PKC-theta inhibitors, compositions, and methods of use

Abstract

The present invention provides a compound of Formula (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 CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 63 / 656,806 filed June 6, 2024 which is incorporated herein in its entirety. FIELD OF THE INVENTION 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. BACKGROUND 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, beta1, 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;361.). 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-^^^^B), 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). 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. SUMMARY 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. These, and other features of the invention will be set forth in expanded form in this disclosure. The first aspect of the present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt wherein, R1is selected from the group consisting of: −CH= and −N=; R2is selected from the group consisting of: −NH− and −O−; R3is selected from the group consisting of:

[0002] , , ; R4is selected from the group consisting of alkyl and −CF2R16; R5is selected from the group consisting of: ; R6is selected from the group consisting of: −H and −F; R7is selected from the group consisting of: (4-fluoropiperidin-4-yl)methyl, , ; R8is selected from the group consisting of: −H, −CH3, and −CF3; R9is selected from the group consisting of: R11is selected from the group consisting of 3-fluoropiperidin-4-yl and 4- (methylamino)cyclohexyl; R12is selected from the group consisting of azetidin-3-yl, 1-(cyanomethyl)cyclobutyl, (4- fluoropiperidin-4-yl)methyl, , , , R13is selected from the group consisting of: −H and −CH3; R14is selected from the group consisting of: −H, −CH3, −F, and −CF3; R15is selected from the group consisting of: −H, −CH3, and cyclopropyl; R16is selected from the group consisting of: −H, −CH3, and −F; R17is selected from the group consisting of: −H and −F; R18is selected from the group consisting of: −H and −F; R19is selected from the group consisting of: −NH2and −NHCH3; R20is selected from the group consisting of: −H and −CH3; R21is selected from the group consisting of: −CO− and −CH(R24)−; R22is selected from the group consisting of: −H and cyclopropyl; R23is selected from the group consisting of: −H, −CH3, −F, and −OCH3; R24is selected from the group consisting of: −H and −CH3. Further disclosed is a compound selected from a group consisting of: 2-(1-{3-[(4S)-4-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-5-yl]-1H-indazol-1- yl}cyclobutyl)acetonitrile; 2-(1-{3-[(4S)-4-methyl-2-oxo-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-1H-indazol-1- yl}cyclobutyl)acetonitrile; (4S)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-indazol-3-yl}-4-methyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; 2-(1-{3-[(4S)-4-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-5-yl]-1H-pyrazolo[3,4- b]pyridin-1-yl}cyclobutyl)acetonitrile; (4S)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-5-methyl-1H-pyrazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-5-(trifluoromethyl)-1H-pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[1-(azetidin-3-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-6-(trifluoromethyl)-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4S)-5-[3-(piperazin-1-yl)-1H-indazol-1-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[3-(piperazin-1-yl)-1H-indazol-1-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(1r,4r)-4-aminocyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(2S,4R)-2-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; 4-{3-[2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-1H-indazol-1- yl}piperidin-2-one; 2-(1-{6-methyl-3-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]- 1H-indazol-1-yl}cyclobutyl)acetonitrile; 2-(1-{6-fluoro-3-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]- 1H-indazol-1-yl}cyclobutyl)acetonitrile; (4R)-5-{1-[(1s,4s)-4-aminocyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(1r,4r)-4-(methylamino)cyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[5-methyl-1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrimido[4,5- d][1,3]oxazin-2-one; (4R)-5-[5-methyl-1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-(1-{2-azaspiro[3.3]heptan-6-yl}-5-methyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-(1-{2-azaspiro[3.3]heptan-6-yl}-1H-indazol-3-yl)-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[1-(piperidin-4-yl)-1H-indazol-3-yl]-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[4-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[5,6-difluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[7-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-(1-{2-azaspiro[3.5]nonan-7-yl}-1H-indazol-3-yl)-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R)-pyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S)-pyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; 2-(1-{3-[(5R)-5-(difluoromethyl)-7-oxo-5H,6H,7H,8H-pyrimido[4,5-d][1,3]diazin-4-yl]-1H- indazol-1-yl}cyclobutyl)acetonitrile; (4R)-4-(difluoromethyl)-5-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{3-[(3S)-3-methylpiperazin-1-yl]-1H-indazol-1-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{3-[(3S)-3-cyclopropylpiperazin-1-yl]-1H-indazol-1-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[1-(piperidin-4-yl)-1H-indazol-3-yl]-1H,2H,4H-pyrimido[4,5- d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(4-methylpiperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(2S,4S)-2-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R)-pyrrolidin-3-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S)-pyrrolidin-3-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(1r,4r)-4-(methylamino)cyclohexyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R)-pyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S)-pyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4R)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4R)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4S)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4R)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-5-(trifluoromethyl)-1H-pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-5-(trifluoromethyl)-1H-pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[5,5-difluoro-5a-methyl-1-(piperidin-4-yl)-1H,4H,4aH,5H,5aH,6H- cyclopropa[f]indazol-3-yl]-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-[5,5-difluoro-5a-methyl-1-(piperidin-4-yl)-1H,4H,4aH,5H,5aH,6H- cyclopropa[f]indazol-3-yl]-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one (4R)-4-(difluoromethyl)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-methoxypiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-pyrazolo[3,4-c]pyridin-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(1r,4r)-4-amino-4-methylcyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4S,5R)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4R,5S)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4S,5S)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4R,5R)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(1-cyclopropylpiperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{5-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-(1-{4-azaspiro[2.5]octan-7-yl}-1H-indazol-3-yl)-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4S)-azepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-{1-[(4R)-azepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; ; or (4R)-5-[1-(pyrrolidin-3-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION 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. Definitions Chemical Definitions 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 chemistry, 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. 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. 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. 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. 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. 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. 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). Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences. 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. 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. Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds. 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. The terms "halo" and "halogen," as used herein, refer to F, Cl, Br, and I. The term "cyano" refers to the group −CN. The term "amino" refers to the group −NH2. The term "oxo" refers to the group =O. 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- methylpentyl, 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. 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. 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. 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. The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes −CH2OH, −CH2CH2OH, and C1−4hydroxyalkyl. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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). 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. "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. 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." 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. 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. 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. 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 compounds 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. 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. "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 administration 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 non- mammalian 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. "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. 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. "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. 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. 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 "co- administer" 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). 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. 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. Cancer 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. 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.

[0003] The first aspect of the present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt wherein, R1is selected from the group consisting of: −CH= and −N=; R2is selected from the group consisting of: −NH− and −O−; R3is selected from the group consisting of: R4is selected from the group consisting of alkyl and −CF2R16; R5is selected from the group consisting of: ; R6is selected from the group consisting of: −H and −F; R7is selected from the group consisting of: (4-fluoropiperidin-4-yl)methyl, , ; R8is selected from the group consisting of: −H, −CH3, and −CF3; R9is selected from the group consisting of: ; R10is selected from the group consisting of: , , , ; R11is selected from the group consisting of 3-fluoropiperidin-4-yl and 4- (methylamino)cyclohexyl; R12is selected from the group consisting of azetidin-3-yl, 1-(cyanomethyl)cyclobutyl, (4- fluoropiperidin-4-yl)methyl, , R13is selected from the group consisting of: −H and −CH3; R14is selected from the group consisting of: −H, −CH3, −F, and −CF3; R15is selected from the group consisting of: −H, −CH3, and cyclopropyl; R16is selected from the group consisting of: −H, −CH3, and −F; R17is selected from the group consisting of: −H and −F; R18is selected from the group consisting of: −H and −F; R19is selected from the group consisting of: −NH2and −NHCH3; R20is selected from the group consisting of: −H and −CH3; R21is selected from the group consisting of: −CO− and −CH(R24)−; R22is selected from the group consisting of: −H and cyclopropyl; R23is selected from the group consisting of: −H, −CH3, −F, and −OCH3; R24is selected from the group consisting of: −H and −CH3. In one embodiment of the compound of formula (I): R4is selected from the group consisting of: −CH3and −CF2R16. In another embodiment of the compound of formula (I): R1is −CH=; R2is −O−; R3is ; ; R13is −H; R14is −H; R16is −F; R18is −H. In one embodiment of the compound of formula (I): R1is −CH=; R2is −O−; R3is ; R4is −CF2R16; R6is −H; R12is ; R13is −H; R14is −H; R16is −F; R18is −H. Further disclosed is a compound selected from a group consisting of: 2-(1-{3-[(4S)-4-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-5-yl]-1H-indazol-1- yl}cyclobutyl)acetonitrile; 2-(1-{3-[(4S)-4-methyl-2-oxo-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-1H-indazol-1- yl}cyclobutyl)acetonitrile; (4S)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-indazol-3-yl}-4-methyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; 2-(1-{3-[(4S)-4-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-5-yl]-1H-pyrazolo[3,4- b]pyridin-1-yl}cyclobutyl)acetonitrile; (4S)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-4-methyl- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-5-methyl-1H-pyrazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-5-(trifluoromethyl)-1H-pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[1-(azetidin-3-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-6-(trifluoromethyl)-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4S)-5-[3-(piperazin-1-yl)-1H-indazol-1-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[3-(piperazin-1-yl)-1H-indazol-1-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(1r,4r)-4-aminocyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(2S,4R)-2-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; 4-{3-[2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-1H-indazol-1- yl}piperidin-2-one; 2-(1-{6-methyl-3-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]- 1H-indazol-1-yl}cyclobutyl)acetonitrile; 2-(1-{6-fluoro-3-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]- 1H-indazol-1-yl}cyclobutyl)acetonitrile; (4R)-5-{1-[(1s,4s)-4-aminocyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(1r,4r)-4-(methylamino)cyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[5-methyl-1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrimido[4,5- d][1,3]oxazin-2-one; (4R)-5-[5-methyl-1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-(1-{2-azaspiro[3.3]heptan-6-yl}-5-methyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-(1-{2-azaspiro[3.3]heptan-6-yl}-1H-indazol-3-yl)-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[1-(piperidin-4-yl)-1H-indazol-3-yl]-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[4-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[5,6-difluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[7-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-(1-{2-azaspiro[3.5]nonan-7-yl}-1H-indazol-3-yl)-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R)-pyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S)-pyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; 2-(1-{3-[(5R)-5-(difluoromethyl)-7-oxo-5H,6H,7H,8H-pyrimido[4,5-d][1,3]diazin-4-yl]-1H- indazol-1-yl}cyclobutyl)acetonitrile; (4R)-4-(difluoromethyl)-5-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{3-[(3S)-3-methylpiperazin-1-yl]-1H-indazol-1-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{3-[(3S)-3-cyclopropylpiperazin-1-yl]-1H-indazol-1-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[1-(piperidin-4-yl)-1H-indazol-3-yl]-1H,2H,4H-pyrimido[4,5- d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(4-methylpiperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(2S,4S)-2-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R)-pyrrolidin-3-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S)-pyrrolidin-3-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(1r,4r)-4-(methylamino)cyclohexyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R)-pyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S)-pyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4R)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4R)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4S)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4R)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-5-(trifluoromethyl)-1H-pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-5-(trifluoromethyl)-1H-pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[5,5-difluoro-5a-methyl-1-(piperidin-4-yl)-1H,4H,4aH,5H,5aH,6H- cyclopropa[f]indazol-3-yl]-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-[5,5-difluoro-5a-methyl-1-(piperidin-4-yl)-1H,4H,4aH,5H,5aH,6H- cyclopropa[f]indazol-3-yl]-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one (4R)-4-(difluoromethyl)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-methoxypiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-pyrazolo[3,4-c]pyridin-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(1r,4r)-4-amino-4-methylcyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4S,5R)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4R,5S)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4S,5S)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4R,5R)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(1-cyclopropylpiperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{5-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-(1-{4-azaspiro[2.5]octan-7-yl}-1H-indazol-3-yl)-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4S)-azepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-{1-[(4R)-azepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; ; or (4R)-5-[1-(pyrrolidin-3-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-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. 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. In one embodiment, the disease or disorder is an inflammatory disease, an autoimmune disorder, a cancer, an oncologic disease, or an autoimmune infection. In another embodiment, the disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis or atopic dermatitis. These embodiments are not intended to limit the scope of the invention. SYNTHETIC METHODS 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. 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

[0004] Preparation of Intermediates INT-1 tert-butyl (S)-5-chloro-4-methyl-2-oxo-2H-pyrido[2,3-d][1,3]oxazine-1(4H)-carboxylate Boc 5-chloro-4-methyl-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one To a solution of tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate (5000 mg, 19.48 mmol) in THF (30 mL) was added methylmagnesium bromide solution in dibutyl ether (3M, 13.0 mL, 39.0 mmol) and the reaction mixture was stirred at 0 °C for 3h. To the reaction mixture was then added sodium carbonate (4.13 g, 39.0 mmol), the reaction mixture was heated to 60 °C for 6 hours. 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 to afford the crude intermediate. The product was used in the next step directly without further purification. LCMS (ESI, m / z): 199 [M+H]+. INT-1 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. The racemate of tert-butyl 5-chloro-4-methyl-2-oxo-2H-pyrido[2,3-d][1,3]oxazine-1(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. RT1(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-1(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-1(4H)-carboxylate (the second eluting peak, 458.1 mg) both as white solid. LCMS (ESI, m / z): 199.1 [M- Boc+H]+. INT-2 (R)-5-chloro-4-(trifluoromethyl)-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 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 NH4Cl (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-chloro-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 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 tert- butyl (R)-(4-chloro-3-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)carbamate (40 g, 90%) as a pink solid. LCMS (ESI, m / z): 327; 329 [M+H]+. INT-2 To a solution of tert-butyl (R)-(4-chloro-3-(2,2,2-trifluoro-1-hydroxyethyl)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. 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). INT-3 (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one 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) portion-wise. After being stirred at this temp for 30 minutes, a premade solution of 1-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 NH4Cl (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-chloro-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-3150 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 0262 Detector Wavelength: 220 nm Injection Volume: 2 µL Sample Preparation: 1.0 mg / mL of the sample in Acetonitrile INT-4 (R)-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid 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)-(1-(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. 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-5 (R)-5-chloro-4-(trifluoromethyl)-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 N-(6-chloropyrimidin-4-yl)carbamate (20 g, 87.09 mmol) in THF (500 mL) was added n-BuLi (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-hydroxyethyl)pyrimidin-4-yl)carbamate 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 (R,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-1-hydroxyethyl)pyrimidin-4-yl)carbamate (7 g, 63.2%) as a light-yellow solid. LCMS (ESI, m / z): 328, 330 [M+H]+. INT-5 To a stirred solution of tert-butyl (R)-(6-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrimidin- 4-yl)carbamate (14 g, 42.72 mmol) in toluene (150 mL) was added N-ethyl-N- 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). INT-6 (R)-5-chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (R)-(4-chloro-3-(2,2-difluoro-1-hydroxyethyl)pyridin-2-yl)carbamate The racemic tert-butyl (4-chloro-3-(2,2-difluoro-1-hydroxyethyl)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(1%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]+. INT-6 To a solution of tert-butyl (R)-(4-chloro-3-(2,2-difluoro-1-hydroxyethyl)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. 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). INT-7 5-chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (6-chloropyrimidin-4-yl)carbamate 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 NNHBocN O ClCF2HA 1 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). 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-1-hydroxyethyl)pyrimidin-4-yl)carbamate 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). INT-7 A mixture of tert-butyl (6-chloro-5-(2,2-difluoro-1-hydroxyethyl)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) INT-8 (R)-5-chloro-4-(difluoromethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one tert-butyl (S)-(6-chloro-5-(2,2-difluoro-1-hydroxyethyl)pyrimidin-4-yl)carbamate N NHBoc N OH Cl CF2H24 g (77.5 mmol) of tert-butyl (6-chloro-5-(2,2-difluoro-1-hydroxyethyl)pyrimidin-4- yl)carbamate was separated by chrial SFC (Chiralcel 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-hydroxyethyl)pyrimidin-4-yl)carbamate. tert-butyl (R)-(5-(1-azido-2,2-difluoroethyl)-6-chloropyrimidin-4-yl)carbamate DBU (0.584 mL, 3.87 mmol) was added to a mixture of tert-butyl (S)-(6-chloro-5-(2,2- difluoro-1-hydroxyethyl)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-(1-azido-2,2-difluoroethyl)-6-chloropyrimidin- 4-yl)carbamate (224 mg, 0.669 mmol, 20.73 % yield). Stereochemical inversion was assumed. LC / MS(ESI, m / z): 278.7 [M+H-56]+INT-8 A mixture of tert-butyl (R)-(5-(1-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]+Example 1 (S)-2-(1-(3-(4-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl)-1H-indazol- 1-yl)cyclobutyl)acetonitrile To a solution of 2-(1-(3-bromo-1H-indazol-1-yl)cyclobutyl)acetonitrile (50 mg, 0.12 mmol) and bis(pinacolato)diboron (22 mg, 0.03 mmol) in 1,4-dioxane (4 mL), were added Pd(dppf)Cl2 (22 mg, 0.03 mmol) and KOAc ( 35 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16h under a nitrogen atmosphere. The reaction mixture was allowed to cool to rt and was used directly for next step without work-up or purification. LCMS (ESI, m / z): 256 [M+H]+boronic acid. To the reaction mixture from previous step were added (S)-5-chloro-4-methyl-1,4-dihydro- 2H-pyrimido[4,5-d][1,3]oxazin-2-one (24 mg, 0.12 mmol), DMF (1 mL), Pd(dppf)Cl2(22 mg, 0.03 mmol) and Cs2CO3(119 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16h. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 21-61 %B (0.0-20.0 min), 61-100 %B (20.0- 20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (9.8 mg). LCMS (ESI, m / z): 375 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.66 min. Example 2 (S)-2-(1-(3-(4-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1- yl)cyclobutyl)acetonitrile To a solution of bis(pinacolato)diboron (48.1 mg, 0.190 mmol), 2-(1-(3-bromo-1H-indazol- 1-yl)cyclobutyl)acetonitrile (50 mg, 0.17 mmol) and KOAc (50.7 mg, 0.517 mmol) in dioxane (4.0 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (25.2 mg, 0.034 mmol). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 3h. Bronic acid intermediate was observed on LCMS. LCMS (ESI, m / z): 256 [M+H]+. The resulting reaction mixture was allowed to cool down to rt. To the crude reaction mixture was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (6.3 mg, 0.0085 mmol), cesium carbonate (168 mg, 0.517 mmol) and tert-butyl (S)-5-chloro-4- methyl-2-oxo-2H-pyrido[2,3-d][1,3]oxazine-1(4H)-carboxylate (51.5 mg, 0.172 mmol), dioxane (1 mL) and H2O (1 mL). The resulting mixture was stirred at 80 °C for 4h under nitrogen atmosphere. The reaction mixture was filtered and concentrated. To the crude mixture was added 3mL 4.0 M HCl in dioxane and the resulting mixture was stirred for 4 hours at 60 °C. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 20-60 %B (0.0-20.0 min), 60-100 %B (20.0- 20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was repurified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.1 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.1 % TFA; Gradient: 18-58 %B (0.0-20.0 min), 58-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (4.7 mg). LCMS (ESI, m / z): 373.8 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.62 min. Example 3 (S)-5-(1-((4-fluoropiperidin-4-yl)methyl)-1H-indazol-3-yl)-4-methyl-1,4-dihydro-2H- pyrimido[4,5-d][1,3]oxazin-2-one tert-butyl (S)-4-fluoro-4-((3-(4-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5- yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate To a solution of tert-butyl 4-((3-bromo-1H-indazol-1-yl)methyl)-4-fluoropiperidine-1- carboxylate (50 mg, 0.12 mmol) and bis(pinacolato)diboron (22 mg, 0.03 mmol) in 1,4- dioxane (4 mL) was added Pd(dppf)Cl2 (22 mg, 0.03 mmol) and KOAc ( 35 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16h under a nitrogen atmosphere. The reaction mixture was allowed to cool to rt and was used directly for next step without work-up or purification. LCMS (ESI, m / z): 358 [M+H]+boronic acid To the reaction mixture from previous step were added (S)-5-chloro-4-methyl-1,4-dihydro- 2H-pyrimido[4,5-d][1,3]oxazin-2-one (24 mg, 0.12 mmol), DMF (1 mL), Pd(dppf)Cl2(22 mg, 0.03 mmol) and Cs2CO3(119 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16h. The reaction was concentrated under vacuum to afford the title compound as a brown oil. LCMS (ESI, m / z): 441 [M+H]+Example 3 To a solution of tert-butyl (S)-4-fluoro-4-((3-(4-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (20 mg, 0.04 mmol) was added 6M HCl in IPA (2 mL). The resulting solution was stirred at 60 °C for 10 min. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.1 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.1 % TFA; Gradient: 7-37 %B (0.0-20.0 min), 37-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (4.9 mg). LCMS (ESI, m / z): 397.1 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.17 min. Example 4 (S)-2-(1-(3-(4-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl)-1H- pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)acetonitrile To a solution 2-(1-(3-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)acetonitrile (50 mg, 0.12 mmol) and bis(pinacolato)diboron (22 mg, 0.03 mmol) in 1,4-dioxane (4 mL) , were added Pd(dppf)Cl2 (22 mg, 0.03 mmol) and KOAc ( 35 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16h under a nitrogen atmosphere. The reaction mixture was allowed to cool to rt and was used directly for next step without work-up or purification. LCMS (ESI, m / z): 256 [M+H]+boronic acid To the reaction mixture from previous step were added (S)-5-chloro-4-methyl-1,4-dihydro- 2H-pyrimido[4,5-d][1,3]oxazin-2-one (24 mg, 0.12 mmol), DMF (1 mL), Pd(dppf)Cl2(22 mg, 0.03 mmol) and Cs2CO3(119 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16h. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 19-59 %B (0.0-20.0 min), 59-100 %B (20.0- 20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (5.3 mg). LCMS (ESI, m / z): 375.8 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.56 min. Example 5 (S)-5-(1-((4-fluoropiperidin-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-methyl-1,4- dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one tert-butyl 4-((3-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)-4-fluoropiperidine-1- carboxylate 3-bromo-1H-pyrazolo[3,4-b]pyridine (63.7 mg, 0.321 mmol), tert-butyl 4-fluoro-4- (hydroxymethyl)piperidine-1-carboxylate (150 mg, 0.643 mmol), CMBP (155 mg, 0.643 mmol), Toluene (1072 µl) were added to a 40 mL vial under nitrogen. The reaction was stirred at 85 °C overnight. The reaction was concentrated and purified by normal phase column (Hex:EtOAc, 0-60%) to afford the title compound. LCMS (ESI, m / z): 359 [M+H]+ tert-butyl 4-fluoro-4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4- b]pyridin-1-yl)methyl)piperidine-1-carboxylate To a solution tert-butyl 4-((3-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)-4- fluoropiperidine-1-carboxylate (50 mg, 0.12 mmol) and bis(pinacolato)diboron (22 mg, 0.03 mmol) in 1,4-dioxane (4 mL), were added Pd(dppf)Cl2(22 mg, 0.03 mmol) and KOAc ( 35 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16h under a nitrogen atmosphere. The reaction mixture was allowed to cool to rt and was used directly for next step without work-up or purification. LCMS (ESI, m / z): 323 [M+H]+boronic acid tert-butyl (S)-4-fluoro-4-((3-(4-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5- yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)piperidine-1-carboxylate To a solution tert-butyl 4-((3-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)-4- fluoropiperidine-1-carboxylate (50 mg, 0.12 mmol) and bis(pinacolato)diboron (22 mg, 0.03 mmol) in 1,4-dioxane (4 mL) , were added Pd(dppf)Cl2 (22 mg, 0.03 mmol) and KOAc ( 35 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16h under a nitrogen atmosphere. The reaction mixture was allowed to cool to rt and was used directly for next step without work-up or purification. LCMS (ESI, m / z): 323 [M+H]+. To the reaction mixture from previous step were added (S)-5-chloro-4-methyl-1,4-dihydro- 2H-pyrimido[4,5-d][1,3]oxazin-2-one (24 mg, 0.12 mmol), DMF (1 mL), Pd(dppf)Cl2(22 mg, 0.03 mmol) and Cs2CO3(119 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 h. The reaction was filtered and concentrated under vacuum to afford the title compound. LCMS (ESI, m / z): 442 [M+H]+Example 5 To a solution of tert-butyl (S)-4-fluoro-4-((3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (20 mg, 0.04 mmol) was added 6 M HCl in IPA (2 mL). The resulting solution was stirred at room temperature for 10 min. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 0-30 %B (0.0-20.0 min), 30-100 %B (20.0- 20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (5.3 mg). LCMS (ESI, m / z): 398[M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.01 min. Example 6 (S)-5-(1-((4-fluoropiperidin-4-yl)methyl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (S)-4-fluoro-4-((3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate To a solution of tert-butyl 4-((3-bromo-1H-indazol-1-yl)methyl)-4-fluoropiperidine-1- carboxylate (50 mg, 0.12 mmol) and bis(pinacolato)diboron (22 mg, 0.03 mmol) in 1,4- dioxane (4 mL) were added Pd(dppf)Cl2 (22 mg, 0.03 mmol) and KOAc ( 35 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to rt and was used directly for next step without work-up or purification. LCMS (ESI, m / z): 378 [M+H]+. To the reaction mixture from previous step was added (S)-5-chloro-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (24 mg, 0.12 mmol), DMF (1 mL), Pd(dppf)Cl2(22 mg, 0.03 mmol) and Cs2CO3(119 mg, 0.36 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 h. The reaction was filtered and concentrated under vacuum to afford the title compound. LCMS (ESI, m / z): 494 [M+H]+. Example 6 To a solution of tert-butyl (S)-4-fluoro-4-((3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (20 mg, 0.04 mmol) was added 6 M HCl in IPA (2 mL). The resulting solution was stirred at room temperature for 10 min. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.1 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.1 % TFA; Gradient: 12-42 %B (0.0-20.0 min), 42-100 %B (20.0- 20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (10.3 mg). LCMS (ESI, m / z): 450.1 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 0.99 min. Example 7 (R)-5-(1-((4-fluoropiperidin-4-yl)methyl)-5-methyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)- 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 4-((3-bromo-5-methyl-1H-pyrazol-1-yl)methyl)-4-fluoropiperidine-1-carboxylate In a vial equipped with a stir bar 3-bromo-5-methyl-1H-pyrazole (200 mg, 1.242 mmol), tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (580 mg, 2.484 mmol), CMBP (899 mg, 3.73 mmol) and toluene (4141 µl) was added. The reaction was stirred at 100 °C overnight. The reaction was allowed to cool to rt and concentrated. The residue was purified using ISCO normal phase (SiO2, 0-50% EtOAc / hexanes) to afford the title compound (300 mg) which was used without additional purification. LCMS (ESI, m / z): 377 [M+H]+ tert-butyl 4-fluoro-4-((5-methyl-3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate To a solution of tert-butyl 4-((3-bromo-5-methyl-1H-pyrazol-1-yl)methyl)-4- fluoropiperidine-1-carboxylate (74.5 mg, 0.198 mmol) and Bis(pinacolato)diboron (75 mg, 0.297 mmol) in 1,4-dioxane (4 mL) , were added Pd(dppf)Cl2 (14 mg, 0.02 mmol) and KOAc (58.3 mg, 0.594 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16h under a nitrogen atmosphere. The reaction mixture was allowed to cool to rt and was used directly for next step without work-up or purification. LCMS (ESI, m / z): 286 [M+H]+ boronic acid. To the reaction mixture from previous step were added 5-chloro-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (50 mg, 0.198 mmol, water (0.5 mL), 1,4- dioxane (1 mL), Pd(dppf)Cl2 (14 mg, 0.02 mmol) and Cs2CO3 (193 mg, 0.594 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The reaction was filtered and concentrated under vacuum to afford the title compound as a brown oil. LCMS (ESI, m / z): 458 [M+H]+Example 7 To a solution of tert-butyl 4-fluoro-4-((5-methyl-3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (20 mg, 0.04 mmol) was added 6M HCl in IPA (2 mL). The resulting solution was stirred at room temperature for 10 min. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 2-32 %B (0.0-20.0 min), 32-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was repurified by preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 4-39 %B (0.0-20.0 min), 39-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (7.5 mg). LCMS (ESI, m / z): 414.2 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.21 min. Example 8 (R)-5-(1-((4-fluoropiperidin-4-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4- (trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 4-((3-bromo-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-4-fluoropiperidine-1- carboxylate In a vial equipped with a stir bar 3-bromo-5-(trifluoromethyl)-1H-pyrazole (30 mg, 0.140 mmol), tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (65.1 mg, 0.279 mmol), CMBP (101 mg, 0.419 mmol) and Toluene (465 µl) was added. The reaction was stirred at 100 °C overnight. The reaction was allowed to cool to rt and concentrated. The residue was purified using ISCO normal phase (SiO2, 0-50% EtOAc / hexanes) to afford the title compound (30 mg) which was used without additional purification. LCMS (ESI, m / z): 431 [M+H]+. tert-butyl 4-fluoro-4-((3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate To a solution tert-butyl 4-((3-bromo-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-4- fluoropiperidine-1-carboxylate (74.5 mg, 0.198 mmol) and Bis(pinacolato)diboron (75 mg, 0.297 mmol) in 1,4-dioxane (4 mL) , were added Pd(dppf)Cl2 (14 mg, 0.02 mmol) and KOAc (58.3 mg, 0.594 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16h under a nitrogen atmosphere. The reaction mixture was allowed to cool to rt and was used directly for next step without work-up or purification. LCMS (ESI, m / z): 340 [M+H]+. To the reaction mixture from previous step were added 5-chloro-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (50 mg, 0.198 mmol, water (0.5 mL), Dioxane (1 mL), Pd(dppf)Cl2(14 mg, 0.02 mmol) and Cs2CO3(193 mg, 0.594 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16h under nitrogen atmosphere. The reaction was concentrated under vacuum to afford the title compound as a brown oil. LCMS (ESI, m / z): 568 [M+H]+Example 8 To a solution of tert-butyl 4-fluoro-4-((3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)piperidine-1- carboxylate (20 mg, 0.04 mmol) was added 6 M HCl in IPA (2 mL). The resulting solution was stirred at room temperature for 10 min. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 9-39 %B (0.0-20.0 min), 39-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporatio. The material was repurified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 10-40 %B (0.0-20.0 min), 40-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (1.0 mg). LCMS (ESI, m / z): 468.2 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.29 min. Example 9 (R)-5-(1-(piperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one tert-butyl 4-(3-bromo-1H-indazol-1-yl)piperidine-1-carboxylate A mixture of 3-bromo-1H-indazole (400 mg, 2.03 mmol), tert-butyl 4-(tosyloxy)piperidine-1- carboxylate (866 mg, 2.44 mmol) and cesium carbonate (992 mg, 3.05 mmol) in DMF (15 mL) was sealed and heated at 85 °C for 2 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 (40 g silica gel column, gradient elution from 0 to 20% of ethyl acetate in hexanes) afforded tert-butyl 4-(3- bromo-1H-indazol-1-yl)piperidine-1-carboxylate (451 mg). LCMS (ESI, m / z): 379.7, 381.7 [M+H]+.1H NMR (500 MHz, chloroform-d) δ 7.68 - 7.59 (m, 1H), 7.46 - 7.39 (m, 2H), 7.24 (ddd, J=8.1, 4.5, 3.5 Hz, 1H), 4.55 (tt, J=11.5, 4.1 Hz, 1H), 4.34 (br s, 2H), 2.96 (br s, 2H), 2.26 (br d, J=10.7 Hz, 2H), 2.02 (br d, J=11.0 Hz, 2H), 1.51 (s, 9H). tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1- carboxylate Boc A degassed mixture of tert-butyl 4-(3-bromo-1H-indazol-1-yl)piperidine-1-carboxylate (100 mg, 0.263 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (73.5 mg, 0.289 mmol), PdCl2(dppf)-CH2Cl2adduct (32 mg, 0.039 mmol) and potassium acetate (77 mg, 0.79 mmol) in DMF (2.5 mL) was sealed and heated at 90 °C for 12 h. The reaction mixture was cooled to rt, poured into water and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The resulting tar was shown to contain tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazol-1-yl)piperidine-1-carboxylate by LCMS and was taken up into DMF (2 mL) and carried on as a crude for the next step. LCMS (ESI, m / z): 345.8 [M+H]+. tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (20 mg, 0.054 mmol), crude tert-butyl 4-(3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (34.4 mg, 0.080 mmol), [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (7.0 mg, 11 µmol) and cesium carbonate (52.4 mg, 0.161 mmol) in DMF (0.5 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo to afford tert-butyl (R)-4-(3-(1-(4- methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)- 1H-indazol-1-yl)piperidine-1-carboxylate. LCMS (ESI, m / z): 638.2 [M+H]+. Example 9 The residue mentioned above was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was taken up into MeOH and purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 16-56 %B (0.0-20.0 min), 56-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (7.6 mg). LCMS (ESI, m / z): 418.4 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.27 min.1H NMR (500 MHz, DMSO-d6) Shift 8.52 (d, J=5.3 Hz, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.77 (d, J=5.3 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.40 - 7.21 (m, 2H), 5.08 - 4.78 (m, 1H), 3.13 (br d, J=11.3 Hz, 2H), 2.76 (br t, J=11.7 Hz, 2H), 2.18 - 1.91 (m, 4H). Example 10 (R)-5-(1-(azetidin-3-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one tert-butyl 3-(3-bromo-1H-indazol-1-yl)azetidine-1-carboxylate A mixture of 3-bromo-1H-indazole (400 mg, 2.03 mmol), tert-butyl 3-bromoazetidine-1- carboxylate (719 mg, 3.05 mmol) and cesium carbonate (1060 mg, 3.25 mmol) in DMF (12 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 to 20% of ethyl acetate in hexanes) afforded tert- butyl 3-(3-bromo-1H-indazol-1-yl)azetidine-1-carboxylate (413 mg, 1.17 mmol). LCMS (ESI, m / z): 351.8 [M+H]+. tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)azetidine-1- carboxylate To a degassed mixture of tert-butyl 3-(3-bromo-1H-indazol-1-yl)azetidine-1-carboxylate (45 mg, 0.130 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (38.9 mg, 0.153 mmol) and potassium acetate (37.6 mg, 0.383 mmol) in DMF (1 mL) was added PdCl2(dppf)- CH2Cl2adduct (16 mg, 0.019 mmol). The reaction mixture was degassed for 5 min., sealed and heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The resulting tar was shown to contain tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)azetidine-1-carboxylate by LCMS and was used without additional purification. LCMS (ESI, m / z): 317.9 [M+H]+. An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (30 mg, 0.080 mmol), tert-butyl 3-(3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)azetidine-1-carboxylate (48.2 mg, 0.121 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (10.5 mg, 0.016 mmol) and cesium carbonate (79 mg, 0.241 mmol) in DMF (1 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was used for the next reaction without further purification. LCMS (ESI, m / z): 610.2 [M+H]+. Example 10 The residue mentioned above was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was taken up into MeOH and purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 16-56 %B (0.0-20.0 min), 56-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (6.4 mg). LCMS (ESI, m / z): 389.7 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.3 min. Example 11 (R)-5-(6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (42 mg, 0.113 mmol), tert-butyl 4-(6-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (75 mg, 0.169 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (14.69 mg, 0.023 mmol) and cesium carbonate (110 mg, 0.338 mmol) in DMF (1 mL) was sealed and heated at 90 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was used for the next reaction without further purification. LCMS (ESI, m / z): 656.2 [M+H]+. Example 11 The residue mentioned above was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was taken up into MeOH and purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 12-42 %B (0.0-20.0 min), 42-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (9.4 mg). LCMS (ESI, m / z): 436 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.34 min. Example 12 (R)-5-(1-((4-fluoropiperidin-4-yl)methyl)-6-(trifluoromethyl)-1H-indazol-3-yl)-4- (trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 4-((3-bromo-6-(trifluoromethyl)-1H-indazol-1-yl)methyl)-4-fluoropiperidine-1- carboxylate A stirred mixture of 3-bromo-6-(trifluoromethyl)-1H-indazole (45 mg, 0.17 mmol), tert-butyl 4-(bromomethyl)-4-fluoropiperidine-1-carboxylate (50 mg, 0.17 mmol) and cesium carbonate (83 mg, 0.25 mmol) in DMF (2 mL) was flushed with nitrogen, sealed and heated at 90 °C ON. The reaction was cooled to rt, diluted with EtOAc, washed with water and brine, and then dried (MgSO4), filtered and concentrated. The residue was purified using ISCO (12g SiO2, 0-25% EtOAc / hex) to afford the title compound (21 mg). LCMS (ESI, m / z): 424, 426 [M+H-tBu]+. tert-butyl 4-fluoro-4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)- 1H-indazol-1-yl)methyl)piperidine-1-carboxylate A mixture of tert-butyl 4-((3-bromo-6-(trifluoromethyl)-1H-indazol-1-yl)methyl)-4- fluoropiperidine-1-carboxylate (21 mg, 0.044 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (12 mg, 0.048 mmol), PdCl2(dppf)-CH2Cl2adduct (5.4 mg, 6.6 µmol) and potassium acetate (13 mg, 0.13 mmol) in dioxane (0.6 mL) was vacuum flushed with nitrogen (4X) and then heated at 100 °C ON. The reaction was diluted with water and brine (1:1), and then extracted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3X). The combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound a dark brown solid, which was used without additional purification. LCMS (ESI, m / z): 390 [M+H-tBu]+(boronic acid). tert-butyl (R)-4-fluoro-4-((3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-5-yl)-6-(trifluoromethyl)-1H-indazol-1-yl)methyl)piperidine-1- carboxylate A mixture of crude tert-butyl 4-fluoro-4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6- (trifluoromethyl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (24 mg, 0.045 mmol), (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (0.013 g, 0.035 mmol), copper(I) chloride (3.5 mg, 0.035 mmol), cesium carbonate (34.1 mg, 0.105 mmol) and cataCXium® A Pd G3 (3.8 mg, 5.2 µmol) in DMF (0.5 mL), was vacuum flushed with nitrogen (3X) and then heated at 50 °C for 16 h. The reaction was added to 1 / 2 saturated brine and extracted with EtOAc. The aqueous layer was diluted with EtOAc, filtered and separated. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound as a dark oil which was used without additional purification. LCMS (ESI, m / z): 738 [M+H]+. Example 12 Crude tert-butyl (R)-4-fluoro-4-((3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-6-(trifluoromethyl)-1H-indazol-1- yl)methyl)piperidine-1-carboxylate (25.8 mg, 0.035 mmol) was dissolved into TFA / DCM (0.8 mL, 1:2) and stirred for 5 min. Then triflic acid (80 µL, 0.90 mmol) was added and the reaction was stirred at rt for 1 hr. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 19-59 %B (0.0-20.0 min), 59-100 %B (20.0- 20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). The material was further purified via preparative Reverse Phase with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 15-55 %B (0-20 min), 55- 100 %B (20-20.1 min), 100%B (20.1-24 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound. LCMS (ESI, m / z): 518.4[M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.56 min. Example 13 (R)-5-(6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one

[0005] tert-butyl 4-(3-bromo-6-methyl-1H-indazol-1-yl)piperidine-1-carboxylate A mixture of 3-bromo-6-methyl-1H-indazole (400 mg, 1.895 mmol), tert-butyl 4- (tosyloxy)piperidine-1-carboxylate (808 mg, 2.274 mmol) and cesium carbonate (926 mg, 2.84 mmol) in DMF (12 mL) was sealed and heated at 85 °C for 2 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 (40 g silica gel column, gradient elution from 0~20% of ethyl acetate in hexanes) afforded the second eluting peak as tert-butyl 4-(3-bromo-6-methyl-1H-indazol-1- yl)piperidine-1-carboxylate (298 mg). LCMS (ESI, m / z): 337.8, 339.7 [M+H]+.1H NMR (499 MHz, chloroform-d) δ 7.50 (d, J=8.3 Hz, 1H), 7.21 (d, J=0.7 Hz, 1H), 7.06 (dd, J=8.3, 0.7 Hz, 1H), 4.57 - 4.46 (m, 1H), 4.33 (br s, 2H), 2.95 (br s, 2H), 2.53 (s, 3H), 2.24 (br d, J=10.5 Hz, 2H), 2.00 (br d, J=10.8 Hz, 2H), 1.51 (s, 9H). tert-butyl 4-(6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1- yl)piperidine-1-carboxylate To a degassed mixture of tert-butyl 4-(3-bromo-6-methyl-1H-indazol-1-yl)piperidine-1- carboxylate (70 mg, 0.178 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (54.1 mg, 0.213 mmol) and potassium acetate (52.3 mg, 0.533 mmol) in 1,4-dioxane (1.5 mL) was added PdCl2(dppf)-CH2Cl2adduct (21.75 mg, 0.027 mmol). The reaction mixture was degassed again for 5 min. Then the sealed tube was heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The resulting tar was shown to contain tert-butyl 4-(6-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1-carboxylate by LC / MS and was taken up into DMF (2 mL) and carried on as crude for the next step. LCMS (ESI, m / z): 359.9 [M+H]+. tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-6-methyl-1H-indazol-1-yl)piperidine-1-carboxylate An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (42 mg, 0.113 mmol), crude tert-butyl 4-(6- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1- carboxylate (74.6 mg, 0.169 mmol), [1,1'-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (14.69 mg, 0.023 mmol) and cesium carbonate (110 mg, 0.338 mmol) in DMF (1 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was used for the next reaction without further purification. LCMS (ESI, m / z): 652.3 [M+H]+. Example 13 The residue mentioned above was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was taken up into MeOH and purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 14-44 %B (0.0-30.0 min), 44-100 %B (30.0-30.1 min), 100 %B (30.1-34.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (12.1 mg). LCMS (ESI, m / z): 432.2[M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.41 min. Example 14 and Example 15 (S)-5-(3-(piperazin-1-yl)-1H-indazol-1-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one and (R)-5-(3-(piperazin-1-yl)-1H-indazol-1-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one tert-butyl 4-(1-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-3-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(1H-indazol-3-yl)piperazine-1-carboxylate (25 mg, 0.083 mmol), racemic (1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid (122 mg, 0.207 mmol), copper(II) acetate (30.0 mg, 0.17 mmol) and triethylamine (0.058 mL, 0.41 mmol) in DCM (3 mL) was stirred at rt overnight. The reaction mixture was diluted with DCM, poured into water and filtered through celite. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, evaporated in vacuo to afford the desired product tert-butyl 4-(1-(1-(4- methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)- 1H-indazol-3-yl)piperazine-1-carboxylate (100 mg) as an orange film. LCMS (ESI, m / z): 639.2 [M+H]+. Example 14 and Example 15 Tert-butyl 4-(1-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-3-yl)piperazine-1-carboxylate (100 mg) was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was taken up into MeOH and purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 10-40 %B (0.0-20.0 min), 40-100 %B (20.0- 20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative SFC with the following conditions: Column: Chiralpak AD-H, 30 mm x 250 mm, 5 µm particles; Mobile Phase A: CO2; Mobile Phase B: MeOH with 0.1% DEA; Gradient: 30 %B over 15.00 min; Flow Rate: 100.00 mL / min; Column Temperature: 50 °C. Fraction collection was triggered by UV (220 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation. The stereochemistry of the cyclic carbamate is assigned based on correlation with close analogs where absolute stereochemistry is verified and the (R)-enantiomer is more active. EXAMPLE 14(first eluting): Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 100%; Observed Mass: 419.3; Retention Time: 1.23 min. Injection 3 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 3 results: Purity: 100%; Observed Mass: 419; Retention Time: 1.22 min. EXAMPLE 15 (second eluting): Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 100%; Observed Mass: 419.2; Retention Time: 1.23 min. Injection 3 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 3 results: Purity: 100%; Observed Mass: 418.9; Retention Time: 1.21 min. Example 16 (R)-5-(1-((4-fluoropiperidin-4-yl)methyl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (R)-4-fluoro-4-((3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (20 mg, 0.054 mmol), tert-butyl 4-fluoro-4-((3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)methyl)piperidine-1- carboxylate (81 mg, 0.177 mmol), [1,1'-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (6.99 mg, 10.73 µmol) and cesium carbonate (52.4 mg, 0.161 mmol) in DMF (0.5 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was used for the next reaction without further purification. LCMS (ESI, m / z): 670.2 [M+H]+. Example 16 The residue mentioned above was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was taken up into MeOH and purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 6-46 %B (0.0-20.0 min), 46-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results:Purity: 100%; Observed Mass: 450.2;Retention Time: 1.27 min. Injection 2 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results:Purity: 100%; Observed Mass: 450; Retention Time: 1.23 min. Example 17 (R)-5-(1-((1r,4R)-4-aminocyclohexyl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl ((1R,4r)-4-(3-((R)-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)cyclohexyl)carbamate An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (50 mg, 0.134 mmol), tert-butyl ((1r,4r)-4-(3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)cyclohexyl)carbamate (89 mg, 0.201 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (17.49 mg, 0.027 mmol) and cesium carbonate (131 mg, 0.402 mmol) in DMF (1.5 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was used for the next reaction without purification. LC / MS LCMS (ESI, m / z): 652.3 [M+H]+. Example 17 The residue mentioned above was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was taken up into MeOH and purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 10-55 %B (0.0-20.0 min), 55-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Analytical conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; 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 + / -). Injection 1 results: Purity: 97.1%; Observed Mass: 432.3; Retention Time: 1.38 min. Injection 2 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results: Purity: 100%; Observed Mass: 432.2; Retention Time: 1.26 min. Example 18 (R)-5-(1-((2S,4R)-2-methylpiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (2S,4R)-4-(3-bromo-1H-indazol-1-yl)-2-methylpiperidine-1-carboxylate To a mixture of 3-bromo-1H-indazole (365 mg, 1.852 mmol) and tert-butyl (2S,4S)-4- hydroxy-2-methylpiperidine-1-carboxylate (439 mg, 2.038 mmol) in Toluene (8 mL) was added 1 M (tributylphosphoranylidene)acetonitrile in toluene (4.63 mL, 3.70 mmol). The resulted mixture was sealed and heated at 90 °C for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc, poured into water. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by FCC (80 g silica gel cartridge, eluted with 0~20% EtOAc-hexanes) to afford a mixture of two regio-isomers.185 mg of this mixture was taken into MeOH (6 mL) and purified by reverse phase prep-HPLC to afford the desired product tert-butyl (2S,4R)-4-(3-bromo-1H-indazol-1- yl)-2-methylpiperidine-1-carboxylate (93 mg) as a colorless gum. LCMS (ESI, m / z): 394.1, 395.9 [M+H]+.1H NMR (499 MHz, chloroform-d) δ 7.64 (dt, J=8.2, 0.9 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.23 (ddd, J=8.1, 4.7, 3.2 Hz, 1H), 4.78 (tt, J=12.3, 3.9 Hz, 1H), 4.73 - 4.55 (m, 1H), 4.25 (br s, 1H), 3.11 (br s, 1H), 2.55 - 2.37 (m, 1H), 2.30 - 2.17 (m, 1H), 2.06 - 1.98 (m, 1H), 1.89 (dt, J=13.0, 1.8 Hz, 1H), 1.51 (s, 9H), 1.33 (d, J=7.1 Hz, 3H). tert-butyl (2S,4R)-4-(3-((R)-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)-2-methylpiperidine-1-carboxylate To a degassed mixture of tert-butyl (2S,4R)-4-(3-bromo-1H-indazol-1-yl)-2- methylpiperidine-1-carboxylate (94 mg, 0.238 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (72.6 mg, 0.286 mmol) and potassium acetate (70.2 mg, 0.715 mmol) in 1,4-dioxane (2 mL) was added PdCl2(dppf)-CH2Cl2adduct (29.2 mg, 0.036 mmol). The reaction mixture was degassed again for 5 min. Then the sealed tube was heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The resulting tar was shown to contain tert-butyl (2S,4R)-2-methyl-4- (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1-carboxylate by LC / MS and was taken up into DMF (2 mL) and carried on crude for the next step. LCMS (ESI, m / z): 360.0 [M+H]+. An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (60 mg, 0.16 mmol), crude tert-butyl (2S,4R)-2- methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1- carboxylate (107 mg, 0.241 mmol), [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (21 mg, 0.032 mmol) and cesium carbonate (157 mg, 0.483 mmol) in DMF (1.5 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was used for the next reaction without purification. LCMS (ESI, m / z): 652.0 [M+H]+. Example 18 The residue mentioned above was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was take up into MeOH and purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 8-48 %B (0.0-20.0 min), 48-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative Reverse Phase with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 10-50 %B (0.0-20.0 min), 50-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 100%; Observed Mass: 431.9; Retention Time: 1.52 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0- 100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results: Purity: 100%; Observed Mass: 432; Retention Time: 1.3 min. Example 19 2-(1-{6-methyl-3-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5- yl]-1H-indazol-1-yl}cyclobutyl)acetonitrile 2-(1-(3-bromo-6-methyl-1H-indazol-1-yl)cyclobutyl)acetonitrile 3-bromo-6-methyl-1H-indazole (0.48 g, 2.274 mmol) was mixed with 2- cyclobutylideneacetonitrile (0.214 ml, 2.274 mmol) in Acetonitrile (11.37 ml). Added DBU (0.686 ml, 4.55 mmol), and 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 (493 mg). LCMS (ESI, m / z): 303.8, 305.6 [M+H]+. (R)-2-(1-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-6-methyl-1H-indazol-1-yl)cyclobutyl)acetonitrile In a microwave vial was added PdCl2dppf dcm (29 mg, 0.036 mmol), Bis(pinacolato)diboron (114 mg, 0.45 mmol), 2-(1-(3-bromo-6-methyl-1H-indazol-1- yl)cyclobutyl)acetonitrile, Example 19-1 (0.091 g, 0.3 mmol) and Potassium Acetate (88 mg, 0.9 mmol). The vial was sealed and purged with N2. DMF (2 ml) was added, and the reaction was heated to 90 °C for 16 hours. Analysis by LCMS showed 2-(1-(6-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)cyclobutyl)acetonitrile as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter into the reaction mixture, estimated ~90% (~72 mg) and used in DMF solution with no purification. To another reaction vial was charged with PdCl2 dppf dcm (8.8 mg, 0.011 mmol), (R)-5- chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2- one, (35.9 mg, 0.096 mmol) and K2CO3(48 mg, 0.35 mmol). Then the crude solution of 2- (1-(6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1- yl)cyclobutyl)acetonitrile from the above borylation (~0.075 mmol) in DMF (~0.8 ml) was added to the reaction mixture. The resultant suspension was then degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 90oC for 16 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml). The filtrate was dried by vacuum to dark residue, which was further purified by column chromatography on silica gel with hexane / ethyl acetate to obtain PMB- protected intermediate, (R)-2-(1-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)- 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-6-methyl-1H-indazol-1- yl)cyclobutyl)acetonitrile (17 mg). Example 19 The above intermediate residue was mixed with 2:1 DCM / TFA (0.8 mL) and Triflic acid (0.1 ml) at 0oC for one hour Still under icy bath the reaction solution was neutralized by excess Na2CO3powder, and the mixture was extracted by EtOAc-aq., and the organic layer was blown dry by N2to a crude residue. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; running gradient from 72%A-28%B to 100%B, hereby mobile phase A (ACN / H2O (5:95) with 10 mM AA)) & mobile phase B (ACN / H2O (95:5) with 10 mM AA)). Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (6 mg). Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 98.7%; Observed Mass: 442.1; Retention Time: 1.91 min. Injection 2 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results: Purity: 100%; Observed Mass: 442; Retention Time: 1.92 min. Example 20 2-(1-{6-fluoro-3-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]- 1H-indazol-1-yl}cyclobutyl)acetonitrile 2-(1-(3-bromo-6-fluoro-1H-indazol-1-yl)cyclobutyl)acetonitrile 3-bromo-6-fluoro-1H-indazole (0.324 g, 1.507 mmol) was mixed with 2- cyclobutylideneacetonitrile (0.142 ml, 1.507 mmol) in Acetonitrile (7.5 ml). Added DBU (0.454 ml, 3.0 mmol), and 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 (356 mg). LCMS (ESI, m / z): 307.8, 309.7 [M+H]+. Example 20 In a microwave vial was added PdCl2dppf dcm (29 mg, 0.036 mmol), Bis(pinacolato)diboron (114 mg, 0.45 mmol), 2-(1-(3-bromo-6-fluoro-1H-indazol-1- yl)cyclobutyl)acetonitrile, (0.092 g, 0.3 mmol) and Potassium Acetate (88 mg, 0.9 mmol). The vial was sealed and purged with N2. DMF (2 ml) was added, and the reaction was heated to 90 °C for 16 hours. Analysis by LCMS showed 2-(1-(6-fluoro-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)cyclobutyl)acetonitrile as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter into the reaction mixture, estimated ~60% (~50 mg) and used in DMF solution with no purification. To another reaction vial was charged with PdCl2dppf dcm (8.3 mg, 0.010 mmol), (R)-5- chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2- one (31.7 mg, 0.085 mmol) and K2CO3(53 mg, 0.38 mmol). Then the crude solution of 2- (1-(6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1- yl)cyclobutyl)acetonitrile from above (~0.085 mmol) in DMF (~0.9 ml) was added to the reaction mixture. The resultant suspension was then degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 90oC for 16 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml). The filtrate was dried by vacuum to dark residue as crude PMB- protected intermediate. The above intermediate residue was mixed with 2:1 DCM / TFA (0.8 mL) and Triflic acid (0.1 ml) at RT for one hour Still under icy bath the reaction solution was neutralized by excess Na2CO3powder, and the mixture was extracted by EtOAc-aq., and the organic layer was blown dry by N2to a crude residue. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 25-55 %B (0.0-20.0 min), 55-100 %B (20.0-20.1 min), 100 %B (20.1- 24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 86.4%; Observed Mass: 446; Retention Time: 1.84 min. Injection 2 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results: Purity: 90.4%; Observed Mass: 446; Retention Time: 1.87 min. Example 21 (R)-4-((3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H- indazol-1-yl)methyl)piperidine-4-carbonitrile tert-butyl 4-((3-bromo-1H-indazol-1-yl)methyl)-4-cyanopiperidine-1-carboxylate To a mixture of 3-bromo-1H-indazole (135 mg, 0.685 mmol) and tert-butyl 4-cyano-4- (hydroxymethyl)piperidine-1-carboxylate (181 mg, 0.754 mmol) in toluene (4 mL) was added 1 M (tributylphosphoranylidene)acetonitrile in toluene (1.370 mL, 1.370 mmol). The resulted mixture was sealed and heated at 85 °C overnight. The reaction mixture was cooled to rt, diluted with EtOAc, poured into water. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by prep- HPLC (CH3CN / water / TFA) to afford the desired product tert-butyl 4-((3-bromo-1H-indazol- 1-yl)methyl)-4-cyanopiperidine-1-carboxylate (158 mg) as a tan gum. LCMS (ESI, m / z): 362.9, 364.9 [M+H]+.1H NMR (499 MHz, chloroform-d) δ 7.65 (dt, J=8.2, 0.9 Hz, 1H), 7.58 - 7.47 (m, 2H), 7.32 - 7.24 (m, 1H), 4.57 (br s, 2H), 4.34 - 4.16 (m, 2H), 3.03 (br t, J=12.5 Hz, 2H), 1.99 (br d, J=12.5 Hz, 2H), 1.70 (td, J=13.1, 4.1 Hz, 2H), 1.47 (s, 9H). tert-butyl (R)-4-cyano-4-((3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate To a degassed mixture of tert-butyl 4-((3-bromo-1H-indazol-1-yl)methyl)-4-cyanopiperidine- 1-carboxylate (94 mg, 0.224 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (68.3 mg, 0.269 mmol) and potassium acetate (66.0 mg, 0.673 mmol) in 1,4- dioxane (2 mL) was added PdCl2(dppf)-CH2Cl2adduct (27.5 mg, 0.034 mmol). The reaction mixture was degassed again for 5 min. Then the sealed tube was heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The resulting tar was shown to contain tert-butyl 4-cyano-4-((3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate by LC / MS and was taken up into DMF (2 mL) and carried on as crude for the next step. LCMS (ESI, m / z): 385.0 [M+H]+. An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (60 mg, 0.161 mmol), crude tert-butyl 4-cyano- 4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)methyl)piperidine-1- carboxylate (105 mg, 0.225 mmol), [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (20.98 mg, 0.032 mmol) and cesium carbonate (157 mg, 0.483 mmol) in DMF (1.5 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by FCC (12 g silica gel cartridge, eluted with gradient 0~40% EtOAc-hexanes) to afford 75 mg of the desired product. LCMS (ESI, m / z): 677.3 [M+H]+. Example 21 Crude tert-butyl (R)-4-cyano-4-((3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (75 mg) was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was take up into MeOH. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 5-45 %B (0.0-20.0 min), 45-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 96.8%; Observed Mass: 457.1; Retention Time: 1.25 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results: Purity: 97.7%; Observed Mass: 456.9; Retention Time: 1.25 min. Example 22 (R)-5-(1-((1s,4S)-4-aminocyclohexyl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl ((1s,4s)-4-(3-bromo-1H-indazol-1-yl)cyclohexyl)carbamate To a mixture of 3-bromo-1H-indazole (500 mg, 2.54 mmol) and tert-butyl ((1r,4r)-4- hydroxycyclohexyl)carbamate (656 mg, 3.05 mmol) in toluene (10 mL) was added 1 M (tributylphosphoranylidene)acetonitrile in toluene (5.08 mL, 5.08 mmol). The resulted mixture was sealed and heated at 85 °C overnight. The reaction mixture was cooled to rt, diluted with EtOAc, and poured into water. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was taken into MeOH (6 mL) and purified by reverse phase prep-HPLC to afford the desired product tert- butyl ((1s,4s)-4-(3-bromo-1H-indazol-1-yl)cyclohexyl)carbamate (291 mg). LCMS (ESI, m / z): 394.1, 395.9 [M+H]+.1H NMR (499 MHz, chloroform-d) δ 7.66 - 7.61 (m, 1H), 7.48 - 7.39 (m, 2H), 7.23 (ddd, J=8.0, 6.4, 1.4 Hz, 1H), 4.94 (br s, 1H), 4.44 (tt, J=10.5, 4.0 Hz, 1H), 4.01 - 3.88 (m, 1H), 2.29 - 2.15 (m, 2H), 2.10 - 2.01 (m, 2H), 2.00 - 1.92 (m, 2H), 1.86 - 1.72 (m, 2H), 1.49 (s, 9H). tert-butyl ((1S,4s)-4-(3-((R)-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)cyclohexyl)carbamate To a degassed mixture of tert-butyl ((1s,4s)-4-(3-bromo-1H-indazol-1- yl)cyclohexyl)carbamate (100 mg, 0.254 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (77 mg, 0.304 mmol) and potassium acetate (74.7 mg, 0.761 mmol) in 1,4- dioxane (2 mL) was added PdCl2(dppf)-CH2Cl2adduct (31.1 mg, 0.038 mmol). The reaction mixture was degassed again for 5 min. Then the sealed tube was heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. This tar (checked by LC / MS) was taken up into DMF (1.5 mL) and carried on as a crude for the next Suzuki coupling. LCMS (ESI, m / z): 360.0 [M+H]+. An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (50 mg, 0.134 mmol), tert-butyl ((1s,4s)-4-(3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)cyclohexyl)carbamate (112 mg, 0.254 mmol), [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (17.49 mg, 0.027 mmol) and cesium carbonate (131 mg, 0.402 mmol) in DMF (1.5 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was used for the next reaction without purification. LCMS (ESI, m / z): 652.3 [M+H]+. Example 22 Crude tert-butyl ((1S,4s)-4-(3-((R)-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)cyclohexyl)carbamate was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was taken up into MeOH. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Gradient: 9-49 %B (0.0-20.0 min), 49-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 94.9%; Observed Mass: 432.1; Retention Time: 1.39 min. Injection 3 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0- 100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 3 results: Purity: 95.5%; Observed Mass: 432; Retention Time: 1.38 min. Example 23 (R)-5-(1-((1r,4R)-4-(methylamino)cyclohexyl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl ((1r,4r)-4-(3-bromo-1H-indazol-1-yl)cyclohexyl)(methyl)carbamate To a mixture of 3-bromo-1H-indazole (210 mg, 1.066 mmol) and tert-butyl ((1s,4s)-4- hydroxycyclohexyl)(methyl)carbamate (244 mg, 1.066 mmol) in toluene (5 mL) was added 1 M (tributylphosphoranylidene)acetonitrile in toluene (2.132 mL, 2.132 mmol). The resulted mixture was sealed and heated at 85 °C for 4 h. The reaction mixture was cooled to rt, diluted with EtOAc, and poured into water. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by FCC (40 g silica gel cartridge, eluted with 0~20% EtOAc-Hexanes) without any separation.500 mg of this material was taken into MeOH (6 mL) and purified by reverse phase prep-HPLC to afford the desired product tert-butyl ((1r,4r)-4-(3-bromo-1H-indazol-1- yl)cyclohexyl)(methyl)carbamate (90 mg). LCMS (ESI, m / z): 408.1, 409.9 [M+H]+.1H NMR (499 MHz, chloroform-d) δ 7.63 (d, J=8.2 Hz, 1H), 7.44 (d, J=3.2 Hz, 2H), 7.22 (dt, J=8.0, 3.9 Hz, 1H), 4.44 - 4.31 (m, 1H), 4.13 - 3.92 (m, 1H), 2.83 (s, 3H), 2.32 - 2.20 (m, 2H), 2.19 - 2.10 (m, 2H), 1.98 - 1.90 (m, 2H), 1.82 - 1.68 (m, 2H), 1.51 (s, 9H). tert-butyl ((1R,4r)-4-(3-((R)-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)cyclohexyl)(methyl)carbamate To a degassed mixture of tert-butyl ((1r,4r)-4-(3-bromo-1H-indazol-1- yl)cyclohexyl)(methyl)carbamate (90 mg, 0.220 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (67.2 mg, 0.264 mmol) and potassium acetate (64.9 mg, 0.661 mmol) in 1,4-dioxane (2 mL) was added PdCl2(dppf)-CH2Cl2adduct (27.0 mg, 0.033 mmol). The reaction mixture was degassed again for 5 min. Then the sealed tube was heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. This tar (checked by LC / MS) was taken up into DMF (1.5 mL) and carried on as a crude for the next Suzuki coupling. LCMS (ESI, m / z): 374 [M+H]+. An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (50 mg, 0.134 mmol), tert-butyl methyl((1r,4r)- 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)cyclohexyl)carbamate (100 mg, 0.220 mmol), [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (17 mg, 0.027 mmol) and cesium carbonate (131 mg, 0.402 mmol) in DMF (1.5 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was used for the next reaction without purification. LCMS (ESI, m / z): 666.3 [M+H]+. Exmple 23 The residue mentioned above was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was take up into MeOH. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 8-48 %B (0.0-20.0 min), 48-100 %B (20.0-20.1 min), 100 %B (20.1- 24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 100%; Observed Mass: 445.7; Retention Time: 1.35 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results: Purity: 100%; Observed Mass: 446.2; Retention Time: 1.33 min. Example 24 (R)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(3-bromo-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (80 mg, 0.22 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (65 mg, 0.26 mmol), PdCl2(dppf)-CH2Cl2adduct (29 mg, 0.035 mmol) and potassium acetate (68 mg, 0.70 mmol) and in dioxane (2.5 mL) was stirrred, vacuum flushed with nitrogen (4X) and then heated at 100 °C ON. The reaction was diluted with water and brine (1:1), and then extracted with EtOAc. The aqueous layer was further extracted with EtOAc (3X), and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound as a dark brown solid, which was used without additional purification. LCMS (ESI, m / z): 310, 601[M+H]+ (boronic acid and diboronic acid). A mixture of crude tert-butyl 4-(5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazol-1-yl)piperidine-1-carboxylate (34 mg, 0.087 mmol) in DMF (0.5 mL) was added to a mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one (25 mg, 0.067 mmol), copper(I) chloride (6.6 mg, 0.067 mmol), cesium carbonate (66 mg, 0.20 mmol) and cataCXium® A Pd G3 (7.3 mg, 10 µmol) in DMF (0.5 mL) and the reaction mixture was vacuum flushed with nitrogen (3X) and then heated at 50 °C for 16h. The reaction was diluted with water and brine (1:1), and then extracted with EtOAc. The aqueous layer was further extracted with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound as a dark oil, which was used without additional purification. LCMS (ESI, m / z): 602 [M+H]+Example 24 Crude tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (40.3 mg, 0.067 mmol) was dissolved into DCM / TFA (1 mL, 2:1 ratio) at rt and stirred 2 min. Then triflic acid (0.10 mL, 1.1 mmol) was added and the reaction was sealed, and stirred at rt for 1 h. The reaction mixture was concentrated under a stream of nitrogen. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 2-42 %B (0.0-20.0 min), 42-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative Reverse Phase with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 6-36 %B (0.0-20.0 min), 36-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 98%; Observed Mass: 382.2; Retention Time: 1.1 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results: Purity: 100%; Observed Mass: 382; Retention Time: 1.14 min. Example 25 (R)-5-(1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 4-(3-bromo-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate A mixture of 3-bromo-5-(trifluoromethyl)-1H-pyrazole (250 mg, 1.16 mmol), tert-butyl 4- (tosyloxy)piperidine-1-carboxylate (496 mg, 1.40 mmol) and cesium carbonate (568 mg, 1.74 mmol) were slurried into DMF (8 mL) and then vaccum flushed with nitrogen (3X). The reaction mixture was then heated at 60°C ON. The reaction was diluted with water and EtOAc and separated. The organic layer was washed with 5% citric acid, brine, dried (MgSO4), filtered, concentrated and purified on an ISCO (40 g SiO20-30% EtOAc / hexanes) to afford the the title compound (73 mg) as the first eluting regioisomer. Regioisomer was assigned based on 1H NMR NOE. LCMS (ESI, m / z): 342, 344 [M+H-tBu]+tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(3-bromo-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1- carboxylate (73 mg, 0.18 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (51 mg, 0.20 mmol), PdCl2(dppf)-CH2Cl2adduct (22 mg, 0.027 mmol) and potassium acetate (54 mg, 0.55 mmol) in dioxane (2 mL) was stirred, vacuum flushed with nitrogen (4X) and then heated 100 °C ON. The reaction was diluted with water and brine (1:1) and then extracted with EtOAc. The aqueous layer was further extracted with of EtOAc (3X) and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound as dark brown solid, which was used without additional purification. LCMS (ESI, m / z): 308 [M+H-tBu]+. A mixture of crude tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate in DMF (0.5 mL) was added to a mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one (25mg, 0.067 mmol), copper(I) chloride (6.6 mg, 0.067 mmol), cesium carbonate (66 mg, 0.20 mmol) and cataCXium® A Pd G3 (7.3 mg, 10 µmol) in DMF (0.5 mL) and the reaction mixture was vacuum flushed with nitrogen (3X) and then heated at 50 °C for 16h. The reaction was diluted with water and brine (1:1) and then extracted with EtOAc. The aqueous layer was further extracted with of EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound as dark oil, which was used without additional purification. LCMS (ESI, m / z): 655 [M+H-tBu]+. Example 25 Crude tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (44 mg, 0.067 mmol) was treated with DCM / TFA (2:1, 1 mL) and stirred at rt for 2 min. Then triflic acid (0.10 mL, 1.1 mmol) was added and the reaction was stirred for 30 min. The reaction mixture was concentrated under a stream of nitrogen. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 7-47 %B (0.0-20.0 min), 47-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 94.8%; Observed Mass: 436; Retention Time: 1.26 min. Injection 3 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 3 results: Purity: 96.4%; Observed Mass: 435.9; Retention Time: 1.24 min. Example 26 (R)-5-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate A solution of crude tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol- 1-yl)piperidine-1-carboxylate (32.9 mg, 0.087 mmol) in DMF (0.5 mL) was added to a mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one (25 mg, 0.067 mmol), copper(I) chloride (6.6 mg, 0.067 mmol), cesium carbonate (66 mg, 0.20 mmol) and cataCXium® A Pd G3 (7.3 mg, 10 µmol) in DMF (0.5 mL) and the reaction mixture was vacuum flushed with nitrogen (3X) and then heated at 50 °C for 16h. The reaction was diluted with water and brine (1:1) and then extracted with EtOAc. The aqueous layer was further extracted with of EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound as dark oil, which was used without additional purification. LCMS (ESI, m / z): 588 [M+H]+Example 26 Crude tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (39 mg, 0.067 mmol) was treated with DCM / TFA (2:1, 1 mL) and stirred at rt for 2 min. Then triflic acid (0.10 mL, 1.1 mmol) was added and the reaction was stirred for 30 min. The reaction mixture was concentrated under a stream of nitrogen The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 0 %B (0.0-2.0 min), 0-40 %B (2.0- 20.0 min), 40-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 100%; Observed Mass: 368.1; Retention Time: 1.09 min. Injection 2 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results: Purity: 100%; Observed Mass: 368; Retention Time: 1.02 min. Example 27 (R)-5-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrimido[4,5-d][1,3]oxazin-2-one tert-butyl (R)-4-(3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5- yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate A mixture of crude tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol- 1-yl)piperidine-1-carboxylate (48.4 mg, 0.128 mmol), (R)-5-chloro-4-(trifluoromethyl)-1,4- dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (25 mg, 0.099 mmol), cesium carbonate (96 mg, 0.30 mmol) and dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (9.6 mg, 0.015 mmol) in DMF (1 mL) was stirred and vacuum flushed with nitrogen (4X) and then heated at 100 °C for 14 h. The reaction was diluted with water and brine (1:1) and then extracted with EtOAc. The aqueous layer was further extracted with of EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound as dark oil, which was used without additional purification. LCMS (ESI, m / z): 469 [M+H]+Example 27 Crude tert-butyl (R)-4-(3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrimido[4,5- d][1,3]oxazin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (46 mg, 0.099 mmol) was treated with DCM / TFA (2:1, 1 mL) and stirred at rt for 30 min. The reaction mixture was concentrated under a stream of nitrogen. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 0-40 %B (0.0-20.0 min), 40-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 98.4%; Observed Mass: 369; Retention Time: 0.91 min. Injection 3 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 3 results: Purity: 100%; Observed Mass: 369.2; Retention Time: 1.03 min. Example 28 (R)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrimido[4,5-d][1,3]oxazin-2-one tert-butyl (R)-4-(5-methyl-3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrimido[4,5- d][1,3]oxazin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate A mixture of crude of tert-butyl 4-(5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazol-1-yl)piperidine-1-carboxylate (50 mg, 0.13 mmol), (R)-5-chloro-4- (trifluoromethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (25 mg, 0.099 mmol), cesium carbonate (96 mg, 0.30 mmol) and dichloro[1,1'-bis(di-t- butylphosphino)ferrocene]palladium(II) (9.64 mg, 0.015 mmol) in DMF (1 mL) was stirred and vacuum flushed with nitrogen (4X) and then heated at 100 °C for 14 h. The reaction was diluted with water and brine (1:1) and then extracted with EtOAc. The aqueous layer was further extracted with of EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound as dark oil, which was used without additional purification. LCMS (ESI, m / z): 483[M+H]+. Example 28 Crude tert-butyl (R)-4-(5-methyl-3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrimido[4,5- d][1,3]oxazin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (48 mg, 0.10 mmol) was treated with DCM / TFA (2:1, 1 mL) and stirred at rt for 30 min. The reaction mixture was concentrated under a stream of nitrogen. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 0-40 %B (0.0-20.0 min), 40-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Analytical Reverse Phase chromatography was used to determine the final purity. Injection 1 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 (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 1 results: Purity: 100%; Observed Mass: 382.9; Retention Time: 0.97 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results: Purity: 100%; Observed Mass: 383.2; Retention Time: 1.07 min. Example 29 (R)-4-(difluoromethyl)-5-(1-(piperidin-4-yl)-1H-indazol-3-yl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one tert-butyl (R)-4-(3-(4-(difluoromethyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)-1H-indazol-1-yl)piperidine-1-carboxylate BocAn argon purged mixture of (R)-5-chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (55 mg, 0.234 mmol), crude tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (150 mg, 0.352 mmol), [1,1'- Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (30.6 mg, 0.047 mmol) and cesium carbonate (229 mg, 0.703 mmol) in DMF (2 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was used for the next reaction without purification. LCMS (ESI, m / z): 500.2 [M+H]+. Example 29 The residue mentioned above was stirred in 2:1 DCM / TFA (0.8 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 6-46 %B (0.0-20.0 min), 46-100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). The material was further purified via preparative Reverse Phase with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 0%B (0-4 min), 0-40 %B (4- 29 min), 40-100 %B (29-29.1 min), 100 %B (29.1-35 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. Fractions containing the desired product were combined and dried via centrifugal evaporation, affording title compound (2.9 mg). LCMS (ESI, m / z): 399.9 [M+H]+. Analytic 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 (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm). Rt: 1.17 min. Example 30 (R)-5-(4-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 4-(3-bromo-4-methyl-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of 3-bromo-4-methyl-1H-indazole (200 mg, 0.95 mmol) and tert-butyl 4-(p- tolylsulfonyloxy)piperidine-1-carboxylate (337 mg, 0.95 mmol) in DMF (5.0 mL) was added Cs2CO3(924 mg, 2.84 mmol). The reaction mixture was stirred at 85℃ for 3 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 reverse flash chromatography with water (0.05%TFA) / MeCN (1 / 2) to give tert-butyl 4-(3-bromo-4- methyl-1H-indazol-1-yl)piperidine-1-carboxylate (200 mg, 54%) as a light-yellow solid. LCMS (ESI, m / z): 394, 396 [M+H]+. tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-4-methyl-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(3-bromo-4-methyl-1H-indazol-1-yl)piperidine-1-carboxylate (50 mg, 0.13 mmol ), [(4R)-1-[(4-methoxyphenyl)methyl]-2-oxo-4-(trifluoromethyl)-4H- pyrido[2,3-d][1,3]oxazin-5-yl]boronic acid (73 mg, 0.19 mmol) and K2CO3(53 mg, 0.38 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was added Pd(dppf)Cl2 (21 mg, 0.03 mmol). The reaction mixture was stirred at 80℃ for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (2x10 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 4-[3-[(4R)-1-[(4-methoxyphenyl)methyl]-2-oxo-4- (trifluoromethyl)-4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4-methyl-indazol-1-yl]piperidine-1- carboxylate (80 mg, 96.8%) as a light-yellow oil. LCMS (ESI, m / z): 652 [M+H]+. Example 30 A solution of tert-butyl 4-[3-[(4R)-1-[(4-methoxyphenyl)methyl]-2-oxo-4-(trifluoromethyl)- 4H-pyrido[2,3-d][1,3]oxazin-5-yl]-4-methyl-indazol-1-yl]piperidine-1-carboxylate (80 mg, 0.13 mmol) in TFA (5 mL) was stirred at 70 ℃ for 1h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[4-methyl-1-(4-piperidyl)indazol-3-yl]-4- (trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one (53.3 mg, 94 %) as a white solid. LCMS (ESI, m / z): 432 [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; 254 nm, hold at 100 % for 0.60 min, 100 % B to 5 % B in 0.02 min; 254 nm; RT: 0.667.1H NMR (400 MHz, DMSO- d6) δ 11.57 (s, 1H), 8.78-8.76 (m, 1H), 8.53-8.41 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.45-7.37 (m, 2H), 7.04 (d, J = 6.8 Hz, 1H), 6.42-6.39 (m, 1H), 5.12-5.05 (m, 1H), 3.53-3.49 (m, 2H), 3.19-3.15 (m, 2H), 2.36-2.13 (m, 7H). Example 31 (R)-5-(5,6-difluoro-1-(piperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 4-(3-bromo-5,6-difluoro-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of 3-bromo-5,6-difluoro-1H-indazole (200 mg, 0.86 mmol) in DMF (4 mL) were added tert-butyl 4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (366 mg, 1.03 mmol) and Cs2CO3(836 mg, 2.57 mmol). The resulting mixture was stirred at 80 °C for 4h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (water (0.5% TFA) : ACN =3:7) to afford tert-butyl 4-(3-bromo-5,6- difluoro-1H-indazol-1-yl)piperidine-1-carboxylate (150 mg, 41%) as an off-white solid. LCMS (ESI, m / z): 416, 418 [M+H]+. tert-butyl (R)-4-(5,6-difluoro-3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(3-bromo-5,6-difluoro-1H-indazol-1-yl)piperidine-1-carboxylate (50 mg, 0.12 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) were added (R)-(1-(4- methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)boronic acid (45 mg, 0.12 mmol), K2CO3(49 mg, 0.36 mmol) and Pd(dppf)Cl2(10 mg, 0.01 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 (2:1) to afford tert-butyl (R)-4-(5,6-difluoro-3-(1-(4- methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)- 1H-indazol-1-yl)piperidine-1-carboxylate (70 mg, 86%) as a light-yellow solid. LCMS (ESI, m / z): 674 [M+H]+. Example 31 To a solution of tert-butyl (R)-4-(5,6-difluoro-3-(1-(4-methoxybenzyl)-2-oxo-4- (trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine- 1-carboxylate (70 mg, 0.10 mmol) in TFA (2 mL) was stirred for 2 h at 70 °C under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (water (0.5% TFA) : ACN =3:2) to afford (R)-5-(5,6-difluoro-1-(piperidin- 4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (30.5 mg, 64%) as a white solid. LCMS (ESI, m / z): 454 [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: 0.641 min.1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.82-8.81 (m, 1H), 8.80-8.52 (m, 2H), 8.21-8.09 (m, 2H), 7.74 (d, J = 5.2 Hz, 1H), 7.18 (q, J = 6.4 Hz, 1H), 5.09-5.07 (m, 1H), 3.56-3.52 (m, 2H), 3.14-3.11 (m, 2H), 2.37-2.28(m, 1H), 2.23-2.20 (m, 3H). Example 32 (R)-5-(7-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 4-(3-bromo-7-methyl-1H-indazol-1-yl)piperidine-1-carboxylate A mixture of 3-bromo-7-methyl-1H-indazole (250 mg, 1.184 mmol), tert-butyl 4- (tosyloxy)piperidine-1-carboxylate (505 mg, 1.421 mmol) and Cs2CO3(579 mg, 1.777 mmol) in DMF (8 mL) was sealed and heated at 85 °C for 12 h. The reaction mixture was cooled it 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. The residue was purified by FCC (40 g silica gel cartrdige, eluted with gradient 0 to 30% EtOAc-Hexanes) to afford the desired product (contaminated by SM indazole) as the second eluting peak. This material was purified further by reverse phase HPLC to afford tert-butyl 4-(3-bromo-7-methyl-1H-indazol-1- yl)piperidine-1-carboxylate (180 mg) as an off-white solid. LCMS (ESI, m / z): 494.0, 495.8 [M+H]+.1H NMR (499 MHz, chloroform-d) δ 7.48 (d, J=7.8 Hz, 1H), 7.20 - 7.15 (m, 1H), 7.13 - 7.07 (m, 1H), 4.92 - 4.79 (m, 1H), 4.48 - 4.22 (m, 2H), 3.02 - 2.84 (m, 2H), 2.74 (s, 3H), 2.30 (br d, J=6.4 Hz, 2H), 2.01 (br dd, J=12.9, 1.9 Hz, 2H), 1.51 (s, 9H). tert-butyl 4-(7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1- yl)piperidine-1-carboxylate To a degassed mixture of tert-butyl 4-(3-bromo-7-methyl-1H-indazol-1-yl)piperidine-1- carboxylate (90 mg, 0.228 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (69.6 mg, 0.274 mmol) and potassium acetate (67.2 mg, 0.685 mmol) in 1,4-dioxane (2 mL) was added PdCl2(dppf)-CH2Cl2adduct (28.0 mg, 0.034 mmol). The reaction mixture was degassed again for 5 min. Then the sealed tube was heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The resulting tar was shown to contain tert-butyl 4-(7-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1-carboxylate by LC / MS and was taken up into DMF (2 mL) and carried on as crude for the next step. LCMS (ESI, m / z): 360.1 [M+H]+. tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-7-methyl-1H-indazol-1-yl)piperidine-1-carboxylate An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (60 mg, 0.161 mmol), crude tert-butyl 4-(7- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1- carboxylate (107 mg, 0.241 mmol), [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (20.98 mg, 0.032 mmol) and Cs2CO3(157 mg, 0.483 mmol) in DMF (1.5 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was The reaction mixture was poured into water and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was used for the next reaction without purification. LCMS (ESI, m / z): 652.3 [M+H]+. Example 32 The crude tert-butyl (R)-4-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-5-yl)-7-methyl-1H-indazol-1-yl)piperidine-1-carboxylate was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 18-48 %B (0-20 min); 48-100 %B (20-20.1 min);100 %B (20.1-24 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (R)-5-(7-methyl-1-(piperidin-4-yl)- 1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one. LCMS (ESI, m / z): 432 [M+H]+. Analytic 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 Flow rate: 1.0 mL / min; 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); 220 nm; RT: 1.35. Example 33 (R)-5-(1-(2-azaspiro[3.5]nonan-7-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 7-(3-bromo-1H-indazol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate To a solution of 3-bromo-1H-indazole (0.20 g, 1.0 mmol) in 5 mL of MeCN was added NaH (0.072 g, 3.0 mmol) at RT and stirred for 15 min. A solution of tert-butyl 7- ((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (0.32 g, 1.0 mmol) in 3 mL of MeCN was then added dropwise. The solution was stirred at RT for 3 h, and then heated to 65 ℃ overnight. The crude was then filtered over celite, concentrated under reduced pressure, and purifed by flash column chromatography (0 to 35% EtOAc / heptanes) to afford tert-butyl 7-(3-bromo-1H-indazol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate. LCMS (ESI, m / z): 364, 366 [M-tBu + H]+. tert-butyl (R)-7-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate A vial containing Xphos Pd Gen 2 (15.0 mg, 0.019 mmol), (R)-(1-(4-methoxybenzyl)-2-oxo- 4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)boronic acid (121 mg, 0.285 mmol), tert-butyl 7-(3-bromo-1H-indazol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate (100 mg, 0.238 mmol), 2M K3PO4in water (0.4 mL, 0.83 mmol), and THF (2.5 mL) was degassed with nitrogen for 15 min, sealed, and heated at 65 ℃ overnight. The crude reaction mixture was concentrated, diluted in MeOH, filtered, and carried forward without further purification. LCMS (ESI, m / z): 678.7 [M+ H]+. Example 33 To crude tert-butyl (R)-7-(3-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate was added TFA (1 mL) and TfOH (0.3 mL). The reaction was heated to 60 ℃ for 2 h, and at RT for 2 days. Due to insufficent deprotection, an additional 0.2 mL of TFOH was added and stirred for 3 additional days. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 15-50 %B (0-20 min); 50-100 %B (20-20.1 min); 100 %B (20.1-24 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound. LCMS (ESI, m / z): 458.2 [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; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; 220 nm; RT: 1.35 min. Example 34 (R)-5-(1-((R)-pyrrolidin-3-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (R)-3-(3-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of 3-bromo-1H-indazole (200 mg, 1.02 mmol) and tert-butyl (3S)-3-(p- tolylsulfonyloxy)pyrrolidine-1-carboxylate (381 mg, 1.12 mmol) in DMF (5 mL) was added Cs2CO3(990 mg, 3.05 mmol). The reaction mixture was stirred at 85℃ for 3 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 reverse flash chromatography with water (0.05%TFA) / MeCN (1 / 2) to give tert-butyl (3R)-3-(3- bromoindazol-1-yl)pyrrolidine-1-carboxylate (250 mg, 67%) as a light-yellow solid. LCMS (ESI, m / z): 366, 368 [M+H]+. tert-butyl (R)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin- 5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl (3R)-3-(3-bromoindazol-1-yl)pyrrolidine-1-carboxylate (100 mg, 0.28 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)boronic acid (86 mg, 0.34 mmol) and K2CO3(113 mg, 0.82 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was added Pd(dppf)Cl2(45 mg, 0.06 mmol). The reaction mixture was stirred at 80℃ for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (2x10 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 (R)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate (100 mg, 73%) as a light- yellow solid. LCMS (ESI, m / z): 504 [M+H]+. Example 34 To a solution of tert-butyl (R)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate (90 mg, 0.18 mmol) in dichloromethane (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[1-[(3R)-pyrrolidin-3-yl]indazol-3-yl]-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-2-one (50.9 mg, 68%) as a white solid. LCMS (ESI, m / z): 432 [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 50 % B in 1.70 min, 50 % 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: 1.125.1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.23 (br, 2H), 8.56 (d, J = 5.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 5.2 Hz, 1H), 7.64-7.58 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 6.8 Hz, 1H), 5.81-5.76 (m, 1H), 3.78-3.50 (m, 4H), 2.67-2.57 (m, 1H), 2.40-2.27 (m, 1H). Example 35 (R)-5-(1-((S)-pyrrolidin-3-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (S)-3-(3-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of 3-bromo-1H-indazole (200 mg, 1.02 mmol) and Cs2CO3(990 mg, 3.05 mmol) in DMF (5 mL) was added tert-butyl (R)-3-(tosyloxy)pyrrolidine-1-carboxylate (416 mg, 1.22 mmol). The resulting mixture was stirred at 85 °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 (1:4) to give tert-butyl (S)-3-(3-bromo-1H-indazol-1- yl)pyrrolidine-1-carboxylate (200 mg, 53%) as an oil. LCMS (ESI, m / z): 366, 368 [M+H]+. tert-butyl (S)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin- 5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl (S)-3-(3-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylate (70 mg, 0.19 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)boronic acid (75 mg, 0.29 mmol) and K2CO3(79 mg, 0.57 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added Pd(dppf)Cl2(31 mg, 0.04 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 (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 petroleum ether / ethyl acetate (1 / 1) to give tert-butyl (S)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate (90 mg, 90%) as a white solid. LCMS (ESI, m / z): 504[M+H]+. Example 35 To a solution of tert-butyl (S)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate (90 mg, 0.18 mmol) in DCM (6 mL) was added dropwise TFA (1.5 mL) . The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: Xselect CSH Prep C18 C18 Column, 30x150 mm, 5 μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 7% B to37 % B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8.68. The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (R)-5-(1-((S)-pyrrolidin-3-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one (73.4 mg, 100%) as a white solid. LCMS (ESI, m / z): 404 [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: 0.607 min.1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.30 (br, 2H), 8.55 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.25-7.21 (m, 1H), 5.78-5.75 (m, 1H), 3.91-3.87 (m, 1H), 3.72-3.64 (m, 1H), 3.46-3.37 (m, 2H), 2.51-2.49 (m, 1H), 2.34-2.29 (m, 1H). Example 36 (R)-5-(1-(piperidin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 4-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of 3-bromo-4,5,6,7-tetrahydro-1H-indazole (150 mg, 0.75 mmol) and Cs2CO3(727 mg, 2.24 mmol) in DMF (5 mL) was added tert-butyl 4-(p-tolylsulfonyloxy)piperidine- 1-carboxylate (318 mg, 0.90 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 (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 petroleum ether / ethyl acetate (5 / 1) to give tert-butyl 4-(3- bromo-4,5,6,7-tetrahydro-1H-indazol-1-yl)piperidine-1-carboxylate (150 mg, 52%) as an oil. LCMS (ESI, m / z): 384, 386 [M+H]+. tert-butyl (R)-4-(3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1-yl)piperidine-1- carboxylate (150 mg, 0.39 mmol), (4R)-5-(dihydroxymethyl)-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-2-one (102 mg, 0.39 mmol) and K2CO3(160 mg, 1.20 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added Pd(dppf)Cl2(63 mg, 0.09 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 (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 (1:4) to tert-butyl (R)-4-(3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)piperidine-1-carboxylate (100 mg, 73%) as a yellow solid. LCMS (ESI, m / z): 522 [M+H]+. Example 36 To a solution of tert-butyl (R)-4-(3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)piperidine-1-carboxylate (90 mg, 0.17 mmol) in DCM (8 mL) was added dropwise TFA (2 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (R)-5-(1-(piperidin-4- yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (51.7 mg, 70%) as a white solid. LCMS (ESI, m / z): 422 [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 50% B in 1.70 min, 50% 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: 1.210 min.1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.69 (br, 1H), 8.41 (br, 1H), 8.40 (d, J = 5.2 Hz, 1H), 7.41- 7.33 (m, 1H), 7.32 (d, J = 5.2 Hz, 1H), 4.53-4.47 (m, 1H), 3.49-3.45 (m, 2H), 3.14-3.10 (m, 2H), 2.73-2.62 (m, 3H), 2.59-2.56 (m, 1H), 2.26-2.06 (m, 4H), 1.91-1.70 (m, 3H), 1.67-1.64 (m, 1H). Example 37 (R)-2-(1-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-1H- indazol-1-yl)cyclobutyl)acetonitrile A mixture of 2-(1-(3-bromo-1H-indazol-1-yl)cyclobutyl)acetonitrile (55.7 mg, 0.192 mmol), bis(pinacolato)diboron (81 mg, 0.320 mmol), potassium acetate (56.5 mg, 0.575 mmol), and Pd(dppf)Cl2 DCM adduct (15.67 mg, 0.019 mmol), and dioxane (1279 µl) was sparged with nitrogen for 5 minutes. The reaction was sealed and the reaction was heated to 100 °C ON. PdCl2(dtbpf) (12.50 mg, 0.019 mmol), Cs2CO3(167 mg, 0.512 mmol), and (R)-5-chloro-4- (difluoromethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (30 mg, 0.128 mmol) (as a suspension in DMA (1279 µl)) were added. The reaction mixture was sparged with nitrogen for 5 minutes. The reaction was sealed and heated to 100 °C for 8 hours. The reaction mixture was filtered through a 0.45 um PTFE frit, concentrated under reduced pressure. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 16-46 %B (0-20 min); 46-100 %B (20-20.1 min); 100 %B (20.1-24 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound. LCMS (ESI, m / z): 410 [M+H]+. Analytic 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; Flow rate: 1.0 mL / min 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); 220 nm; RT: 1.59 min. Example 38 (R)-4-(difluoromethyl)-5-(6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (R)-4-(3-(4-(difluoromethyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)- 6-fluoro-1H-indazol-1-yl)piperidine-1-carboxylate An argon purged mixture of (R)-5-chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (20 mg, 0.085 mmol), tert-butyl 4-(6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (57.0 mg, 0.128 mmol), XPHOS PD G3 (14.43 mg, 0.017 mmol), copper (I) chloride (8.44 mg, 0.085 mmol) and Cs2CO3(83 mg, 0.256 mmol) in DMF (1 mL) was sealed and heated at 90 °C for 5 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo to afford tert-butyl (R)-4-(3-(4-(difluoromethyl)-2-oxo-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-6-fluoro-1H-indazol-1-yl)piperidine-1- carboxylate, which was used without further purification. LCMS (ESI, m / z): 518 [M+H]+. Example 38 Crude tert-butyl (R)-4-(3-(4-(difluoromethyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-6-fluoro-1H-indazol-1-yl)piperidine-1-carboxylate was stirred in DCM / TFA (0.8 mL, 2:1) at rt for 1 h. Removed the volatiles with a steady stream of N2. The residue was taken up into MeOH (2 mL). The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 4-44 %B (0-20 min); 44-100 %B (20- 20.1 min); 100 %B (20.1-24 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound. LCMS (ESI, m / z): 417.8 [M+H]+. Analytic Conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Flow rate: 1.0 mL / min 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); 220 nm; RT: 1.19 min. Example 39 (R)-5-(3-((S)-3-methylpiperazin-1-yl)-1H-indazol-1-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole To a solution of 3-bromo-1H-indazole (200 mg, 1.02 mmol) and 3,4-dihydro-2H-pyran (128 mg, 1.52 mmol) in chloroform (5 mL) was added p-TSA (18 mg, 0.10 mmol). The reaction mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x20 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 (2 / 1) to give 3- bromo-1-tetrahydropyran-2-yl-indazole (250 mg, 88%) as a light-yellow oil. LCMS (ESI, m / z): 281, 283 [M+H]+. tert-butyl (2S)-2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)piperazine-1- carboxylate To a solution of 3-bromo-1-tetrahydropyran-2-yl-indazole (200 mg, 0.71 mmol), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (157 mg, 0.78 mmol), EPhos Pd G4 (65 mg, 0.07 mmol) and K2CO3(294 mg, 2.13 mmol) in 1,4-dioxane (5 mL) was added EPhos (82 mg, 0.14 mmol). The reaction mixture was stirred at 90 ℃ for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x20 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)-2-methyl-4-(1-tetrahydropyran-2- ylindazol-3-yl)piperazine-1-carboxylate (200 mg, 70%) as a light-yellow solid. LCMS (ESI, m / z): 401 [M+H]+. (S)-3-(3-methylpiperazin-1-yl)-1H-indazole To a solution of tert-butyl (2S)-2-methyl-4-(1-tetrahydropyran-2-ylindazol-3-yl)piperazine- 1-carboxylate (220 mg, 0.55 mmol) in dichloromethane (3 mL) was added TFA (3 mL). 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 water (20 mL) and extracted with dichloromethane (3x20 mL). The combined organic layers were washed with brine (2x20 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 (2 / 1) to give (S)-3-(3-methylpiperazin-1-yl)-1H-indazole (120 mg, 92%) as a light-yellow solid. LCMS (ESI, m / z): 217 [M+H]+. tert-butyl (S)-4-(1H-indazol-3-yl)-2-methylpiperazine-1-carboxylate To a solution of (S)-3-(3-methylpiperazin-1-yl)-1H-indazole (120 mg, 0.55 mmol), Boc2O (122 mg, 0.55 mmol), DMAP (7 mg, 0.06 mmol) in dichloromethane (5 mL) was added TEA (215 mg, 1.65 mmol). 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 water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x20 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 tert-butyl (S)-4-(1H- indazol-3-yl)-2-methylpiperazine-1-carboxylate (75 mg, 43%) as a light-yellow oil. LCMS (ESI, m / z): 317 [M+H]+. tert-butyl (S)-2-methyl-4-(1-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-3-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(1H-indazol-3-yl)-2-methylpiperazine-1-carboxylate (65 mg, 0.21 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)boronic acid (81 mg, 0.31 mmol) and Cu(OAc)2(65 mg, 0.41 mmol) in dichloromethane (2 mL) was added TEA (133 mg, 1.03 mmol). 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 water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x20 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 (S)- 2-methyl-4-(1-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)-1H-indazol-3-yl)piperazine-1-carboxylate (45 mg, 41%) as a light-yellow solid. LCMS (ESI, m / z): 533 [M+H]+. Example 39 To a solution of tert-butyl (S)-2-methyl-4-(1-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-3-yl)piperazine-1-carboxylate (45 mg, 0.08 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (R)-5-(3- ((S)-3-methylpiperazin-1-yl)-1H-indazol-1-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one (27.2 mg, 71%) as a white solid. LCMS (ESI, m / z): 433 [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: Acetonitrile / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5 % B to 50 % B in 1.70 min, 50 % 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: 1.224.1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.09 (s, 1H), 8.74 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.60-7.53 (m, 2H), 7.35-7.31 (m, 1H), 7.24-7.18 (m, 1H), 4.10-4.06 (m, 2H), 3.55-3.19 (m, 4H), 3.11-3.01 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H). Example 40 (R)-5-(3-((S)-3-cyclopropylpiperazin-1-yl)-1H-indazol-1-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (2S)-2-cyclopropyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)piperazine-1- carboxylate To a solution of 3-bromo-1-tetrahydropyran-2-yl-indazole (300 mg, 1.07 mmol), tert-butyl (2S)-2-cyclopropylpiperazine-1-carboxylate (290 mg, 1.28 mmol), EPhos Pd G4 (98 mg, 0.11 mmol) and K2CO3(442 mg, 3.20 mmol) in 1,4-dioxane (5 mL) was added EPhos (62 mg, 0.11 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 (2x30 mL). The combined organic layers were washed with brine (30 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 tert-butyl (2S)-2-cyclopropyl-4-(1- tetrahydropyran-2-ylindazol-3-yl)piperazine-1-carboxylate (230 mg, 50%) as a white solid. LCMS (ESI, m / z): 427 [M+H]+. (S)-3-(3-cyclopropylpiperazin-1-yl)-1H-indazole To a solution of tert-butyl (2S)-2-cyclopropyl-4-(1-tetrahydropyran-2-ylindazol-3- yl)piperazine-1-carboxylate (230 mg, 0.54 mmol) in DCM (3 mL) was added dropwise TFA (3 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (3:1). The product was concentrated under reduced pressure to give (S)-3-(3-cyclopropylpiperazin- 1-yl)-1H-indazole (130 mg, 99%) as an oil. LCMS (ESI, m / z): 243 [M+H]+. tert-butyl (S)-2-cyclopropyl-4-(1H-indazol-3-yl)piperazine-1-carboxylate To a solution of (S)-3-(3-cyclopropylpiperazin-1-yl)-1H-indazole (130 mg, 0.54 mmol), di- tert-butyl dicarbonate (70 mg, 0.32 mmol) and TEA (163 mg, 1.61 mmol) in DCM (5 mL) was added DMAP (13 mg, 0.11 mmol). The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (50 mL) and extracted with dichloromethane (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 petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (S)-2-cyclopropyl-4-(1H-indazol-3-yl)piperazine-1-carboxylate (95 mg, 51%) as a white solid. LCMS (ESI, m / z): 343 [M+H]+. tert-butyl (S)-2-cyclopropyl-4-(1-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-3-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-2-cyclopropyl-4-(1H-indazol-3-yl)piperazine-1-carboxylate (95 mg, 0.28 mmol), Cu(OAc)2(101 mg, 0.56 mmol) and TEA (140 mg, 1.39 mmol) in dichloromethane (5 mL) was added (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)boronic acid (109 mg, 0.42 mmol). The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (20 mL) and extracted with dichloromethane (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 column chromatography on silica gel with petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (S)-2-cyclopropyl-4-(1-((R)-2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-3-yl)piperazine-1-carboxylate (50 mg, 32%) as a yellow solid. LCMS (ESI, m / z): 559 [M+H]+. Example 40 To a solution of tert-butyl (S)-2-cyclopropyl-4-(1-((R)-2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-3-yl)piperazine-1-carboxylate (50 mg, 0.09 mmol) in dichloromethane (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography. The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[3-[(3S)-3-cyclopropylpiperazin-1- yl]indazol-1-yl]-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one (33.7 mg, 79%) as a yellow solid. LCMS (ESI, m / z): 459 [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: 0.641 min.1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 9.05 (br, 2H), 8.48 (d, J = 5.6 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.60-7.53 (m, 2H) 7.36-7.32 (m, 1H), 7.24-7.19 (m, 2H), 4.07-3.98 (m, 2H), 3.35-3.29 (m, 4H), 2.82-2.78 (m, 1H), 1.09-1.07 (m, 1H), 0.67-0.51 (m, 4H). Example 41 (R)-4-(difluoromethyl)-5-(1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (R)-4-(3-(4-(difluoromethyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate A mixture of crude of tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (62 mg, 0.14 mmol), (R)-5- chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (25 mg, 0.107 mmol), Cs2CO3(104 mg, 0.320 mmol) and Dichloro[1,1'-bis(di-t- butylphosphino)ferrocene]palladium(II) (10.42 mg, 0.016 mmol) in DMF (1 mL) was stirred and vacuum flushed with nitrogen (4X) and then heated at 90 °C ON. The reaction was diluted with water and brine (1:1) and then extracted with EtOAc. The aqueous layer was further extracted with of EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound as a solid, which was used without additional purification. LCMS (ESI, m / z): 540[M+Na]+Example 41 Crude tert-butyl (R)-4-(3-(4-(difluoromethyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.190 g, 0.11 mmol) was treated with DCM / TFA (2:1, 1 mL) and stirred at rt for 30 min. The reaction mixture was concentrated under a stream of nitrogen. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 2-42 %B (0-20 min); 42- 100 %B (20-20.1 min); 100 %B (20.1-24 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound. LCMS (ESI, m / z): 418.1 [M+H]+. Analytic 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; Gradient: 0-100 %B (0-3 min), 100 %B (3-3.5 min); Flow rate: 1 mL / min; 220 nm; RT: 1.13 min. Example 42 (R)-4-(difluoromethyl)-5-(1-(piperidin-4-yl)-1H-indazol-3-yl)-1,4-dihydro-2H-pyrimido[4,5- d][1,3]oxazin-2-one tert-butyl (R)-4-(3-(4-(difluoromethyl)-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5- yl)-1H-indazol-1-yl)piperidine-1-carboxylate An argon purged mixture of (R)-5-chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrimido[4,5- d][1,3]oxazin-2-one (40 mg, 0.170 mmol), crude tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (109 mg, 0.255 mmol), XPhos Pd G3 (28.7 mg, 0.034 mmol), copper(I) chloride (16.81 mg, 0.170 mmol) and Cs2CO3(166 mg, 0.509 mmol) in DMF (1.5 mL) was sealed and heated at 90 °C for 6 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was used for the next reaction without purification. LCMS (ESI, m / z): 501.2 [M+H]+. Example 42 Crude tert-butyl (R)-4-(3-(4-(difluoromethyl)-2-oxo-1,4-dihydro-2H-pyrimido[4,5- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate was stirred in DCM / TFA (0.8 mL, 2:1) at rt for 1 h. Removed the volatiles with a steady stream of N2. The residue was taken up into MeOH (2 mL). The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Gradient: 3-43 %B (0-20 min); 43-100 %B (20-20.1 min); 100 %B (20.1-24 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound. LCMS (ESI, m / z): 400.9 [M+H]+. Analytic Conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05% TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05% TFA; Gradient: 0-100 %B (0-3 min), 100 %B (3-3.5 min); Flow rate: 1 mL / min; 220 nm; RT: 1.18 min. Example 43 and Example 44 (R)-5-(1-((3S,4R)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-2-one and (R)-5-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-2-one racemic tert-butyl (3S,4R)-4-(3-bromo-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate To a mixture of 3-bromo-1H-indazole (245 mg, 1.243 mmol) and racemic tert-butyl (3S,4S)- 3-fluoro-4-hydroxypiperidine-1-carboxylate (273 mg, 1.243 mmol) in toluene (8 mL) was added 1M (tributylphosphoranylidene)acetonitrile in toluene (2.487 mL, 2.487 mmol). The resulted mixture was sealed and heated at 85 °C overnight. The reaction mixture was cooled to rt, diluted with EtOAc, and poured into water. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by FCC (40 g silica gel cartridge, eluted with 0~40% EtOAc-Hexanes) to afford racemic tert- butyl (3S,4R)-4-(3-bromo-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate (326 mg). LCMS (ESI, m / z): 398.1, 399.9. [M+H]+.1H NMR (499 MHz, chloroform-d) δ 7.65 (dt, J=8.2, 0.8 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.45 (ddd, J=8.5, 7.1, 1.1 Hz, 1H), 7.25 (ddd, J=8.0, 7.1, 0.7 Hz, 1H), 5.04 - 4.85 (m, 1H), 4.83 - 4.69 (m, 1H), 4.49 (br s, 2H), 3.36 - 2.97 (m, 2H), 2.95 - 2.81 (m, 1H), 2.06 - 1.99 (m, 1H), 1.52 (s, 9H). racemic tert-butyl (3S,4R)-3-fluoro-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate To a degassed mixture of racemic tert-butyl (3S,4R)-4-(3-bromo-1H-indazol-1-yl)-3- fluoropiperidine-1-carboxylate (200 mg, 0.502 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (153 mg, 0.603 mmol) and potassium acetate (148 mg, 1.506 mmol) in 1,4-dioxane (2 mL) was added PdCl2(dppf)-CH2Cl2adduct (61.5 mg, 0.075 mmol). The reaction mixture was degassed again for 5 min. Then the sealed tube was heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The resulting tar was shown to contain racemic tert-butyl (3S,4R)-3- fluoro-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1- carboxylate by LC / MS and was taken up into DMF (2 mL). Next, an argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (65 mg, 0.174 mmol), crude solution of racemic tert-butyl (3S,4R)-3- fluoro-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1- carboxylate (116 mg, 0.262 mmol) in DMF, [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (22.73 mg, 0.035 mmol) and cesium carbonate (170 mg, 0.523 mmol) in DMF (1.5 mL) was sealed and heated at 90 °C for 6 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by FCC (24 g silica gel cartridge, eluted with gradient 0~40% EtOAc-hexanes) to afford 95 mg of racemic tert-butyl (3S,4R)-3- fluoro-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)- 1H-indazol-1-yl)piperidine-1-carboxylate. LCMS (ESI, m / z): 656.3 [M+H]+. Example 43 and Example 44 Racemic tert-butyl (3S,4R)-3-fluoro-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (95 mg) was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The racemic material was purified by preparative SFC chromotography with the following conditions: Column: Chiralpak AS-H, 30 mm x 250 mm, 5 µm particles; Mobile Phase A: CO2; Mobile Phase B: MeOH with 0.1% DEA; Gradient: 20 %B over 18.00 min; Flow Rate: 100.00 mL / min; Fraction collection was triggered by UV (220 nm). Example 43 (first eluting): LCMS (ESI, m / z): 436.1 [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; Gradient: 0-100 %B (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; 220 nm; RT: 1.39 min. Example 44 (second eluting): LCMS (ESI, m / z): 436.1 [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; Gradient: 0- 100 %B (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; 220 nm; RT: 1.39 min.1H NMR (500 MHz, DMSO-d6) δ 8.53 (d, J=5.2 Hz, 1H), 8.04 (br d, J=8.1 Hz, 1H), 7.94 (br d, J=8.5 Hz, 1H), 7.70 (d, J=5.2 Hz, 1H), 7.54 (br t, J=7.7 Hz, 1H), 7.40 - 7.30 (m, 2H), 5.21 - 5.05 (m, 1H), 4.88 - 4.68 (m, 1H), 3.30 - 3.10 (m, 2H), 3.06 - 2.90 (m, 1H), 2.84 - 2.73 (m, 1H), 2.68 - 2.58 (m, 1H), 1.97 - 1.81 (m, 1H). Example 45 (R)-5-(1-(4-methylpiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-(1H-indazol-1-yl)piperidine-1-carboxylate To a solution of 1H-indazole (3.0 g, 25.39 mmol) and tert-butyl 4-(2-ethoxy-2-oxo- ethylidene)piperidine-1-carboxylate (10.3 g, 38.09 mmol) in MeCN (60 mL) was added DBU (7.6 mL, 50.79 mmol). The reaction mixture was stirred at 85℃ for 1 day 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 (5 / 1) to give tert-butyl 4-(2-ethoxy-2-oxo-ethyl)- 4-indazol-1-yl-piperidine-1-carboxylate (1.1 g, 11.18%) as a yellow oil. LCMS (ESI, m / z): 388 [M+H]+. tert-butyl 4-(2-hydroxyethyl)-4-(1H-indazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-ethoxy-2-oxo-ethyl)-4-indazol-1-yl-piperidine-1-carboxylate (1.10 g, 2.84 mmol) in THF (20 mL) was added LiBH4(311 mg, 14.2 mmol) at 0°C. The resulting mixture was stirred at 40°C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was diluted with saturated NH4Cl, 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 (4 / 1) to give tert-butyl 4-(2-hydroxyethyl)-4-indazol-1-yl-piperidine-1-carboxylate (800 mg, 81%) as a yellow solid. LCMS (ESI, m / z): 346 [M+H]+. tert-butyl 4-(1H-indazol-1-yl)-4-(2-oxoethyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-hydroxyethyl)-4-indazol-1-yl-piperidine-1-carboxylate (800 mg, 2.32 mmol) in dichloromethane (15 mL) was added DMP (1472.9 mg, 3.47 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 0.5 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with sodium thiosulfate aqueous solution (100 mL) and extracted with dichloromethane (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 4- indazol-1-yl-4-(2-oxoethyl)piperidine-1-carboxylate (550 mg, 69%) as a light-yellow oil. LCMS (ESI, m / z): 344 [M+H]+. tert-butyl 4-(1H-indazol-1-yl)-4-methylpiperidine-1-carboxylate To a solution of tert-butyl 4-indazol-1-yl-4-(2-oxoethyl)piperidine-1-carboxylate (550 mg, 1.6 mmol) in toluene (15 mL) was added (Ph3P)3RhCl (1.48 g, 1.6 mmol). The reaction mixture was stirred at 105 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was concentrated under reduced pressure to give crude e as a yellow solid. 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 (5 / 1) to give tert-butyl 4-indazol-1-yl-4-methyl-piperidine-1-carboxylate (250 mg, 49%) as a light-yellow oil. LCMS (ESI, m / z): 316 [M+H]+. 3-bromo-1-(4-methylpiperidin-4-yl)-1H-indazole To a solution of tert-butyl 4-indazol-1-yl-4-methyl-piperidine-1-carboxylate (250 mg, 0.79 mmol) in acetic acid (10 mL) was added Br2(127 mg, 0.79 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x20 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 (2 / 1) to give 3- bromo-1-(4-methylpiperidin-4-yl)-1H-indazole (160 mg, 69%) as a light-yellow oil. LCMS (ESI, m / z): 294, 296 [M+H]+. tert-butyl 4-(3-bromo-1H-indazol-1-yl)-4-methylpiperidine-1-carboxylate To a solution of 3-bromo-1-(4-methylpiperidin-4-yl)-1H-indazole (150 mg, 0.51 mmol), (Boc)2O (222 mg, 1.02 mmol) and DMAP (6.23 mg, 0.05 mmol) in DCM (5 mL) was added TEA (206 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3x20 mL). The combined organic layers were washed with brine (2x20 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 / 2) to give tert-butyl 4-(3- bromoindazol-1-yl)-4-methyl-piperidine-1-carboxylate (150 mg, 75%) as a light-yellow oil. LCMS (ESI, m / z): 394, 396 [M+H]+. tert-butyl (R)-4-methyl-4-(3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(3-bromoindazol-1-yl)-4-methyl-piperidine-1-carboxylate (150 mg, 0.38 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)boronic acid (110 mg, 0.42 mmol) and K2CO3(157 mg, 1.14 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl2(62 mg, 0.08 mmol). The reaction mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with sodium thiosulfate aqueous solution (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (2x20 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 / 2) to give tert-butyl 4-methyl-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)- 1,4-dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]piperidine-1-carboxylate (100 mg, 49%) as a light-yellow oil. LCMS (ESI, m / z): 532 [M+H]+. Example 45 To a solution of tert-butyl 4-methyl-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]piperidine-1-carboxylate (100 mg, 0.19 mmol) in dichloromethane (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[1- (4-methyl-4-piperidyl)indazol-3-yl]-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin- 2-one (69.1 mg, 84%) as a white solid. LCMS (ESI, m / z): 432 [M+H]+. Analytic Conditions: Column: HALO 90A C18. Column 3.0*30 mm, 2.0 μm; Mobile Phase A: Water / 0.1%TFA, Mobile Phase B: Acetonitrile / 0.1%TFA; Flow rate: 1.50 mL / min; Gradient: 5 % B to 50 % B in 1.70 min, 50 % 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: 1.284.1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.60-8.58 (m, 2H), 8.55 (d, J = 5.2 Hz, 1H), 8.09-8.05 (m, 2H), 7.74 (d, J = 5.2 Hz, 1H), 7.56-7.52 (m, 1H), 7.37 (dd, J = 8.4, 6.8 Hz, 1H), 7.03-6.98 (m, 1H), 3.34 -3.08 (m, 4H), 2.97-2.78 (m, 2H), 2.33-2.27 (m, 2H), 1.68 (s, 3H). Example 46 (R)-5-(1-((2S,4S)-2-methylpiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (2S,4S)-4-(3-bromo-1H-indazol-1-yl)-2-methylpiperidine-1-carboxylate Boc To a mixture of 3-bromo-1H-indazole (450 mg, 2.284 mmol) and tert-butyl (2S,4R)-4- hydroxy-2-methylpiperidine-1-carboxylate (492 mg, 2.284 mmol) in Toluene (5 mL) was added 1 M tributylphosphoranylidene)acetonitrile in toluene (4.57 mL, 4.57 mmol). The resulted mixture was sealed and heated at 85 °C for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc, and poured into water. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by FCC (80 g silica gel cartridge, eluted with 0~20% EtOAc-Hexanes) without any separation.660 mg of this material was taken into MeOH (6 mL) and purified by reverse phase prep-HPLC to afford the desired product tert-butyl (2S,4S)-4-(3-bromo-1H-indazol-1-yl)-2- methylpiperidine-1-carboxylate (360 mg). LCMS (ESI, m / z): 394.1,396.0 [M+H]+.1H NMR (499 MHz, chloroform-d) 7.63 (dt, J=8.1, 0.8 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.23 (ddd, J=8.0, 6.4, 1.4 Hz, 1H), 4.85 - 4.55 (m, 1H), 4.25 - 4.07 (m, 1H), 3.98 (ddd, J=14.0, 7.1, 2.6 Hz, 1H), 3.51 (ddd, J=14.1, 10.5, 6.0 Hz, 1H), 2.40 - 2.19 (m, 3H), 2.16 - 2.08 (m, 1H), 1.53 (s, 9H), 1.18 (d, J=6.5 Hz, 3H). tert-butyl (2S,4S)-2-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1- yl)piperidine-1-carboxylate Boc To a degassed mixture of tert-butyl (2S,4S)-4-(3-bromo-1H-indazol-1-yl)-2- methylpiperidine-1-carboxylate (100 mg, 0.254 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (77 mg, 0.304 mmol) and potassium acetate (74.7 mg, 0.761 mmol) in DMF (2 mL) was added PdCl2(dppf)-CH2Cl2adduct (31.1 mg, 0.038 mmol). The reaction mixture was degassed again for 5 min. Then the sealed tube was heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The resulting tar was shown to contain tert-butyl (2S,4S)-2-methyl-4-(3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1-carboxylate by LC / MS and was taken up into DMF (2 mL) and carried on as a crude for the next step. LCMS (ESI, m / z): 360.0 [M+H (boronic acid)]+. tert-butyl (2S,4S)-4-(3-((R)-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)-2-methylpiperidine-1-carboxylate An argon purged mixture of crude tert-butyl (2S,4S)-2-methyl-4-(3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (108 mg, 0.244 mmol), (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (70 mg, 0.188 mmol), XPhos Pd G3 (31.8 mg, 0.038 mmol), copper(I) chloride (18.59 mg, 0.188 mmol) and cesium carbonate (184 mg, 0.563 mmol) in DMF (2 mL) was sealed and heated at 90 °C for 6 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by FCC (12 g silica gel cartridge, eluted with gradient 0~20% EtOAc / hexanes) to afford the desired product tert-butyl (2S,4S)-4-(3-((R)-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)- 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)-2-methylpiperidine-1- carboxylate (75 mg) as a light yellow film LCMS (ESI, m / z): 652 [M+H]+. Example 46 tert-butyl (2S,4S)-4-(3-((R)-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)-2-methylpiperidine-1-carboxylate (75 mg) was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2. The residue was take up into MeOH and purified by prepartive reverse flash chromatography with the following conditions: column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Gradient: 11-51 %B (0.0-20.0 min), 51- 100 %B (20.0-20.1 min), 100 %B (20.1-24.0 min); Flow Rate: 20 mL / min; fractions containing the desired product were combined and dried via centrifugal evaporation. LCMS (ESI, m / z): 432.3 [M+H]+. Analyitcal 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; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0- 3.5 min); Flow: 1.0 mL / min; 220 nm; RT: 1.28 min. Example 47 (R)-5-(1-((R)-pyrrolidin-3-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (R)-3-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of 3-bromo-4,5,6,7-tetrahydro-1H-indazole (150 mg, 0.75 mmol ), tert-butyl (3S)-3-(p-tolylsulfonyloxy)pyrrolidine-1-carboxylate (280 mg, 0.82 mmol) in DMF (5 mL) was added Cs2CO3(727 mg, 2.24 mmol). The reaction mixture was stirred at 85 ℃ for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with saturated ammonia carbonate aqueous (20 mL), extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with brine (2x20 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 / 2) to give tert- butyl (R)-3-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrrolidine-1-carboxylate (180 mg, 65%) as a light-yellow solid. LCMS (ESI, m / z): 370, 372 [M+H]+. tert-butyl (R)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin- 5-yl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl (R)-3-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrrolidine-1- carboxylate (80 mg, 0.22 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid (68 mg, 0.26 mmol) and K2CO3(89 mg, 0.65 mmol) in 1,4- dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl2(35 mg, 0.04 mmol). The reaction mixture was stirred at 80 ℃ for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x20 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 (3R)-3-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3- d][1,3]oxazin-5-yl]-4,5,6,7-tetrahydroindazol-1-yl]pyrrolidine-1-carboxylate (100 mg, 91%) as a light-yellow solid. LCMS (ESI, m / z): 508 [M+H]+. Example 47 To a solution of tert-butyl (3R)-3-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3- d][1,3]oxazin-5-yl]-4,5,6,7-tetrahydroindazol-1-yl]pyrrolidine-1-carboxylate (95 mg, 0.19 mmol) in dichloromethane (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[1-[(3R)-pyrrolidin-3-yl]-4,5,6,7-tetrahydroindazol-3-yl]-4-(trifluoromethyl)- 1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one (68.7 mg, 90%) as a white solid. LCMS (ESI, m / z): 408 [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 50 % B in 1.70 min, 50 % 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: 1.269.1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 5.2 Hz, 1H), 7.34-7.27 (m, 2H), 5.16-5.14 (m, 1H), 3.66-3.61 (m, 1H), 3.54-3.37 (m, 3H), 2.72-2.66 (m, 3H), 2.54-2.50 (m, 1H), 2.50-2.41 (m, 1H), 2.20-2.19 (m, 1H), 1.89-1.55 (m, 4H). Example 48 (R)-5-(1-((S)-pyrrolidin-3-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (S)-3-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of 3-bromo-4,5,6,7-tetrahydro-1H-indazole (150 mg, 0.75 mmol), tert-butyl (3R)-3-(p-tolylsulfonyloxy)pyrrolidine-1-carboxylate (280 mg, 0.82 mmol) in DMF (5.0 mL) was added Cs2CO3(727 mg, 2.24 mmol). The reaction mixture was stirred at 85 ℃ for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with saturated aqueous ammonia carbonate (20 mL), extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with brine (2x20 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 / 2) to give tert- butyl (S)-3-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrrolidine-1-carboxylate (180 mg, 65%) as a light-yellow solid. LCMS (ESI, m / z): 370, 372 [M+H]+. tert-butyl (S)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin- 5-yl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl (S)-3-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrrolidine-1- carboxylate (80 mg, 0.22 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid (68 mg, 0.26 mmol) and K2CO3(89 mg, 0.65 mmol) in 1,4- dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl2(35 mg, 0.04 mmol). The reaction mixture was stirred at 80 ℃ for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x20 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 (3S)-3-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3- d][1,3]oxazin-5-yl]-4,5,6,7-tetrahydroindazol-1-yl]pyrrolidine-1-carboxylate (100 mg, 91%) as a light-yellow solid. LCMS (ESI, m / z): 508 [M+H]+. Example 48 To a solution of tert-butyl (3S)-3-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3- d][1,3]oxazin-5-yl]-4,5,6,7-tetrahydroindazol-1-yl]pyrrolidine-1-carboxylate (95 mg, 0.19 mmol) in dichloromethane (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (R)-5-(1-((S)-pyrrolidin-3-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-4-(trifluoromethyl)- 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (72.3 mg, 80%) as a white solid. LCMS (ESI, m / z): 408 [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 50 % B in 1.70 min, 50 % 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: 1.236.1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 5.2 Hz, 1H), 7.30-7.24 (m, 2H), 5.15-5.11 (m, 1H), 3.75-3.70 (m, 1H), 3.52-3.48 (m, 1H), 3.38-3.34 (m, 2H), 2.72-2.69 (m, 3H), 2.47-2.34 (m, 2H), 2.22-2.14 (m, 1H), 1.90-1.70 (m, 3H), 1.67-1.55 (m, 1H). Example 49 (R)-5-(1-((1r,4R)-4-(methylamino)cyclohexyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-4- (trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (1s,4s)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl methanesulfonate To a stirred solution of tert-butyl N-(4-hydroxycyclohexyl)-N-methyl-carbamate (140 mg, 0.61 mmol) and triethylamine (185 mg, 1.83 mmol) in dichloromethane (6 mL) was added methanesulfonyl chloride (91 mg, 0.79 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The mixture was quenched with water, extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The reaction crude was used in the next step directly without further purification. LCMS (ESI, m / z): 308 [M+H]+. tert-butyl ((1r,4r)-4-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1- yl)cyclohexyl)(methyl)carbamate To a stirred solution of (1s,4s)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl methanesulfonate (150 mg, 0.49 mmol) and 3-bromo-4,5,6,7-tetrahydro-1H-indazole (88 mg, 0.44 mmol) in DMF (3 mL) was added Cs2CO3 (475 mg, 1.46 mmol) under nitrogen atmosphere. The mixture was stirred at 50°C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The mixture was quenched with water, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc =8:1) to obtain tert-butyl ((1r,4r)-4-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1- yl)cyclohexyl)(methyl)carbamate (70 mg, 34.7%) as yellow oil. LCMS (ESI, m / z): 412, 414 [M+H]+. tert-butyl methyl((1R,4r)-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)cyclohexyl)carbamate To a stirred solution of tert-butyl ((1r,4r)-4-(3-bromo-4,5,6,7-tetrahydro-1H-indazol-1- yl)cyclohexyl)(methyl)carbamate (15 mg, 0.04 mmol) and (R)-(2-oxo-4-(trifluoromethyl)- 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)boronic acid (12 mg, 0.05 mmol) in DMF (1 mL) was added XPhos Pd G3 (6 mg, 0.01 mmol), CuCl (1 mg, 0.01 mmol) and Cs2CO3(35.47 mg, 0.11 mmol) under nitrogen atmosphere. The mixture was stirred at 90°C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The mixture was purified directly by reverse phase flash (MeCN in water (10 mmol / L TFA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to obtain tert-butyl methyl((1R,4r)-4-(3- ((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-4,5,6,7- tetrahydro-1H-indazol-1-yl)cyclohexyl)carbamate (10 mg, 50.0%) as yellow oil. LCMS (ESI, m / z): 550 [M+H]+. Example 49 To a stirred solution of tert-butyl methyl((1R,4r)-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-4,5,6,7-tetrahydro-1H-indazol-1- yl)cyclohexyl)carbamate (30 mg, 0.05 mmol) in DCM (2 mL) was added TFA (1 mL, 0.05 mmol) under nitrogen atmosphere. The mixture was stirred at room temperature for 1 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 20 min; detector, UV 254 nm) to obtain R)-5-(1-((1r,4R)-4-(methylamino)cyclohexyl)- 4,5,6,7-tetrahydro-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (14.9 mg, 60.6%) as a white solid. LCMS (ESI, m / z): 450 [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: 1.230 min.1H NMR (400 MHz, DMSO- d6) δ 11.28 (s, 1H), 8.51 (s, 2H), 8.39 (d, J = 5.2 Hz, 1H), 7.36-7.29 (m, 2H), 4.23-4.10 (m, 1H), 3.16-3.00 (m, 1H), 2.75-2.66 (m, 3H), 2.65-2.56 (m, 4H), 2.22-2.11 (m, 2H), 2.07-1.97 (m, 2H), 1.93-1.63 (m, 7H), 1.59-1.42 (m, 2H). Example 50 (R)-5-(1-((R)-pyrrolidin-3-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-4- (trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (R)-3-(3-iodo-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)pyrrolidine-1-carboxylate A solution of 3-iodo-1,4,5,6-tetrahydrocyclopenta[d]pyrazole (150 mg, 0.64 mmol,), tert-butyl (3S)-3-(p-tolylsulfonyloxy)pyrrolidine-1-carboxylate (241 mg, 0.71 mmol) and Cs2CO3(625 mg, 1.92 mmol) in DMF (2 mL) was stirred at 50 °C for 4h 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 tert-butyl (R)-3-(3-iodo-5,6- dihydrocyclopenta[c]pyrazol-1(4H)-yl)pyrrolidine-1-carboxylate (160 mg, 62%) as a white solid. LCMS (ESI, m / z): 404 [M+H]+. tert-butyl (R)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin- 5-yl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl (R)-3-(3-iodo-5,6-dihydrocyclopenta[c]pyrazol-1(4H)- yl)pyrrolidine-1-carboxylate (140 mg, 0.34 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)boronic acid (90 mg, 0.34 mmol) and K2CO3(144 mg, 1.04 mmol) in 1,4-dioxane (4.0 mL) and water (0.8 mL) was added Pd(dppf)Cl2(28 mg, 0.04 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 (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 (2:1) to give tert-butyl (R)-3-(3-((R)-2-oxo-4-(trifluoromethyl)- 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)- yl)pyrrolidine-1-carboxylate (70 mg, 41%) as a yellow solid. LCMS (ESI, m / z): 494 [M+H]+. Example 50 To a solution of tert-butyl (R)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)pyrrolidine-1- carboxylate (70 mg, 0.14 mmol) in DCM (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 2 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: Xselect CSH Prep C18 Column, 30x250 mm, 10 μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to 39% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 9.6. The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (R)-5-(1-((R)-pyrrolidin-3-yl)-1,4,5,6- tetrahydrocyclopenta[c]pyrazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (33.6 mg, 60%) as a white solid. LCMS (ESI, m / z): 394 [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: 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: 0.731 min.1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.18 (s, 2H), 8.39 (d, J = 5.2 Hz, 1H), 7.51-7.41 (m, 1H), 7.28 (d, J = 5.2 Hz, 1H), 5.15-5.05 (m, 1H), 3.72-3.62 (m, 1H), 3.48 (s, 3H), 2.95-2.78 (m, 4H), 2.64-2.53 (m, 2H), 2.48-2.41 (m, 1H), 2.33-2.20 (m, 1H). Example 51 (R)-5-(1-((S)-pyrrolidin-3-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-4- (trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (S)-3-(3-iodo-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)pyrrolidine-1-carboxylate To a solution of 3-iodo-1,4,5,6-tetrahydrocyclopenta[d]pyrazole (150 mg, 0.64 mmol) and tert-butyl (3R)-3-(p-tolylsulfonyloxy)pyrrolidine-1-carboxylate (241 mg, 0.71 mmol) in DMF (5 mL) was added Cs2CO3(625 mg, 1.92 mmol). The reaction mixture was stirred at 50 °C for 1 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 reverse flash chromatography with water (0.05%TFA) / MeCN (1 / 2) to give tert-butyl (S)-3-(3-iodo-5,6- dihydrocyclopenta[c]pyrazol-1(4H)-yl)pyrrolidine-1-carboxylate (170 mg, 65%) as a white solid. LCMS (ESI, m / z): 404 [M+H]+. tert-butyl (S)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin- 5-yl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl (S)-3-(3-iodo-5,6-dihydrocyclopenta[c]pyrazol-1(4H)- yl)pyrrolidine-1-carboxylate (70 mg, 0.17 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)boronic acid (55 mg, 0.21 mmol) and K2CO3(72 mg, 0.52 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL) was added Pd(dppf)Cl2(28 mg, 0.03 mmol). The reaction mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x20 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 / 2) to give tert-butyl (S)-3-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)- yl)pyrrolidine-1-carboxylate (55 mg, 64%) as a light-yellow solid. LCMS (ESI, m / z): 494 [M+H]+. Example 51 To a solution of tert-butyl (3S)-3-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3- d][1,3]oxazin-5-yl]-5,6-dihydro-4H-cyclopenta[d]pyrazol-1-yl]pyrrolidine-1-carboxylate (50 mg, 0.10 mmol) in dichloromethane (3 mL) was added dropwise TFA (2 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[1- [(3S)-pyrrolidin-3-yl]-5,6-dihydro-4H-cyclopenta[d]pyrazol-3-yl]-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-2-one (35.6 mg, 88%) as a white solid. LCMS (ESI, m / z): 394 [M+H]+. Analytic Conditions: Column: Shim‐pack Scepter HALO 90A C18. Column 30*3.0 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 50 % B in 1.70 min, 50 % 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: 1.145.1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.24 (s, 1H), 9.04 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 7.44 (q, J = 6.8 Hz, 1H), 7.28 (d, J = 5.2 Hz, 1H), 5.15-5.03 (m, 1H), 3.79-3.70 (m, 1H), 3.56-3.36 (m, 3H), 2.94-2.76 (m, 4H), 2.68-2.54 (m, 2H), 2.48-2.37 (m, 1H), 2.34- 2.22 (m, 1H). Example 52 (R)-5-(1-(piperidin-4-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-4-(trifluoromethyl)- 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl 4-(3-iodo-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-1-carboxylate BocA mixture of 3-iodo-1,4,5,6-tetrahydrocyclopenta[d]pyrazole (150 mg, 0.64 mmol), tert-butyl 4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (273 mg, 0.77 mmol) and Cs2CO3(625 mg, 1.92 mmol) in DMF (5 mL) was stirred at 50oC for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with DMF. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1:3) to give tert- butyl 4-(3-iodo-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-1-carboxylate (130 mg, 48%) as a colorless oil. LCMS (ESI, m / z): 418 [M+H]+tert-butyl (R)-4-(3-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(3-iodo-5,6-dihydro-4H-cyclopenta[d]pyrazol-1-yl)piperidine-1- carboxylate (80 mg, 0.19 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid (50 mg, 0.19 mmol) and K2CO3(79 mg, 0.58 mmol) in 1,4- dioxane (2 mL) and water (0.2 mL) was added Pd(dppf)Cl2(16 mg, 0.02 mmol). The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. 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 reverse flash chromatography with water (0.05% TFA) / MeCN (1:2) to give tert-butyl 4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]-5,6-dihydro-4H-cyclopenta[d]pyrazol-1-yl]piperidine- 1-carboxylate (50 mg, 51%) as a yellow solid. LCMS (ESI, m / z): 508 [M+H]+. Example 52 To a solution of tert-butyl 4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3- d][1,3]oxazin-5-yl]-5,6-dihydro-4H-cyclopenta[d]pyrazol-1-yl]piperidine-1-carboxylate (50 mg, 0.10 mmol) in DCM (3 mL) was added dropwise TFA (1 mL) . The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep- HPLC using the following conditions: Column: XselectCSH Prep Fluoro-Phenyl OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to32% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8.68. The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[1-(4-piperidyl)-5,6-dihydro-4H- cyclopenta[d]pyrazol-3-yl]-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one (14.6 mg, 36%) as a white solid. LCMS (ESI, m / z): 408 [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: 0.982 min.1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 7.47-7.42 (m, 1H), 7.27 (d, J = 5.2 Hz, 1H), 4.50-4.43 (m, 1H), 3.09-3.07 (m, 4H), 2.87-2.78 (m, 4H), 2.63-2.55 (m, 2H), 2.18- 2.08 (m, 4H). Example 53 and Example 54 (R)-5-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one and (R)-5-(6-fluoro-1-((3S,4R)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one racemic tert-butyl (3R,4S)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)-3-fluoropiperidine-1- carboxylate To a mixture of 3-bromo-6-fluoro-1H-indazole (500 mg, 2.325 mmol) and racemic tert-butyl (3S,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (510 mg, 2.325 mmol) in toluene (8 mL) was added 1 M tributylphosphoranylidene)acetonitrile in toluene (4.65 mL, 4.65 mmol). The resulted mixture was sealed and heated at 85 °C overnight. The reaction mixture was cooled to rt, diluted with EtOAc, and poured into water. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by FCC (80 g silica gel cartridge, eluted with 0~30% EtOAc-Hexanes) to afford racemic tert- butyl (3R,4S)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate (554 mg) as a light yellow foam. LCMS (ESI, m / z): 360.0, 361.8 [M-tBu+H]+.1H NMR (499 MHz, chloroform-d) δ 7.58 (dd, J=8.9, 5.1 Hz, 1H), 7.22 (dd, J=9.5, 1.5 Hz, 1H), 7.02 (td, J=8.9, 2.1 Hz, 1H), 5.06 - 4.85 (m, 1H), 4.76 - 4.61 (m, 1H), 4.48 (br d, J=2.2 Hz, 2H), 3.32 - 2.95 (m, 2H), 2.81 (qd, J=12.1, 4.2 Hz, 1H), 2.01 (br dd, J=13.1, 3.5 Hz, 1H), 1.52 (s, 9H). racemic tert-butyl (3S,4R)-3-fluoro-4-(6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-indazol-1-yl)piperidine-1-carboxylate To a degassed mixture of racemic tert-butyl (3S,4R)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)- 3-fluoropiperidine-1-carboxylate (200 mg, 0.480 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (146 mg, 0.577 mmol) and potassium acetate (141 mg, 1.441 mmol) in 1,4-Dioxane (3 mL) was added PdCl2(dppf)-CH2Cl2adduct (58.9 mg, 0.072 mmol). The reaction mixture was degassed again for 5 min. Then the sealed tube was heated at 100 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The resulting tar was shown to contain crude racemic tert-butyl (3S,4R)-3-fluoro-4-(6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1- yl)piperidine-1-carboxylate by LC / MS and was taken up into DMF (2 mL) and carried on as crude for the next step. LCMS (ESI, m / z): 382 [M+H (boronic acid)]+. tert-butyl (3S,4R)-3-fluoro-4-(6-fluoro-3-((R)-1-(4-methoxybenzyl)-2-oxo-4- (trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1- yl)piperidine-1-carboxylate (mix of diastereomers) mixture of diastereomers An argon purged mixture of (R)-5-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (130 mg, 0.349 mmol), crude racemic tert-butyl (3S,4R)-3-fluoro-4-(6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1- yl)piperidine-1-carboxylate (242 mg, 0.523 mmol), XPhos Pd G3 (59.0 mg, 0.070 mmol), copper(I) chloride (34.5 mg, 0.349 mmol) and cesium carbonate (341 mg, 1.046 mmol) in DMF (3 mL) was sealed and heated at 90 °C for 6 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. The separated organic layer was washed with 5% citric acid and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by FCC (24 g silica gel cartridge, eluted with gradient 0~40% EtOAc-hexanes) to afford 190 mg of the desired product tert-butyl (3S,4R)-3-fluoro-4-(6-fluoro-3-((R)-1-(4- methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)- 1H-indazol-1-yl)piperidine-1-carboxylate (201 mg) as a mixture of two diastereomers. LCMS (ESI, m / z): 674 [M+H]+. The mixture of diastereomers of tert-butyl (3S,4R)-3-fluoro-4-(6-fluoro-3-((R)-1-(4- methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)- 1H-indazol-1-yl)piperidine-1-carboxylate (201 mg) was stirred in 2:1 DCM / TFA (0.8 mL) and triflic acid (0.1 mL) at rt for 1 h. Removed volatiles with a steady stream of N2, and the racemic material was purified by prepartive SFC chromatography with the following conditions: Column: Chiralpak IC-H, 19 mm x 200 mm, 5 µm particles; Mobile Phase A: CO2; Mobile Phase B: MeOH with 0.1% DEA; Gradient: 30 %B over 20.00 min; Flow Rate: 100.00 mL / min; Fraction collection was triggered by UV (220 nm). Example 53 (first eluting): LCMS m / z: 454 [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; Gradient: 0-100 %B (0.0- 3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; 220 nm; RT: 1.52 min.1H NMR (500 MHz, DMSO-d6) 8.53 (d, J=5.1 Hz, 1H), 8.06 (dd, J=9.0, 5.0 Hz, 1H), 7.88 (br d, J=9.9 Hz, 1H), 7.68 (d, J=5.2 Hz, 1H), 7.32 - 7.08 (m, 2H), 5.20 - 4.97 (m, 1H), 4.89 - 4.60 (m, 1H), 3.15 (br d, J=13.0 Hz, 2H), 3.04 - 2.89 (m, 1H), 2.74 (br t, J=12.8 Hz, 1H), 2.59 (br dd, J=12.8, 3.3 Hz, 1H), 1.97 - 1.76 (m, 1H). Example 54 (second eluting): LCMS m / z: 454 [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; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; 220 nm; RT: 1.53 min. Example 55 (R)-5-(1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (3R,4S)-4-(3-bromo-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate A mixture of 3-bromo-1H-indazole (300 mg, 1.52 mmol), tert-butyl (3R,4R)-4-hydroxy-3- methyl-piperidine-1-carboxylate (360 mg, 1.67 mmol) and CMBP (734 mg, 3.05 mmol) in toluene (10 mL) was stirred at 85 °C overnight 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 (0.05% TFA) / MeCN (1:3) to give tert- butyl (3R,4S)-4-(3-bromoindazol-1-yl)-3-methyl-piperidine-1-carboxylate (240 mg, 41%) as a colorless oil. LCMS (ESI, m / z): 394; 396 [M+H]+. tert-butyl (3R,4S)-3-methyl-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl (3R,4S)-4-(3-bromoindazol-1-yl)-3-methyl-piperidine-1- carboxylate (70 mg, 0.18 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid (46 mg, 0.18 mmol) and K2CO3(73 mg, 0.53 mmol) in 1,4- dioxane (2 mL) and water (0.2 mL) was added Pd(dppf)Cl2(14 mg, 0.02 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 (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 petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (3R,4S)-3-methyl-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (80 mg, 84%) as a white solid. LCMS (ESI, m / z): 532 [M+H]+. Example 55 To a solution of tert-butyl (3R,4S)-3-methyl-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (80 mg, 0.15 mmol) in DCM (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (3:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (R)-5-(1-((3R,4S)-3- methylpiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-2-one (49.7 mg, 76%) as a white solid. LCMS (ESI, m / z): 432 [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 60% B in 1.70 min, 60% 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: 1.108 min.1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.80 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.53 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.14-7.11 (m, 1H), 5.32-5.30 (m, 1H), 3.55-3.52 (m, 2H), 3.25-3.21 m, 2H), 2.62-2.61 (m, 1H), 2.51-2.45 (m, 1H), 2.29-2.25 (m, 1H), 0.66 (d, J = 6.8 Hz, 3H).

[0006] Example 56 (R)-5-(1-((3S,4R)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (3S,4R)-4-(3-bromo-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate A mixture of 3-bromo-1H-indazole (300 mg, 1.52 mmol), tert-butyl (3S,4S)-4-hydroxy-3- methyl-piperidine-1-carboxylate (360 mg, 1.67 mmol) and CMBP (734 mg, 3.05 mmol) in toluene (10 mL) was stirred at 85 °C overnight 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 (0.05% TFA) / MeCN (1:3) to give tert- butyl (3S,4R)-4-(3-bromoindazol-1-yl)-3-methyl-piperidine-1-carboxylate (240 mg, 41%) as a colorless oil. LCMS (ESI, m / z): 394; 396 [M+H]+. tert-butyl (3S,4R)-3-methyl-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl (3S,4R)-4-(3-bromoindazol-1-yl)-3-methyl-piperidine-1- carboxylate (70 mg, 0.18 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid (46 mg, 0.18 mmol) and K2CO3(73 mg, 0.53 mmol) in 1,4- dioxane (2 mL) and water (0.2 mL) was added Pd(dppf)Cl2(14 mg, 0.02 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 (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 petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (3S,4R)-3-methyl-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]piperidine-1-carboxylate (80 mg, 84%) as a white solid. LCMS (ESI, m / z): 532 [M+H]+. BMT-852519 To a solution of tert-butyl (3S,4R)-3-methyl-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]piperidine-1-carboxylate (80 mg, 0.15 mmol) in DCM (3 mL) was added dropwise TFA (1 mL). The reaction mixture was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (3:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[1-[(3S,4R)-3- methyl-4-piperidyl]indazol-3-yl]-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-2- one (56.8 mg, 76%) as a white solid. LCMS (ESI, m / z): 432 [M+H]+. Analytic Conditions: Column: HALO C18100*4.6 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: 2.732 min.1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.80 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.53 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.14-7.11 (m, 1H), 5.32-5.30 (m, 1H), 3.56- 3.53 (m, 2H), 3.27-3.21 (m, 2H), 2.62-2.61 (m, 1H), 2.51-2.45 (m, 1H), 2.29-2.25 (m, 1H), 0.69 (d, J = 6.8 Hz, 3H). Example 57 (R)-5-(1-((3R,4R)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (3R,4R)-4-(3-bromo-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate To a solution of 3-bromo-1H-indazole (150 mg, 0.76 mmol), tert-butyl (3R,4S)-4-hydroxy-3- methyl-piperidine-1-carboxylate (180 mg, 0.84 mmol) and CMBP (367 mg, 1.52 mmol) in toluene (5 mL). The resulting mixture was stirred at 85 °C overnight under nitrogen atmosphere. LCMS showed that some of the starting material was remaining and two products with desired mass were formed. 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 (0.05% TFA) / MeCN (1:3) to give tert-butyl (3R,4R)-4-(3-bromoindazol-1-yl)-3-methyl-piperidine-1-carboxylate (90 mg, 30%) as a colorless oil. LCMS (ESI, m / z): 394, 396 [M+H]+. tert-butyl (3R,4R)-3-methyl-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl (3R,4R)-4-(3-bromoindazol-1-yl)-3-methyl-piperidine-1- carboxylate (90 mg, 0.23 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid (60 mg, 0.23 mmol) and K2CO3(94 mg, 0.68 mmol) in 1,4- dioxane (2 mL) and water (0.2 mL) was added Pd(dppf)Cl2(19 mg, 0.02 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 (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 petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (3R,4R)-3-methyl-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]piperidine-1-carboxylate (80 mg, 66%) as a colorless semi-solid. LCMS (ESI, m / z): 532 [M+H]+. Example 57 To a solution of tert-butyl (3R,4R)-3-methyl-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]piperidine-1-carboxylate (80 mg, 0.15 mmol) in DCM (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (3:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[1-[(3R,4R)-3- methyl-4-piperidyl]indazol-3-yl]-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-2- one (51.4 mg, 79%) as a white solid. LCMS (ESI, m / z): 432 [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: 0.632 min.1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.87-8.83 (m, 1H), 8.69-8.65 (m, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 5.2 Hz, 1H), 7.61-7.57 (m, 1H), 7.39-7.29 (m, 2H), 4.87-4.81 (m, 1H), 3.16-3.12 (m, 1H), 2.95-2.85 (m, 1H), 2.62 (s, 1H), 2.32-2.28 (m, 1H), 2.15-2.11 (m, 1H), 0.65 (d, J = 6.5 Hz, 3H). Example 58 (R)-5-(1-((3R,4R)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (3S,4S)-4-(3-bromo-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate To a solution of 3-bromo-1H-indazole (150 mg, 0.76 mmol), tert-butyl (3S,4R)-4-hydroxy-3- methyl-piperidine-1-carboxylate (180 mg, 0.84 mmol) and CMBP (367 mg, 1.52 mmol) in toluene (5 mL). The resulting mixture was stirred at 85 °C overnight under nitrogen atmosphere. LCMS showed that some of the starting material was remaining and two products with desired mass were formed. 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 (0.05% TFA) / MeCN (1:3) to give tert-butyl (3S,4S)-4-(3-bromoindazol-1-yl)-3-methyl-piperidine-1-carboxylate (75 mg, 30%) as a colorless oil. LCMS (ESI, m / z): 394, 396 [M+H]+. tert-butyl (3S,4S)-3-methyl-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl (3S,4S)-4-(3-bromoindazol-1-yl)-3-methyl-piperidine-1- carboxylate (75 mg, 0.23 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)boronic acid (55 mg, 0.23 mmol) and K2CO3(80 mg, 0.68 mmol) in 1,4- dioxane (2 mL) and water (0.2 mL) was added Pd(dppf)Cl2(16 mg, 0.02 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 (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 petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (3S,4S)-3-methyl-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]piperidine-1-carboxylate (70 mg, 66%) as a colorless semi-solid. LCMS (ESI, m / z): 532 [M+H]+. Example 58 To a solution of tert-butyl (3S,4S)-3-methyl-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]piperidine-1-carboxylate (70 mg, 0.15 mmol) in DCM (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (3:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[1-[(3S,4S)-3- methyl-4-piperidyl]indazol-3-yl]-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-2- one (57.1 mg, 79%) as a white solid. LCMS (ESI, m / z): 432 [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 60% B in 1.70 min, 60% 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: 1.043 min.1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.89-8.85 (dm, 1H), 8.67-8.63 (m, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 5.2 Hz, 1H), 7.60-7.56 (m, 1H), 7.38-7.34 (m, 2H), 4.89-4.82 (m, 1H), 3.52-3.48 (m, 1H), 3.17-3.13 (m, 1H), 2.95- 2.86 (m, 1H), 2.56-2.52 (dm, 1H), 2.44-2.29 (m, 1H), 2.15-2.09 (m, 1H), 0.58 (d, J = 6.8 Hz, 3H). Example 59 (R)-5-(1-((3R,4S)-4-fluoropyrrolidin-3-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (3R,4S)-3-(3-bromo-1H-indazol-1-yl)-4-fluoropyrrolidine-1-carboxylateBocA solution of 3-bromo-1H-indazole (300 mg, 1.52 mmol), tert-butyl (3S,4S)-3-fluoro-4- hydroxy-pyrrolidine-1-carboxylate (312 mg, 1.52 mmol) and CMBP (734 mg, 3.05 mmol) in toluene (3 mL) was stirred at 85 °C overnight 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 (1:3) to give tert-butyl (3R,4S)-3-(3-bromo-1H-indazol-1-yl)-4-fluoropyrrolidine-1-carboxylate (150 mg, 25%) as a yellow solid. LCMS (ESI, m / z): 384, 386 [M+H]+. tert-butyl (3S,4R)-3-fluoro-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)boronic acid (50 mg, 0.19 mmol), tert-butyl (3R,4S)-3-(3-bromo-1H-indazol-1-yl)-4- fluoropyrrolidine-1-carboxylate (81 mg, 0.21 mmol) and K2CO3(79 mg, 0.57 mmol) in 1,4- dioxane (2 mL) and water (0.4 mL) was added Pd(dppf)Cl2(16 mg, 0.02 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 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 (1:2) to give tert-butyl (3S,4R)-3-fluoro-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin- 5-yl]indazol-1-yl]pyrrolidine-1-carboxylate (60 mg, 60%) as a yellow solid. LCMS (ESI, m / z): 522 [M+H]+. Example 59 To a solution of tert-butyl (3S,4R)-3-fluoro-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]pyrrolidine-1-carboxylate (60. mg, 0.12 mmol) in dichloromethane (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (3:2) to give (4R)-5-[1- [(3R,4S)-4-fluoropyrrolidin-3-yl]indazol-3-yl]-4-(trifluoromethyl)-1,4-dihydropyrido[2,3- d][1,3]oxazin-2-one (40 mg, 80%) as a white solid. LCMS (ESI, m / z): 422 [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: 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: 0.624 min.1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.97-9.41 (m, 2H), 8.56 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.12-7.02 (m, 1H), 5.95-5.79 (m, 1H), 5.78-5.59 (m, 1H), 4.26-4.16 (m, 1H), 4.09-3.99 (m, 1H), 3.86-3.76 (m, 1H), 3.75-3.61 (m, 1H). Example 60 (R)-5-(1-((3S,4R)-4-fluoropyrrolidin-3-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (3S,4R)-3-(3-bromo-1H-indazol-1-yl)-4-fluoropyrrolidine-1-carboxylate A solution of 3-bromo-1H-indazole (300 mg, 1.52 mmol), tert-butyl (3R,4R)-3-fluoro-4- hydroxy-pyrrolidine-1-carboxylate (312 mg, 1.52 mmol) and CMBP (734 mg, 3.05 mmol) in toluene (3 mL) was stirred at 85 °C overnight 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 (1:3) to give tert-butyl (3S,4R)-3-(3-bromo-1H-indazol-1-yl)-4-fluoropyrrolidine-1-carboxylate (150 mg, 25%) as a yellow solid. LCMS (ESI, m / z): 384, 386 [M+H]+. tert-butyl (3R,4S)-3-fluoro-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylateBocTo a solution of (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)boronic acid (50 mg, 0.19 mmol), tert-butyl (3S,4R)-3-(3-bromo-1H-indazol-1-yl)-4- fluoropyrrolidine-1-carboxylate (81 mg, 0.21 mmol) and K2CO3(79 mg, 0.570 mmol) in 1,4- dioxane (2 mL) and water (0.4 mL) was added Pd(dppf)Cl2(16 mg, 0.02 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 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 (1:2) to give tert-butyl (3R,4S)-3-fluoro-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin- 5-yl]indazol-1-yl]pyrrolidine-1-carboxylate (60 mg, 60%) as a yellow solid. LCMS (ESI, m / z): 522 [M+H]+. Example 60 To a solution of tert-butyl (3R,4S)-3-fluoro-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]pyrrolidine-1-carboxylate (60 mg, 0.12 mmol) in dichloromethane (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (3:2) to give (4R)-5-[1- [(3S,4R)-4-fluoropyrrolidin-3-yl]indazol-3-yl]-4-(trifluoromethyl)-1,4-dihydropyrido[2,3- d][1,3]oxazin-2-one (45 mg, 91%) as a white solid. LCMS (ESI, m / z): 422 [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: 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: 0.640 min.1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.75 (s, 2H), 8.57 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.73-7.60 (m, 2H), 7.45-7.37 (m, 1H), 7.28-7.18 (m, 1H), 5.95-5.79 (m, 1H), 5.73-5.51 (m, 1H), 4.24 (t, J = 10.8 Hz, 1H), 4.05-3.95 (m, 1H), 3.85-3.83 (m, 1H), 3.72-3.69 (m, 1H). Example 61 (R)-5-(1-((3R,4R)-4-fluoropyrrolidin-3-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4- dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (3R,4R)-3-(3-bromo-1H-indazol-1-yl)-4-fluoropyrrolidine-1-carboxylate A solution of 3-bromo-1H-indazole (150 mg, 0.76 mmol), tert-butyl (3R,4S)-3-fluoro-4- hydroxy-pyrrolidine-1-carboxylate (156 mg, 0.76 mmol) and CMBP (367 mg, 1.52 mmol) in toluene (3 mL) was stirred at 85 °C overnight 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 (1:2) to give tert-butyl (3R,4R)-3-(3-bromo-1H-indazol-1-yl)-4-fluoropyrrolidine-1-carboxylate (140 mg, 47%) as a brown solid. LCMS (ESI, m / z): 384, 386 [M+H]+. tert-butyl (3R,4R)-3-fluoro-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)boronic acid (50 mg, 0.19 mmol), tert-butyl (3R,4R)-3-(3-bromo-1H-indazol-1-yl)-4- fluoropyrrolidine-1-carboxylate (81 mg, 0.21 mmol) and K2CO3(79 mg, 0.57 mmol) in 1,4- dioxane (2 mL) and water (0.4 mL) was added Pd(dppf)Cl2(16 mg, 0.02 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 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 (1:2) to give tert-butyl (3R,4R)-3-fluoro-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin- 5-yl]indazol-1-yl]pyrrolidine-1-carboxylate (80 mg, 80%) as a yellow solid. LCMS (ESI, m / z): 522 [M+H]+. Example 61 To a solution of tert-butyl (3R,4R)-3-fluoro-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]pyrrolidine-1-carboxylate (80 mg, 0.15 mmol) in dichloromethane (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 2 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep- HPLC using the following conditions: Column: Xselect CSH Prep C18 Column, 30x250 mm, 10 μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to36 % B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8.9. The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[1-[(3R,4R)-4-fluoropyrrolidin-3-yl]indazol-3-yl]-4- (trifluoromethyl)-1,4-dihydropyrido [2,3-d][1,3]oxazin-2-one (39.9 mg, 61%) as a white solid. LCMS (ESI, m / z): 422 [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: Acetonitrile / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 50% B in 1.70 min, 50% 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: 1.181 min.1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.88 (s, 2H), 8.56 (d, J = 5.2 Hz, 1H), 8.03-7.95 (m, 2H), 7.68-7.59 (m, 2H), 7.44-7.36 (m, 1H), 7.20-7.10 (m, 1H), 6.05-5.94 (m, 1H), 5.70-5.47 (m, 1H), 4.14-4.04 (m, 1H), 3.93-3.84 (m, 1H), 3.83-3.54 (m, 2H). Example 62 (R)-5-(1-((3S,4S)-4-fluoropyrrolidin-3-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)-1,4-dihydro- 2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (3S,4S)-3-(3-bromo-1H-indazol-1-yl)-4-fluoropyrrolidine-1-carboxylate BocA solution of 3-bromo-1H-indazole (150 mg, 0.76 mmol), tert-butyl (3S,4R)-3-fluoro-4- hydroxy-pyrrolidine-1-carboxylate (156 mg, 0.76 mmol) and CMBP (367 mg, 1.52 mmol) in toluene (3 mL) was stirred at 85 °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 (1:2) to give tert-butyl (3S,4S)-3-(3-bromo-1H-indazol-1-yl)-4-fluoropyrrolidine-1-carboxylate (140 mg, 47%) as a brown solid. LCMS (ESI, m / z): 384 [M+H]+. tert-butyl (3S,4S)-3-fluoro-4-(3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3- d][1,3]oxazin-5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5- yl)boronic acid (50 mg, 0.19 mmol), tert-butyl (3S,4S)-3-(3-bromo-1H-indazol-1-yl)-4- fluoropyrrolidine-1-carboxylate (80 mg, 0.21 mmol) and K2CO3(79 mg, 0.57 mmol) in 1,4- dioxane (2 mL) and water (0.4 mL) was added Pd(dppf)Cl2(15 mg, 0.02 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 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 (1:2) to give tert-butyl (3S,4S)-3-fluoro-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin- 5-yl]indazol-1-yl]pyrrolidine-1-carboxylate (80 mg, 80%) as a yellow solid. LCMS (ESI, m / z): 522 [M+H]+. Example 62 To a solution of tert-butyl (3S,4S)-3-fluoro-4-[3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4- dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]pyrrolidine-1-carboxylate (80 mg, 0.15 mmol) in dichloromethane (3 mL) was added dropwise TFA (1 mL) . The resulting solution was stirred for 2 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep- HPLC using the following conditions: Column: Xselect CSH Prep C18 Column, 30x250 mm, 10 μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% B to37 % B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8.87. The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[1-[(3S,4S)-4-fluoropyrrolidin-3-yl]indazol-3-yl]-4- (trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one (49.5 mg, 76%) as a white solid. LCMS (ESI, m / z): 422 [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: Acetonitrile / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 50% B in 1.70 min, 50% 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: 1.200 min.1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.83 (s, 2H), 8.56 (d, J = 5.2 Hz, 1H), 8.05-7.95 (m, 2H), 7.68-7.60 (m, 2H), 7.45-7.36 (m, 1H), 7.12-7.02 (m, 1H), 5.98 (d, J = 16.4 Hz, 1H), 5.85-5.66 (m, 1H), 4.06-3.96 (m, 1H), 3.94-3.80 (m, 2H), 3.78-3.60 (m, 1H). Example 63 (R)-5-(6-fluoro-1-((3R,4S)-4-fluoropyrrolidin-3-yl)-1H-indazol-3-yl)-4-(trifluoromethyl)- 1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one tert-butyl (3S,4R)-3-fluoro-4-(6-fluoro-3-iodo-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of 6-fluoro-3-iodo-1H-indazole (200 mg, 0.76 mmol) and tert-butyl (3S,4S)-3- fluoro-4-hydroxy-pyrrolidine-1-carboxylate (235 mg, 1.14 mmol) in toluene (7 mL) was added CMBP (368 mg, 1.53 mmol). The reaction mixture was stirred at 85 °C for 1 day under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with sodium thiosulfate aqueous solution (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (2x20 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 / 2) to give tert-butyl (3S,4R)-3-fluoro-4-(6-fluoro-3-iodo-1H-indazol-1-yl)pyrrolidine-1-carboxylate (60 mg, 17.5%) as a light-yellow solid. LCMS (ESI, m / z): 450 [M+H]+. tert-butyl (3S,4R)-3-fluoro-4-(6-fluoro-3-((R)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl (3S,4R)-3-fluoro-4-(6-fluoro-3-iodo-1H-indazol-1-yl)pyrrolidine- 1-carboxylate (60 mg, 0.13 mmol), (R)-(2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H- pyrido[2,3-d][1,3]oxazin-5-yl)boronic acid (39 mg, 0.15 mmol) and K2CO3(55 mg, 0.40 mmol) in 1,4-dioxane (4 mL) and water (0.8 mL) was added Pd(dppf)Cl2(22 mg, 0.03 mmol). The reaction mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with sodium thiosulfate aqueous solution (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (2x20 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 / 2) to give tert-butyl (3S,4R)-3- fluoro-4-[6-fluoro-3-[(4R)-2-oxo-4-(trifluoromethyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-5- yl]indazol-1-yl]pyrrolidine-1-carboxylate (45 mg, 62 %) as a light-yellow solid. LCMS (ESI, m / z): 540 [M+H]+. Example 63 To a solution of tert-butyl (3S,4R)-3-fluoro-4-[6-fluoro-3-[(4R)-2-oxo-4-(trifluoromethyl)- 1,4-dihydropyrido[2,3-d][1,3]oxazin-5-yl]indazol-1-yl]pyrrolidine-1-carboxylate (40 mg, 0.07 mmol0) in dichloromethane (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The pure fractions were collected and concentrated. The residue was lyophilized with water / ACN to afford (4R)-5-[6- fluoro-1-[(3R,4S)-4-fluoropyrrolidin...

Claims

CLAIMS What is claimed is:

1. A compound of Formula I:or a pharmaceutically acceptable salt wherein, R1is selected from the group consisting of: −CH= and −N=; R2is selected from the group consisting of: −NH− and −O−; R3is selected from the group consisting of:,R4is selected from the group consisting of alkyl and −CF2R16; R5is selected from the group consisting of:; R6is selected from the group consisting of: −H and −F; R7is selected from the group consisting of: (4-fluoropiperidin-4-yl)methyl,, ; R8is selected from the group consisting of: −H, −CH3, and −CF3;R9is selected from the group consisting of:; R10is selected from the group consisting of: ,; R11is selected from the group consisting of: 3-fluoropiperidin-4-yl and 4- (methylamino)cyclohexyl; R12is selected from the group consisting of: azetidin-3-yl, 1- (cyanomethyl)cyclobutyl, (4-fluoropiperidin-4-yl)methyl,, , ,; R13is selected from the group consisting of: −H and −CH3; R14is selected from the group consisting of: −H, −CH3, −F, and −CF3; R15is selected from the group consisting of: −H, −CH3, and cyclopropyl; R16is selected from the group consisting of: −H, −CH3, and −F; R17is selected from the group consisting of: −H and −F; R18is selected from the group consisting of: −H and −F; R19is selected from the group consisting of: −NH2and −NHCH3; R20is selected from the group consisting of: −H and −CH3; R21is selected from the group consisting of: −CO− and −CH(R24)−; R22is selected from the group consisting of: −H and cyclopropyl; R23is selected from the group consisting of: −H, −CH3, −F, and −OCH3; R24is selected from the group consisting of: −H and −CH3.

2. The compound according to Claim 1, wherein: R4is selected from the group consisting of: −CH3and −CF2R16.

3. The compound according to Claim 1, wherein: R1is −CH=; R2is −O−;R3is ;; R13is −H; R14is −H; R16is −F; R18is −H.

4. The compound according to Claim 1, wherein: R1is −CH=; R2is −O−; R3is; R4is −CF2R16; R6is −H;R12is; R13is −H; R14is −H; R16is −F; R18is −H.

5. The compound of claim 1 wherein the compound is selected from the group consisting of: 2-(1-{3-[(4S)-4-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-5-yl]-1H- indazol-1-yl}cyclobutyl)acetonitrile; 2-(1-{3-[(4S)-4-methyl-2-oxo-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-1H-indazol- 1-yl}cyclobutyl)acetonitrile; (4S)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-indazol-3-yl}-4-methyl-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; 2-(1-{3-[(4S)-4-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-5-yl]-1H- pyrazolo[3,4-b]pyridin-1-yl}cyclobutyl)acetonitrile; (4S)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-4- methyl-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4S)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-5-methyl-1H-pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-5-(trifluoromethyl)-1H-pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-[1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(azetidin-3-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-2-one; (4R)-5-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-6-(trifluoromethyl)-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4S)-5-[3-(piperazin-1-yl)-1H-indazol-1-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[3-(piperazin-1-yl)-1H-indazol-1-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4-fluoropiperidin-4-yl)methyl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(1r,4r)-4-aminocyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(2S,4R)-2-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; 4-{3-[2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-5-yl]-1H- indazol-1-yl}piperidin-2-one; 2-(1-{6-methyl-3-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-5-yl]-1H-indazol-1-yl}cyclobutyl)acetonitrile; 2-(1-{6-fluoro-3-[(4R)-2-oxo-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3- d][1,3]oxazin-5-yl]-1H-indazol-1-yl}cyclobutyl)acetonitrile; (4R)-5-{1-[(1s,4s)-4-aminocyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{1-[(1r,4r)-4-(methylamino)cyclohexyl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[5-methyl-1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-[5-methyl-1-(piperidin-4-yl)-1H-pyrazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-(1-{2-azaspiro[3.3]heptan-6-yl}-5-methyl-1H-pyrazol-3-yl)-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-(1-{2-azaspiro[3.3]heptan-6-yl}-1H-indazol-3-yl)-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[1-(piperidin-4-yl)-1H-indazol-3-yl]-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[4-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[5,6-difluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[7-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-(1-{2-azaspiro[3.5]nonan-7-yl}-1H-indazol-3-yl)-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R)-pyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{1-[(3S)-pyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; 2-(1-{3-[(5R)-5-(difluoromethyl)-7-oxo-5H,6H,7H,8H-pyrimido[4,5-d][1,3]diazin-4- yl]-1H-indazol-1-yl}cyclobutyl)acetonitrile; (4R)-4-(difluoromethyl)-5-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{3-[(3S)-3-methylpiperazin-1-yl]-1H-indazol-1-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{3-[(3S)-3-cyclopropylpiperazin-1-yl]-1H-indazol-1-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-[1-(piperidin-4-yl)-1H-indazol-3-yl]-1H,2H,4H- pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(4-methylpiperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(2S,4S)-2-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R)-pyrrolidin-3-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S)-pyrrolidin-3-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{1-[(1r,4r)-4-(methylamino)cyclohexyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}- 4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R)-pyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S)-pyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(piperidin-4-yl)-1H,4H,5H,6H-cyclopenta[c]pyrazol-3-yl]-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4R)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4R)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4S)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one;(4R)-5-{6-fluoro-1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4R)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-5-(trifluoromethyl)-1H-pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-5-(trifluoromethyl)-1H-pyrazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[5,5-difluoro-5a-methyl-1-(piperidin-4-yl)-1H,4H,4aH,5H,5aH,6H- cyclopropa[f]indazol-3-yl]-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5- d][1,3]oxazin-2-one; (4R)-5-[5,5-difluoro-5a-methyl-1-(piperidin-4-yl)-1H,4H,4aH,5H,5aH,6H- cyclopropa[f]indazol-3-yl]-4-(difluoromethyl)-1H,2H,4H-pyrimido[4,5- d][1,3]oxazin-2-one (4R)-4-(difluoromethyl)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol- 3-yl}-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol- 3-yl}-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-methoxypiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{1-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H,4H,5H,6H-cyclopenta[c]pyrazol-3- yl}-4-(trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-pyrazolo[3,4-c]pyridin-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(1r,4r)-4-amino-4-methylcyclohexyl]-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4S,5R)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4R,5S)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4S,5S)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4R,5R)-5-fluoroazepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-[1-(1-cyclopropylpiperidin-4-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one;(4R)-4-(difluoromethyl)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-4-(difluoromethyl)-5-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{5-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-(1-{4-azaspiro[2.5]octan-7-yl}-1H-indazol-3-yl)-4-(trifluoromethyl)- 1H,2H,4H-pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4S)-azepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{1-[(4R)-azepan-4-yl]-1H-indazol-3-yl}-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one; (4R)-5-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-4- (trifluoromethyl)-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-2-one; or (4R)-5-[1-(pyrrolidin-3-yl)-1H-indazol-3-yl]-4-(trifluoromethyl)-1H,2H,4H- pyrido[2,3-d][1,3]oxazin-2-one.

6. A pharmaceutical composition comprising the compound of Formula I, and a pharmaceutically acceptable carrier.

7. 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 1-5 or a pharmaceutical composition of claim 6 to the subject.

8. The method of claim 7, wherein the disease or disorder is an inflammatory disease, an autoimmune disorder, a cancer, an oncologic disease, or an autoimmune infection.

9. The method of claim 7, wherein the disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, or atopic dermatitis.

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