.0 mg, 35%) both as white solid.

[0987] LCMS (ESI, m / z): 250 [M+H]+. Analytic Conditions: column: HALO 90A C18, 3.0*30 mm, 2.0 μm; mobile phase A: water (0.05%TFA), mobile phase B: acetonitrile (0.05%TFA); flow rate: 1.50 mL / min; gradient: 5% B to 40% B in 1.70 min, 40% B to 95% B in 0.60 min, hold at 95% for 0.50 min, 95% B to 5% B in 0.03 min; 254 nm; RT: 1.151 min. LCMS (ESI, m / z): 250 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.65 (s, 1H), 5.93 (dd, J = 19.2, 4.4 Hz, 1H), 1.82 (t, J = 19.6 Hz„ 3H).

[0988] INT-22

[0989] (R)-5-bromo-4-( 1 , 1 -difluoroethyl)- 1 ,4-dihydro-2H-pyrimido[4,5-d] [1,3 ]oxazin-2-one

[0990] To a solution of (R)-5-chloro-4-(1,1-difluoroethyl)-1,4-dihydro-2H-pyrimido[4,5- d][1,3]oxazin-2-one (220 mg, 0.88 mmol) in acetone (5 mL) was added TMSBr (669 mg, 4.41 mmol). The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2: 1) to afford (R)-5-bromo-4-(1,1-difluoroethyl)-1,4-dihydro-2H- pyrimido[4,5-d][1,3]oxazin-2-one (230 mg, 88%) as an off-white solid. LCMS (ESI, m / z): 294, 296 [M+H]+.

[0991] INT-23 tert-butyl ( 4-chloro-3-(l -hydroxyethyl)pyridin-2-yl)carbamate

[0992] To a mixture of tert-butyl (4-chl oro-3 -formylpyridin-2-yl)carbamate (105 mg, 0.409 mmol) in THF (4.1 mL) at -20 °C was added 3M MeMgBr in MeTHF (0.3 mL, 0.9 mmol). The mixture was stirred at -20 °C for 1 h and then warmed up to rt. The reaction was quenched by addition of water and extracted with EtOAc, and the crude title compound was used directly in the next step without further purification. LCMS (ESI, m / z): 217 [M+H-tBu]+

[0993] INT-24 tert-butyl 5-chloro-4-methyl-2-oxo-4H-pyrido[2,3-d][1,3]oxazine-l -carboxylate

[0994] To a stirred solution of 5-chloro-4-methyl-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one (700 mg, 3.52 mmol) in dichloromethane (30 mL) were added triethylamine (1.78 g, 17.62 mmol) and di-tert-butyl dicarbonate (1.15 g, 5.29 mmol) under nitrogen atmosphere. The mixture was stirred at room temperature for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The mixture was quenched with water (30 mL), extracted with di chloromethane (3x30 mL). The organic layer was dried over sodium sulphate and concentrated. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (5: 1) to obtain tert-butyl 5-chloro-4-methyl-2-oxo-4H-pyrido[2,3- d][1,3]oxazine-1-carboxylate (1 g, 94.9%) as colorless oil. LCMS (ESI, m / z): 299, 301 [M+H]+.

[0995] INT-25 tert-butyl (S)-5-chloro-4-methyl-2-oxo-2H-pyrido[2,3-d][1,3]oxazine-l(4H)-carboxylate

[0996] 5-chloro-4-methyl-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one

[0997] INT-25

[0998] To a crude 5-chloro-4-methyl-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one in DCM (20 mL) was added Boc2O (6.38 g, 29.2 mmol), TEA (13.56 mL, 97 mmol) and DMAP (2.38 G, 19.5 mmol) . The resulting mixture was stirred at rt for 3h . Then the reaction was quenched with water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The crude was purified by silica gel column.

[0999] The racemate of tert-butyl 5-chloro-4-methyl-2-oxo-2H-pyrido[2,3-d][1,3]oxazine-l(4H)- carboxylate was resolved by chiral-SFC (Chiralpak AD-H, 30 mm x 250 mm, 5 μm particles; Flow Rate: 90 mL / min; Column Temperature: 45 °C. Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% Ammonium hydroxide); Fraction collection was triggered by UV (220 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation. RTl(min): 5.1; RT2(min): 6.2) to afford the tert-butyl (S)-5-chloro-4-methyl-2- oxo-2H-pyrido[2,3-d][1,3]oxazine-l(4H)-carboxylate (the first eluting peak, 558.3 mg) and the tert-butyl (R)-5-chloro-4-methyl-2-oxo-2H-pyrido[2,3-d][1,3]oxazine-l(4H)-carboxylate (the second eluting peak, 458.1 mg) both as white solid. LCMS (ESI, m / z): 199.1 [M- Boc+H]+.

[1000] INT-26

[1001] 5-chloro-4-ethyl-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one

[1002] Prepared in same manner as 5-chloro-4-cyclopropyl-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one. LC / MS(ESI, m / z) 213.3, 215.3 [M+H]+.

[1003] INT-27

[1004] 5-chloro-4-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one

[1005] 1 -(4-amino-6-chloropyrimidin-5-yl)propan- 1 -ol A solution of 4-amino-6-chloropyrimidine-5-carbaldehyde (0.158 g, 1.00 mmol) in THF (5.00 ml) was cooled to -40 °C then treated with ethylmagnesium bromide (1.000 ml, 3.00 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was then diluted with aq. NH4CI and extracted with DCM. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was used as is in the next step without further purification. LCMS (ESI, m / z): 188 [M+H]+

[1006] INT-27

[1007] A stirring mixture of l-(4-amino-6-chloropyrimidin-5-yl)propan-1-ol (188 mg, 1.002 mmol), and DIPEA (875 μl, 5.01 mmol) in THF (5010 μl) was cooled to 0 C then treated with triphosgene (892 mg, 3.01 mmol). The resulting mixture was stirred at 0 °C for 16 h. The crude mixture was purified via flash column chromatography (silica gel, 0-50% EtOAc in hexanes) to afford the title compound. LCMS (ESI, m / z): 211.8 [M-H]-

[1008] INT-28

[1009] (S)-5-chloro-4-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one

[1010] 5-chloro-4-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one was purified via preparative SFC chromatography with the following conditions: Column: Chiralpak AD-H, 30 mm x 250 mm, 5 μm particles; Flow Rate: 90 mL / min; Column Temperature: 35 °C. 10 min run; 80% CO2 / 20% IPA (with 0.1% diethylamine). First eluting isomer. LC / MS(ESI, m / z) 214.0, 216.0 [M+H]+.

[1011] INT-29

[1012] 5-chloro-4-isopropyl-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (4-chloro-3-(l-hydroxy-2-methylpropyl)pyridin-2-yl)carbamate

[1013] To a solution of tert-butyl (4-chl oro-3 -formylpyri din-2 -yl)carbamate (500 mg, 1.948 mmol) in THF (3068 μl) was added isopropylmagnesium chloride (1948 μl, 3.90 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 2h. LCMS after 2h showed SM. So the reaction was stirred overnight at room temperture. When completed, saturated aqueous NH4CI was added and extracted with EtOAc (3x 20mL).The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure. Crude material was columned (0-50% EtOAc / Heptanes). Crude material was columned to give tert-butyl (4-chloro-3-(l-hydroxy-2-methylpropyl)pyridin-2- yl)carbamate (0.219 g, 0.728 mmol, 37.4 % yield). LCMS (ESI, m / z): 201 [M+H]+.

[1014] INT-29

[1015] To a stirred solution of tert-butyl (4-chloro-3-(l-hydroxy-2-methylpropyl)pyridin-2- yl)carbamate ( 0.219 g, 0.728 mmol) in EtOH (3.64 ml) was added Na2CO3(0.617 g, 5.82 mmol). The reaction was stirred at 60 °C. LCMS after 2h showed some starting material. So the reaction was stirred overnight. When completed, saturated aqueous NH4CI was added and extracted with DCM. The organic layers were dried over sodium sulfate and concentrated. Crude material was columned to (0-50% EtOAc / heptanes) give 5-chloro-4-isopropyl-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one. LCMS (ESI, m / z): 227 [M+H]+.

[1016] INT-30

[1017] 5-chloro-4-propyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one l-(4-amino-6-chloropyrimidin-5-yl)butan-1-ol

[1018] To a solution of 4-amino-6-chloropyrimidine-5-carbaldehyde (1 g, 6.35 mmol) in THF (10 mL) was added propylmagnesium chloride (9.52 ml, 19.04 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 2h. LCMS after 2h showed some starting material. So the reaction was stirred overnight at rt. When completed, saturated aqueous NH4CI was added and extracted with EtOAc.The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure to give l-(4- amino-6-chloropyrimidin-5-yl)butan-1-ol. LCMS (ESI, m / z): 202 [M+H]+.

[1019] INT-30

[1020] To a solution of l-(4-amino-6-chloropyrimidin-5-yl)butan-1-ol (1.28 g, 6.35 mmol) and DIEA (5.54 ml, 31.7 mmol) in THF (21.16 ml) was added triphosgene (5.65 g, 19.04 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C to room tempeature overnight. When completed, sat NaHCO3 was added and extracted with EtOAc. Crude material was column (0-100% EtOAc / heptanes) to give 5-chloro-4-propyl-1,4-dihydro-2H- pyrimido[4,5-d][1,3]oxazin-2-one. LCMS (ESI, m / z): 228 [M+H]+.

[1021] INT-31

[1022] 5-chloro-4-cyclopropyl-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (4-chloro-3-(cyclopropyl(hydroxy)methyl)pyridin-2-yl)carbamate To a roundbottom was added tert-butyl (4-chl oro-3 -formylpyri din-2 -yl)carbamate (500 mg, 1.948 mmol) and THF (3068 μl). Next, the roundbottom was cooled to 0 °C, and cyclopropylmagnesium chloride (7792 μl, 3.90 mmol) was added. The reaction was stirred at 0 °C overnight. The reaction mixture was added to sat NH4C1 and extracted with DCM. Crude material was columned (0-100% Hex:EtOAC) to give tert-butyl (4-chloro-3- (cyclopropyl(hydroxy)methyl)pyridin-2-yl)carbamate (293 mg, 0.981 mmol, 50.3 % yield).

[1023] INT-31

[1024] To a vial was added tert-butyl (4-chloro-3-(cyclopropyl(hydroxy)methyl)pyridin-2- yl)carbamate (0.293 g, 0.981 mmol) and EtOH (4.90 ml). Na2CO3(0.520 g, 4.90 mmol) was added and the reaction was stirred at 60 °C overnight. The reaction mixture was added to sat NH4CI and extracted with DCM Crude material was columned to give the title compound. LCMS (ESI, m / z): 225.2 [M+H]+.

[1025] INT-32

[1026] 5-chloro-4-cyclopropyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one tert-butyl (6-chloro-5-(cyclopropyl(hydroxy)methyl)pyrimidin-4-yl)carbamate

[1027] To a solution of tert-butyl A-(6-chloropyrimidin-4-yl)carbamate (6.0 g, 26.13 mmol) in dry THF (40 mL) was added dropwise LDA (2M in THF, 26.1 mL, 52.26 mmol) at -78 °C under nitrogen atmosphere. After 30 min, a solution of cyclopropanecarbaldehyde (9256 mg, 130.65 mmol) in THF (20 mL) was added dropwise to the resulting mixture at -78 °C. The reaction mixture was stirred at -78 °C for 2h and allowed to warm to room temperature and stirred for another 8h. The reaction was diluted with saturated aqueous NH4CI (200 mL) and extracted with EtOAc(3xl00 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (6-chloro-5-(cyclopropyl(hydroxy)methyl)pyrimidin-4-yl)carbamate (1.66 g, 21%) as a yellow solid. LCMS (ESI, m / z): 300, 302 [M+H]+.

[1028] INT-32

[1029] A solution of tert-butyl (6-chloro-5-(cyclopropyl(hydroxy)methyl)pyrimidin-4-yl)carbamate (1.55 g, 5.17 mmol) and DIPEA (1.8 mL, 10.34 mmol) in toluene (20 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (1 : 1) to give 5-chloro-4-cyclopropyl-1,4- dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (1.08 g, 92%) as an off-white solid.

[1030] LCMS (ESI, m / z): 226 [M+H]+. Analytic Conditions: Column: HALO 90A C18 Column 4.6*100 mm, 2.7 μm; Mobile Phase A: water / 0.05%TFA, Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B in 8.00 min, hold at 95% for 2.00 min; 254 nm; Rt: 2.921 min.1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.66 (s, 1H), 5.16 (d, J = 8.4 Hz, 1H), 1.42-1.30 (m, 1H), 0.69-0.59 (m, 3H), 0.57-0.46 (m, 1H).

[1031] INT-33

[1032] 5-chloro-4-cyclobutyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one

[1033] To a solution of (4-amino-6-chloro-pyrimidin-5-yl)-cyclobutyl-methanol (150 mg, 0.70 mmol), triphosgen (625 mg, 2.11 mmol) and DIEA (453 mg, 3.51) in THF (5 mL). The resulting mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (5 / 1) to give 5-chloro-4- cyclobutyl-1,4-dihydropyrimido[4,5-d][1,3]oxazin-2-one (40 mg, 23%) as a yellow solid. LCMS (ESI, m / z): 240, 242 [M+H]+.

[1034] INT-34

[1035] 5-chloro-4-( 1 -fluorocyclopropyl)- 1 ,4-dihydro-2H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one tert-butyl (4-chloro-3-(l -fluorocyclopropane- l-carbonyl)pyridin-2-yl)carbamate

[1036] To a solution of tert-butyl (4-chloropyridin-2-yl)carbamate (400 mg, 1.75 mmol) in THF (4 mL) was added nBuLi (1.6 M in hexane, 2.40 mL, 3.85 mmol) at -78 °C. The reaction mixture was stirred at -78°C for 0.5 h. Then methyl 1 -fluorocyclopropane- 1 -carboxylate (516 mg, 4.37 mmol) was added slowly to the reaction at -78°C. The resulting mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with MeOH (0.2 mL) and 1.0 M HCl (10 mL). The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (2x300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound (260 mg). LCMS (ESI, m / z): 259 [M+H]+.

[1037] INT-34

[1038] To a solution of tert-butyl (4-chloro-3-(l -fluorocyclopropane- l-carbonyl)pyri din-2- yl)carbamate (240 mg, 0.763 mmol) in methanol (4 mL) was added NaBH4 (87 mg, 2.3 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 h. Then to the reaction mixture was added potassium carbonate (527 mg, 3.81 mmol), the reaction mixture was heated to 60 °C for 6 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (150 mg). The product was used in the next step directly without further purification. LCMS (ESI, m / z): 243 [M+H]+.

[1039] INT-35 5-chloro-4-(l -fluoroethyl)- 1,4-dihydro-2H-pyrido[2, 3-d] [1,3]oxazin-2-one

[1040] Prepared in an similar manner as INT-34 using ethyl 2-fluoropropanoate as a starting material instead of 1 -fluorocyclopropane- 1 -carboxylate. The product (220 mg) was used in the next step directly without further purification. LCMS (ESI, m / z): 231 [M+H]+. INT-36

[1041] 5-chloro-4-( 1 -fluoroethyl)- 1 ,4-dihydro-2H-pyrimido[4,5-d] [1,3 ]oxazin-2-one

[1042] Prepared in an similar manner as INT-34 using ethyl 2-fluoropropanoate and tert-butyl (6- chloropyrimidin-4-yl)carbamate as a starting material instead of 1 -fluorocyclopropane- 1- carboxylate and tert-butyl (4-chloropyri din-2 -yl)carbamate. The product (160mg) was used in the next step directly without further purification. LCMS (ESI, m / z): 232 [M+H]+.

[1043] INT-37

[1044] 5-chloro-4-(1,1 -difluoropropyl)- 1 ,4-dihydro-2H-pyrido[2,3 -d] [1,3 ]oxazin-2-one tert-butyl (4-chloro-3-(2,2-difluorobutanoyl)pyridin-2-yl)carbamate

[1045] To a solution of tert-butyl N-(4-chloro-2-pyridyl)carbamate (2.0 g, 8.75 mmol) in THF (30 mL) was added nBuLi (2M in THF, 8.7 mL, 17.49 mmol) at -78 °C. The reaction mixture was stirred at -78°C for 0.5 h under nitrogen atmosphere. Then ethyl 2,2-difluorobutanoate (5.32 g, 35 mmol) in THF (5 mL) was added slowly to the reaction at -78°C. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2 / 1) to give tert-butyl N-[4-chloro-3-(2,2-difluorobutanoyl)-2- pyridyl]carbamate (1400 mg, 48%) as a white solid. LCMS (ESI, m / z): 335, 337 [M+H]+. tert-butyl (4-chloro-3-(2,2-difluoro-1-hydroxybutyl)pyridin-2-yl)carbamate

[1046] To a solution of tert-butyl N-[4-chloro-3-(2,2-difluorobutanoyl)-2-pyridyl]carbamate (1.40 g, 4.18 mmol) in methanol (15 mL) was added NaBH4(475 mg, 12.55 mmol) at 0°C. The reaction mixture was stirred at room temperature for 0.5 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction crude was used in the next step directly without further purification. LCMS (ESI, m / z): 337 [M+H]+.

[1047] INT-37

[1048] To the reaction mixture from previous step was added K2CO3(2.87 g, 20.79 mmol). The reaction mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (4 / 1) to give 5-chloro-4-(1,1-difluoropropyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-2- one (1 g, 92%) as a light-yellow oil. LCMS (ESI, m / z): 263, 265 [M+H]+.

[1049] INT-38

[1050] 5-chloro-4-(cyclopropyldifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (4-chloro-3-(2-cyclopropyl-2,2-difluoroacetyl)pyridin-2-yl)carbamate

[1051] Boc

[1052] To a solution of tert-butyl N-(4-chloro-2-pyridyl)carbamate (400 mg, 1.75 mmol) in dry THF (2 mL) was added n-BuLi (1.4 mL, 2M in THF) at -78 °C under an argon atmosphere, and the reaction mixture was stirred at this temperature for 30 min. Then a solution of ethyl 2- cyclopropyl-2,2-difluoro-acetate (1.15 g, 7.00 mmol) in dry THF (2.0 mL) was added at - 78 °C and the mixture stirred for further 2h. LCMS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2: 1) to give tert- butyl N-[4-chloro-3-(2-cyclopropyl-2,2-difluoro-acetyl)-2-pyridyl]carbamate (440 mg, 43%) as a yellow solid. LCMS (ESI, m / z): 347, 349 [M+H]+. tert-butyl (4-chloro-3-(2-cyclopropyl-2,2-difluoro-1-hydroxyethyl)pyridin-2-yl)carbamate

[1053] To a solution of tert-butyl N-[4-chloro-3-(2-cyclopropyl-2,2-difluoro-acetyl)-2- pyridyl]carbamate (400 mg, 1.15 mmol) in methanol (5 mL) was added NaBH4(131 mg, 3.46 mmol). The resulting solution was stirred for 15 min at room temperature. LCMS showed the reaction was completed. The reaction mixture was directly used for next step without further purification. LCMS (ESI, m / z): 349 [M+H]+.

[1054] INT-38

[1055] To the reaction mixture from previous step was added K2CO3(475 mg, 3.44 mmol) in methanol (2.0 mL). The resulting mixture was stirred at 60 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2: 1) to give 5-chloro-4-[cyclopropyl(difluoro)methyl]-1,4-dihydropyrido[2,3- d][1,3]oxazin-2-one (190 mg, 60%) as a yellow solid. LCMS (ESI, m / z): 275, 277 [M+H]+.

[1056] INT-39

[1057] 5-chloro-4-(hydroxymethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (4-chl oro-3 -vinylpyri din-2 -yl)carbamate To a solution of potassium tert-butoxide (0.787 g, 7.01 mmol) in THF (15 mL) was added methyltriphenylphosphonium bromide (2.227 g, 6.23 mmol) at 22 °C. The resulting mixture was stirred for 10 min. Then tert-butyl (4-chloro-3-formylpyridin-2-yl)carbamate (1g, 3.90 mmol) was added to the reaction mixture and stirred at 22 °C for 3h. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (720 mg). LCMS (ESI, m / z): 255.2 [M+H]+.

[1058] INT-39

[1059] To a solution of tert-butyl (4-chloro-3-vinylpyridin-2-yl)carbamate (300 mg, 1.18 mmol) in tBuOH (2 mL) and H2O (2 mL) was added NMO (414 mg, 3.53 mmol), potassium osmate dihydrate (43.4 mg, 0.118 mmol). The resulting mixture was stirred at 22 °C ON. The crude reaction was concentrated and purified by column chromatography on silica gel with petroleum ether / ethyl acetate to afford title compound (30 mg). LCMS (ESI, m / z): 215.0 [M+H]+.

[1060] INT-40

[1061] 5-chloro-4-methyl-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one tert-butyl (4-chloro-3-(l-hydroxyethyl)pyridin-2-yl)carbamate

[1062] To a solution of tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate (1.0 g, 3.9 mmol) in THF (5 mL) was added Methylmagnesium bromide solution (3M, 2.60 mL, 7.79 mmol) at 0 °C. The resulting mixture was stirred for 15 min. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (1.0 g). LCMS (ESI, m / z): 217.1 [M+H]+ . tert-butyl (3-(l-azidoethyl)-4-chloropyridin-2-yl)carbamate

[1063] To a solution of tert-butyl (4-chl oro-3 -(l-hydroxyethyl)pyri din-2 -yl)carbamate (1g, 3.67 mmol) in PhCH3 (8 mL) was added DBU (0.663 mL, 4.40 mmol) and diphenyl phosphoryl azide (0.948 mL, 4.40 mmol) at 0 °C. The resulting mixture was stirred at rt ON. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (800 mg). LCMS (ESI, m / z): 242 [M+H]+ .

[1064] INT-40

[1065] To a solution of tert-butyl (3-(l-azidoethyl)-4-chloropyridin-2-yl)carbamate (500 mg, 1.18 mmol) in THF (15 mL) and H2O (2 mL) was added triphenylphosphine (0.881 g, 3.36 mmol). The resulting mixture was stirred at 22 °C ON . The reaction mixture was added water and extracted with EA. The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The crude residue was added 4 mL acetic acid and the reaction mixture was allowed to be stirred at 60 °C for 2h. The crude reaction was concentrated and purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (160 mg). LCMS (ESI, m / z): 198.1 [M+H]+.

[1066] INT-41

[1067] 5-chl oro-3, 4-dimethyl-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one tert-butyl (4-chloro-3-(l-(methylamino)ethyl)pyri din-2 -yl)carbamate

[1068] To a solution of tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate (1000 mg, 3.90 mmol) in DCM (20 mL) was added methylamine solution (2M in THF, 3.90 mL, 7.79 mmol) at 22 °C. The resulting mixture was stirred ON. Then reaction mixture was concentrated and the crude reaction was dissolved in THF (10 mL) and cooled down to 0 °C. Methylmagnesium bromide solution in dibutyl ether (3M, 2.60 mL, 7.79 mmol) was added to the reaction mixture and the reaction mixture was stirred at 0 °C for 3h. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (210 mg). LCMS (ESI, m / z): 230.2 [M+H]+ .

[1069] INT-41

[1070] To a solution of tert-butyl (4-chl oro-3 -(l-(methylamino)ethyl)pyri din-2 -yl)carbamate (100 mg, 0.350 mmol) in DMF (2 mL) was added K2CO3 (97 mg, 0.700 mmol). The resulting mixture was stirred at 130 °C for 2h . The crude reaction was concentrated and purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (50 mg). LCMS (ESI, m / z): 212.1 [M+H]+.

[1071] INT-42

[1072] 5-chloro-4-(fluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one

[1073] Prepared in an similar manner as INT-34 using methyl 2-fluoroacetate as a starting material instead of 1 -fluorocyclopropane- 1 -carboxylate. The product (80 mg) was used in the next step directly without further purification. LCMS (ESI, m / z): 217 [M+H]+.

[1074] INT-43

[1075] 5-chloro-4-(trifluoromethyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one tert-butyl (4-chloro-3-(2,2,2-trifluoro-l -hydroxy ethyl)pyridin-2-yl)carbamate To a solution of tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate (1.0 g, 3.90 mmol) in DMF (4 mL) was added trimethyl(trifluoromethyl)silane (2.303 ml, 15.58 mmol) and K2CO3 (108 mg, 0.779 mmol) at 0 °C. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (1.0 g). LCMS (ESI, m / z): 271 [M+H]+ . tert-butyl (3-(l-azido-2,2,2-trifluoroethyl)-4-chloropyridin-2-yl)carbamate Prepared in an similar manner as tert-butyl (3-(l-azidoethyl)-4-chloropyridin-2-yl)carbamate using tert-butyl (4-chloro-3-(2,2,2-trifluoro-l -hydroxy ethyl)pyridin-2-yl)carbamate as a starting material instead of tert-butyl (4-chloro-3-(l-hydroxyethyl)pyridin-2-yl)carbamate to afford the title compound (900 mg). LCMS (ESI, m / z): 296.1 [M+H]+.

[1076] INT-43

[1077] Prepared in an similar manner as INT-40 using tert-butyl (3-(l-azido-2,2,2-trifluoroethyl)-4- chloropyridin-2-yl)carbamate as a starting material instead of tert-butyl (3-(l-azidoethyl)-4- chloropyridin-2-yl)carbamate to afford the title compound (210 mg). LCMS (ESI, m / z): 252.0 [M+H]+.

[1078] INT-44

[1079] 5-chl oro-4, 4-dimethyl-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one

[1080] To a solution of tert-Butyl 2-{[(tert-butoxy)carbonyl]amino}-4-chloropyridine-3-carboxylate (500 mg, 1.521 mmol) in THF (5 mL) was added methylmagnesium bromide solution in dibutyl ether (3M, 1267 μl, 3.80 mmol) at 0 °C. The resulting mixture was allowed to be warmed up to rt. Then the reactionw as heated to 40 °C for 2h. The reaction mixture was concentrated down and dissolved in EtOH (3 mL). Na2CO3 (322 mg, 3.04 mmol) was added to the resulting mixture. Then the reaction mixture was heated at 60 °C for 2h. The resulting reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (66 mg). LCMS (ESI, m / z): 213.1 [M+H]+ . INT-45

[1081] (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(1,1-difluoroethyl)pyridin-2-yl)boronic acid

[1082] To a solution of tert-butyl 4-(6-chloro-4-(1,1-difluoroethyl)pyridin-2-yl)piperazine-1- carboxylate (300 mg, 0.83 mmol) and B2pin2(421 mg, 1.66 mmol) in 1,4-dioxane (4 mL), were added Pd(dppf)Cl2(68 mg, 0.08 mmol) and KOAc (244 mg, 2.49 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was used directly for next step without purification. LCMS (ESI, m / z): 372 [M+H]+

[1083] INT-46 tert-butyl (S)-4-(6-chloro-4-(1,1-difluoro-2-m ethoxy ethyl)pyri din-2 -yl)-2-methylpiperazine- 1 -carboxylate

[1084] A solution of 2,6-dichloro-4-(1,1-difluoro-2-methoxy-ethyl)pyridine (500 mg, 2.07 mmol), tert-butyl (2S)-2-methylpiperazine-l -carboxylate (414 mg, 2.07 mmol) and K2CO3(855 mg, 6.20 mmol) in DMSO (5 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere.

[1085] LCMS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2: 1) to give tert-butyl (2S)-4-[6-chloro-4-(1,1-difluoro-2- methoxy-ethyl)-2-pyridyl]-2-methyl-piperazine-1-carboxylate (650 mg, 77%) as a colorless oil. LCMS (ESI, m / z): 406, 408 [M+H]+. INT-47 tert-butyl 4-(6-chloro-4-(1,1-difluoropropyl)pyridin-2-yl)piperazine-l -carboxylate l-(2,6-dichloropyridin-4-yl)propan-1-one

[1086] To a solution of 2,6-dichloro-N-methoxy-N-methylisonicotinamide (470 mg, 2 mmol) in THF (4 ml) at -50°C was added c ethylmagnesium bromide (2.4 ml, 2.4 mmol) IM solution in THF and the reaction was stirred at 0 °C for one and half hour. Analysis by LCMS showed starting material all consumed and the major peak as product. The reaction was then quenched by excess NH4Cl (sat. aq.), then extracted by EtOAc-brine, and the organic layer was concentrated by blowing N2to crude residue, which was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (172 mg). LCMS (ESI, m / z): 203.8, 205.7 [M+H]+ .

[1087] 2,6-dichloro-4-(1,1-difluoropropyl)pyridine2,6-dichloropyridin-4-yl)propan-1-one

[1088] At 0 °C to a solution of l-(2,6-dichloropyridin-4-yl)propan-1-one (173 mg, 0.848 mmol) in dichloromethane (2.1 ml) was added DAST, N,N-di ethyl- 1,1,1-trifluoro-14-sulfanamine (1.37 g, 8.5 mmol). Under icy -water bath, two drops of EtOH were added to the reaction mixture, which was allowed to stir at RT for 15 hours. Analysis by LCMS showed starting ketone completely converted to the difluoro product. To another flask charged with MeOH (~2 ml), EtOAc (~ 4ml), and excess Na2CO3powder under icy bath was SLOWLY added the above reaction mixture to CAREFULLY quench unreacted excess DAST reagent while avoiding thermal runoff. After completion the resultant slurry was stirred for more than one hour and was then filtered through a layer of silica gel. The filtrate was dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (141 mg). LCMS (ESI, m / z): 225.8, 227.6 [M+H]+ .

[1089] INT-47

[1090] 2,6-dichloro-4-(1,1-difluoropropyl)pyridine (249 mg, 1.1 mmol) was mixed with tert-butyl piperazine- 1 -carboxylate (287 mg, 1.540 mmol) in N,N-Dimethylacetamide (2.8 ml). Added sodium bicarbonate (444 mg, 5.3 mmol). The reaction was heated in microwave synthesizer at 90 °C for 16 hours. The reaction was quenched with water (~2 mL) and extracted with ethyl acetate (3x4 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (389 mg). LCMS (ESI, m / z): 375.9, 377.6 [M+H]+.

[1091] INT-48 tert-butyl 4-(6-chloro-4-( 1 , 1 -difluoropropyl)pyridin-2-yl)-4-(difluoromethyl)piperidine- 1 - carboxylate

[1092] To a solution of tert-butyl 4-[6-chloro-4-(1,1-difluoropropyl)-2-pyridyl]-4-formyl-piperidine- 1-carboxylate (1.38 g, 3.43 mmol) in dichloromethane (15 mL) was added DAST (4.53 mL, 34.26 mmol) at 0°C. Then EtOH (158 mg, 3.43 mmol) was slowly added to the reaction. The resulting mixture was stirred at room temperature for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. LCMS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05%TFA) / MeCN (1 / 1) to give tert-butyl 4-(6-chloro-4- (1,1-difluoropropyl)pyridin-2-yl)-4-(difluoromethyl)piperidine-1-carboxylate (1.10 g, 76%) as a light-yellow oil. LCMS (ESI, m / z): 425, 427 [M+H]+.

[1093] INT-49

[1094] (6-(l-(tert-butoxycarbonyl)-4-(difluoromethyl)piperidin-4-yl)-4-(1,1-difluoropropyl)pyridin- 2-yl)boronic acid

[1095] To a solution of tert-butyl 4-[6-chloro-4-(1,1-difluoropropyl)-2-pyridyl]-4- (difluoromethyl)piperidine-l -carboxylate (250 mg, 0.59 mmol) and bis(pinacolato)diboron (373 mg, 1.47 mmol) in 1,4-dioxane (5 mL) , were added Pd(dppf)Cl2(48 mg, 0.06 mmol) and KO Ac (245 mg, 1.77 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 4h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was used directly for next step without purification. LCMS (ESI, m / z): 435 [M+H]+

[1096] INT-50 tert-butyl 4-(6-chloro-4-( 1,1 -difluoropropyl)pyri din-2 -yl)-4-(fluoromethyl)piperi dine- 1- carb oxy late

[1097] 1 -(tert-butyl) 4-methyl 4-(6-chloro-4-(1,1-difluoropropyl)pyridin-2-yl)piperi dine- 1,4- di carb oxy late

[1098] To a solution of 2,6-dichloro-4-(1,1-difluoropropyl)pyridine (6.3 g, 27.8 mmol) and l-(tert- butyl) 4-methyl piperidine-1,4-dicarboxylate (8.1 g, 33.4 mmol) in THF (120 mL) was added LiHMDS (42 mL, 42.0 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h and the temperature was allowed to warm to room temperature naturally. LCMS showed the reaction was completed. The reaction was then quenched with aqueous ammonium chloride saturated solution (600 mL) and extracted with ethyl acetate (3x200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3: 1) to afford 1 -(tert-butyl) 4-methyl 4-(6-chloro-4-(1,1-difluoropropyl)pyridin-2-yl)piperidine-1,4-dicarboxylate (9.9 g, 82%) as an orange oil. LCMS (ESI, m / z): 433, 435 [M+H]+. tert-butyl 4-(6-chloro-4-(1,1-difluoropropyl)pyridin-2-yl)-4-(hydroxymethyl)piperidine-1- carboxylate

[1099] To a solution of 1 -(tert-butyl) 4-methyl 4-(6-chloro-4-(l, l-difluoropropyl)pyri din-2 - yl)piperidine-1,4-dicarboxylate (9.9 g, 22.8 mmol) in THF (100 mL) was added LiBH4(1.0 g, 45.7 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred overnight and the temperature was allowed to warm to room temperature naturally. LCMS showed the reaction was completed. The reaction was then quenched with saturated ammonium chloride solution (600 mL) and extracted with ethyl acetate (3x200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2: 1) to afford tert-butyl 4- (6-chloro-4-(1,1-difluoropropyl)pyridin-2-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (9.0 g, 97%) as a yellow oil. LCMS (ESI, m / z): 405, 407 [M+H]+.

[1100] INT-50

[1101] To a solution of tert-butyl 4-(6-chloro-4-(1,1-difluoropropyl)pyri din-2 -yl)-4- (hydroxymethyl)piperidine-l -carboxylate (1.2 g, 2.96 mmol) and DBU (586 mg, 3.85 mmol in toluene (25 mL) was added sulfoxfluor (1.23 g, 3.56 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 60 °C overnight. LCMS showed the reaction was completed. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by reverse flash chromatography (water (0.5% TFA) : ACN =1 :9) to afford tertbutyl 4-(6-chloro-4-(1,1-difluoropropyl)pyridin-2-yl)-4-(fluoromethyl)piperidine-1- carboxylate (577 mg, 47%) as an off-white solid. LCMS (ESI, m / z): 407, 409 [M+H]+.

[1102] INT-51 tert-butyl (S)-4-(6-chl oro-4-(difluoromethyl)pyri din-2 -yl)-2-m ethylpiperazine- 1 -carboxylate

[1103] 2,6-dichloro-4-(difluoromethyl)pyridine

[1104] At 0 °C to a solution of 2,6-Dichloroisonicotinaldehyde (0.85 g, 4.83 mmol) in dichloromethane (6.9 ml) was added DAST, N,N-di ethyl- 1,1,l-trifluoro-14-sulfanamine (3.9 g, 24 mmol). Under icy -water bath, five drops of EtOH were added to the reaction mixture, which was allowed to stir at RT for 15 hours. Analysis by LCMS showed starting ketone completely converted to the difluoro product.

[1105] To another flask charged with MeOH (~6 ml), EtOAc (~ 12ml), and excess Na2CO3powder under icy bath was SLOWLY added the above reaction mixture to CAREFULLY quench unreacted excess DAST reagent while avoiding thermal runoff. After completion the resultant slurry was stirred for more than one hour and was then filtered through a layer of silica gel. The filtrate was dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (706 mg). LCMS (ESI, m / z): 238.7, 240.6 [M+H+MeCN]+.1H NMR (500 MHz, CDCl3) δ 7.42 (s, 2H), 6.62 (t, J = 55.2 Hz, 1H).19F NMR (471 MHz, CDCl3) δ -116.43.

[1106] INT-51

[1107] 2,6-dichloro-4-(difluoromethyl)pyridine (283 mg, 1.429 mmol) was mixed with tert-butyl (S)-2-methylpiperazine-l -carboxylate (400 mg, 2.0 mmol) in N,N-Dimethylacetamide (2.8 ml). Added sodium bicarbonate (540 mg, 6.4 mmol). The reaction was heated in microwave synthesizer at 90 °C for 16 hours. The reaction was quenched with water (~2 mL) and extracted with ethyl acetate (3x4 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (487 mg). LCMS (ESI, m / z): 305.7, 307.5 [M+H-tBu]+.

[1108] INT-52 tert-butyl (S)-4-(4-(1,1-difluoroethyl)-6-(tributylstannyl)pyridin-2-yl)-2-methylpiperazine-1- carb oxy late

[1109] To a solution of tert-butyl (2S)-4-[6-chloro-4-(1,1-difluoroethyl)-2-pyridyl]-2-methyl- piperazine-1 -carboxylate (200 mg, 0.53 mmol), tributyl(tributylstannyl) stannane (1852 mg, 3.19 mmol) and LiCl (178 mg, 1.06 mmol) in DMF (5 mL) was added Pd(PPh3)2Cl2(37 mg, 0.05 mmol). The resulting mixture was stirred at 80 °C for 4h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (10: 1) to give tert-butyl (S)-4-(4-( l , l -difluoroethyl)-6- (tributylstannyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (200 mg, 59%) as a colorless oil. LCMS (ESI, m / z): 632 [M+H]+.

[1110] INT-53 tert-butyl (S)-4-(4-fluoro-6-(tributylstannyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate

[1111] To a solution of tert-butyl (S)-4-(6-bromo-4-fluoropyridin-2-yl)-2-methylpiperazine-1- carboxylate (120 mg, 0.32 mmol) in DMF (2 mL) were added tributyl(tributylstannyl)stannane (1116 mg, 1.92 mmol), LiCl (107 mg, 0.64 mmol) and Pd(PPh3)2Cl2(22 mg, 0.03 mmol). The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether (0.5% TEA) / ethyl acetate (6: 1) to give tert-butyl (S)-4-(4- fluoro-6-(tributylstannyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (85 mg, 45%) as a colorless oil. LCMS (ESI, m / z): 586 [M+H]+.

[1112] INT-54

[1113] (R)-(6-(4-(tert-butoxycarbonyl)-2-ethylpiperazin- 1 -yl)-4-( 1 , 1 -difluoroethyl)pyri din-2 - yl)boronic acid

[1114] To a stirred solution of tert-butyl (3R) -4-[6-chloro-4-(1,1-difluoroethyl)-2-pyridyl]-3-ethyl- piperazine-1 -carboxylate (150 mg, 0.38 mmol) and B2pin2(146 mg, 0.58 mmol) in DMF (4 mL) were added KOAc (113 mg, 1.15 mmol) and Pd(dppf)Cl2- di chloromethane (56 mg, 0.08 mmol) under nitrogen atmosphere. The mixture was stirred at 90°C for 4h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was used in the next step directly without further purification. LCMS (ESI, m / z): 400 [M+H]+.

[1115] INT-55 tert-butyl (S)-4-(6-chloro-4-(cy cl opentyldifluoromethyl)pyri din-2 -yl)-2-m ethylpiperazine- 1- carb oxy late cyclopentyl(2,6-dichloropyridin-4-yl)methanone

[1116] To a solution of 2,6-dichloro-N-methoxy-N-methylisonicotinamide (470 mg, 2 mmol) in THF (4 ml) at -50°C was added cyclopentylmagnesium bromide 2M solution in ether (2.4 ml 4.8 mmol) and the reaction was stirred at 0 °C for 2.5 hours, then warmed up to RT. Analysis by LCMS showed starting material all consumed and the major peak as product. The reaction was then quenched by excess NH4Cl(sat. aq.), then extracted by EtOAc-brine, and the organic layer was concentrated by blowing N2to crude residue, which was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (158 mg). LCMS (ESI, m / z): 243.7, 245.6 [M+H]+.

[1117] 2,6-dichloro-4-(cyclopentyldifluoromethyl)pyridine

[1118] At 0 °C to a solution of cyclopentyl(2,6-dichloropyridin-4-yl)methanone, cyclopentyl(2,6- dichloropyridin-4-yl)methanone (158 mg, 0.65 mmol) in dichloromethane (1.6 ml) was added DAST, N,N-diethyl-1,1,l-trifluoro-14-sulfanamine (1.04 g, 6.5 mmol). Under icy- water bath, two drops of EtOH were added to the reaction mixture, which was allowed to stir at RT for 15 hours. Analysis by LCMS showed starting ketone completely converted to the difluoro product.

[1119] To another flask charged with MeOH (~2 ml) and excess Na2CO3powder under icy bath was SLOWLY added the above reaction mixture to CAREFULLY quench unreacted excess DAST reagent while avoiding thermal runoff. After completion the resultant slurry was stirred for more than one hour and was then filtered through a layer of silica gel. The filtrate was dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (167 mg). LCMS (ESI, m / z): 265.7, 267.7 [M+H]+.

[1120] INT-55

[1121] 2,6-dichloro-4-(cyclopentyldifluoromethyl)pyridine (167 mg, 0.628 mmol) was mixed with (S)-1-N-Boc-2-methyl piperazine (176 mg, 0.879 mmol) in N,N-Dimethylacetamide (1.6 ml). Added sodium bicarbonate (253 mg, 3.0 mmol). The reaction was heated in microwave synthesizer at 90 °C for 12 hours. The reaction was quenched with water (~2 mL) and extracted with ethyl acetate (3x3 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (232 mg). LCMS (ESI, m / z): 429.9 [M+H]+. INT-56 cyclopropyl(2,6-dichloropyridin-4-yl)methanone

[1122] To a solution of 2,6-dichloro-N-methoxy-N-methylisonicotinamide (470 mg, 2 mmol) in THF (4 ml) at -50°C was added cyclopropylmagnesium bromide (4.8 mL, 2.4 mmol) 0.5M solution in THF and the reaction was stirred at 0 °C for one and half hour. Analysis by LCMS showed starting material all consumed and the major peak as product. The reaction was then quenched by excess NH4Cl (sat. aq.), then extracted by EtOAc-brine, and the organic layer was concentrated by blowing N2to crude residue, which was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (365 mg). LCMS (ESI, m / z): 215.7, 217.7 [M+H]+.

[1123] INT-57

[1124] 2,6-dichloro-4-(cyclopropyldifluoromethyl)pyridine

[1125] At 0 °C to a solution of cyclopropyl(2,6-dichloropyridin-4-yl)methanone (183 mg, 0.847 mmol) in dichloromethane (2.1 ml) was added DAST, N,N-di ethyl- 1,1,1 -trifluoro-14- sulfanamine (2.73 g, 17 mmol). Under icy -water bath, two drops of EtOH were added to the reaction mixture, which was allowed to stir at RT for 15 hours. Analysis by LCMS showed starting ketone completely converted to the difluoro product.

[1126] To another flask charged with MeOH (~2 ml) and excess Na2CO3powder under icy bath was SLOWLY added the above reaction mixture to CAREFULLY quench unreacted excess DAST reagent while avoiding thermal runoff. After completion the resultant slurry was stirred for more than one hour and was then filtered through a layer of silica gel. The filtrate was dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (111 mg). LCMS (ESI, m / z): 237.8, 239.7 [M+H]+.

[1127] INT-58 tert-butyl (S)-4-(6-chloro-4-(trifluoromethyl)pyri din-2 -yl)-2-methyl-l, 4-di azepane- 1- carb oxy late

[1128] 2,6-dichloro-4-(trifluoromethyl)pyridine (238 mg, 1.1 mmol) was mixed with tert-butyl (S)- 2-methyl-1,4-diazepane-l -carboxylate (248 mg, 1.155 mmol) in N,N-Dimethylacetamide (2.8 ml). Added sodium bicarbonate (444 mg, 5.3 mmol). The reaction was heated in microwave synthesizer at 90 °C for 16 hours. The reaction was quenched with water (~2 mL) and extracted with ethyl acetate (3x4 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (403 mg). LCMS (ESI, m / z): 393.9 [M+H]+.

[1129] INT-59 tert-butyl (S)-4-(6-chloro-4-(1,1-difluoro-2,2-dimethylpropyl)pyridin-2-yl)-2- methylpiperazine- 1 -carboxylate

[1130] 1 -(2,6-dichloropyridin-4-yl)-2,2-dimethylpropan- 1 -ol

[1131] To a solution of 2,6-dichloroisonicotinaldehyde (1.0 g, 5.57 mmol) in THF (11 ml) at -65°C was added tert-Butylmagnesium chloride 2M solution in ether (3.6 ml, 7.2 mmol) and the reaction was stirred at -65°C for one and half hour, then warmed up to RT. Analysis by LCMS showed starting material all consumed and the major peak as product. The reaction was then quenched by excess NH4Cl(sat. aq.), then extracted by EtOAc-brine, and the organic layer was concentrated by blowing N2to crude residue, which was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (558 mg). LCMS (ESI, m / z): 233.7, 235.6 [M+H]+. l-(2,6-dichloropyridin-4-yl)-2,2-dimethylpropan-1-one

[1132] To the solution of l-(2,6-dichloropyridin-4-yl)-2,2-dimethylpropan-1-ol, l-(2,6- dichloropyridin-4-yl)-2,2-dimethylpropan-1-ol (0.518 g, 1.55 mmol) in Dichloromethane (6.45 ml) was added leq Dess-Martin periodinane (0.821 g, 1.94 mmol) in Dichloromethane (1.5ml) slurry, and the reaction was stirred at RT for one hour.. Analysis by LCMS showed starting material all consumed and the major peak as product. The reaction was then quenched by excess Na2S2O3(aq.), then extracted by EtOAc-brine, and the organic layer was concentrated by blowing N2to crude residue, which was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (402 mg). LCMS (ESI, m / z): 231.6, 233.5 [M+H]+.

[1133] 2,6-dichloro-4-(1,1-difluoro-2,2-dimethylpropyl)pyridine At 0 °C to a solution of l-(2,6-dichloropyridin-4-yl)-2,2-dimethylpropan-1-one, l-(2,6- dichloropyridin-4-yl)-2,2-dimethylpropan-1-one (395 mg, 1.702 mmol) in dichloromethane (4.2 ml) was added DAST, N,N-diethyl-1,1,l-trifluoro-14-sulfanamine (2.5 g, 15 mmol). Under icy -water bath, two drops of EtOH were added to the reaction mixture, which was allowed to stir at RT for 15 hours. Analysis by LCMS showed starting ketone completely converted to the difluoro product.

[1134] To another flask charged with MeOH (~4 ml), EtOAc (~ 8 ml), and excess Na2CO3powder under icy bath was SLOWLY added the above reaction mixture to CAREFULLY quench unreacted excess DAST reagent while avoiding thermal runoff. After completion the resultant slurry was stirred for more than one hour and was then filtered through a layer of silica gel. The filtrate was dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (307 mg). LCMS (ESI, m / z): 253.9, 255.8 [M+H]+.

[1135] INT-59

[1136] 2,6-dichloro-4-(1,1-difluoro-2,2-dimethylpropyl)pyridine, 2,6-dichloro-4-(1,1-difluoro-2,2- dimethylpropyl)pyridine (93 mg, 0.366 mmol) was mixed with (S)-1-N-Boc-2-methyl piperazine (103 mg, 0.512 mmol) in N,N-Dimethylacetamide (1 ml). Added sodium bicarbonate (148 mg, 1.8 mmol). The reaction was heated in microwave synthesizer at 90 °C for 16 hours. The reaction was quenched with water (~2 mL) and extracted with ethyl acetate (3x3 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (141 mg). LCMS (ESI, m / z): 418.1, 419.7 [M+H]+.

[1137] INT-60 tert-butyl (R) -4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-methyl-1,4-diazepane-1- carboxylate

[1138] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (300 mg, 1.39 mmol), tert-butyl (2R)- 2-methyl-1,4-diazepane-l -carboxylate (327 mg, 1.53 mmol) and K2CO3(575 mg, 4.17 mmol) in DMSO (5 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (2R) -4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2- m ethyl- 1,4-diazepane-l -carboxylate (390 mg, 71%) as a colorless oil. LCMS (ESI, m / z): 394, 396 [M+H]+.

[1139] INT-61

[1140] (6-(l-(tert-butoxycarbonyl)-4-(fluoromethyl)piperidin-4-yl)-4-(1,1-difluoropropyl)pyridin-2- yl)boronic acid

[1141] To a solution of tert-butyl 4-[6-chloro-4-(1,1-difluoropropyl)-2-pyridyl]-4- (fluoromethyl)piperidine-l -carboxylate (200 mg, 0.49 mmol) and bis(pinacolato)diboron (312 mg, 1.23 mmol) in 1,4-dioxane (5 mL) , were added Pd(dppf)Cl2(40 mg, 0.05 mmol) and KO Ac (144 mg, 1.47 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 4h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was used directly for next step without purification. LCMS (ESI, m / z): 417 [M+H]+ INT-62 tert-butyl (R) -4-(6-chl oro-4-(trifluoromethyl)pyridin-2-yl)-2-m ethylpiperazine- 1 -carboxylate

[1142] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (700 mg, 3.24 mmol), (R)-1-boc-2- methylpiperazine (649 mg, 3.24 mmol) and DIEA (1.132 mL, 6.48 mmol) in DMF (10 mL) was sealed and heated at 100 °C for 4 h. The reaction mixture was cooled to rt, poured into water, and extracted with ethyl acetate (25 mL). The separated organic layer was washed with 5% citric acid and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography purification using an ISCO system (80 g silica gel column, gradient elution from 0-20% of ethyl acetate in hexanes) afforded tert-butyl (R) -4-(6-chloro- 4-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (1.16 g) as a colorless gum. LCMS (ESI, m / z): 323.9 [M-t-Bu +H],1H NMR (499 MHz, chloroform-d) δ 6.78 (s, 1H), 6.62 (s, 1H), 4.35 (br s, 1H), 4.11 (br d, J=12.5 Hz, 1H), 4.04 - 3.90 (m, 2H), 3.39 (dd, J=13.2, 4.1 Hz, 1H), 3.28 (ddd, J=13.6, 11.2, 3.7 Hz, 1H), 3.11 (td, J=11.9, 3.9 Hz, 1H), 1.51 (s, 9H), 1.21 (d, J=6.7 Hz, 3H).

[1143] INT-63

[1144] / crt-butyl (R)-4-(6-chloro-4-(trifluoromethyl)pyri din-2 -yl)-3 -ethylpiperazine- 1 -carboxylate

[1145] To a solution of tert-butyl (3R)-3 -ethylpiperazine- 1 -carboxylate (1.0 g, 4.67 mmol) in DMSO (20 mL) were added 2,6-dichloro-4-(trifluoromethyl)pyridine (1.21 g, 5.61 mmol) and K2CO3(1.93 g, 14.01 mmol). The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (3x60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (92:8) to afford tert-butyl (R)-4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-3-ethylpiperazine-1-carboxylate (330 mg, 17%) as an orange oil. LCMS (ESI, m / z): 394, 396 [M+H]+.

[1146] INT-64 tert-butyl (R)-3-ethyl-4-(6-(tributylstannyl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1- carboxylate

[1147] To a solution of tert-butyl (R)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3- ethylpiperazine-1 -carboxylate (200 mg, 0.51 mmol) and tributyl(tributylstannyl)stannane (1.5 g, 2.54 mmol) in DMF (5 mL), were added Pd(PPh3)2Cl2(36 mg, 0.05 mmol) and LiCl (64 mg, 1.52 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was concentrated under vacuum. The crude product was purified by purified by flash column chromatography on C18 silica (Mobile Phase A: water (0.5% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 100% B in 25 min; 254 / 210 nm) to afford tertbutyl (R)-3-ethyl-4-(6-(tributylstannyl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1- carboxylate (300 mg, 91.1%) as a colorless oil. LCMS (ESI, m / z): 650 [M+H]+.

[1148] INT-65 tert-butyl (R)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-isopropylpiperazine-1- carboxylate To a solution of tert-butyl (R)-3-isopropylpiperazine-1-carboxylate (1000 mg, 4.38 mmol) in DMSO (2.0 mL) was added 2,6-dichloro-4-(trifluoromethyl)pyridine (0.943 mL, 6.57 mmol) and DIPEA (2.295 mL, 13.14 mmol). Then the reaction mixture was heated to 100 °C ON. The reaction was then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel to afford the title compound (210 mg). LCMS (ESI, m / z): 352 [M+H]+.

[1149] INT-66 tert-butyl (R)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(hydroxymethyl)piperazine-1- carb oxy late

[1150] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (1.00 g, 4.63 mmol), tert-butyl (R)-2- (hydroxymethyl)piperazine-l -carboxylate (1.202 g, 5.56 mmol) and DIEA (1.213 mL, 6.94 mmol) in DMF (10 mL) was sealed and heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with ethyl acetate (25 mL). The separated organic layer was washed with 5% citric acid and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography purification using an ISCO system (80 g silica gel column, gradient elution from 0-30% of ethyl acetate in hexanes) afforded tert-butyl (R)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2- (hydroxymethyl)piperazine-l -carboxylate (1.73 g) as a white foam. LCMS (ESI, m / z): 396.1[M+H]+.

[1151] INT-67 tert-butyl (S)-4-(6-chloro-4-(trifluoromethyl)pyri din-2 -yl)-3-(fluorom ethyl)piperazine- 1- carb oxy late tert-butyl (S)-4-benzyl -3 -(hydroxymethyl )piperazine- l -carboxylate

[1152] To a solution of tert-butyl (S)-3-(hydroxymethyl)piperazine-l -carboxylate (2 g, 9.25 mmol) in MeCN (20 mL) were added TEA (2.8 g, 27.74 mmol) and BnBr (1.89 g, 11.10 mmol). The resulting mixture was stirred overnight at 80°C under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3 / 1) to give tertbutyl (S)-4-benzyl-3-(hydroxymethyl)piperazine- l -carboxylate (1.2 g, 42%) as a white solid. LCMS (ESI, m / z): 307 (M+H)+. tert-butyl (S)-4-benzyl -3 -(fluoromethyl)piperazine- 1 -carboxylate

[1153] To a solution of tert-butyl (S)-4-benzyl-3-(hydroxymethyl)piperazine-l -carboxylate (1.2 g, 3.92 mmol) in DCM (15 mL) was added DAST (1.46 g, 9.08 mmol) dropwise at -78°C under a nitrogen atmosphere. The reaction mixture was stirred for 15 min at -78°C and was allowed to warm to room temperature. The mixture was stirred 2 h at room temperature under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with saturated sodium bicarbonate at 0°C and extracted with DCM (100 mL). The organic extracts were concentrated. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1 : 1) to give tert-butyl (S)-4-benzyl-3- (fluoromethyl)piperazine-l -carboxylate (1.2 g, purity 60%, a mixture with tert-butyl 6- (fluoromethyl)-5-phenyl-1,4-diazepane-1-carboxylate) as colorless oil. LCMS (ESI, m / z): 309 (M+H)+. tert-butyl (S)-3 -(fl uoromethyl)piperazine- l -carboxyl ate

[1154] To a solution of tert-butyl (S)-4-benzyl-3-(fluoromethyl)piperazine-1-carboxylate (1.2 g, purity 60%) in methanol (10 mL) was added Pd / C (240 mg) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. LCMS showed the reaction was completed. The solid was filtered out and the filtration was concentrated under reduced pressure. The residue was used in the next step directly without further purification. LCMS (ESI, m / z): 219 (M+H)+.

[1155] INT-67

[1156] To a solution of tert-butyl (S)-3-(fluoromethyl)piperazine- l -carboxylate (the crude product of previous step) and 2,6-dichloro-4-(trifluoromethyl)pyridine (892 mg, 4.13 mmol) in DMSO (10 mL) was added K2CO3(1.6 g, 11.27 mmol). The resulting mixture was stirred at 100°C for 2 h. LCMS showed the reaction was completed. The reaction was then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (9 / 1) to give tert-butyl (S)-4-(6-chl oro-4-(trifluoromethyl)pyri din-2 -yl)-3-(fluoromethyl)piperazine-1- carboxylate (202 mg, 13%) as colorless oil.

[1157] LCMS (ESI, m / z): 398 [M+H]+. Analytic Conditions: Column: HALO C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 80% B in 1.70 min, 80% B to 95% B in 0.60 min, hold at 95% for 0.50 min, 950% B to 5% B in 0.03 min; 254 nm; Rt: 1.228 min.1H NMR (400 MHz, DMSO-d6) δ 7.08 (d, J = 12.0 Hz, 1H), 6.97 (d, J = 6.0 Hz, 1H), 5.07-4.71 (m, 1H), 4.09-3.83 (m, 3H), 3.77-3.63 (m, 2H), 3.61-3.49 (m, 3H), 1.33-1.25 (m, 9H). INT-68 tert-butyl (2S,3S)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2,3-dimethylpiperazine-1- carb oxy late

[1158] Tert-butyl (2R,3R)-2,3-dimethylpiperazine-1-carboxylate (20 mg, 0.093 mmol), 2,6- dichloro-4-(trifluoromethyl)pyridine (20.09 μl, 0.140 mmol), DMSO (467 μl), and DIPEA (48.9 μl, 0.280 mmol) were added to a vial and stirred at 100 C for 2 hours. The reaction was quenched with water, extracted with EtOAc, and concentrated down to be run on a normal phase column (0-100% Hex:EtOAc). The desired fractions were collected and concentrated down. LCMS (ESI, m / z): 394 [M+H]+.

[1159] INT-69 tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazine- 1 -carboxylate- 2,2,3,3,5,5,6,6-d8

[1160] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (0.67 g, 3.1 mmol), tert-butyl piperazine-1-carboxylate-2,2,3,3,5,5,6,6-d8 (0.50 g, 2.6 mmol), and potassium carbonate (0.71 g, 5.2 mmol) in acetonitrile (8.6 ml) was heated at 80 °C overnight. The crude was diluted with EtOAc, washed with H2O, and dried over Na2SO4. The crude was purified using ISCO normal phase (0-100% EtOAC / hexanes) to afford the title compound. LCMS (ESI, m / z): 318 [M+H-tBu]+

[1161] INT-70 tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-oxopiperazine-l -carboxylate

[1162] To a solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (0.539 mL, 3.75 mmol) in DMSO (2.0 mL) was added tert-butyl 2-oxopiperazine-l -carboxylate (500 mg, 2.497 mmol) and K2CO3 (690 mg, 4.99 mmol). Then the reaction mixture was heated to 60 °C ON. The reaction was then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel to afford the title compound (320 mg). LCMS (ESI, m / z): 280 [M+H]+.

[1163] INT-71 tert-butyl 8-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3- carb oxy late

[1164] To a solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (1 g, 4.63 mmol) in DMSO (15 mL) were added tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1179 mg, 5.56 mmol), K2CO3(1916 mg, 13.89 mmol). The resulting mixture was stirred overnight at 140 °C under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by reverse flash chromatography (water (0.5% TFA): ACN =4: 1) to afford tert-butyl 8-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (950 mg, 52%) as a yellow solid. LCMS (ESI, m / z): 392, 394 [M+H]+. INT-72 tert-butyl (lS,6R)-3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3,8- di azabi cy cl o [4.2.0] octane- 8 -carb oxyl ate

[1165] A 20ml reaction vial was charged with 2,6-dichloro-4-(trifluoromethyl)pyridine (50.9 mg, 0.236 mmol), tert-butyl (lS,6R)-3,8-diazabicyclo[4.2.0]octane-8-carboxylate (50 mg, 0.236 mmol), potassium carbonate (71.6 mg, 0.518 mmol), and acetonitrile (1178 μl). The vial was heated to 85 °C on a heating block overnight. The reaction was filtered through a pad of silica. The precipitate was washed with ethyl acetate 3 times. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (20g silica column). The pure fractions were concentrated in vacuo to give product as a white solid. LC / MS(ESI, m / z): 336 [M+H-56]+

[1166] INT-73 tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-(fluoromethyl)piperidine-1- carb oxy late

[1167] 1 -(tert-butyl) 4-methyl 4-(6-chloro-4-(trifluoromethyl)pyri din-2 -yl)piperi dine- 1 ,4- di carb oxy late To a solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (2 g, 9.26 mmol) and 01 -tert-butyl 04-methyl piperidine-1,4-dicarboxylate (2.7 g, 11.11 mmol) in THF (30 mL) was added LiHMDS (1 M in THF, 19 mL, 19 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure to afford 1 -(tert-butyl) 4-m ethyl 4-(6-chloro-4-(trifluoromethyl)pyri din-2 - yl)piperidine-1,4-dicarboxylate (3.9 g, 99 %) as a brown oil crude. LCMS (ESI, m / z): 367, 369 [M-56]+. tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-(hydroxymethyl)piperidine-1- carb oxy late

[1168] To a solution of 1 -(tert-butyl) 4-methyl 4-(6-chloro-4-(trifluoromethyl)pyridin-2- yl)piperidine-1,4-dicarboxylate (3.9 g, 9.22 mmol) in THF (50 mL) was added LiBH4(2 M in THF, 23 mL, 46 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 day under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was diluted with aqueous saturated ammonium chloride (100 mL), extracted with di chloromethane (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with ethyl acetate / petroleum ether (1 :2) to give tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyridin- 2-yl)-4-(hydroxymethyl)piperidine-l -carboxylate (2.4 g, 66%) as a colorless oil. LCMS (ESI, m / z): 339, 341 [M-56]+.

[1169] INT-73 tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-(fluoromethyl)piperidine-1- carboxylate To a solution of tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-4- (hydroxymethyl)piperidine-l -carboxylate (1 g, 2.55 mmol) in toluene (15 mL) were added DBU (0.5 g, 3.31 mmol) and SulfoxFluor (1.06 g, 3.05 mmol) dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 60°C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (6 / 1) to give tert-butyl 4-(6-chl oro-4-(trifluoromethyl)pyri din-2 -yl)-4-(fluoromethyl)piperi dine- 1- carboxylate (692 mg, 65%) as a white solid.

[1170] LCMS (ESI, m / z): 341, 343 [M-56]+. Analytic Conditions: Column: HALO C18, 4.6*100 mm, 2.7 μm; Mobile Phase A: Water / 0.1%FA, Mobile Phase B: Acetonitrile / 0.1%FA; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B in 8.00 min, hold at 95% for 2.00 min; 254 nm; Rt: 7.468 min.1H NMR (400 MHz, DMSO-d6) δ 8.05-7.82 (m, 2H), 4.76-4.46 (m, 2H), 3.78-3.53 (m, 2H), 3.13-2.87 (m, 2H), 2.36-2.15 (m, 2H), 1.84-1.68 (m, 2H), 1.39 (s, 9H).

[1171] INT-74 tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyri din-2 -yl)-4-methylpiperi dine- 1 -carboxylate

[1172] DIC (0.078 ml, 0.500 mmol) was added to a mixture of 2-hydroxyisoindoline-l, 3-dione (82 mg, 0.500 mmol), DMAP (3.05 mg, 0.025 mmol), l-(tert-butoxycarbonyl)-4- methylpiperidine-4-carboxylic acid (122 mg, 0.5 mmol), and DMSO (2.5 mL). The reaction was sealed and stirred at room temperature ON. 2-chloro-4-(trifluoromethyl)pyridine (363 mg, 2.000 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (3.20 mg, 5.00 μmol), and DMSO (7.5 ml) were added. The reaction was sparged with nitrogen for 5 minutes. The vial was sealed and irradiated with blue LEDs in a BMS photoreactor for 4 hours. Some product was observed. The crude reaction mixture was directly loaded on a reversed phase MPLC column and purified in acetonitrile and water with 0.1% TFA to title compound (20 mg, 0.053 mmol, 10.56 % yield) as a thin film. LC / MS(ESI, m / z): 323 [M+H-56]+ INT-75 rac-tert-butyl (3S,4S)-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-fluoro-piperidine-1- carb oxy late tert-butyl 6-chloro-4-(trifluoromethyl)-3',6'-dihydro-[2,4'-bipyridine]- 1'(2'H)-carboxylate

[1173] To a solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (5 g, 23.15 mmol), tert-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (7.9 g, 25.46 mmol) and K2CO3(9.6 g, 69.45 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was added Pd(dppf)Cl2(1.5 g, 1.85 mmol). The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (300 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (11 / 1) to give tert-butyl 4-[6-chloro-4- (trifluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (5.8 g, 69%) as a yellow oil. LCMS (ESI, m / z): 363, 365 [M+H]+. rac-tert-butyl (3 S,4S)-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3 -hydroxy-piperidine- 1- carb oxy late To a solution of NaBH4(1.3 g, 35.56 mmol) in THF (120 mL) was added dropwise BF3-Et2O (4.4 mL, 35.56 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C until the reaction mixture became a white suspension. The reaction was warmed to room temperature and stirred for 30 min. Tert-butyl 4-[6-chloro-4-(trifluoromethyl)-2- pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (4.3 g, 11.85 mmol) in THF (60 mL) was added dropwise over 15 min, and the resulting mixture was stirred at room temperature for 2 h. The reaction was then quenched by the slow addition of water (14 mL). Then ethanol (14 mL), NaOH (10% aq., 77 mL) and H2O2(7 mL) were also added. The resulting mixture was stirred for 3 h at 70 °C. The reaction was then cooled down to 10 °C and diluted with DCM (300 mL). Aqeous HCl (3N) was slowly added until the pH turned to 6-7. The aqueous layer was further extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (1 :3) to give the 3,4-trans mixture of tert-butyl -4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-hydroxy- piperidine-1 -carboxylate (730 mg, 16%) as an off-white solid. LCMS (ESI, m / z): 381, 383 [M+H]+.

[1174] INT-75

[1175] To a solution of the 3,4-trans mixture of-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3- hydroxy-piperidine-1 -carboxylate (600 mg, 1.58 mmol) in DCM (10 mL) was added BAST (1.3 g, 7.88 mmol) dropwise at -10 °C under nitrogen atmosphere. The resulting mixture was stirred at -10 °C for 2 h. LCMS showed the reaction was completed. The mixture was quenched with 5% aqueous NaOH (150 mL), then the mixture was extracted with dichloromethane (3 x 60 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Xselect CSH Prep C18 C18 Column, 30*150 mm, 5μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 56% B to 86 % B in 10 min; Wave Length: 254nm / 220nm; RTl(min): 7.78.) to obtain (3,4-trans) tert-butyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-fluoro-piperidine-1- carboxylate (203.1 mg, 27%) as an off-white solid.

[1176] LCMS (ESI, m / z): 383, 385 [M+H]+. Analytic Conditions: Column: HALO 90A C18

[1177] Column 3.0*30 mm, 2.0 μm; Mobile Phase A: water / 0.05%TFA, Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.5 mL / min; Gradient: 30 % B to 100% B in 1.2 min, hold at 95% for 0.6 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 0.988.1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.90 (s, 1H), 4.90-4.78 (m, 1H), 4.37-4.24 (m, 1H), 3.93-3.96 (m, 1H), 3.32-3.22 (m, 1H), 3.00-2.81 (m, 2H), 1.89-2.00 (m, 1H), 1.71- 1.58(m, 1H), 1.43 (s, 9H).

[1178] INT-76 tert-butyl 5-(6-chloro-4-(trifluoromethyl)pyri din-2 -yl)-2-azabicyclo[3.1.1 ]heptane-2- carb oxy late Prepared in similar manner as INT-74 affording title compound (31 mg) as a thin film.

[1179] LC / MS(ESI, m / z): 362 [M+H]+

[1180] INT-77 tert-butyl 3 -(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperidine-l -carboxylate Prepared in similar manner as INT-74 affording title compound (20 mg) as a thin film.

[1181] LC / MS(ESI, m / z): 365 [M+H]+

[1182] INT-78

[1183] 6-chloro-2'-m ethoxy -4-(trifluoromethyl)-2,4'-bipyri dine

[1184] To a stirred solution of 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1 g, 4.25 mmol) in 1,4-dioxane (30 mL) and water (6 mL) were added 2,6-dichloro-4- (trifluoromethyl)pyridine (1.38 g, 6.38 mmol), Pd(dppf)Cl2(694 mg, 0.85 mmol) and Cs2CO3(4.14 g, 12.76 mmol) under nitrogen atmosphere. The mixture was stirred at 100°C for 5 h under nitrogen atmosphere. LCMS showed the reaction was completed. The mixture was quenched with water (50 mL), extracted with ethyl acetate (3x50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase flash chromatography to obtain 6-chloro-2'-methoxy-4-(trifluoromethyl)-2,4'- bipyridine (1.2 g, 97.7%) as a yellow solid. LCMS (ESI, m / z): 289, 291 [M+H]+.

[1185] INT-79 tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-(fluoromethyl)pyrrolidine-1- carb oxy late

[1186] 1 -(tert-butyl) 3-methyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-l,3- di carb oxy late

[1187] To a solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (1 g, 4.63 mmol) and 1 -(tert-butyl)

[1188] 3-methyl pyrrolidine- 1, 3 -dicarboxylate (1.27 g, 5.56 mmol) in THF (30 mL) was added dropwise LiHMDS (1 M in THF, 9.2 mL, 9.2 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure. This resulted in 1 -(tert-butyl) 3-methyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2- yl)pyrrolidine- 1,3 -dicarboxylate (1.40 g, 74%) as a brown oil. LCMS (ESI, m / z): 353, 355 [M-56]+. tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)pyrrolidine-1- carb oxy late

[1189] To a solution of 1-tert-butyl 3-methyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]pyrrolidine- 1,3 -di carb oxy late (1.40 g, 3.42 mmol) in THF (30 mL) was added LiBH4(2 M in THF, 5.1 mL, 10.2 mmol)at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated under reduce pressure. This resulted in tert-butyl 3-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)pyrrolidine-l -carboxylate (1.20 g, 92%) as a yellow oil. LCMS (ESI, m / z): 325, 327 [M-56]+.

[1190] INT-79

[1191] To a solution of tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3- (hydroxymethyl)pyrrolidine-l -carboxylate (700 mg, 1.84 mmol) in toluene (7 mL) was added dropwise DBU (364 mg, 2.39 mmol) at 0 °C under nitrogen atmosphere, and then SulfoxFluor (767 mg, 2.21 mmol) was added in the resulting mixture at 0°C. The reaction mixture was stirred at room temperature for 48 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (3: 1) to give tert-butyl 3-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-3-(fluorornethyl)pyrrolidine-l -carboxylate (300 mg, 42%) as a white solid.

[1192] LCMS (ESI, m / z): 327, 329 [M-56]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 80% B in 1.70 min, 80% B to 95% B in 0.60 min, hold at 95% for 0.50 min, 95% B to 5% B in 0.03 min; 254 nm; Rt: 1.069 min.1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.86-7.84 (m, 1H), 4.81-4.72 (m, 1H), 4.69-4.60 (m, 1H), 3.79-3.73 (m, 1H), 3.61-3.58 (m, 1H), 3.43-3.39 (m, 1H), 3.35-3.33 (m, 1H), 2.31-2.24 (m, 2H), 1.41 (s, 9H).

[1193] INT-80 tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-(difluoromethyl)pyrrolidine-1- carboxylate tert-butyl 3 -(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-formylpyrrolidine-l -carboxylate

[1194] To a solution of tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3- (hydroxymethyl)pyrrolidine-l -carboxylate (650 mg, 1.71 mmol) in dichloromethane (10 mL) was added DMP (1.09 g, 2.56 mmol) at 0 °C under nitrogen atmosphere. The resulting solution was stirred for 0.5 h at room temperature under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was quenched by aqueous Na2SO3(20 mL) at 0 °C and extracted with dichloromethane (2x20 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum at 0 °C to afford tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-formylpyrrolidine-1- carboxylate (550 mg, 85.1%) as a light-yellow oil. LCMS (ESI, m / z): 323, 325 [M-56]+.

[1195] INT-80

[1196] To a solution of afford tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3- formylpyrrolidine-1 -carboxylate (540 mg, 1.43 mmol) in dichloromethane (20 mL) was added DAST (2.3 g, 14.3 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting solution was stirred for 4 h at room temperature under nitrogen atmosphere. The reaction was successful and confirmed by LCMS. The resulting mixture was diluted with water (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduce pressure. The crude product was purified by purified by flash column chromatography on C18 silica (Mobile Phase A: water (0.5% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 80% B in 25 min; 254 / 210 nm) to afford tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3- (difluoromethyl)pyrrolidine-l -carboxylate (330 mg, 51.9%) as a colorless oil.

[1197] LCMS (ESI, m / z): 345, 347 [M-56]+. Analytic Conditions: column: HALO 90A C18 Column 3*30 mm, 2.0 μm; mobile phase A: water / 0.05%TFA, mobile phase B: acetonitrile / 0.05%TFA; flow rate: 1.5 mL / min; gradient: 30% B to 70% B in 1.7 min, 70% B to 100% B in 0.6 min, hold at 100% for 0.5 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.695 min.1H NMR (400 MHz, Chloroform-d) δ 7.54 (s, 1H), 7.47 (s, 1H), 6.15 (t, J = 55.9 Hz, 1H), 3.98-3.86 (m, 2H), 3.67-3.52 (m, 1H), 3.49-3.37 (m, 1H), 2.59-2.41 (m, 2H), 1.48 (s, 9H).

[1198] INT-81 tert-butyl 3 -(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylpyrrolidine-l -carboxylate tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-(iodomethyl)pyrrolidine-1- carb oxy late

[1199] To a solution of tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3- (hydroxymethyl)pyrrolidine-l -carboxylate (430 mg, 1.13 mmol), PPh3(1.18 g, 4.52 mmol) and imidazole (308 mg, 4.52 mmol) in THF (10 mL) was added I2 (1.14 g, 4.52 mmol). The reaction mixture was stirred at 80°C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2 / 1) to give tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-(iodomethyl)pyrrolidine-1- carboxylate (400 mg, 72%) as a light yellow oil. LCMS (ESI, m / z): 435, 437 [M-56]+.

[1200] INT-81

[1201] To a solution of tert-butyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3- (iodomethyl)pyrrolidine-l -carboxylate (400 mg, 0.82 mmol) and AIBN (54 mg, 0.33 mmol) in toluene (10 mL) was added BusSnH (593 mg, 2.04 mmol). The reaction mixture was stirred at 80°C for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. LCMS showed the reaction was completed. The reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduce pressure. The resulting was purified by reverse flash chromatography with water(0.05%TFA) / MeCN (1 / 1) to give tertbutyl 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylpyrrolidine-1-carboxylate(201.2 mg, 68%) as a white solid.

[1202] LCMS (ESI, m / z): 309, 311 [M-56]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 1.176 min.1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.81-7.79 (m, 1H), 3.75-3.65 (m, 1H), 3.43-3.35 (m, 2H), 3.34-3.26 (m, 1H), 2.37- 2.24 (m, 1H), 2.13-1.99 (m, 1H), 1.40 (s, 9H), 1.37 (s, 3H).

[1203] INT-82 tert-butyl (R)-(l-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate

[1204] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (700 mg, 3.24 mmol), (R)-3-(boc- amino)pyrrolidine (664 mg, 3.57 mmol) and DIEA (1.132 mL, 6.48 mmol) in DMF (10 mL) was sealed and heated at 90 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with ethyl acetate (25 mL). The separated organic layer was washed with 5% citric acid and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography purification using an ISCO system (80 g silica gel column, gradient elution from 0-20% of ethyl acetate in hexanes) afforded tert-butyl (R)-(l-(6-chloro- 4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (932 mg) as a white solid. LCMS (m / z) 366.1 [M+H] Retention time: 1.05 min.

[1205] INT-83 tert-butyl (S)-(l-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate

[1206] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (600 mg, 2.78 mmol), (S)-3-(boc- amino)pyrrolidine (569 mg, 3.06 mmol) and DIEA (0.970 mL, 5.56 mmol) in DMF (8 mL) was sealed and heated at 100 °C for 4 h. The reaction mixture was cooled to rt, poured into water, and extracted with ethyl acetate (25 mL). The separated organic layer was washed with 5% citric acid and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography purification using an ISCO system (80 g silica gel column, gradient elution from 0-20% of ethyl acetate in hexanes) afforded tert-butyl (S)-(l-(6-chloro- 4-(trifluorom ethyl)pyri din-2 -yl)pyrrolidin-3-yl)carbamate (909 mg) as a white solid. LCMS (m / z) 366.0 [M+H], RT: 1.15 min.

[1207] INT-84 tert-butyl (S)-4-(6-chloro-4-(fluoromethyl)pyri din-2 -yl)-2-methylpiperazine- 1 -carboxylate

[1208] 2,6-dichloro-4-(fluoromethyl)pyridine

[1209] To a solution of (2,6-dichloro-4-pyridyl)methanol (10 g, 56.1 mmol) in dichloromethane (100 mL) was added diethylaminosulfur trifluoride (45.3 g, 280.8 mmol) at -20°C under nitrogen atmosphere. The resulting solution was stirred for 1 h at -20°C. The reaction was quenched by of water (100 mL), and extracted with dichloromethane (2x100 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 2,6- dichloro-4-(fluoromethyl)pyridine (9.8 g, 96.9%) as a light-yellow oil. LCMS (ESI, m / z): 180, 182 [M+H]+.

[1210] INT-84

[1211] To a solution of 2,6-dichloro-4-(fluoromethyl)pyridin (5.4 g, 29.9 mmol) in DMSO (50 mL), were added tert-butyl (2S)-2-methylpiperazine-l -carboxylate (5 g, 24.97 mmol) and K2CO3(10.3 g, 74.9 mmol) under nitrogen atmosphere. The resulting solution was stirred at 100 °C for 16h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by water (200 mL) and extracted with ethyl acetate (2x200 mL), washed with water (2x200 mL) and brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 :7) to afford tert-butyl (2S)-4-[6-chloro-4-(fluoromethyl)- 2-pyridyl]-2-methyl-piperazine-l -carboxylate (4.5 g, 52.4%) as a light-yellow solid. LCMS (ESI, m / z): 344, 346 [M+H]+.

[1212] INT-85 tert-butyl (S)-4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloropyridin-2-yl)-2- methylpiperazine- 1 -carboxylate

[1213] 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-di chloropyridine

[1214] To a solution of (2,6-dichloro-4-pyridyl)methanol (5.5 g, 30.9 mmol) and imidazole (6.3 g, 92.6 mmol) in dichloromethane (20 mL) was added TBSC1 (5.6 g, 37.1 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0 °C. LCMS showed the reaction was completed. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (3x80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (4 / 1) to afford 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyridine (9 g, 99%) as an off- white solid. LCMS (ESI, m / z): 292, 294 [M+H]+.

[1215] INT-85

[1216] To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-di chloropyridine (3 g, 10.2 mmol) in DMSO (50 mL) were added tert-butyl (2S)-2-methylpiperazine-l -carboxylate (2 g, 10.2 mmol) and K2CO3(4 g, 30.8 mmol). The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (300 mL) and extracted with ethyl acetate (3x300 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (9: 1) to afford tert-butyl (S)- 4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloropyridin-2-yl)-2-methylpiperazine-1- carboxylate (490 mg, 10%) as an orange oil. LCMS (ESI, m / z): 456 [M+H]+.

[1217] INT-86

[1218] (6-(4-(tert-butoxycarbonyl)piperazin- 1 -yl)-4-chloropyridin-2-yl)boronic acid

[1219] To a solution of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-l -carboxylate (190 mg, 0.48 mmol) and bis(pinacolato)diboron (245 mg, 0.96 mmol) in 1,4-dioxane (4 mL), were added Pd(dppf)Cl2(39 mg, 0.05 mmol) and KO Ac (142 mg, 1.45 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was used directly for next step without work up or purification. LCMS (ESI, m / z): 263 [M+H]+.

[1220] INT-87 tert-butyl (S)-4-(6-bromo-4-chloropyri din-2 -yl)-2-methylpiperazine- 1 -carboxylate

[1221] To a solution of 2,6-dibromo-4-chloro-pyridine (2.4 g, 8.84 mmol), tert-butyl (S)-2- m ethylpiperazine- 1 -carboxylate (1.47 g, 7.37 mmol) and t-BuONa (849 mg, 8.84 mmol) in 1,4-Dioxane (15 mL) was added XPhos Pd G4 (634 mg, 0.74 mmol). The reaction mixture was stirred at 120°C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was diluted with water (50 mL), extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting was purified by reverse flash chromatography with water(0.05%TFA) / MeCN (1 / 1) to give tert-butyl (S)-4-(6-bromo-4-chloropyridin-2-yl)-2-methylpiperazine- l -carboxylate (512.8 mg, 18%) as a light yellow solid.

[1222] LCMS (ESI, m / z): 390, 392 [M+H]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 1.228 min.1H NMR (400 MHz, DMSO-d6) δ 6.96-6.90 (m, 2H), 4.21-4.13 (m, 1H), 4.11-3.96 (m, 2H), 3.79-3.74 (m, 1H), 3.25-3.10 (m, 2H), 3.00-2.94 (m, 1H), 1.42 (s, 9H), 1.06 (d, J = 6.4 Hz, 3H).

[1223] INT-88 tert-butyl 4-(6-bromo-4-fluoro-2-pyridyl)piperazine- 1 -carboxylate

[1224] To a solution of 2,6-dibromo-4-fluoro-pyridine (400 mg, 1.56 mmol) in 1,4-dioxane (8 mL) were added tert-butyl piperazine- 1 -carboxylate (292 mg, 1.56 mmol), Cs2CO3(1530 mg, 4.70 mmol) and Pd2(dba)3(143 mg, 0.16 mmol), XantPhos (180 mg, 0.32 mmol). The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by reverse flash chromatography (water (0.5% TFA) : ACN =3:7) to afford tert-butyl 4-(6-bromo-4-fluoro-2-pyridyl)piperazine-l -carboxylate (80 mg, 14%) as a yellow solid. LCMS (ESI, m / z): 360, 362 [M+H]+ INT-89 tert-butyl fS)-4-(6-chloro-4-fluoropyri din-2 -yl)-2-methylpiperazine- 1 -carboxylate

[1225] To a solution of 2,6-dichloro-4-fluoro-pyridine (380 mg, 2.29 mmol) in 1,4-di oxane (7 mL) was added tert-butyl (2S)-2-methylpiperazine-l -carboxylate (458 mg, 2.29 mmol), Cs2CO3(2232 mg, 6.87 mmol) and Pd2(dba)3(209 mg, 0.23 mmol), XantPhos (264 mg, 0.46 mmol). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3: 1) to afford tert-butyl fS)-4-(6-chloro-4-fluoropyridin-2-yl)-2- m ethylpiperazine- 1 -carboxylate (85 mg, 11%) as a yellow oil. LCMS (ESI, m / z): 330 [M+H]+.

[1226] INT-90 tert-butyl (S)-4-(6-bromo-4-fluoropyridin-2-yl)-2-methylpiperazine- 1 -carboxylate

[1227] To a solution of 2,6-dibromo-4-fluoro-pyridine (450 mg, 1.77 mmol) in 1,4-dioxane (8 mL) was added tert-butyl (2S)-2-methylpiperazine-l -carboxylate (353 mg, 1.77 mmol), Cs2CO3(1721 mg, 5.30 mmol) and EPhos Pd G4(162mg, 0.18 mmol), EPhos (204 mg, 0.35 mmol). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3: 1) to afford tert-butyl (S)-4-(6-bromo-4-fluoropyri din-2 -yl)-2- m ethylpiperazine- 1 -carboxylate (120 mg, 18%) as a yellow oil. LCMS (ESI, m / z): 374 [M+H]+.

[1228] INT-91 tert-butyl (S)-4-(6-chl oro-4-methylpyri din-2 -yl)-2-methylpiperazine-l -carboxylate

[1229] To a solution of 2,6-dichloro-4-methyl-pyridine (300 mg, 1.85 mmol) in DMSO (5 mL) were added tert-butyl (2S)-2-methylpiperazine-l -carboxylate (482 mg, 2.41 mmol), K2CO3(766 mg, 5.55 mmol). The resulting mixture was stirred at 100 °C for 6 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by reverse flash chromatography (water (0.5% TFA) : ACN =3: 17) to afford tert-butyl (S)-4-(6-chloro-4-methylpyridin-2-yl)-2- m ethylpiperazine- 1 -carboxylate (170 mg, 28%) as an orange solid. LCMS (ESI, m / z): 326, 328 [M+H]+.

[1230] INT-92 tert-butyl (S)-4-(6-chloro-4-methylpyridin-2-yl)-2-ethylpiperazine- 1 -carboxylate

[1231] 2,6-dichloro-4-methylpyridine (291 mg, 1.795 mmol), tert-butyl (S)-2-ethylpiperazine-1- carboxylate (500 mg, 2.333 mmol), potassium carbonate (546 mg, 3.95 mmol), and DMSO (4487 μl) were added to a microwave vial and heated to 100 C for 16 hours. The reaction was filtered, concentrated down, and run on normal phase column (0-50% Hex:EtOAc). The fractions were collected and concentrated down.LCMS (ESI, m / z): 340 [M+H]+.

[1232] INT-93 tert-butyl (S)-2-cy cl opropyl-4-(4-methyl-6-(tributylstannyl)pyri din-2 -yl)piperazine- 1- carb oxy late tert-butyl (S)-4-(6-chloro-4-methylpyridin-2-yl)-2-cyclopropylpiperazine-l -carboxylate

[1233] To a solution of 2,6-dichloro-4-methyl-pyridine (429 mg, 2.65 mmol) in DMSO (20 mL), were added K2CO3(921 mg, 6.63 mmol) and tert-butyl (2S)-2-cyclopropylpiperazine-1- carboxylate (500 mg, 2.21 mmol) under nitrogen atmosphere. The resulting solution was stirred at 100 °C for 3 days under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by water (100 mL) and extracted with ethyl acetate (200 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by purified by flash column chromatography on C18 silica (Mobile Phase A: water (0.5% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 90% B in 25 min; 254 / 210 nm) to afford tert-butyl (2S)-4-(6-chloro-4-methyl-2-pyridyl)-2-cyclopropyl-piperazine-l - carboxylate (400 mg, 51.4%) as a yellow solid. LCMS (ESI, m / z): 352, 354 [M+H]+

[1234] INT-93

[1235] To a solution of tert-butyl (S)-4-(6-chloro-4-methylpyridin-2-yl)-2-cyclopropylpiperazine-1- carboxylate (400 mg, 1.14 mmol) and tributyl(tributylstannyl)stannane (6.6 g, 11.4 mmol) in DMF (15 mL), were added Pd(PPh3)2Cl2(80 mg, 0.11 mmol) and LiCl (5 mg, 0.11 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 48 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by water (100 mL) and extracted with ethyl acetate (2x100 mL). The organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (Mobile Phase A: petroleum ether (0.5% TEA), Mobile Phase B: ethyl acetate (0.5% TEA); Flow rate: 60 mL / min; Gradient: 0% B to 5% B in 30 min; 254 / 280 nm) to afford tert-butyl (2S)-2-cyclopropyl-4-(4-methyl-6-tributylstannyl-2- pyridyl)piperazine-l -carboxylate (230 mg, 33.3%) as a colorless oil. LCMS (ESI, m / z): 608 [M+H]+

[1236] INT-94 tert-butyl (S)-4-(6-(6-amino-5-formylpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-2- methylpiperazine- 1 -carboxylate

[1237] To a solution of tert-butyl (S)-2-methyl-4-(6-(tributylstannyl)-4-(trifluoromethyl)pyridin-2- yl)piperazine-l -carboxylate (450 mg, 0.71 mmol) and 4-amino-6-chloropyrimidine-5- carbaldehyde (134 mg, 0.85 mmol) in toluene (8 mL), were added Pd(PPh3)4(65 mg, 0.07 mmol) and CuI (13 mg, 0.07 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: water (0.5% TFA), Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 20% B to 80% B in 25 min; 254 / 210 nm) to afford tert-butyl (S)-4-(6-(6-amino-5-formylpyrimidin-4-yl)-4-(trifluoromethyl)pyri din-2 -yl)-2- m ethylpiperazine- 1 -carboxylate (120 mg, 36.2%) as a light-yellow solid. LCMS (ESI, m / z): 467 [M+H]+. INT-95 tert-butyl (S)-4-(2'-amino-3'-formyl-4-(trifluoromethyl)-[2,4'-bipyridin]-6-yl)-2- methylpiperazine- 1 -carboxylate

[1238] (S)-(6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyri din-2- yl)boronic acid

[1239] To a solution of tert-butyl (2S)-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl- piperazine-1 -carboxylate (500 mg, 1.32 mmol), bis(pinacolato)diboron (501 mg, 1.97 mmol) and KO Ac (258 mg, 2.63 mmol) in DMF (10 mL) was added Pd(dppf)Cl2(108 mg, 0.13 mmol). The resulting mixture was stirred at 90 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was used directly for next step without further purification. LCMS (ESI, m / z): 390 [M+H]+.

[1240] INT-95

[1241] To a solution of [6-[(3S)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl]-4- (trifluoromethyl)-2-pyridyl]boronic acid (400 mg, 1.03 mmol), tert-butyl N-(4-chl oro-3 - formyl-2-pyridyl)carbamate (264 mg, 1.03 mmol) and K2CO3(426 mg, 3.08 mmol) in DMF (5 mL) was added Pd(dppf)Cl2(84 mg, 0.10 mmol). The resulting mixture was stirred at 90 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (2: 1) to give tert-butyl (S)-4-(2'- amino-3'-formyl-4-(trifluoromethyl)-[2,4'-bipyridin]-6-yl)-2-methylpiperazine-l -carboxylate (150 mg, 31%) as a yellow solid. LCMS (ESI, m / z): 466 [M+H]+.

[1242] INT-96 tert-butyl 4-[6-chloro-4-(l, l-difluoro-2-methoxy-ethyl)-2-pyridyl]piperazine-l -carboxylate ethyl 2-(2,6-dichloropyridin-4-yl)-2,2-difluoroacetate

[1243] A solution of 2,6-dichloro-4-iodo-pyridine (5.0 g, 18.26 mmol), ethyl 2-bromo-2,2-difluoro- acetate (5.56 g, 27.38 mmol) and Cu (17.4 g, 273.83 mmol) in DMSO (50 mL) was stirred at 55 °C for 4h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3x300 mL). The combined organic layers were washed with brine (2x300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3 : 1) to give ethyl 2-(2,6-dichloro-4-pyridyl)-2,2-difluoro-acetate (3.5 g, 53%) as a yellow oil. LCMS (ESI, m / z): 270, 272 [M+H]+.

[1244] 2-(2,6-dichloropyridin-4-yl)-2,2-difluoroethan-1-ol To a solution of ethyl 2-(2,6-dichloro-4-pyridyl)-2,2-difluoro-acetate (3.45 g, 12.77 mmol) in THF (50.0 mL) was added LiBH4(1.46 g, 38.32 mmol). The resulting mixture was stirred at room temperature for 4h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3: 1) to give 2-(2,6-dichloro-4-pyridyl)-2,2-difluoro-ethanol (1.65 g, 57%) as a yellow oil. LCMS (ESI, m / z): 228, 230 [M+H]+.

[1245] 2, 6-dichloro-4-(1,1-difluoro-2 -methoxy ethyl)pyri dine

[1246] To a solution of 2-(2,6-dichloropyridin-4-yl)-2,2-difluoroethan-1-ol (1.6 g, 7.02 mmol) and CH3I (2.2 mL, 35.080 mmol) in THF (20 mL) was added NaH (60% w / w, 337 mg, 14.03 mmol). The reaction mixture was stirred at 0 °C for 2h and then was allowed to warm to room temperature. LCMS showed the reaction was completed. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2: 1) to give 2,6-dichloro-4- (1,1-difluoro-2-methoxy-ethyl)pyridine (1.4 g, 82%) as a yellow oil. LCMS (ESI, m / z): 242, 244 [M+H]+.

[1247] INT-96

[1248] A solution of 2,6-dichloro-4-(1,1-difluoro-2-methoxy-ethyl)pyridine (600 mg, 2.48 mmol), tert-butyl piperazine- 1 -carboxylate (462 mg, 2.48 mmol) and K2CO3(1.03 g, 7.44 mmol) in DMSO (10 mL) was stirred at 100 °C for 4h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3: 1) to give tert-butyl 4-[6-chloro-4-(1,1-difluoro-2-methoxy-ethyl)-2- pyridyl]piperazine-l -carboxylate (680 mg, 70%) as a colorless oil. LCMS (ESI, m / z): 392, 394 [M+H]+.

[1249] INT-97 tert-butyl (R) -4-[6-(6-amino-5-formyl-pyrimidin-4-yl)-4-(trifluoromethyl)-2-pyridyl]-3- ethyl-piperazine- 1 -carboxylate

[1250] To a solution of tert-butyl (R)-3-ethyl-4-(6-(tributylstannyl)-4-(trifluoromethyl)pyridin-2- yl)piperazine-l -carboxylate (400 mg, 0.62 mmol) and 4-amino-6-chloro-pyrimidine-5- carbaldehyde (146 mg, 0.93 mmol) in toluene (6 mL), were added Pd(PPh3)4(71 mg, 0.06 mmol) and CuI (12 mg, 0.06 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was concentrated under vacuum. The crude product was purified by purified by flash column chromatography on C18 silica (Mobile Phase A: water (0.5% TFA), Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 20% B to 80% B in 25 min; 254 / 210 nm) to afford tert-butyl (R) -4-[6-(6-amino-5-formyl-pyrimidin-4-yl)-4-(trifluoromethyl)-2-pyridyl]- 3-ethyl-piperazine-1-carboxylate (140 mg, 47.2%) as a yellow solid. LCMS (ESI, m / z): 481 [M+H]+

[1251] INT-98 tert-butyl 8-(6-(6-amino-5-formylpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate

[1252] To a stirred solution of tert-butyl 8-(6-(tributylstannyl)-4-(trifluoromethyl)pyridin-2-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (220 mg, 0.34 mmol) and 4-amino-6- chloropyrimidine-5-carbaldehyde (54 mg, 0.34 mmol) in toluene (3 mL) were added Pd(PPh3)4(62 mg, 0.07 mmol) and CuI (13 mg, 0.07 mmol) under nitrogen atmosphere. The mixture was stirred at 100°C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The solids were filtered out. The filtrate was concentrated. The residue was purified by Prep-TLC (di chloromethane: MeOH =20: 1) to obtain tert-butyl 8-(6- (6-amino-5-formylpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (150 mg, 92.1%) as a yellow solid. LCMS (ESI, m / z): 479 [M+H]+.

[1253] INT-99

[1254] (6-(4-(tert-butoxycarbonyl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-4-(trifluoromethyl)pyridin-2- yl)boronic acid

[1255] A mixture of tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate- 2,2,3,3,5,5,6,6-d8 (0.60 g, 1.6 mmol), potassium acetate (0.47 g, 4.8 mmol), bis(pinacolato)diboron (0.49 g, 1.9 mmol), and [1,T Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.13 g, 0.16 mmol) in dioxane (8.00 ml) was flushed with nitrogen for 10 min, sealed, and heated at 80 °C for 30 min. The crude material was used directly without further purification. LCMS (ESI, m / z): 384 [M+H]+. INT-100

[1256] (R)-(4-(1,1-difluoroethyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)boronic acid

[1257] Prepared in same manner as (R)-(4-(difluoromethyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid. LC / MS (ESI, m / z): 259 [M+H]+

[1258] INT-101

[1259] 4-chloro-2-(piperazin- 1 -yl)-6-(trifluoromethyl)pyrimidine

[1260] 2-chloro-4-ethoxy-6-(trifluoromethyl)pyrimidine

[1261] To a solution of 2,4-dichloro-6-(trifluoromethyl)pyrimidine (2 g, 9.22 mmol) in ethanol (20 mL) was added sodium ethoxide (627 mg, 9.22 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. Next the reaction mixture was warmed to room temperature and stirred for 2 hours. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3: 1) to give 2-chloro-4-ethoxy-6-(trifluoromethyl)pyrimidine (1.05 g, 4.634 mmol, 50.27 % yield) as a yellow solid. LC / MS (ESI, m / z): 227 [M+H]+tert-butyl 4-(4-ethoxy-6-(trifluoromethyl)pyrimidin-2-yl)piperazine- 1 -carboxylate

[1262] A reaction vial was charged with 2-chloro-4-ethoxy-6-(trifluoromethyl)pyrimidine (1.05 g, 4.63 mmol) and K2CO3 (1.92 g, 13.9 mmol) in DMSO (10 mL). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2: 1) to give tert-butyl 4-(4-ethoxy-6- (trifluoromethyl)pyrimidin-2-yl)piperazine-l -carboxylate (1.1 g, 2.923 mmol, 63.07 % yield) as a yellow solid. LC / MS (ESI, m / z): 377 [M+H]+

[1263] 2-(piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-4-ol

[1264] A reaction vial was charged with tert-butyl 4-(4-ethoxy-6-(trifluoromethyl)pyrimidin-2- yl)piperazine-l -carboxylate (1 g, 2.66 mmol) in HCl (10 mL, 2.66 mmol) (12M). The resulting mixture was stirred at 80 °C for 3 h. The residue was purified by reverse phase flash chromatography with water (0.5 % TFA) / MeCN (3: 1) to give 2-(piperazin-1-yl)-6- (trifluoromethyl)pyrimidin-4-ol (780 mg, 2.51 mmol, 94.62 % yield, 80 % purity) as a yellow solid. LC / MS(ESI, m / z): 249 [M+H]+

[1265] INT-101

[1266] A reaction vial was charged with 2-(piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-4-ol (750 mg, 2.41 mmol, 80 % purity) and POC13 (463.31 mg, 3.02 mmol). The resulting mixture was stirred at 70 °C for 3 h. The solid was was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5 % TFA) / MeCN (2:3) to give 4-chloro-2-(piperazin-1-yl)-6- (trifluoromethyl)pyrimidine (370 mg, 1.39 mmol, 57.7 % yield) as an off-white solid.

[1267] LC / MS(ESI, m / z): 267 [M+H]+

[1268] Example 1 and Example 2

[1269] (R)-4-methyl-5-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-1,4- dihydro-2H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one and

[1270] (S)-4-methyl-5-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-1,4- dihydro-2H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one

[1271] tert-butyl 5-[6-[(3S)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl]-4-(trifluoromethyl)-2- pyridyl]-4-methyl-2-oxo-4H-pyrido[2,3-d][1,3]oxazine-1-carboxylate

[1272] To a stirred solution of tert-butyl (2S)-2-methyl-4-[6-tributylstannyl-4-(trifluoromethyl)-2- pyridyl]piperazine-l -carboxylate (200 mg, 0.32 mmol) in DMF (5 mL) were added tert-butyl 5-chloro-4-methyl-2-oxo-4H-pyrido[2,3-d][1,3]oxazine-1-carboxylate (94 mg, 0.32 mmol), P(o-Tol)3 (19 mg, 0.06 mmol) and Pd2(dba)3(29 mg, 0.03 mmol) under nitrogen atmosphere. The mixture was stirred at 100°C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The mixture was quenched with water (20 mL), extracted with ethyl acetate (2x20 mL). The organic layer was washed with brine (2x30 mL), dried over sodium sulphate and concentrated. The residue was purified by Prep- TLC with petroleum ether / ethyl acetate (2: 1) to obtain tert-butyl 5-[6-[(3S)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl]- 4-(trifluoromethyl)-2-pyridyl]-4-methyl-2-oxo-4H-pyrido[2,3-d][1,3]oxazine-1-carboxylate (70 mg, 36.5%) as yellow oil. LCMS (ESI, m / z): 608 [M+H]+.

[1273] Example 1 and Example 2

[1274] To a stirred solution of tert-butyl 5-[6-[(3S)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl]- 4-(trifluoromethyl)-2-pyridyl]-4-methyl-2-oxo-4H-pyrido[2,3-d][1,3]oxazine-1-carboxylate (10 mg, 0.02 mmol) in dichloromethane (1 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 3 h. LCMS showed the reaction was completed. The mixture was concentrated. The residue was purified by prep-HPLC to obtain 4-methyl-5-[6-[(3S)-3- methylpiperazin-1-yl]-4-(trifluoromethyl)-2-pyridyl]-1,4-dihydropyrido[2,3-d][1,3]oxazin-2- one (3.5 mg, 50.8%) as a white solid.

[1275] The racemic 4-methyl-5-[6-[(3S)-3-methylpiperazin-l -yl]-4-(trifluoromethyl)-2 -pyridyl]- 1,4- dihydropyrido[2,3-d][1,3]oxazin-2-one (50 mg) was resolved by Prep-chiral-HPLC (Column: CHIRALPAK-IG, 20x250 mm, 5 μm; Mobile Phase A: Hex— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: 50% B to 50% B in 12 min; Wave Length: 220 / 254 nm; RTl(min): 5.188; RT2(min): 11.369) to afford the Example2 (the first eluting peak, 20.5 mg) as an off-white solid and Example2 (the second eluting peak, 9.8 mg) as an off-white solid.

[1276] Example 1 (first eluting) : LCMS (ESI, m / z): 408 [M+H]+. Analytic Conditions: column: HALO C18, 3*30 mm; mobile phase A: Water / 0.05%TFA, mobile phase B: Acetonitrile / 0.05%TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 50% B in 1.7 min, 50% B to 100% B in 0.6 min, hold at 100% for 0.5 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.128 min. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.23-9.13 (m, 1H), 8.89-8.79 (m, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J = 5.2 Hz, 1H), 7.31 (s, 1H), 5.98 (q, J = 6.8 Hz, 1H), 4.51-4.40 (m, 2H), 3.49-3.35 (m, 2H), 3.33-3.22 (m, 1H),

[1277] 3.20-3.00 (m, 2H), 1.53 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H).

[1278] Example 2 (second eluting): LCMS (ESI, m / z): 408 [M+H]+. Analytic Conditions: column: HALO C18, 3*30 mm; mobile phase A: Water / 0.05%TFA, mobile phase B: Acetonitrile / 0.05%TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 50% B in 1.7 min, 50% B to 100% B in 0.6 min, hold at 100% for 0.5 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.116 min. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.19-9.11 (m, 1H), 8.87-8.75 (m, 1H), 8.33 (d, J = 5.2 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J = 5.2 Hz, 1H), 7.31 (s, 1H), 6.00 (q, J = 6.4 Hz, 1H), 4.52-4.41 (m, 2H), 3.48-3.32 (m, 2H), 3.30-3.20 (m, 1H),

[1279] 3.20-3.02 (m, 2H), 1.53 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H).

[1280] Example 3 and Example 4

[1281] (R)-5-(4-(1,1 -difluoroethyl)-6-((S)-3 -methylpiperazin- 1 -yl)pyridin-2-yl)-4-m ethyl- 1 ,4- dihydro-2H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one and

[1282] (S)-5-(4-(1,1 -difluoroethyl)-6-((S)-3 -methylpiperazin- 1 -yl)pyridin-2-yl)-4-m ethyl- 1 ,4- dihydro-2H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one

[1283] Prepared in a similar manner as Example 1 employing tert-butyl (2S)-4-[4-(1,1 - difluoroethyl)-6-tributylstannyl-2-pyridyl]-2-methyl-piperazine-1-carboxylate.

[1284] The racemic 5 - [4-( 1 , 1 -difluoroethyl)-6- [(3 S)-3 -methylpiperazin- 1 -yl]-2-pyridyl]-4-methyl- 1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one (70 mg) was resolved by Prep-chiral-HPLC (Column: CHIRALPAK IG-3, 4.6*50mm, 3μm; Mobile Phase A: Hex(0.1%DEA): EtOH=50: 50; Flow rate: 1 mL / min; Gradient: 0% B to 0% B) to afford Example 3 (the first eluting peak, 22.5 mg) as a white solid and Example 4 (the second eluting peak, 20.7 mg) as an off white solid.

[1285] Example 3 (second eluting): LCMS (ESI, m / z): 404 [M+H]+. Analytic Conditions: Column: HALO C18, 3.0*30 mm; Mobile Phase A: Water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 95% B in 1.20 min, hold at 95% for 0.60 min, 95% B to 5% B in 0.02 min; 254 nm; Rt: 0.620 min. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.18-8.63 (m, 2H), 8.31 (d, J = 5.2 Hz, 1H), 7.32 (d, J = 5.2 Hz, 1H), 7.19 (s, 2H), 6.04-5.90 (m, 1H), 4.49-4.35 (m, 2H), 3.47-3.31 (m, 3H), 3.29- 2.94 (m, 3H), 2.02 (t, J = 19.0 Hz, 3H), 1.53 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H).

[1286] Example 4 (second eluting): LCMS (ESI, m / z): 404 [M+H]+. Analytic Conditions: Column: HALO C18, 3.0*30 mm; Mobile Phase A: Water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 95% B in 1.20 min, hold at 95% for 0.60 min, 95% B to 5% B in 0.02 min; 254 nm; Rt: 0.630 min. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.37-8.25 (m, 1H), 7.42-7.22 (m, 1H), 7.15-7.02 (m, 2H), 6.12-5.98 (m, 1H), 4.40-4.15 (m, 2H), 3.16-2.79 (m, 4H), 2.73-2.57 (m, 2H), 2.14-1.92 (m, 3H), 1.52 (dd, J = 6.7, 2.9 Hz, 3H), 1.11 (dd, J = 6.5, 2.9 Hz, 3H). Example 5 and Example 6

[1287] (5)-4-methyl-5-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-1,4-dihydro-2H- pyrimido[4,5-d][1,3]oxazin-2-one and

[1288] (R)-4-methyl-5-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-1,4-dihydro-2H- pyrimido[4,5-d][1,3]oxazin-2-one tert-butyl 4-(6-(4-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl)-4- (trifluoromethyl)pyridin-2-yl)piperazine- 1 -carboxylate

[1289] To a solution of tert-butyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine-1-carboxylate (100 mg, 0.27 mmol) in DMF (2 mL) were added B2pin2(104 mg, 0.41 mmol), KOAc (53 mg, 0.55 mmol) and Pd(dppf)Cl2(44 mg, 0.05 mmol). The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The crude product was used for the next step directly without further purification. LCMS (ESI, m / z): 376 [M+H]+.

[1290] To the reaction crude of (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)boronic acid (100 mg, 0.27 mmol) were added a solution of 5- chloro-4-methyl-1,4-dihydropyrimido[4,5-d][1,3]oxazin-2-one (53 mg, 0.27 mmol) in DMF (1 mL), K2CO3(110 mg, 0.80 mmol) and Pd(dppf)Cl2(43 mg, 0.05 mmol). The resulting mixture was stirred at 90 °C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3x40 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse flash chromatography (water (0.5% TFA) : ACN =2:3) to afford tert-butyl 4-(6-(4- methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl)-4-(trifluoromethyl)pyridin- 2-yl)piperazine-l -carboxylate (65 mg, 49%) as a brown semi-solid. LCMS (ESI, m / z): 495 [M+H]+. Example 5 and Example 6

[1291] To a solution of tert-butyl 4-(6-(4-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin- 5-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (65 mg, 0.13 mmol) in DCM (2 mL) was added TFA (0.4 mL). The resulting solution was stirred at room temperature for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: SunFire Prep C18 OBD Column, 19x150 mm, 5 μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 35% B to 55% B in 5.36 min, 55% B; Wave Length: 254 / 210 nm; RTl(min): 5.32) to afford 4-methyl-5-(6-(piperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (25.2 mg, 48%) as a yellow solid.

[1292] SFC separation was performed to separate enantiomers: Chiralpak IC, 21 mm x 250 mm, 5 μm particles, CO2 / IPA w / 0.1% DEA (65:35).

[1293] Example 5 (first eluting): LCMS m / z: 395 [M+H]+. Analytical Conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: ACN / H2O (5:95) with 0.1% TFA; Mobile Phase B: ACN / H2O (95:5) with 0.1 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -); Rt 1.32 min.1H NMR (DMSO-d6, 500 MHz) δ 8.83 (s, 1H), 7.81 (s, 1H), 7.25 (s, 1H), 6.59 (q, 1H, J=6.3 Hz), 2.8-2.9 (m, 2H), 1.58 (d, 3H, J=6.6 Hz) (two protons obscured by solvent)

[1294] Example 6 (second eluting): LCMS m / z: 395 [M+H]+. Analytical conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: ACN / H2O (5:95) with 0.1% TFA; Mobile Phase B: ACN / H2O (95:5) with 0.1 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -); Rt 1.32 min.1H NMR (DMSO-d6, 500 MHz) δ 8.80 (s, 1H), 7.80 (s, 1H), 7.24 (s, 1H), 6.4-6.6 (m, 1H), 2.8-2.9 (m, 2H), 1.56 (d, 2H, J=6.6 Hz) (two protons obscured by solvent) Example 7

[1295] 4-methyl-5-(2'-oxo-4-(trifluoromethyl)- 1',2'-dihydro-[2,4'-bipyridin]-6-yl)-1,4-dihydro-2H- pyrido[2, 3 -d] [ 1 , 3 ] oxazin-2-one tert-butyl 5-(2'-methoxy-4-(trifluoromethyl)-[2,4'-bipyridin]-6-yl)-4-methyl-2-oxo-2H- pyrido[2,3 -d] [ 1 ,3 ] oxazine- 1 (4H)-carb oxy late

[1296] To a stirred solution of 6-chloro-2'-methoxy-4-(trifluoromethyl)-2,4'-bipyridine (100 mg, 0.35 mmol) in DMF (3 mL) were added bis(pinacolato)diboron (132 mg, 0.52 mmol), Pd(dppf)Cl2(56 mg, 0.07 mmol) and KO Ac (102 mg, 1.04 mmol) under nitrogen atmosphere. The mixture was stirred at 90°C for 2 h under nitrogen atmosphere. The reaction mixture was used in the next step directly without further purification. LCMS (ESI, m / z): 299 [M+H]+.

[1297] To the crude reaction mixture for the synthesis of (2'-methoxy-4-(trifluoromethyl)-[2,4'- bipyridin]-6-yl)boronic acid was added tert-butyl 5-chloro-4-methyl-2-oxo-4H-pyrido[2,3- d][1,3]oxazine-1-carboxylate (130 mg, 0.44 mmol), Pd(dppf)Cl2(55 mg, 0.07 mmol) and K2CO3(139 mg, 1.01 mmol) under nitrogen atmosphere. The mixture was stirred at 90°C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The mixture was quenched with water (20 mL), extracted with ethyl acetate (2x20 mL). The organic layer was washed with brine (2x50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-TLC with petroleum ether / ethyl acetate (1 : 1) to obtain tert-butyl 5-(2'-methoxy-4-(trifluoromethyl)-[2,4'-bipyridin]-6-yl)-4-methyl-2-oxo-2H-pyrido[2,3- d][1,3]oxazine-l(4H)-carboxylate (100 mg, 57.7%) as a yellow solid. LCMS (ESI, m / z): 517 [M+H]+.

[1298] Example 7

[1299] To a stirred solution of tert-butyl 5-(2' -methoxy -4-(trifluoromethyl)-[2,4'-bipyridin]-6-yl)-4- methyl-2-oxo-2H-pyrido[2,3-d][1,3]oxazine-l(4H)-carboxylate (80 mg, 0.15 mmol) in DMF (2 mL) was added TsOH (133 mg, 0.77 mmol) and LiCl (32 mg, 0.77 mmol) under nitrogen atmosphere. The mixture was stirred at 100°C for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The mixture was purified directly by reverse flash column to obtain 4-methyl-5-(2'-oxo-4-(trifluoromethyl)-l',2'-dihydro-[2,4'-bipyridin]-6-yl)- 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (52.9 mg, 82.5%) as an off-white solid.

[1300] LCMS (ESI, m / z): 403 [M+H]+. Analytic Conditions: column: HALO C18, 3*30 mm, 2.5 μm; mobile phase A: Water / 0.05%TFA, mobile phase B: Acetonitrile / 0.05%TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 50% B in 1.7 min, 50% B to 100% B in 0.6 min, hold at 100% for 0.5 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.247 min.1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 11.01 (s, 1H), 8.48 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 7.61 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 6.92 (dd, J = 6.8, 1.8 Hz, 1H), 6.03 (q, J = 6.8 Hz, 1H), 1.65 (d, J = 6.8 Hz, 3H).

[1301] Example 8

[1302] 4-methyl-5-(6-((S)-3 -methylpiperazin- 1 -yl)-4-(trifluoromethyl)pyri din-2 -yl)- 1 ,4-dihydro- 2H-pyrimido[4, 5 -d] [ 1 , 3 ] oxazin-2-one Prepared in a similar manner as Example 5 , employing tert-butyl (2S)-4-[6-chloro-4- (trifluoromethyl)-2-pyridyl]-2-methyl-piperazine-l -carboxylate.

[1303] LCMS (ESI, m / z): 409 [M+H]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: Water / 0.05%TFA, Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 95% B in 1.20 min, hold at 95% for 0.60 min, 95% B to 5% B in 0.02 min; 254 nm; Rt: 0.643.1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.16 (s, 1H), 8.89 (s, 1H), 8.88 (s, 1H), 7.92 (d, J = 4.4 Hz, 1H), 7.49 (s, 1H), 6.56 (q, J = 6.4 Hz, 1H), 4.43-4.39 (m, 2H), 3.49-3.08 (m, 5H), 1.63 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 6.8 Hz, 3H).

[1304] Example 9 and Example 10

[1305] (R)-5-(4-(1,1 -difluoroethyl)-6-((S)-3 -methylpiperazin- 1 -yl)pyri din-2 -yl)-4-methyl- 1 ,4- dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one

[1306] And

[1307] (S)-5-(4-(1,1 -difluoroethyl)-6-((S)-3 -methylpiperazin- 1 -yl)pyri din-2 -yl)-4-methyl- 1 ,4- dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one

[1308] Prepared in a similar manner Example 5 , employing tert-butyl (2S)-4-[6-chloro-4-(1,1- difluoroethyl)-2-pyridyl]-2-methyl-piperazine-l -carboxylate. The racemic material was purified via preparative SFC chromatography with the following conditions: Column: Chiralcel OJ-H, 30 mm x 250 mm, 5 μm particles; Mobile Phase A: CO2; Mobile Phase B: MeOH with 0.1% Ammonium Hydroxide; Gradient: 10 %B over 10 min; Flow Rate: 100 mL / min; Column Temperature: 40 °C. Fraction collection was triggered by UV (230 nm).

[1309] Example 9 (first eluting): LCMS m / z: 405.1 [M+H]+. Analytical Conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Temperature: 50 °C;

[1310] Gradient: 0-100 %B (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Rt 1.15 min.1H NMR (DMSO-d6, 500 MHz) δ 8.85 (s, 1H), 7.79 (s, 1H), 7.10 (s, 1H), 6.64 (q, 1H, 7=6.7 Hz), 4.1-4.2 (m, 2H), 3.01 (br d, 1H, 7=11.9 Hz), 2.8- 2.9 (m, 1H), 2.7-2.8 (m, 2H), 2.00 (t, 3H, 7=19.2 Hz), 1.61 (d, 3H, 7=6.6 Hz), 1.07 (d, 3H, 7=6.2 Hz) (one proton obscured by solvent)

[1311] Example 10 (second eluting): LCMS m / z: 405 [M+H]+. Analytical Conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Temperature: 50 °C; Gradient: 0-100 %B (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Rt 1.15 min1H NMR (DMSO-d6, 500 MHz) δ 8.84 (s, 1H), 7.78 (s, 1H), 7.09 (s, 1H), 6.64 (q, 1H, 7=6.8 Hz), 4.0-4.2 (m, 2H), 3.01 (br d, 1H, 7=11.3 Hz), 2.8-2.9 (m, 1H), 2.7-2.8 (m, 2H), 2.00 (t, 3H, 7=19.1 Hz), 1.60 (d, 3H, 7=6.6 Hz), 1.07 (d, 3H, 7=6.3 Hz) (one proton obscured by solvent)

[1312] Example 11 and Example 12

[1313] (S)-5-(6-((R)-2-ethylpiperazin- 1 -yl)-4-(trifluoromethyl)pyridin-2-yl)-4-methyl- 1 ,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-2-one and

[1314] (R) -5-(6-((R)-2-ethylpiperazin-l -yl)-4-(trifluoromethyl)pyri din-2 -yl)-4-m ethyl- 1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-2-one

[1315] Prepared in a similar manner as Example 2 employing tert-butyl (3R)-4-[6-chloro-4- (trifluoromethyl)-2-pyridyl]-3-ethyl-piperazine-1-carboxylate. Separation by SFC: The racemic...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:X is N(R1), S, or O;Y is O or S, wherein X is O or N(R1) when Y is S;A is C(R11) or N;B is C(R6) or N;Z is C(R12) or N;R1is H or C1-C4alkyl;R2is C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl, wherein the alkyl, haloalkyl, and cycloalkyl of R2is each independently optionally substituted with one or more R5; each R3is independently H or C1-C4alkyl;R4= HRing D is aryl optionally substituted with one or more R10;each R5is independently OH, halogen, C1-C4alkyl, C1-C4haloalkyl, C3-C8cycloalkyl; or aryl; or two geminal R5, together with the intervening geminal carbon atom form a C3-C6cycloalkyl;R6is H, C1-C6alkyl, C1-C4alkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, 3- to 9- membered heterocyclyl, C1-C6, haloalkyl, -C(O)OR9, cyano, or halogen, wherein the alkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and haloalkyl of R6are each independently optionally substituted with one or more halogen, phenyl, benzyl, C3-C6cycloalkyl, hydroxy, C1-C3alkoxy, or C1-C3haloalkyl;W is H, halogen, N(R7)2, 3- to 10-membered heterocyclyl, C3-C8cycloalkyl, C1-C3alkyl, wherein the heterocyclyl, cycloalkyl, and alkyl of W are each independently optionally substituted with one or more R8; each instance of R7is independently H, C1-C4alkyl, C3-C6cycloalkyl, wherein the alkyl and the cycloalkyl of R7are each independently optionally substituted with one or more R8, or two R7, together with the intervening N atom form: a 3- to 12-membered heterocyclyl optionally substituted with one or more R8; each R8is independently deuterium, C1-C4alkyl, C1-C4haloalkyl, C1-C6hydroxyalkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl, hydroxy, -(CH2)n-C(O)O(R9), N(R9)2, -NHC(O)R9, -COOH, OXO, thio, -SO3H, halogen, cyano, or C1-C3 alkoxy, or two geminal R8, together with the intervening carbon attom form a C3-C6cycloalkyl; each R9is independently H, or C1-C3alkyl; each R10is independently H, or C1-C3alkoxy; each R11is H, C1-C6alkyl, or halogen; n is an integer from 0 to 6;R12is H, NO2, or when B is CR6, R12is H NO2, or R12and R6when taken together form a 6-membered aryl.

2. The compound of claim 1, wherein R2is H, -CH2-, -CH3, -CH2CH3, -CH2CH(CH3)2, - CH2CH2CH3, -C(CH3)3, -CF2CH3, -CHFCH3, -CHF2, or -CF3.

3. The compound of claim 1, wherein R2is methyl.

4. The compound of claim 1, wherein R6is C1-C6alkyl, C1-C6haloalkyl, C1-C3aminoalkyl, or C1-C3hydroxyalkyl.

5. The compound of any one of claims 1-4, wherein the compound is of Formula la: or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1 to 5, wherein W is:

7. The compound of claim 1, wherein the compound is of formula la-1 : or a pharmaceutically acceptable salt thereof, wherein W issubstituted with one or more R8.

8. The compound of claim 1, wherein the compound is of formula la-2: or a pharmaceutically acceptable salt thereof, wherein p is 2.

9. The compound of claim 1, wherein the compound is of formula la-3 :or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein the compound is of formula la-4: or a pharmaceutically acceptable salt thereof, wherein W issubstituted with one or more R8.

11. The compound of claim 1, wherein the compound is of formula la-5: or a pharmaceutically acceptable salt thereof, wherein W issubstituted with one or more R8.

12. The compound of claim 1, wherein the compound is of formula la-6:or a pharmaceutically acceptable salt thereof, wherein W issubstituted with one or more R8.

13. The compound of claim 1, wherein the compound is of formula la-7:or a pharmaceutically acceptable salt thereof, wherein W is substituted with one or more R8.

14. The compound of claim 1, wherein the compound is of formula la-8:or a pharmaceutically acceptable salt thereof, wherein p is 0,1, 2, or 3.

15. The compound of claim 1, wherein the compound is of formula Ib-1 :or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein the compound is of formula Ib-2:or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, wherein the compound is of formula Ib-3 :or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound is of formula Ib-4:or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is of formula Ib-5 : or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound is of formula Ic-1 : or a pharmaceutically acceptable salt thereof, wherein W issubstituted with one or more R8.

21. The compound of claim 1, wherein the compound is of formula Ic-2:or a pharmaceutically acceptable salt thereof, wherein W issubstituted with one or more R8.

22. The compound of claim 1, wherein the compound is of formula Ic-3:or a pharmaceutically acceptable salt thereof, wherein W is substituted with one or more R8.

23. The compound of claim 1, wherein the compound is of formula Ic-4: or a pharmaceutically acceptable salt thereof, wherein W issubstituted with one or more R8.

24. The compound of claim 1, wherein the compound is of formula Ic-5:or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 selected from the group consisting of:

6. The compound of claim 1 wherein the compound is selected from the group consisting of:(4R)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-4-methyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-methyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;6-{4-methyl-2-oxo-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl}-4-(trifluoromethyl)- 1',2'-dihydro-[2,4'-bipyridine]-2'-one;4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-methyl-5-{6-[(3R)-3-methyl-1,4-diazepan-1-yl]-4-(trifluoromethyl)pyri din-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;(4S)-4-methyl-5-{6-[(3R)-3-methyl-1,4-diazepan-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(2- methylpropyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-ethyl-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-ethyl-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrido[2, 3 -d] [ 1 , 3 ]oxazin-2-one;(4S)-4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrido[2, 3 -d] [ 1 , 3 ]oxazin-2-one;4-cyclobutyl-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-tert-butyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;(4R)-4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl } - 1H,2H,4H-pyrido[2, 3 - d] [ 1 , 3 ]oxazin-2-one;(4S)-4-cyclobutyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrido[2, 3 - d] [ 1 , 3 ]oxazin-2-one;(4R)-4-cyclobutyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-cyclobutyl-5-[6-(piperazin-l -yl)-4-(trifluoromethyl)pyri din-2 -yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (1,1,2,2,2-pentafluoroethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(1,1,2,2,2-pentafluoroethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(1,1,2,2,2- pentafluoroethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-5-[4-(1,1-difluoroethyl)-6-[(2R)-2-ethylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoroethyl)-6-[(2R)-2-ethylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(1,1,2,2,2- pentafluoroethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5 - {6- [(2R)-2-ethylpiperazin- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl } -4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[(2R)-2-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4S)-5-{6-[(2R)-2-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-(6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-fluoro-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;(4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-methylpyridin-2-yl}-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(1,1 -difluoroethyl)-5-[4-( 1 , 1 -difluoroethyl)-6-[(3 S)-3 -methylpiperazin- 1 - yl]pyridin-2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin- 2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(1,1-difluoroethyl)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(1,1-difluoroethyl)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(1,1-difluoroethyl)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5 - { 6- [(3 S)-3 -cy clopropylpiperazin- 1 -yl] -4-methylpyridin-2-yl }-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-(1,1-difluoropropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(1,1-difluoropropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-4-(cyclopropyldifluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin- 2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(cyclopropyldifluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin- 2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4-yl]pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[4-(difluoromethyl)piperidin-4-yl]-4-(1,1-difluoropropyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4S)-4-( 1 , 1 -difluoroethyl)-5-[6-(piperazin- 1 -yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4- (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(1,1-difluoroethyl)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-( 1 , 1 -difluoroethyl)-5-[4-(1,1 -difluoroethyl)-6-(piperazin- 1 -yl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(1,1-difluoroethyl)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-( 1 , 1 -difluoro-2-methoxyethyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl]pyridin-2- yl]-4-(difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-( 1 , 1 -difluoro-2-methoxyethyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl]pyridin-2- yl]-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoro-2-methoxyethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-( 1 , 1 -difluoro-2-methoxyethyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl]pyridin-2- yl]-4-(trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4- yl]pyridin-2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[4-(fluoromethyl)piperidin-4- yl]pyridin-2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[4-(difluoromethyl)piperidin-4-yl]-4-(1,1- difluoropropyl)pyridin-2-yl } - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[4-(difluoromethyl)piperidin-4-yl]-4-(1,1- difluoropropyl)pyridin-2-yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;(4R)-5-[4-(1,1 -difluoro-2-methoxyethyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl]pyridin-2- yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin- 2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-(fluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4S)-5-{6-[(3R)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5 - {6- [(3R)-3 -methylpiperazin- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl } -4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;5-{6-[(3R)-3-aminopyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(2R)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4S)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{6-[(2S)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;5-[6-(6-methyl-1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(3S)-3-(methylamino)pyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{6-[(3S)-3-aminopiperidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[6-(6-hydroxy-1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[6-(6-hydroxy-1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(3R)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[6-(3-aminoazetidin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one; l-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}pyrrolidine-3 -carbonitrile; l-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}pyrrolidine-3 -carbonitrile;(4R)-5-[l-(piperazin-1-yl)isoquinolin-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;(4R)-5-{6-[(lS,6R)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;(4R)-5-{6-[(l S,6S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;(4R)-5-{6-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{6-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-4-(trifluoromethyl)pyri din-2- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;5-{6-[(2-aminoethyl)amino]-4-(trifluoromethyl)pyridin-2-yl}-4-(tri fluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;5-{6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-(6-{[l-(aminomethyl)cyclopropyl]amino}-4-(trifluoromethyl)pyridin-2-yl)-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(4aS,8aR)-decahydroquinoxalin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(tri fluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(4aS,8aR)-decahydroquinoxalin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[6-(3,3-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5 - { 6- [(3 S, 5 S)-3 , 5 -dimethylpiperazin- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl } -4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(4aS,7aR)-octahydro-1H-cyclopenta[b]piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;(4R)-5-{6-[(4aS,7aR)-octahydro-1H-cyclopenta[b]piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;(4R)-5-{6-[(4aR,7aS)-octahydropyrrolo[3,4-b]morpholin-6-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;(4R)-5-{6-[(4aS,7aR)-octahydropyrrolo[3,4-b]morpholin-6-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d] [ 1 ,3 ] oxazin-2-one;(4R)-5 - { 6- [(3 S)-3 -methyl - 1 ,4-diazepan- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl }-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-(6-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{6-[(2R)-2-(hydroxymethyl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{6-[(2S)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[6-(4-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(3S)-3-aminopyrrolidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;N-[(3S)-1-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5- yl]-4-(trifluoromethyl)pyridin-2-yl}pyrrolidin-3-yl]acetamide(4R)-4-(difluoromethyl)-5-{6-[(2R)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[(3R)-3-(hydroxymethyl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-(6- {octahydro- 1H-cy cl openta[b]piperazin- 1 -yl } -4- (trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-(6- {octahydro- 1H-cy cl openta[b]piperazin- 1 -yl } -4- (trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;4-(difluoromethyl)-5-[6-(piperazin-l -yl)-4-(trifluoromethyl)pyri din-2 -yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;(4R)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2- yl } -4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ] oxazin-2-one;(4S)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2- yl } -4-m ethyl- 1H,2H,4H-pyrido[2, 3 -d] [ 1 , 3 ] oxazin-2-one;(4S)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-methyl-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-(difluoromethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-(difluoromethyl)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5 - { 6- [(3 S)-3 -(propan-2-yl)piperazin- 1 -yl ] -4-(trifluoromethyl)pyridin-2-yl }-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[(lS,6R)-3,8-diazabicyclo[4.2.0]octan-3-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-(6-{2,6-diazabicyclo[3.2.1]octan-6-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-(6-{2,6-diazabicyclo[3.2.1]octan-6-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[(3aR,6aS)-octahydropyrrolo[3,4-c]pyrrol-2-yl]-4-(trifluoromethyl)pyridin- 2-yl}-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-(6-{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4-(trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-(6-{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-4-(trifluoromethyl)pyridin-2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(propan- 2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(propan- 2-yl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4S)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1- yl]pyridin-2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1- yl]pyridin-2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-ethylpiperazin-1- yl]pyridin-2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-ethylpiperazin-1- yl]pyridin-2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl }- 1H,2H,4H-pyrimido[4,5-d] [1,3 ]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl } - 1H,2H,4H-pyrido[2, 3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1- yl]pyridin-2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1- yl]pyridin-2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-(cyclopropyldifluoromethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(cyclopropyldifluoromethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoro-2,2-dimethylpropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin- 2-yl]-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(cyclopropyldifluoromethyl)-6-(piperazin-1-yl)pyridin-2-yl]-4- (difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoro-2,2-dimethylpropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin- 2-yl]-4-(difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-(difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-(6-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-(6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-ethyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;5-{6-[(4aS,7aR)-octahydrofuro[3,4-b]piperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl}-4-ethyl-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5 - { 6- [(3 S)-3 -aminopiperi din- 1 -yl] -4-(trifluoromethyl)pyridin-2-yl } -4-ethyl - 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-{6-[(lR,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin- 2-yl}-4-ethyl-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;4-ethyl-5-{6-[(3S,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl }- 1H,2H,4H-pyrimido[4,5-d] [1,3 ]oxazin-2-one;5-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-{6-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;4-ethyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethoxy)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;4-ethyl-5-{6-[3-(2-hydroxypropan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;4-ethyl-5-[4-(2-hydroxypropan-2-yl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-{6-[(2R)-2-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-{6-[(lR,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-4-(trifluoromethyl)pyridin- 2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;5-[4-(1,1-difluoroethyl)-6-[(2R)-2-ethylpiperazin-1-yl]pyridin-2-yl]-4-ethyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;4-(1,1-difluoroethyl)-5-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-propyl- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-cyclopropyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;(4S)-4-cyclopropyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl } - 1H,2H,4H-pyrimido[4, 5-d] [ 1 ,3 ]oxazin-2-one;(4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;5-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-ethyl-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;(4R)-4-cyclopropyl-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin- 2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-cyclopropyl-5-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin- 2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-cy cl opropyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyri din-2 -yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-cyclopropyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[6-(3-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2- yl ] - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[6-(3-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2- yl ] - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;(4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(difluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-methylpyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5 - { 6- [(3 S)-3 -ethylpiperazin- 1 -yl ] -4-methylpyridin-2-yl } -4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5 - { 6- [(3 S)-3 -ethylpiperazin- 1 -yl] -4-methylpyridin-2-yl } -4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[(3S)-3-ethylpiperazin-1-yl]-4-methylpyridin-2-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H-pyrimido[4,5- d] [ 1 ,3 ] oxazin-2-one; methyl 2-[(4R)-4-(difluoromethyl)-2-oxo-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]- 6-(piperazin- 1 -yl)pyridine-4-carboxylate(4R)-4-(difluoromethyl)-5-[6-(piperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-[5-nitro-6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-( 1 , 1 -difluoroethyl)-5-[6-(piperazin- 1 -yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;5-{6-[(2S,3S)-2,3-dimethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[6-(4-methylpiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[6-(piperidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[6-(piperidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,3H,4H-pyrimido[4,5-d][1,3]diazin-2-one;(4R)-5-(6-{2-azabicyclo[3.1.1]heptan-5-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (difluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-methyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;3 - { 4- [(3 -chi oro-5 -{ [(2-chloro-4-fluoro-3 - hydroxyphenyl)methyl]amino}phenyl)methoxy]-1-oxo-1H,2H,3H-pyrrolo[3,4- c]pyridin-2-yl}piperidine-2, 6-dione;(4R)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;(4S)-4-ethyl-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;(4S)-4-ethyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-ethyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-4-methyl-5-{6-[(2,2,3,3,5,5,6,6-2H8)piperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl } - 1H,2H,4H-pyrido[2, 3 -d] [ 1 , 3 ]oxazin-2-one;(4S)-4-methyl-5-{6-[(2,2,3,3,5,5,6,6-2H8)piperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl }- 1H,2H,4H-pyrimido[4,5-d] [1,3 ]oxazin-2-one;5-[4-(cyclopentyldifluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[4-(1,1-difluoro-2-methylpropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2- yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-(cyclopropyldifluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]- 4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoropropyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoroethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-cyclopropyl-5-[4-(1,1-difluoropropyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin- 2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-cy clopropyl-5-[4-(1,1 -difluoropropyl)-6-[(3 S)-3 -methylpiperazin- 1 -yl]pyridin- 2-yl]-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(cyclopropyldifluoromethyl)-6-(1,4-diazepan-1-yl)pyridin-2-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoro-2-methylpropyl)pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;4-cyclopropyl-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoro-2-methylpropyl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;4-cyclopropyl-5-[6-(1,4-diazepan-1-yl)-4-(1,1-difluoro-2-methylpropyl)pyridin-2-yl]- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-[4-(1,1-difluoropropyl)-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{4-[difluoro(phenyl)methyl]-6-(piperazin-1-yl)pyridin-2-yl}-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{4-[difluoro(phenyl)methyl]-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4- (trifluoromethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;4-{6-[2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4- (trifluoromethyl)pyridin-2-yl}piperidin-2-one;(4R)-5-(6-{octahydropyrrolo[3,4-b]morpholin-4-yl}-4-(trifluoromethyl)pyridin-2-yl)-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;5-(6-{octahydropyrrolo[3,4-b]morpholin-6-yl}-4-(trifluoromethyl)pyridin-2-yl)-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[6-(piperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(trifluoromethyl)-5-[4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[6-(pyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[6-(pyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[6-(2,5-dihydro-1H-pyrrol-3-yl)-4-(trifluoromethyl)pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-4-(trifluoromethyl)-5-[4-(trifluoromethyl)- 1',2',5',6'-tetrahydro-[2,3'-bipyridine]-6-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[5'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4-(trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[3'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[3'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluoromethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[3'-ethyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[3'-ethyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[2'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[2'-methyl-4-(trifluoromethyl)- 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;(4R)-4-methyl-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;(4R)-5-{6-[(3 S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;(4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;(4S)-5-{6-[(2R)-2-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;(4R)-5-{6-[(2R)-2-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;(4S)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;(4R)-5-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl- 1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-2-one;4-(l-fluorocyclopropyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4- (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-4-(l-fluorocyclopropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;4-(l-fluorocyclopropyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-4-(fluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(fluoromethyl)-5-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4S)-4-( 1 -fluoroethyl)-5 - { 6- [(3 S)-3 -methylpiperazin- 1 -yl ] -4-(trifluoromethyl)pyridin- 2-yl } - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;(4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl } - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;(4S)-4-( 1 -fluoroethyl)-5 - { 6- [(3 S)-3 -methylpiperazin- 1 -yl] -4-(trifluoromethyl)pyridin- 2-yl } - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;(4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl } - 1H,2H,4H-pyrido[2,3 -d] [ 1 ,3 ]oxazin-2-one;(4S)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl }- 1H,2H,4H-pyrimido[4,5-d] [1,3 ]oxazin-2-one;(4S)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl }- 1H,2H,4H-pyrimido[4,5-d] [1,3 ]oxazin-2-one;(4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl }- 1H,2H,4H-pyrimido[4,5-d] [1,3 ]oxazin-2-one;(4R)-4-(l-fluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl }- 1H,2H,4H-pyrimido[4,5-d] [1,3 ]oxazin-2-one;(4R)-4-(1,1-difluoroethyl)-5-[6-(piperazin-1-yl)pyridin-2-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;4-{6-[(4R)-4-(1,1-difluoroethyl)-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-5-yl]-4-(trifluoromethyl)pyridin-2-yl}piperazin-2-one;5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2 -yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2 -yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one; methyl 3-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5- yl]-4-(trifluoromethyl)pyridin-2-yl}pyrrolidine-3-carboxylate methyl 3-{6-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5- yl]-4-(trifluoromethyl)pyridin-2-yl}pyrrolidine-3-carboxylate(4R)-5-{6-[3-(hydroxymethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{6-[3-(hydroxymethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(difluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-5-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;5-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;5-{6-[3-(difluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyri din-2 -yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;5-{6-[3-(difluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[4-cyclopropyl-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;2-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-6- (piperazin-1-yl)pyridine-4-carbonitrile(4R)-5-[4-ethyl-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;(4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;(4R)-5-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-4-(difluoromethyl)-1H,2H,4H- pyrido[2,3 -d] [1,3 ]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4- (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(1,1-difluoroethyl)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4- (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4- (trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(1,1 -difluoroethyl)-5-[4-( 1 , 1 -difluoroethyl)-6-[(3 S)-3 -methylpiperazin- 1 - yl]pyridin-2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4S)-4-( 1 , 1 -difluoroethyl)-5-[4-(1,1 -difluoroethyl)-6-[(3 S)-3 -methylpiperazin- 1 - yl]pyridin-2-yl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{6-[3-(fluoromethyl)pyrrolidin-3-yl]-4-(trifluoromethyl)pyridin-2-yl}-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[6-(3-fluoropiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one;(4R)-5-[6-(3-fluoropiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-4- (trifluorom ethyl)- 1H,2H,4H-pyrido[2,3 -d] [ 1 , 3 ]oxazin-2-one; or(4R)-4-(1,1-difluoroethyl)-5-[2-(piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one.

27. A pharmaceutical composition comprising the compound of Formula I, and a pharmaceutically acceptable carrier.

28. A method of treating, preventing, or managing a disease or disorder mediated by a protein kinase C theta (PKC-theta) mutant in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound of any one of claims 1-27 or a pharmaceutical composition of claim 28 to the subject.

29. The method of claim 29, wherein the disease or disorder is an inflammatory disease, an autoimmune disorder, a cancer, an oncologic disease, or an autoimmune infection.

30. The method of claim 30, wherein the disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, or atopic dermatitis.

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