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 / 656794 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 thereof, wherein: R1is selected from the group consisting of: −CH= and −N=; R2is selected from the group consisting of: −N= and −C(R5)=; R3is selected from the group consisting of: 1,4-diazepan-1-yl, ; R4is selected from the group consisting of: −H, alkyl, haloalkyl, −CCH3F2, and −CF3; R5is selected from the group consisting of: alkyl, halogen, −CN, −CHF2, −CCH3F2, and R6is selected from the group consisting of: alkyl and haloalkyl; R7is selected from the group consisting of: −CH2− and −CO−; R8is selected from the group consisting of: −H and alkyl; R9is selected from the group consisting of: −H, alkyl, branched alkyl, and cyclyl. . Further disclosed is a compound selected from a group consisting of: (5S)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-fluoro-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-[4-fluoro-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-one; (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-one; 4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; 4-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5H,6H,7H,8H-pyrido[2,3- d]pyrimidin-7-one; (5S)-5-methyl-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-methyl-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5-methyl- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5-methyl- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-5-(difluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(difluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(1,1-difluoroethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(1,1-difluoroethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(2S)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(2S)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(2R)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-5- (difluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-5-(difluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; 4-[6-(4-methylpiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (6S)-4-{6-[(5R)-5-(difluoromethyl)-7-oxo-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-4- (trifluoromethyl)pyridin-2-yl}-6-methylpiperazin-2-one; (5S)-4-{6-[(3S)-3-methylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-ethylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; 2-[(3S)-3-methylpiperazin-1-yl]-6-[(5S)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3- d]pyrimidin-4-yl]pyridine-4-carbonitrile; (5R)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one (5R)-4-{6-[(3S)-3-ethylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one (5R)-4-{6-[(3S)-3-methylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one 2-[(3S)-3-methylpiperazin-1-yl]-6-[(5R)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3- d]pyrimidin-4-yl]pyridine-4-carbonitrile; (5R)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]pyrazin-2-yl}-5-(difluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one (5R)-5-(difluoromethyl)-4-{6-[(3S)-3-ethylpiperazin-1-yl]pyrazin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]pyrazin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; 2-[(5R)-5-(difluoromethyl)-7-oxo-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-6-[(3S)-3- methylpiperazin-1-yl]pyridine-4-carbonitrile; (5R)-4-{6-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; or (5R)-5-(difluoromethyl)-4-{6-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-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. 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.

[0002] The first aspect of the present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of: −CH= and −N=; R2is selected from the group consisting of: −N= and −C(R5)=; R3is selected from the group consisting of: 1,4-diazepan-1-yl, ; R4is selected from the group consisting of : −H, alkyl, haloalkyl, −CCH3F2, and −CF3; R5is selected from the group consisting of: alkyl, halogen, −CN, −CHF2, −CCH3F2, and −CF3; R6is selected from the group consisting of: alkyl and haloalkyl; R7is selected from the group consisting of: −CH2− and −CO−; R8is selected from the group consisting of: −H and alkyl; R9is selected from the group consisting of: −H, alkyl, branched alkyl, , and cyclyl. In one embodiment of the compound: R4is selected from the group consisting of: −H, −CH3, −CHF2, −CCH3F2, and −CF3; R5is selected from the group consisting of: −CH3, −F, −Cl, −CN, −CHF2, −CCH3F2, and −CF3; R6is selected from the group consisting of: −CH3and −CH2F; R8is selected from the group consisting of: −H, −CH3, and −CH2CH3; R9is selected from the group consisting of: −H, −CH3, −CH2CH3, −CH(CH3)2, and cyclopropyl. In one embodiment of the compound: R2is −C(R5)=; R4is selected from the group consisting of: −H, alkyl, haloalkyl, and −CF3; R5is selected from the group consisting of: −CH3, −F, −Cl, −CN, −CHF2, −CF2CH3, and −CF3; R9is selected from the group consisting of: −H, alkyl, and cyclyl. In another embodiment of the compound: R1is −N=; R2is −C(R5)=; R3is ; R4is −H; R5is −CF3; R7is −CH2−; R8is −H; R9is alkyl. In one embodiment of the compound: R1is −N=; R2is −C(R5)=; R3is ; R4is selected from the group consisting of: −H and haloalkyl; R5is selected from the group consisting of halogen and −CF3; R7is −CH2−; R8is −H; R9is selected from the group consisting of: −H and alkyl. Further disclosed is a compound selected from a group consisting of: (5S)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-fluoro-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-[4-fluoro-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-one; (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-one; 4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; 4-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5H,6H,7H,8H-pyrido[2,3- d]pyrimidin-7-one; (5S)-5-methyl-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-methyl-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5-methyl- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5-methyl- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-5-(difluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(difluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(1,1-difluoroethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(1,1-difluoroethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(2S)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(2S)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(2R)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-5- (difluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-5-(difluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; 4-[6-(4-methylpiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (6S)-4-{6-[(5R)-5-(difluoromethyl)-7-oxo-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-4- (trifluoromethyl)pyridin-2-yl}-6-methylpiperazin-2-one; (5S)-4-{6-[(3S)-3-methylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-ethylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; 2-[(3S)-3-methylpiperazin-1-yl]-6-[(5S)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3- d]pyrimidin-4-yl]pyridine-4-carbonitrile; (5R)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one (5R)-4-{6-[(3S)-3-ethylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one (5R)-4-{6-[(3S)-3-methylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one 2-[(3S)-3-methylpiperazin-1-yl]-6-[(5R)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3- d]pyrimidin-4-yl]pyridine-4-carbonitrile; (5R)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]pyrazin-2-yl}-5-(difluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one (5R)-5-(difluoromethyl)-4-{6-[(3S)-3-ethylpiperazin-1-yl]pyrazin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]pyrazin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; 2-[(5R)-5-(difluoromethyl)-7-oxo-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-6-[(3S)-3- methylpiperazin-1-yl]pyridine-4-carbonitrile; (5R)-4-{6-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; or (5R)-5-(difluoromethyl)-4-{6-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-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 one embodiment, the invention provides for a method of treating, preventing, or managing a disease or disorder mediated by a protein kinase C theta (PKC-theta) or PKC theta mutant, in a subject, wherein the disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, or atopic dermatitis. 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

[0003] Preparation of Intermediates INT-1 4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one trimethyl 2-(trifluoromethyl)propane-1,1,3-tricarboxylate To a solution of MeONa (17.5 mL, 307.30 mmol) in Methanol (800 mL) was added dimethyl propanedioate (50 g, 378.48 mmol) and ethyl (E)-4,4,4-trifluorobut-2-enoate (63 g, 378.47 mmol) at 70 °C under nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The solvent was evaporated. The residue was diluted with ethyl acetate and the mixture was acidified to pH 7 with HCl (4 N). The resulting mixture was further diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduce pressure to give trimethyl 2-(trifluoromethyl)propane-1,1,3-tricarboxylate (70 g, 64%) as a yellow liquid. The product was used in the next step directly without further purification. LCMS (ESI, m / z): 287 [M+H]+. methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4,4-trifluorobutanoate To a solution of MeONa (148 mL, 1295.82 mmol) in Methanol (1000 mL) was added FAA (51 g, 489.16 mmol) at -15 °C under nitrogen atmosphere. After 30 min, a solution of trimethyl 2-(trifluoromethyl)propane-1,1,3-tricarboxylate (70 g, 244.58 mmol) in Methanol was added dropwise. The resulting solution was stirred for 12 h at room temperature. LCMS showed the reaction was completed. The reaction was then cooled to 0oC and was acidified to pH 2 with HCl (4 N). Most of the solvent was removed under reduced pressure. The residue was diluted with water. The precipitated solid was collected by filter and washed with water (50 mL), and then dried in vacuo to obtain methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4,4-trifluoro- butanoate (40 g, 70%) as a yellow solid. The product was used in the next step directly without further purification. LCMS (ESI, m / z): 267 [M+H]+. methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluorobutanoate To a solution of methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4,4-trifluoro-butanoate (33 g, 123.98 mmol) in POCl3(330 mL) was added dropwise DIEA (79.96 g, 619.88 mmol) at 0oC under nitrogen atmosphere. The reaction mixture was stirred for 15 min at 0oC and was allowed to warm to 100 °C slowly. The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The solvent was removed under reduced pressure. The resulting mixture was then diluted with ice water (500 mL) at 0oC and extracted with ethyl acetate (2 x 1.5 L). The organic layer was washed with brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure to give methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluoro-butanoate (30 g, 79%) as a brown oil. The product was used in the next step directly without further purification. LCMS (ESI, m / z): 303, 305 (M+H)+. INT-1 A solution of methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluoro-butanoate (30 g, 98.99 mmol) in NH3(2.5 M in IPA, 400 mL) was stirred at 100 °C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (1.5 L) and extracted with ethyl acetate (2 x 2 L). The organic layer was washed with brine (2 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (2:1) to give 4-chloro-5-(trifluoromethyl)-6,8-dihydro-5H-pyrido[2,3- d]pyrimidin-7-one (13.12 g, 52%) as an off-white solid. LCMS (ESI, m / z): 252; 254 [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: 0.941 min..1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.70 (s, 1H), 4.47-4.33 (m, 1H), 3.33 (dd, J = 17.6, 7.6 Hz, 1H), 2.72 (d, J = 17.6 Hz, 1H). INT-2 (R)-4-bromo-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (R)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one The racemic 4-chloro-5-(trifluoromethyl)-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one (1.6 g, 6.35 mmol) was resolved by Prep-SFC (Column: CHIRALPAK IH 3*25 cm, 5µm; Mobile Phase A: CO2, Mobile Phase B: MeOH(1%-2M-NH3-MeOH); Flow rate: 90 mL / min; Gradient: isocratic 12% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 4.08; RT2(min): 6.68) to obtain (R)-4-chloro-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 650 mg, 40.6%) (isomer 2) as a yellow solid. LCMS (ESI, m / z): 252, 254 [M+H]+. INT-2 To a solution of (R)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (400 mg, 1.59 mmol) in MeCN (5 mL) was added TMSBr (1208 mg, 7.95 mmol) . The resulting mixture was stirred at 80 °C for 3 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 (1:2) to give (R)-4-bromo-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (335 mg, 62%) as a brown solid. LCMS (ESI, m / z): 296, 298 [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: 0.966 min.1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.62 (s, 1H), 4.34-4.30 (m, 1H), 3.38-3.31 (m, 1H), 2.74-2.50 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -70.26. INT-3 (S)-4-bromo-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (S)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one The racemic 4-chloro-5-(trifluoromethyl)-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one (1.6 g, 6.35 mmol) was resolved by Prep-SFC (Column: CHIRALPAK IH 3*25 cm, 5µm; Mobile Phase A: CO2, Mobile Phase B: MeOH(1%-2M-NH3-MeOH); Flow rate: 90 mL / min; Gradient: isocratic 12% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 4.08; RT2(min): 6.68) to obtain (S)-4-chloro-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 650 mg, 40.6%) (isomer 1) as a yellow solid. LCMS (ESI, m / z): 252, 254 [M+H]+. INT-3 To a solution of (S)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (400 mg, 1.59 mmol) in MeCN (5 mL) was added TMSBr (1208 mg, 7.95 mmol). The resulting mixture was stirred at 80 °C for 3 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 (1:2) to give (S)-4-bromo-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (268.8 mg, 49%) as a brown solid. LCMS (ESI, m / z): 296, 298 [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: 0.962 min.1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.62 (s, 1H), 4.34-4.30 (m, 1H), 3.37-3.31 (m, 1H), 2.75-2.51 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -70.26. INT-4 4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one trimethyl 2-(difluoromethyl)propane-1,1,3-tricarboxylate To a solution of NaOMe (0.6 g, 11.11 mmol) in methanol (20 mL) was added a solution of dimethyl propanedioate (1.8 g, 13.63 mmol) and ethyl (E)-4,4-difluorobut-2-enoate (2.05 g, 13.63 mmol) in methanol (5 mL) at 70 °C . The reaction mixture was stirred at 70 ℃ overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was neutralized to ~pH 7 with 4M HCl at 0 ℃. The resulting solution was extracted with 3x50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give trimethyl 2-(difluoromethyl)propane-1,1,3- tricarboxylate (3.1 g, 84%) as a yellow oil. LCMS (ESI, m / z): 269 [M+H]+. methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4-difluorobutanoate A solution of NaOMe (7.5 g, 138.89 mmol) and FAA (2.52 g, 24.17 mmol) in methanol (20 mL) was stirred at -15°C for 30 min. Then a solution of trimethyl 2-(difluoromethyl)propane- 1,1,3-tricarboxylate (3.0 g, 11.19 mmol) in methanol (5 mL) was added slowly. The reaction mixture was stirred at room temperature overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was acidified to pH 2 with 1M HCl and the resulting solution was concentrated under reduced pressure. The residue was diluted with water. The precipitate was collected by filter and washed with water. The solid was further dried azeotropically with toluene under reduced pressure (3 times) to give methyl 3-(4,6- dihydroxypyrimidin-5-yl)-4,4-difluoro-butanoate (1.8 g, 64%) as a yellow solid. LCMS (ESI, m / z): 249 [M+H]+. methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4-difluorobutanoate To a solution of methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4-difluoro-butanoate (1.8 g, 7.25 mmol) in POCl3(20 mL) was added DIPEA (0.94 g, 7.25 mmol) at 0℃. The reaction was heated up from 0℃ to 100℃ slowly over 1 h and then stirred at 100℃ overnight 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 methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4-difluoro- butanoate (1.2 g, 58%) as a light-yellow oil. LCMS (ESI, m / z): 285, 287 [M+H]+. INT-4 To a solution of NH3in IPA (2M, 20 mL) was added methyl 3-(4,6-dichloropyrimidin-5-yl)- 4,4-difluoro-butanoate (1.14 g, 4 mmol). The reaction mixture was stirred at 100 °C overnight 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 / 1) to give 4-chloro-5-(difluoromethyl)-6,8- dihydro-5H-pyrido[2,3-d]pyrimidin-7-one (850 mg, 91%) as a white solid. LCMS (ESI, m / z): 234, 236 [M+H]+. INT-5 (R)-4-bromo-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (R)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one The racemic 4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (850 mg) was resolved by Prep-chiral-HPLC(Column: CHIRALPAK IH 3x25 cm, 5 µm; Mobile Phase A: CO2, Mobile Phase B: MeOH(1%-2M-NH3-MeOH); Flow rate: 90 mL / min; Gradient: isocratic 24% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 3.23; RT2(min): 4.63) to obtain (R)-4-chloro-5-(difluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 350 mg, 41%) as a white solid. LCMS (ESI, m / z): 234, 236 [M+H]+. INT-5 To a solution of (R)-5-chloro-4-(difluoromethyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin- 2-one (1000 mg, 4.24 mmol) in MeCN (15 mL) was added TMS-Br (2.75 mL, 21.22 mmol) . The resulting mixture was stirred at 80 °C for 30 min under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to afford the title compound (R)-4-bromo-5-(difluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (780 mg, 66%) as a brown solid. LCMS (ESI, m / z): 281, 283 [M+H]+. INT-6 (S)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one The racemic 4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (850 mg) was resolved by Prep-chiral-HPLC(Column: CHIRALPAK IH 3x25 cm, 5 µm; Mobile Phase A: CO2, Mobile Phase B: MeOH(1%-2M-NH3-MeOH); Flow rate: 90 mL / min; Gradient: isocratic 24% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 3.23; RT2(min): 4.63) to obtain 4-chloro-5-(difluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (isomer 1) (the first eluting peak, 250 mg, 29%) as a white solid. LCMS (ESI, m / z): 234, 236 [M+H]+. INT-7 4-chloro-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ethyl 4,4-difluoro-3-oxopentanoate LiHMDS (1 M in THF, 144.8 mL, 144.81 mmol) was cooled at -78 °C and EtOAc (14 mL, 144.81 mmol) was added dropwise with stirring. Stirring was continued for 1 h at -78 °C, then ethyl 2,2-difluoropropanoate (10 g, 72.41 mmol) in THF (20 mL) was added dropwise with stirring. The resulting mixture was stirred at -78 °C for 4 h and then a saturated solution of ammonium chloride was added dropwise. The mixture was allowed to reach room temperature, acidified with HCl (1 N, 50 mL) and left standing overnight. The resulting mixture was then extracted with ethyl acetate (2x200 mL). The combined organic layers were washed with HCl (1 N), and brine, dried over sodium sulfate and concentrated under reduce pressure to give ethyl 4,4-difluoro-3-oxopentanoate (7.3 g, 56%) as a yellow liquid. The product was used in the next step directly without further purification. LCMS (ESI, m / z): 181 [M+H]+. ethyl 4,4-difluoro-3-hydroxypentanoate To a solution of ethyl 4,4-difluoro-3-oxopentanoate (7.3 g, 40.52 mmol) in Toluene (40 mL) was added NaBH4(1.7 g, 44.57 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred overnight and was allowed to warm to room temperature. The mixture was then cooled to 0 °C and acidified with HCl (1 N). The phases were separated. The aqueous phase was extracted two times with ethyl acetate (200 mL), the organic phases was dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was dissolved in a minimum amount of methanol, and the resulting solution was filtered. The filter cake was washed with methanol and the filtrate was concentrated under reduced pressure to give ethyl 4,4-difluoro-3-hydroxypentanoate (4.5 g, 61%) as a yellow liquid. The product was used in the next step directly without further purification. LCMS (ESI, m / z): 183 [M+H]+. ethyl (E)-4,4-difluoropent-2-enoate To a solution of ethyl 4,4-difluoro-3-hydroxypentanoate (4.5 g, 24.70 mmol) in DCM (100 mL) was added TEA (2.5 g, 24.70 mmol). A solution of MsCl (4.5 mL, 37.05 mmol) in DCM (5 mL) was added dropwise the resulting mixture at 0 °C and was stirred for 4 h. Then the mixture was cooled in an ice bath and TEA (5 g, 49.40 mmol) was charged dropwise. The mixture was stirred overnight at room temperature. The reaction was then quenched with water (100 mL) and extracted with DCM (2x100 mL). The combined organic layers were washed with HCl (1 N, 50 mL), dried over sodium sulfate and concentrated under reduce pressure to give crude ethyl (E)-4,4-difluoropent-2-enoate (4.2 g, 103%) as a yellow liquid. The product was used in the next step directly without further purification. LCMS (ESI, m / z): 165 [M+H]+. trimethyl 2-(1,1-difluoroethyl)propane-1,1,3-tricarboxylate To a solution of NaOMe (1.2 g, 21.88 mmol) in Methanol (45 mL) was stirred at 70 °C. Then a solution of ethyl (E)-4,4-difluoropent-2-enoate (4.2 g, 25.59 mmol) and dimethyl propanedioate (3.4 g, 25.59 mmol) in Methanol was added to the resulting mixture at 70 °C. The resulting mixture was stirred at 70 °C for 3 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The liquid was evaporated. Ethyl acetate was added and the pH value of the solution was adjusted to 7 with HCl (4 N). The reaction was then diluted with water (50 mL) and extracted with ethyl acetate (2x50 mL). The organic phase was dried over sodium sulfate and concentrated under reduce pressure to give trimethyl 2-(1,1- difluoroethyl)propane-1,1,3-tricarboxylate (6 g, 83%) as a yellow liquid. The product was used in the next step directly without further purification. LCMS (ESI, m / z): 391 [M+H]+. methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4-difluoropentanoate To a solution of NaOMe (10.71 g, 198.41 mmol) in Methanol (50 mL) was added FAA (4.13 g, 39.68 mmol) at -15 °C under a nitrogen atmosphere. After 30 min, a solution of trimethyl 2- (1,1-difluoroethyl)propane-1,1,3-tricarboxylate (5.6 g, 19.84 mmol) in Methanol (10 mL) was added dropwise the resulting mixture. The reaction mixture was stirred overnight at room temperature. LCMS showed the reaction was completed. The pH value of the resulting solution was adjusted to 2 with HCl (1 N) and concentrated under reduce pressure. Then added water (20 mL) and the solid was precipitated. The resulting mixture was filtered, and the filter cake was washed with water. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (2:1) to give crude methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4- difluoropentanoate (1.9 g, 36%) as a white solid. LCMS (ESI, m / z): 263 [M+H]+. methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4-difluoropentanoate To a solution of methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4-difluoropentanoate (10 g, 38.14 mmol) in POCl3(100 mL, 38.14 mmol) was added DIEA (24.6 g, 190.69 mmol) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred for 15 min at 0°C and was allowed to warm slowly to 100°C. After overnight, the solvent was distilled off under reduced pressure. The resulting mixture was then diluted with ice water (50 mL) and extracted with ethyl acetate (2x100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to give methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4-difluoropentanoate (9 g, 78.9%) as a brown oil. The product was used in the next step directly without further purification. LCMS (ESI, m / z): 299 [M+H]+. INT-7 A solution of methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4-difluoropentanoate (6 g, 20.06 mmol) in NH3(4 M in IPA, 200 mL) was stirred at 100°C for overnight. LCMS showed the reaction was complete, and the mixture was concentrated. The residue was diluted with EA, and the solid was collected by filtration. This resulted in 4-chloro-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (2.0408 g, 40.4%) as a brown solid. LCMS (ESI, m / z): 248, 250 [M+H]+. Analytic Conditions: Column: CORTECS T3, 2.1*30 mm, 2.7 μm; Mobile Phase A: water / 0.1%FA, Mobile Phase B: ACN / 0.1%FA; Flow rate: 1.20 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: 0.500 min.1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.62 (s, 1H), 3.94-3.74 (m, 1H), 3.15-3.11 (m, 1H), 2.82-2.62 (m, 1H), 1.71 (t, J = 19.6 Hz, 3H). INT-8 4-bromo-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of 4-chloro-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (200 mg, 0.81 mmol) in MeCN (5 mL) was added TMSBr (123 mg, 0.81 mmol). The resulting mixture was stirred at 80 °C for 2 d under a nitrogen atmosphere. The reaction was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (2:1) to give 4-bromo-5-(1,1-difluoroethyl)-6,8-dihydro-5H-pyrido[2,3- d]pyrimidin-7-one (180 mg, 76%) as a yellow solid. LCMS (ESI, m / z): 292; 294 [M+H]+. INT-9 and INT-10 (R)-4-bromo-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (S)-4-bromo-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one The racemic 4-bromo-5-(1,1-difluoroethyl)-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one (140 mg, 0.48 mmol) was resovled by Prep-chiral-HPLC (Column: CHIRAL ART Amylose- SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 254 / 220 nm; RT1(min): 7.867; RT2(min): 10.229) to obtain (R)-4-bromo-5-(1,1- difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 55 mg, 40%) as a white solid and (S)-4-bromo-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (the second elutin peak, 60 mg, 40%) a white solid. LCMS (ESI, m / z): 292; 294 [M+H]+. INT-11 tert-butyl 4-(6-(tributylstannyl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine-1-carboxylate (3 g, 8.2 mmol), tributyl(tributylstannyl)stannane (23.7 g, 41.0 mmol) and LiCl (1.03 g, 24.6 mmol) in DMF (50 mL) was added Pd(PPh3)2Cl2(0.69 g, 0.82 mmol). The reaction mixture was stirred at 80℃ for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was quenched with water (100 mL), extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with ethyl acetate / petroleum ether (1:5) to give tert-butyl 4-[6-tributylstannyl-4-(trifluoromethyl)-2-pyridyl]piperazine-1-carboxylate (2.1 g, 41.2%) as colorless oil. LCMS (ESI, m / z): 618, 620, 622 [M+H]+. INT-12 tert-butyl (S)-2-methyl-4-(6-(tributylstannyl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1- carboxylate To a solution of tert-butyl (2S)-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl- piperazine-1-carboxylate (3.5 g, 9.22 mmol), tributyl(tributylstannyl)stannane (8.02 g, 13.82 mmol) and LiCl (1.16 g, 27.65 mmol) in DMF (50 mL) was added Pd(PPh3)2Cl2(0.65 g, 0.92 mmol). The reaction mixture was stirred at 80℃ for 3h under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was diluted with water (200 mL), extracted with ethyl acetate (3x100 mL). The combined organic layer was washed with brine (2x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with ethyl acetate / petroleum ether (1:5) to give tert-butyl (2S)-2-methyl-4-[6-tributylstannyl-4-(trifluoromethyl)-2- pyridyl]piperazine-1-carboxylate (4.5 g, 77%) as a light yellow oil. LCMS (ESI, m / z): 632, 634, 636 [M+H]+. INT-13 tert-butyl (2S)-4-(6-bromo-4-chloro-2-pyridyl)-2-methyl-piperazine-1-carboxylate To a solution of 2,6-dibromo-4-chloro-pyridine (2.4 g, 8.84 mmol), tert-butyl (2S)-2- methylpiperazine-1-carboxylate (1.47 g, 7.37 mmol) and t-BuONa (849 mg, 8.84 mmol) in 1,4-Dioxane (15 mL) was added XPhos Pd G4 (634 mg, 0.74 mmol). The reaction mixture was stirred at 120℃ for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was diluted with water (50 mL), extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting was purified by reverse flash chromatography with water(0.05%TFA) / MeCN (1 / 1) to give tert-butyl (2S)-4-(6-bromo- 4-chloro-2-pyridyl)-2-methyl-piperazine-1-carboxylate (512.8 mg, 18%) as a light yellow solid. LCMS (ESI, m / z): 390, 392 [M+H]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 1.228 min.1H NMR (400 MHz, DMSO-d6) δ 6.96- 6.90 (m, 2H), 4.21-4.13 (m, 1H), 4.11-3.96 (m, 2H), 3.79-3.74 (m, 1H), 3.25-3.10 (m, 2H), 3.00-2.94 (m, 1H), 1.42 (s, 9H), 1.06 (d, J = 6.4 Hz, 3H). INT-14 tert-butyl (3R)-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-ethyl-piperazine-1-carboxylate To a solution of tert-butyl (3R)-3-ethylpiperazine-1-carboxylate (1.0 g, 4.67 mmol) in DMSO (20 mL) were added 2,6-dichloro-4-(trifluoromethyl)pyridine (1.21 g, 5.61 mmol) and K2CO3(1.93 g, 14.01 mmol). The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (3x60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (92:8) to afford tert-butyl (3R)-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]- 3-ethyl-piperazine-1-carboxylate (330 mg, 17%) as an orange oil. LCMS (ESI, m / z): 394, 396 [M+H]+. INT-15 tert-butyl 4-[6-chloro-4-(1,1-difluoroethyl)-2-pyridyl]piperazine-1-carboxylate To a solution of 2,6-dichloro-4-(1,1-difluoroethyl)pyridine (1.0 g, 4.72 mmol) in DMSO (15 mL) were added tert-butyl piperazine-1-carboxylate (1.0 g, 5.66 mmol) and K2CO3(1.95 g, 14.15 mmol). The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by reverse flash chromatography (water (0.5% TFA) : ACN =1:4) to afford tert-butyl 4-[6-chloro-4-(1,1-difluoroethyl)-2-pyridyl]piperazine-1- carboxylate (1.2 g, 70%) as an off-white solid. LCMS (ESI, m / z): 362, 364 [M+H]+. INT-16 tert-butyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-4-(fluoromethyl)piperidine-1- carboxylate tert-butyl (3R,4S)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate To a solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (2 g, 9.26 mmol) and O1-tert-butyl O4-methyl piperidine-1,4-dicarboxylate (2.7 g, 11.11 mmol) in THF (30 mL) was added LiHMDS (1 M in THF, 19 mL, 19 mmol) at 0℃ under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure to afford O1-tert-butyl O4-methyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperidine-1,4- dicarboxylate (3.9 g, 99 %) as a brown oil crude. LCMS (ESI, m / z): 367, 369 [M-56]+. tert-butyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-4-(hydroxymethyl)piperidine-1- carboxylate To a solution of O1-tert-butyl O4-methyl 4-[6-chloro-4-(trifluoromethyl)-2- pyridyl]piperidine-1,4-dicarboxylate (3.9 g, 9.22 mmol) in THF (50 mL) was added LiBH4(2 M in THF, 23 mL, 46 mmol) at 0℃ under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 day under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was diluted with aqueous saturated ammonium chloride (100 mL), extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with ethyl acetate / petroleum ether (1:2) to give tert-butyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-4- (hydroxymethyl)piperidine-1-carboxylate (2.4 g, 66%) as a colorless oil. LCMS (ESI, m / z): 339, 341 [M-56]+. INT-16 To a solution of tert-butyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-4-formyl-piperidine-1- carboxylate (1 g, 2.55 mmol) in toluene (15 mL) were added DBU (0.5 g, 3.31 mmol) and SulfoxFluor (1.06 g, 3.05 mmol) dropwise at 0℃ under nitrogen atmosphere. The reaction mixture was stirred at 60℃ for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (6 / 1) to give tert-butyl 4-[6-chloro-4- (trifluoromethyl)-2-pyridyl]-4-(fluoromethyl)piperidine-1-carboxylate (692 mg, 65%) as a white solid. LCMS (ESI, m / z): 341, 343 [M-56]+. Analytic Conditions: Column: HALO C18, 4.6*100 mm, 2.7 μm; Mobile Phase A: Water / 0.1%FA, Mobile Phase B: Acetonitrile / 0.1%FA; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B in 8.00 min, hold at 95% for 2.00 min; 254 nm; Rt: 7.468 min.1H NMR (400 MHz, DMSO-d6) δ 8.05-7.82 (m, 2H), 4.76-4.46 (m, 2H), 3.78-3.53 (m, 2H), 3.13-2.87 (m, 2H), 2.36-2.15 (m, 2H), 1.84-1.68 (m, 2H), 1.39 (s, 9H). INT-17 tert-butyl (S)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-isopropylpiperazine-1- carboxylate A stirred solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (1.7 mL, 12 mmol), tert-butyl (S)-2-isopropylpiperazine-1-carboxylate (3.44 g, 15.1 mmol) and potassium carbonate (3.52 g, 25.5 mmol) in acetonitrile (25 mL) was sealed and heated to 80 ° ON. The reaction was allowed to cool to room temperature, filtered, and concentrated. The crude material was purified via ISCO (SiO2, 0-50% EtOAc / hexanes) to afford the title compound (4.4 g). LCMS (ESI, m / z): 351.8 [M+ – tBu].1H NMR (400 MHz, CHLOROFORM-d) δ 6.75 (s, 1H), 6.61 (s, 1H), 4.45 (br d, J=13.4 Hz, 1H), 4.22 - 4.00 (m, 2H), 3.82 (br s, 1H), 3.14 - 2.95 (m, 3H), 1.52 - 1.46 (m, 9H), 1.04 (d, J=6.6 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H). INT-18 tert-butyl (S)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (800 mg, 3.70 mmol), tert-butyl (S)-3- methylpiperazine-1-carboxylate (816 mg, 4.07 mmol) and DIEA (1.29 mL, 7.41 mmol) in DMF (10 mL) was sealed and heated at 110 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with ethyl acetate (25 mL). The separated organic layer was washed with 5% citric acid and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography purification using an ISCO system (80 g silica gel column, gradient elution from 0~20% of ethyl acetate in hexanes) afforded tert-butyl (S)- 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate (750 mg) as a colorless gum. LCMS (ESI, m / z): 378 [M+H]+. INT-19 tert-butyl (S)-4-(6-chloro-4-(1,1-difluoroethyl)pyridin-2-yl)-2-methylpiperazine-1- carboxylatecarboxylate 2,6-dichloro-4-(1,1-difluoroethyl)pyridine (0.928 ml, 5.09 mmol) was mixed with (S)-1-N- Boc-2-methylpiperazine (1.456 g, 7.12 mmol) in N,N-Dimethylacetamide (12.7 ml). Added sodium bicarbonate (2.14 g, 25.4 mmol). The reaction was heated in microwave synthesizer at 90 °C for 14 hours. The reaction was quenched with water (8 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (20 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 (1.32 g). LCMS (ESI, m / z): 375.9, 377.6 [M+H]+. INT-20 tert-butyl (S)-4-(6-chloro-4-(1,1-difluoroethyl)pyridin-2-yl)-2-methylpiperazine-1- carboxylatecarboxylate 2,6-dichloro-4-(trifluoromethyl)pyridine (0.140 mL, 1 mmol) was mixed with tert-butyl 1,4- diazepane-1-carboxylate (200 mg, 1.000 mmol) in DMF (5.0 ml). Then potassium carbonate (276 mg, 2.000 mmol) was added. The reaction was heated at 90 °C for ON. The reaction was filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (301 mg). LCMS (ESI, m / z): 380 [M+H]+. INT-21 tert-butyl (S)-4-(6-chloro-4-(difluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate 2,6-dichloro-4-(difluoromethyl)pyridine (283 mg, 1.429 mmol) was mixed with tert-butyl (S)- 2-methylpiperazine-1-carboxylate (400 mg, 2.0 mmol) in N,N-Dimethylacetamide (2.8 ml). Added sodium bicarbonate (540 mg, 6.4 mmol). The reaction was heated in microwave synthesizer at 90 °C for 16 hours. The reaction was quenched with water (~2 mL) and extracted with ethyl acetate (3x4 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to afford title compound (487 mg). LCMS (ESI, m / z): 305.7, 307.5 [M+H-tBu]+. INT-22 tert-butyl (R)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (700 mg, 3.24 mmol), tert-butyl (R)-3- methylpiperazine-1-carboxylate (779 mg, 3.89 mmol) and DIEA (0.849 mL, 4.86 mmol) in DMF (10 mL) was sealed and heated at 100 °C for 4 h. The reaction mixture was cooled to rt, poured into water, and extracted with ethyl acetate (25 mL). The separated organic layer was washed with 5% citric acid and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography purification using an ISCO system (80 g silica gel column, gradient elution from 0~20% of ethyl acetate in hexanes) afforded tert-butyl (R)- 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate (730 mg) as a colorless gum.1H NMR (499 MHz, chloroform-d) δ 6.79 (s, 1H), 6.61 (s, 1H), 4.48 (br s, 1H), 4.27 - 3.87 (m, 3H), 3.29 - 2.90 (m, 3H), 1.51 (s, 9H), 1.21 (d, J=6.7 Hz, 3H). LCMS (ESI, m / z): 378 [M+H]+. INT-23 (S)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-6-methylpiperazin-2-one A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (441 mg, 2.044 mmol) and (R)-6- methylpiperazin-2-one (280 mg, 1.307 mmol) and DIPEA (0.380 mL, 2.178 mmol) in DMSO (3 mL). The reaction was heated to 130 °C in the microwave. LCMS revealed major product was generated. The crude material was purified on a normal phase column (0-100% Hex:EtOAC). Desired fractions were concentrated down to give (R)-4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-6-methylpiperazin-2-oneas a white solid (300 mg, 85%) LCMS (ESI, m / z): 294 [M+H]+. INT-24 tert-butyl 4-(6-bromo-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidine-1-carboxylate A solution of 2-hydroxyisoindoline-1,3-dione (122 mg, 0.750 mmol), DMAP (4.58 mg, 0.038 mmol), 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (182 mg, 0.750 mmol), dic (0.117 mL, 0.750 mmol), and DMSO (2.5 mL) was stirred at room temperature overnight. 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (4.81 mg, 7.50 µmol) and 2-bromo-4- (trifluoromethyl)pyridine (339 mg, 1.500 mmol) were added. The reaction mixture was degassed by sparging with nitrogen for 5 minutes. The vial was sealed and irradiated with blue LEDs (450 nm) in a BMS paint bucket photoreactor for 24 hours. The crude reaction mixture was diluted with 1 N NaOH and DCM. The layers were separated. The organic layer was washed with brine and concentrated under reduced pressure to give crude product. The crude product was suspended in DCM and purified by flash chromatography (12 g silica cartridge, 50 ml / min, 0-100% ethyl acetate in hexanes). The product was concentrated under reduced pressure and dried on high vacuum overnight to give tert-butyl 4-(6-bromo-4- (trifluoromethyl)pyridin-2-yl)-4-methylpiperidine-1-carboxylate (83 mg, 26.1 % yield). LC / MS (ESI, m / z) 367, 369 [M+H-56]+. INT-25 tert-butyl (R)-4-(6-chloropyrazin-2-yl)-3-methylpiperazine-1-carboxylate 2,6-Dichloropyrazine (298 mg, 2 mmol) was mixed with (R)-4-N-Boc-2-methylpiperazine (461 mg, 2.30 mmol) in N,N-Dimethylacetamide (2.7 mL). Added sodium bicarbonate (504 mg, 6.00 mmol). The reaction was heated in microwave synthesizer at 90 °C for 15 hours. The reaction was quenched with water (3 mL) and extracted with ethyl acetate (3x5 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 heptane / ethyl acetate to afford title compound (0.59 g). LCMS (ESI, m / z): 313.0, 314.9 [M+H]+. INT-26 tert-butyl (S)-4-(6-chloro-4-cyanopyridin-2-yl)-2-methylpiperazine-1-carboxylate 2,6-Dichloroisonicotinonitrile (381 mg, 2.21 mmol) was mixed with tert-butyl (S)-2- methylpiperazine-1-carboxylate (421 mg, 2.1 mmol) in N,N-Dimethylacetamide (2.8 mL). Added sodium bicarbonate (504 mg, 6.00 mmol). The reaction was heated in microwave synthesizer at 90 °C for 5 hours. The reaction was quenched with water (3 mL) and extracted with ethyl acetate (3x5 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 heptane / ethyl acetate to afford title compound (0.70 g). LCMS (ESI, m / z): 236.8, 238.6 [M+H-Boc]+. & 280.7, 282.6 [M+H-tBu]+. INT-27 tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2-cyclopropylpiperazine-1-carboxylate 2,6-Dichloropyrazine (149 mg, 1 mmol) was mixed with tert-butyl (S)-2- cyclopropylpiperazine-1-carboxylate (189 mg, 0.833 mmol) in N,N-Dimethylacetamide (1.1 mL). Added sodium bicarbonate sodium bicarbonate (210 mg, 2.500 mmol). The reaction was heated in microwave synthesizer at 90 °C for 12 hours. The reaction was quenched with water (1 mL) and extracted with ethyl acetate (3x3 mL). The combined organic layers were washed with brine (1 mL), dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with heptane / ethyl acetate to afford title compound (0.28 g). LCMS (ESI, m / z): 338.8, 340.6 [M+H]+. INT-28 tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2-methylpiperazine-1-carboxylate 2,6-Dichloropyrazine (298 mg, 2 mmol) was mixed with tert-butyl (S)-2-methylpiperazine-1- carboxylate (461 mg, 2.30 mmol) in N,N-Dimethylacetamide (2.8 mL). Added sodium bicarbonate (504 mg, 6.00 mmol). The reaction was heated in microwave synthesizer at 90 °C for 15 hours. The reaction was quenched with water (3 mL) and extracted with ethyl acetate (3x5 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 heptane / ethyl acetate to afford title compound (0.63 g). LCMS (ESI, m / z): 313.1, 315.0 [M+H]+. INT-29 tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2-ethylpiperazine-1-carboxylate 2,6-Dichloropyrazine (149 mg, 1 mmol) was mixed with tert-butyl (S)-2-ethylpiperazine-1- carboxylate (179 mg, 0.833 mmol) in N,N-Dimethylacetamide (1.1 mL). Added sodium bicarbonate (210 mg, 2.5 mmol). The reaction was heated in microwave synthesizer at 90 °C for 15 hours. The reaction was quenched with water (1 mL) and extracted with ethyl acetate (3x3 mL). The combined organic layers were washed with brine (1 mL), dried over anhydrous magnesium sulphate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with heptane / ethyl acetate to afford title compound (0.27 g). LCMS (ESI, m / z): 326.8, 328.7 [M+H]+. Example 1 (S)-4-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)boronic acid To a solution of tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazine-1- carboxylate (100 mg, 0.27 mmol), B2pin2(76 mg, 0.30 mmol) and KOAc (53 mg, 0.55 mmol) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl2(22 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was directly used for next step without further purification. LCMS (ESI, m / z): 376 [M+H]+. tert-butyl (S)-4-(6-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate To the reaction mixture of previous step were added (S)-4-bromo-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (55 mg, 0.19 mmol), K2CO3(110 mg, 0.80 mmol), water (0.2 mL) and Pd(dppf)Cl2(21 mg, 0.03 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 (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by reverse flash chromatography ((0.5% TFA) : ACN = 3:7) to afford tert-butyl (S)-4-(6-(7-oxo-5- (trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin- 2-yl)piperazine-1-carboxylate (35 mg, 23%) as a yellow solid. LCMS (ESI, m / z): 547 [M+H]+. Example 1 To a solution of tert-butyl (S)-4-(6-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (35 mg, 0.06 mmol) in dichloromethane (2 mL) was added TFA (0.4 mL) dropwise. 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 (Column: Xselect CSH 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: 9% B to 30% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 8.68) to afford (S)-4-(6- (piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (27.5 mg, 96%) as a light-yellow solid. LCMS (ESI, m / z): 447 [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: 0.600 min.1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.00-8.80 (m, 3H), 7.72 (s, 1H), 7.46 (s, 1H), 5.62-5.57 (m, 1H), 3.92-3.80 (m, 4H), 3.48- 3.41 (m, 1H), 3.35-3.15 (m, 4H), 2.77-2.72 (m, 1H). Example 2 (R)-4-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (R)-4-(6-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazine-1- carboxylate (100 mg, 0.27 mmol), B2pin2 (76 mg, 0.30 mmol) and KOAc (53 mg, 0.55 mmol) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl2 (22 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was directly used for next step without further purification. LCMS (ESI, m / z): 376 [M+H]+. To the reaction mixture of previous step were added (R)-4-bromo-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (55 mg, 0.19 mmol), K2CO3(110 mg, 0.80 mmol), water (0.2 mL) and Pd(dppf)Cl2(21 mg, 0.03 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 (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by reverse flash chromatography ((0.5% TFA) : ACN = 3:7) to afford tert-butyl (R)-4-(6-(7-oxo-5- (trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin- 2-yl)piperazine-1-carboxylate (35 mg, 23%) as a yellow solid. LCMS (ESI, m / z): 547 [M+H]+. Example 2 To a solution of tert-butyl (R)-4-(6-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (35 mg, 0.06 mmol) in dichloromethane (2 mL) was added TFA (0.4 mL) dropwise. 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 (Column: Xselect CSH Prep C18 Column, 30x150 mm, 5 μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 38% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 8.5) to afford (R)-4-(6-(piperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (25.7 mg, 88%) as a light-yellow solid. LCMS (ESI, m / z): 447 [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: 0.659 min.1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.94-8.91 (m, 3H), 7.72 (s, 1H), 7.46 (s, 1H), 5.62-5.57 (m, 1H), 3.93-3.81 (m, 4H), 3.48- 3.41 (m, 1H), 3.30-3.20 (m, 4H), 2.77-2.73 (m, 1H). Example 3 (R)-5-(difluoromethyl)-4-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (R)-4-(6-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate To a solution of (R)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (45 mg, 0.19 mmol ), tert-butyl 4-[6-tributylstannyl-4-(trifluoromethyl)-2- pyridyl]piperazine-1-carboxylate (179 mg, 0.29 mmol) and CuI (4 mg, 0.02 mmol) in toluene (2 mL) was added Pd(PPh3)4(22 mg, 0.02 mmol). The reaction mixture was stirred at 100 °C for 2 days 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 (2x2mL), 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)-4-(6-(5- (difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (35 mg, 34%) as a light-yellow solid. LCMS (ESI, m / z): 529 [M+H]+. Example 3 To a solution of tert-butyl (R)-4-(6-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (35 mg, 0.07 mmol) in dichloromethane (3 mL) was added TFA (1 mL) dropwise. 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- (difluoromethyl)-4-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (19.1 mg, 66%) as a light-yellow solid. LCMS (ESI, m / z): 429 [M+H]+. Analytic Conditions: Column: Shim‐pack Scepter C18‐120. Column 33*3.0 mm, 3.0 μm; Mobile Phase A: Water / 5mM NH4HCO3, Mobile Phase B: Acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10 % B to 90 % B in 1.20 min, hold at 90 % for 0.60 min, 90 % B to 10 % B in 0.02 min; 254 nm; RT: 0.823.1H NMR (400 MHz, DMSO- d6) δ 11.23 (s, 1H), 8.91 (s, 1H), 8.87 (s, 1H), 7.70 (s, 1H), 7.43 (s, 1H), 6.53-6.25 (m, 1H), 4.77-4.66 (m, 1H), 3.84-3.82 (m, 4H), 3.25-3.21 (m, 4H), 3.11-3.05 (m, 1H), 2.70-2.66 (m, 1H). Example 4 (S)-5-(difluoromethyl)-4-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (S)-4-(6-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate To a solution of (S)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (45 mg, 0.19 mmol ), tert-butyl 4-[6-tributylstannyl-4-(trifluoromethyl)-2- pyridyl]piperazine-1-carboxylate (179 mg, 0.29 mmol) and CuI (4 mg, 0.02 mmol) in toluene (2 mL) was added Pd(PPh3)4(22 mg, 0.02 mmol). The reaction mixture was stirred at 100 °C for 2 days 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 (2x2mL), 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)-4-(6-(5- (difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (45 mg, 44%) as a light-yellow solid. LCMS (ESI, m / z): 529 [M+H]+. Example 4 To a solution of tert-butyl (S)-4-(6-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (35 mg, 0.07 mmol) in dichloromethane (3 mL) was added TFA (1 mL) dropwise. 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 (S)-5- (difluoromethyl)-4-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (33.5 mg, 88%) as a light-yellow solid. LCMS (ESI, m / z): 429 [M+H]+. Analytic Conditions: Column: HALO C18. Column 100*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: 2.380.1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.95 (s, 2H), 8.87 (s, 1H), 7.70 (s, 1H), 7.43 (s, 1H), 6.53-6.26 (m, 1H), 4.77-4.66 (m, 1H), 3.94-3.77 (m, 4H), 3.24 (s, 4H), 3.11-3.07 (m, 1H), 2.70-2.66 (m, 1H). Example 5 (S)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (S)-(6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- yl)boronic acid To a solution of tert-butyl (2S)-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl- piperazine-1-carboxylate (100 mg, 0.26 mmol) , B2pin2(134 mg, 0.53 mmol) and KOAc (52 mg, 0.53 mmol) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl2(22 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C for 4h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was directly used for next step without further purification. LCMS (ESI, m / z): 390 [M+H]+. tert-butyl (S)-2-methyl-4-(6-((S)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate To the reaction mixture from previous step were added (S)-4-bromo-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (76 mg, 0.26 mmol), K2CO3(106 mg, 0.77 mmol), water (0.4 mL) and Pd(dppf)Cl2(21 mg, 0.03 mmol) . The resulting solution was stirred at 80 °C for 2h 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 (S)-2- methyl-4-(6-((S)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (50 mg, 34%) as a yellow solid. LCMS (ESI, m / z): 561 [M+H]+. Example 5 To a solution of tert-butyl (S)-2-methyl-4-(6-((S)-7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1- carboxylate (50 mg, 0.09 mmol) in dichloromethane (3 mL) was added TFA (1 mL) dropwise. 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 C18 Column, 30x150 mm, 5 μm; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to39 % 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 (S)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)- 5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (23.6 mg, 57%) as a light- yellow solid. LCMS (ESI, m / z): 461 [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: 0.616 min.1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 7.83 (s, 1H), 7.39 (s, 1H), 5.69-5.56 (m, 1H), 4.59-4.52 (m, 1H), 4.52-4.44 (m, 1H), 3.61-3.44 (m, 2H), 3.43-3.34 (m, 2H), 3.33-3.23 (m, 1H), 3.19-3.08 (m, 1H), 2.98-2.89 (m, 1H), 1.44 (d, J = 6.8 Hz, 3H).19F NMR (376 MHz, methanol-d4) δ - 66.49, -72.84, -77.03. Example 6 (R)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (S)-2-methyl-4-(6-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate To a solution of tert-butyl (2S)-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl- piperazine-1-carboxylate (100 mg, 0.26 mmol) , B2pin2 (134 mg, 0.53 mmol) and KOAc (52 mg, 0.53 mmol) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl2 (22 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C for 4h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was directly used for next step without further purification. LCMS (ESI, m / z): 390 [M+H]+. To the reaction mixture from previous step were added (R)-4-bromo-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (76 mg, 0.26 mmol), K2CO3(106 mg, 0.77 mmol), water (0.4 mL) and Pd(dppf)Cl2(21 mg, 0.03 mmol) . The resulting solution was stirred at 80 °C for 2h 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 (S)-2- methyl-4-(6-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)- 4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (50 mg, 34%) as a yellow solid. LCMS (ESI, m / z): 561 [M+H]+. Example 6 To a solution of tert-butyl (S)-2-methyl-4-(6-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1- carboxylate (50 mg, 0.09 mmol) in dichloromethane (3 mL) was added TFA (1 mL) dropwise. 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 C18 Column, 30x150 mm, 5 μm; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to29 % 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)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)- 5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (31 mg, 75%) as an off- white solid. LCMS (ESI, m / z): 461 [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: 0.623 min.1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 7.83 (s, 1H), 7.40 (s, 1H), 5.69-5.56 (m, 1H), 4.63-4.48 (m, 2H), 3.63-3.40 (m, 1H), 3.39-3.34 (m, 1H), 3.33-3.22 (m, 2H), 3.20-3.09 (m, 1H), 3.00-2.88 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H).19F NMR (376 MHz, methanol-d4) δ -66.49, -72.85, -76.98. Example 7 (S)-5-(difluoromethyl)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (S)-4-(6-((S)-5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin- 4-yl)-4-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate To a solution of (S)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (50 mg, 0.21 mmol), tert-butyl (2S)-2-methyl-4-[6-tributylstannyl-4-(trifluoromethyl)-2- pyridyl]piperazine-1-carboxylate (204 mg, 0.32 mmol) and CuI (4 mg, 0.02 mmol) in toluene (2 mL) was added Pd(PPh3)4(25 mg, 0.02 mmol). The reaction mixture was stirred at 100 °C for 3 days 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)-4-(6-((S)-5- (difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (60 mg, 51%) as a light- yellow solid. LCMS (ESI, m / z): 543 [M+H]+. Example 7 To a solution of tert-butyl (S)-4-(6-((S)-5-(difluoromethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine- 1-carboxylate (60 mg, 0.11 mmol) in dichloromethane (4 mL) was added TFA (2 mL) dropwise. 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 (S)-5-(difluoromethyl)-4-(6-((S)-3-methylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (34.8 mg, 71%) as a light-yellow solid. LCMS (ESI, m / z): 443 [M+H]+. Analytic Conditions: Column: HALO 90A C18. Column 30*3.0 mm, 2.0 μm; Mobile Phase A: Water / 0.1%FA, Mobile Phase B: Acetonitrile / 0.1%FA; 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: 0.603.1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.20-9.19 (m, 1H), 8.88-8.86 (s, 2H), 7.72 (s, 1H), 7.46 (s, 1H), 6.55-6.27 (m, 1H), 4.75-4.67 (m, 1H), 4.41-4.35 (m, 2H), 3.45-3.22 (m, 3H), 3.12-3.02 (m, 3H), 2.70-2.66 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H). Example 8 (R)-5-(difluoromethyl)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (S)-4-(6-((R)-5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin- 4-yl)-4-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate To a solution of (R)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (50 mg, 0.21 mmol), tert-butyl (2S)-2-methyl-4-[6-tributylstannyl-4-(trifluoromethyl)-2- pyridyl]piperazine-1-carboxylate (204 mg, 0.32 mmol) and CuI (4 mg, 0.02 mmol) in toluene (2 mL) was added Pd(PPh3)4 (25 mg, 0.02 mmol). The reaction mixture was stirred at 100 °C for 3 days 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)-4-(6-((R)-5- (difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (60 mg, 51%) as a light- yellow solid. LCMS (ESI, m / z): 543 [M+H]+. Example 8 To a solution of tert-butyl (S)-4-(6-((R)-5-(difluoromethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine- 1-carboxylate (60 mg, 0.11 mmol) in dichloromethane (4 mL) was added TFA (2 mL) dropwise. 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-(difluoromethyl)-4-(6-((S)-3-methylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (33.5 mg, 68%) as a light-yellow solid. LCMS (ESI, m / z): 443 [M+H]+. Analytic Conditions: Column: Shim‐pack Scepter C18‐120. Column 33*3.0 mm, 3.0 μm; Mobile Phase A: Water / 5mM NH4HCO3, Mobile Phase B: Acetonitrile; 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: 0.597.1H NMR (400 MHz, DMSO- d6) δ 11.23 (s, 1H), 9.15 (s, 1H), 8.88 (s, 1H), 8.82 (s, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 6.41 (t, J = 16.0 Hz, 1H), 4.77-4.67 (m, 1H), 4.43-4.39 (m, 2H), 3.35-2.22 (m, 6H), 2.71-2.67 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H). Example 9 and Example 10 (S)-5-(1,1-difluoroethyl)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (R)-5-(1,1-difluoroethyl)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (2S)-4-(6-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-4-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2- methylpiperazine-1-carboxylate (200 mg, 0.53 mmol), bis(pinacolato)diboron (200 mg, 0.79 mmol) and KOAc (103 mg, 1.05 mmol) in 1,4-Dioxane (4 mL) was added Pd(dppf)Cl2 (42.97 mg, 0.05 mmol). The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was used directly for next step without further purification. LCMS (ESI, m / z): 390 [M+H]+. To the reaction mixture from previous step were added 4-bromo-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (120 mg, 0.41 mmol), K2CO3 (170 mg, 1.23 mmol), water (0.5 mL) and Pd(dppf)Cl2(34 mg, 0.04 mmol). The resulting mixture was stirred at 80 °C overnight under a 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 sodium sulfate and concentrated under reduce pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1 / 1) to give tert-butyl (2S)-4-(6-(5-(1,1- difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (70 mg, 30%) as a yellow solid. LCMS (ESI, m / z): 557 [M+H]+. 5-(1,1-difluoroethyl)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of tert-butyl (2S)-4-(6-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine- 1-carboxylate (70 mg, 0.13 mmol) in DCM (4 mL) was added drowpwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (2:1) to give 5-(1,1- difluoroethyl)-4-[6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)-2-pyridyl]-6,8-dihydro- 5H-pyrido[2,3-d]pyrimidin-7-one (60 mg, 99%) as a yellow solid. LCMS (ESI, m / z): 457 [M+H]+. Example 9 and Example 10 5-(1,1-difluoroethyl)-4-[6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)-2-pyridyl]-6,8- dihydro-5H-pyrido[2,3-d]pyrimidin-7-one (60 mg, 0.13 mmol) was isolated by Prep-chiral- HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3- MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 25; Wave Length: 254 / 220nm; Rt1(min): 7.958; Rt2(min): 9.965) to obtain (S)-5- (1,1-difluoroethyl)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 16.9 mg, 28%) and (R)-5- (1,1-difluoroethyl)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 17.4 mg, 28%) both as yellow solid. Example 9 LCMS (ESI, m / z): 457 [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: 0.604 min.1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.54 (s, 1H), 7.25 (s, 1H), 5.31 (td, J = 15.6, 7.2 Hz, 1H), 4.20-4.11 (m, 2H), 3.24 (dd, J = 17.2, 7.6 Hz, 1H), 2.97 (d, J = 12.0 Hz, 1H), 2.89 (t, J = 12.0 Hz, 1H), 2.77-2.76 (m, 1H), 2.74-2.67 (m, 2H), 2.56-2.55 (m, 1H), 1.37 (t, J = 19.6 Hz, 3H), 1.04 (d, J = 6.2 Hz, 3H). Example 10 LCMS (ESI, m / z): 457 [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: 0.603 min.1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.54 (s, 1H), 7.25 (s, 1H), 5.31 (td, J = 15.6, 7.2 Hz, 1H), 4.23-4.20 (m, 2H), 3.24 (dd, J = 17.2, 7.6 Hz, 1H), 2.97-2.89 (m, 2H), 2.77-2.67 (m, 3H), 2.56-2.54 (m, 1H), 1.37 (t, J = 19.6 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H). Example 11 (R)-5-(1,1-difluoroethyl)-4-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)boronic acid To a solution of tert-butyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine-1-carboxylate (100 mg, 0.28 mmol) , bis(pinacolato)diboron (70 mg, 0.28 mmol) and KOAc (54 mg, 0.54 mmol) in 1,4-Dioxane (2 mL) was added Pd(dppf)Cl2(24 mg, 0.02 mmol). The resulting mixture was stirred at 90 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was used directly for next step without further purification. LCMS (ESI, m / z): 376 [M+H]+. tert-butyl (R)-4-(6-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate To the reaction mixture from previous step were added (R)-4-bromo-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (62 mg, 0.22 mmol), K2CO3(88 mg, 0.64 mmol) , water (0.2 mL) and Pd(dppf)Cl2(17 mg, 0.02 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 (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (R)-4-(6-(5-(1,1- difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (50 mg, 43%) as a yellow solid. LCMS (ESI, m / z): 543 [M+H]+. Example 11 To a solution of tert-butyl (R)-4-(6-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (50 mg, 0.09 mmol) in DCM (4 mL) was added drowpwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The product was concentrated under reduce pressure and lyophilized. Purification resulted in desired (R)- 5-(1,1-difluoroethyl)-4-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (18.5 mg, 45%) as a yellow solid. LCMS (ESI, m / z): 443 [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: 1.086 min.1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.86 (s, 3H), 7.61 (s, 1H), 7.40 (s, 1H), 5.26-5.07 (m, 1H), 3.92- 3.78 (m, 4H), 3.27-3.22 (m, 4H), 2.77-2.73 (m, 1H), 1.39 (t, J = 19.6 Hz, 3H). Example 12 (S)-5-(1,1-difluoroethyl)-4-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (S)-4-(6-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine-1-carboxylate (100 mg, 0.28 mmol) , bis(pinacolato)diboron (70 mg, 0.28 mmol) and KOAc (54 mg, 0.54 mmol) in 1,4-Dioxane (2 mL) was added Pd(dppf)Cl2 (24 mg, 0.02 mmol). The resulting mixture was stirred at 90 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was used directly for next step without further purification. LCMS (ESI, m / z): 376 [M+H]+. To the reaction mixture from previous step were added (S)-4-bromo-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (62 mg, 0.22 mmol), K2CO3 (88 mg, 0.64 mmol), water (0.2 mL) and Pd(dppf)Cl2(17 mg, 0.02 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 (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (S)-4-(6-(5-(1,1- difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (50 mg, 43%) as a yellow solid. LCMS (ESI, m / z): 543 [M+H]+. Example 12 To a solution of tert-butyl (S)-4-(6-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (50 mg, 0.09 mmol) in DCM (3 mL) was added drowpwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1). The product was concentrated under reduce pressure and lyophilized. Purification resulted in desired (S)-5- (1,1-difluoroethyl)-4-(6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (18.2 mg, 45%) as a yellow solid. LCMS (ESI, m / z): 443 [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: 1.084 min.1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.88 (d, J = 15.9 Hz, 3H), 7.61 (s, 1H), 7.40 (s, 1H), 5.07-5.02 (m, 1H), 3.92-3.78 (m, 4H), 3.27-3.21 (m, 4H), 2.77-2.74 (m, 2H), 1.39 (t, J = 19.6 Hz, 3H). Example 13 and Example 14 (S)-5-(1,1-difluoroethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-5-(1,1-difluoroethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (S)-4-(6-bromo-4-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxylate To a solution of 2,6-dibromo-4-fluoropyridine (2 g, 7.85 mmol) in 1,4-dioxane (40 mL) were added Cs2CO3(7.6 g, 23.55 mmol), EPhos Pd G4 (720 mg, 0.78 mmol), EPhos (838 mg, 1.57 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (1.57 g, 7.85 mmol). The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The solids were removed by filtration through Celite and washed with ethyl acetate (3x10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (93 / 7) to give tert-butyl (S)-4-(6-bromo-4-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxylate (600 mg, 20%) as an orange oil. LCMS (ESI, m / z): 374, 376 [M+H]+. tert-butyl (S)-4-(4-fluoro-6-(trimethylstannyl)pyridin-2-yl)-2-methylpiperazine-1- carboxylate To a solution of tert-butyl (S)-4-(6-bromo-4-fluoropyridin-2-yl)-2-methylpiperazine-1- carboxylate (100 mg, 0.27 mmol) in 1,4-dioxane (2 mL) were added 1,1,1,2,2,2- hexamethyldistannane (105 mg, 0.32 mmol) and Pd(PPh3)4(30 mg, 0.03 mmol). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The crude was used directly in next step without further purification. LCMS (ESI, m / z): 460 [M+H]+. tert-butyl (2S)-4-(6-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-4-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxylate To the reaction mixture from previous step were added 4-chloro-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (65 mg, 0.27 mmol), Pd2(dba)3(24 mg, 0.03 mmol) and P(t-Bu)3·HBF4(15 mg, 0.05 mmol). The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was filtered through silica and washed with ethyl acetate. The filtration was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / ACN (1:1) and further by column chromatography on silica gel with petroleum ether / ethyl acetate (1 / 1) to afford tert-butyl (2S)-4-(6-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4-fluoropyridin-2-yl)-2-methylpiperazine-1- carboxylate (40 mg, 29%) as a yellow solid. LCMS (ESI, m / z): 507 [M+H]+. 5-(1,1-difluoroethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of tert-butyl (2S)-4-(6-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4-fluoropyridin-2-yl)-2-methylpiperazine-1- carboxylate (40 mg, 0.08 mmol) in DCM (2 mL) was added dropwise TFA (0.4 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and the residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (4:1) to give rac-5-(1,1- difluoroethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (30 mg, 93%) as a yellow solid. LCMS (ESI, m / z): 407 [M+H]+. Example 13 and 14 5-(1,1-difluoroethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (30 mg, 0.07 mmol) was separated by chiral-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-- HPLC, Mobile Phase B: IPA: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 254 / 220 nm; RT1(min): 13.572; RT2(min): 19.169) to afford (S)-5-(1,1- difluoroethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 10.5 mg, 34%) and (R)-5- (1,1-difluoroethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 9.1 mg, 30%) both as yellow solid. Example 13 LCMS (ESI, m / z): 407 [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: 0.555 min.1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.82 (s, 1H), 7.20 (dd, J = 9.2, 1.2 Hz, 1H), 6.87 (dd, J = 12.8, 1.6 Hz, 1H), 5.37 (td, J = 16.0, 6.8 Hz, 1H), 4.13-4.01 (m, 2H), 3.25-3.18 (m, 1H), 3.19- 2.96 (m, 1H), 2.96-2.81 (m, 1H), 2.78-2.65 (m, 3H), 2.52-2.51 (m, 1H), 1.36 (t, J = 19.2 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H). Example 14 LCMS (ESI, m / z): 407 [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: 0.560 min.1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.82 (s, 1H), 7.18 (dd, J = 9.6, 1.6 Hz, 1H), 6.87 (dd, J = 12.8, 2.0 Hz, 1H), 5.36 (td, J = 16.0, 7.6 Hz, 1H), 4.13-4.09 (m, 2H), 3.52-3.20 (m, 1H), 2.97- 2.93 (m, 1H), 2.89-2.81 (m, 1H), 2.77-2.65 (m, 3H), 1.35 (t, J = 19.6 Hz, 3H), 1.03 (d, J = 6.0 Hz, 3H). Example 15 and Example 16 (S)-5-(difluoromethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-5-(difluoromethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (S)-4-(4-fluoro-6-(trimethylstannyl)pyridin-2-yl)-2-methylpiperazine-1- carboxylate To a solution of tert-butyl (S)-4-(6-bromo-4-fluoropyridin-2-yl)-2-methylpiperazine-1- carboxylate (100 mg, 0.27 mmol) in 1,4-dioxane (2 mL) were added 1,1,1,2,2,2- hexamethyldistannane (105 mg, 0.32 mmol) and Pd(PPh3)4(30 mg, 0.03 mmol). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The crude was used directly in next step without further purification. LCMS (ESI, m / z): 460 [M+H]+. tert-butyl (2S)-4-(6-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-4-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxylate To the reaction mixture from previous step were added 4-chloro-5-(difluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (62 mg, 0.27 mmol), Pd2(dba)3(24 mg, 0.03 mmol) and P(t-Bu)3·HBF4(15 mg, 0.05 mmol). The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was flitered through silica and washed with ethyl acetate. The filtration was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / ACN (1:1) and purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1 / 1) to afford tert-butyl (2S)-4-(6-(5-(difluoromethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-4-fluoropyridin-2-yl)-2-methylpiperazine-1- carboxylate (60 mg, 45%) as a yellow solid. LCMS (ESI, m / z): 493 [M+H]+. 5-(difluoromethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of tert-butyl (2S)-4-(6-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-4-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxylate (60. mg, 0.12 mmol) in DCM (2 mL) was added dropwise TFA (0.4 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and the residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (4:1) to give 5-(difluoromethyl)-4-(4-fluoro- 6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (50 mg, 99%) as a yellow solid. LCMS (ESI, m / z): 393 [M+H]+. Example 15 and Example 16 5-(Difluoromethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (50 mg, 0.13 mmol) was separated by chiral-HPLC (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-- HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 254 / 220 nm; RT1(min): 6.827; RT2(min): 9.985) to afford (S)-5- (difluoromethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 12.8 mg, 25%) and (R)-5- (difluoromethyl)-4-(4-fluoro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 13.4 mg, 26%) both as yellow solid. Example 15 LCMS (ESI, m / z): 393 [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: 0.535 min.1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.83 (s, 1H), 7.29 (dd, J = 9.6, 2.0 Hz, 1H), 6.89 (dd, J = 12.4, 2.0 Hz, 1H), 6.52-6.23 (m, 1H), 4.93-4.81 (m, 1H), 4.05-4.00 (m, 2H), 3.08 (dd, J = 17.2, 8.0 Hz, 1H), 2.97-2.93 (m, 1H), 2.84-2.70 (m, 1H), 2.70-2.66 (m, 3H), 2.47-2.41 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H). Example 16 LCMS (ESI, m / z): 393 [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: 0.534 min.1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.83 (s, 1H), 7.26 (dd, J = 9.6, 1.6 Hz, 1H), 6.88 (dd, J = 12.8, 2.0 Hz, 1H), 6.51-6.22 (m, 1H), 4.93-4.81 (m, 1H), 4.07-3.99 (m, 2H), 3.08 (dd, J = 17.6, 8.0 Hz, 1H), 2.96-2.92 (m, 1H), 2.84-2.77 (m, 1H), 2.72-2.65 (m, 3H), 2.51-2.40 (m, 1H), 1.02 (d, J = 6.2 Hz, 3H). Example 17 and Example 18 (S)-4-(4-chloro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-4-(4-chloro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (S)-4-(4-chloro-6-(trimethylstannyl)pyridin-2-yl)-2-methylpiperazine-1- carboxylate To a solution of (S)-1-(6-bromo-4-chloropyridin-2-yl)-3-methylpiperazine (80 mg, 0.28 mmol) in 1,4-dioxane (2 mL) were added Sn2Me6(108 mg, 0.33 mmol) and Pd(PPh3)4(31 mg, 0.03 mmol). The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The crude was used in next step without further purification. LCMS (ESI, m / z): 476, 478 [M+H]+. tert-butyl (2S)-4-(4-chloro-6-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate To the reaction mixture from previous step were added 4-chloro-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (77 mg, 0.31 mmol), Pd2(dba)3(18 mg, 0.02 mmol) and P(t-Bu)3HBF4(11 mg, 0.04 mmol). The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (70 mL) and extracted with ethyl acetate (3x30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (1:4) to afford tert-butyl (2S)-4-(4-chloro-6-(7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (50 mg, 46%) as a yellow solid. LCMS (ESI, m / z): 527, 529 [M+H]+. 4-(4-chloro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of tert-butyl (2S)-4-(4-chloro-6-(7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.4 mL). The resulting mixture was stirred at room temperature for 1 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and the residue was purified by Prep-HPLC (Column: Xselect CSH Prep C18 Column, 30*250 mm, 10 μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 12% B to 42% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8.5) to afford rac-4-(4-chloro-6-((S)-3-methylpiperazin-1- yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (22.6 mg, 55%) as a white solid. LCMS (ESI, m / z): 427, 429 [M+H]+. Example 17 and Example 18 4-(4-Chloro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (22.6 mg, 0.05 mmol) was purified by Prep-chiral- HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3- MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 254 / 220 nm; RT1(min): 13.387; RT2(min): 16.209) to afford (S)- 4-(4-chloro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 10.0 mg, 44%) and (R)-4- (4-chloro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 8.0 mg, 35%) both as yellow solid. Example 17 LCMS (ESI, m / z): 427, 429 [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: 1.202 min.1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.89 (s, 1H), 7.48 (s, 1H), 7.15 (s, 1H), 5.86 (q, J = 9.2 Hz, 1H), 4.14-4.04 (m, 2H), 3.49-3.33 (m, 1H), 3.01-2.89 (m, 1H), 2.87- 2.83 (m, 1H), 2.76-2.71 (m, 3H), 2.51-2.46 (m, 1H), 1.04 (d, J = 6.0 Hz, 3H). Example 18 LCMS (ESI, m / z): 427, 429 [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% to 95% in 0.6 min, hold at 95% for 0.50 min, 95% B to 5% B in 0.03 min; 254 nm; Rt: 1.202 min.1H NMR (400 MHz, DMSO-d6) δ 11.46-11.32 (m, 1H), 8.89 (s, 1H), 7.45 (s, 1H), 7.15 (s, 1H), 5.87-5.82 (m, 1H), 4.14-4.13 (m, 2H), 3.48-3.46 (m, 1H), 2.98-2.95 (m, 1H), 2.89-2.85 (m, 1H), 2.76-2.67 (m, 3H), 2.54-2.50 (m, 1H), 1.04 (d, J = 6.0 Hz, 3H). Example 19 and Example 20 (R)-4-(4-fluoro-6-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one and (S)-4-(4-fluoro-6-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one tert-butyl 4-(6-bromo-4-fluoropyridin-2-yl)piperazine-1-carboxylate To a solution of 2,6-dibromo-4-fluoropyridine (800 mg, 3.14 mmol), tert-butyl piperazine-1- carboxylate (585 mg, 3.14 mmol) and Cs2CO3(3.1 g, 9.42 mmol) in 1,4-dioxane (10 mL) were added Pd2(dba)3(144 mg, 0.16 mmol) and XantPhos (182 mg, 0.31 mmol). The resulting mixture was stirred at 80°C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (4:1) to give tert-butyl 4-(6-bromo-4-fluoropyridin-2-yl)piperazine-1-carboxylate (250 mg, 22%) as a yellow solid. LCMS (ESI, m / z): 360, 362 [M+H]+. tert-butyl 4-(4-fluoro-6-(trimethylstannyl)pyridin-2-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(6-bromo-4-fluoropyridin-2-yl)piperazine-1-carboxylate (240 mg, 0.67 mmol) and 1,1,1,2,2,2-hexamethyldistannane (262 mg, 0.8 mmol) in 1,4-dioxane (3 mL) was added Pd(PPh3)4(77 mg, 0.07 mmol). The resulting mixture was stirred at 100°C for 4 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was used directly for next step without further purification. LCMS (ESI, m / z): 446 [M+H]+. tert-butyl 4-(4-fluoro-6-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)pyridin-2-yl)piperazine-1-carboxylate To the reaction mixture from previous step were added 4-chloro-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (136 mg, 0.54 mmol), P(t-Bu)3·HBF4(31 mg, 0.11 mmol) and Pd2(dba)3(49 mg, 0.05 mmol). The resulting mixture was stirred at 100°C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1) to give tert- butyl 4-(4-fluoro-6-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)pyridin-2-yl) piperazine-1-carboxylate (100 mg, 37%) as a yellow solid. LCMS (ESI, m / z): 497 [M+H]+. 4-(4-fluoro-6-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one To a solution of tert-butyl 4-(4-fluoro-6-(7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)pyridin-2-yl)piperazine-1-carboxylate (100 mg, 0.2 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 mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1) to give 4-(4-fluoro-6-(piperazin-1- yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (50 mg, 62%) as a white solid. LCMS (ESI, m / z): 397 [M+H]+. Example 19 and Example 20 4-(4-Fluoro-6-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (40 mg, 0.1 mmol) was purified by Chiral-HPLC (Column: Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.3% IPAmine)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 254 / 220 nm; RT1(min): 14.129; RT2(min): 16.652) to afford (R)-4-(4-fluoro-6- (piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (the first eluting peak, 10.1 mg, 25%) as a white solid and (S)-4-(4-fluoro-6-(piperazin-1- yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 10.2 mg, 25%) as a white solid. Example 19 LCMS (ESI, m / z): 397 [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: 1.5 mL / min; Gradient: 5% B to 100% B in 1.20 min, hold at 100% for 0.50 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 0.587 min.1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.00-8.77 (m, 2H), 8.91 (s, 1H), 7.38 (dd, J = 9.2, 2.0 Hz, 1H), 7.04 (dd, J = 12.0, 2.0 Hz, 1H), 5.71-5.61 (m, 1H), 3.85-3.68 (m, 4H), 3.48-3.38 (m, 1H), 3.28-3.16 (m, 4H), 2.76-2.67 (m, 1H). Example 20 LCMS (ESI, m / z): 397 [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: 1.5000 mL / min; Gradient: 5% B to 100% B in 1.20 min, hold at 100% for 0.50 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 0.579 min.1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.00-8.80 (m, 2H), 8.91 (s, 1H), 7.37 (dd, J = 9.6, 2.0 Hz, 1H), 7.06 (dd, J = 12.0, 2.0 Hz, 1H), 5.71-5.62 (m, 1H), 3.87-3.69 (m, 4H), 3.48-3.38 (m, 1H), 3.30-3.16 (m, 4H), 2.74-2.67 (m, 1H). Example 21 and Example 22 (S)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-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 N-[4-chloro-3-(2,2,2- trifluoroacetyl)-2-pyridyl]carbamate (51 g, 80%) as a light-yellow solid. LCMS (ESI, m / z): 325; 327 [M+H]+. methyl 3-(2-((tert-butoxycarbonyl)amino)-4-chloropyridin-3-yl)-4,4,4-trifluorobut-2-enoate To a solution of tert-butyl N-[4-chloro-3-(2,2,2-trifluoroacetyl)-2-pyridyl]carbamate (3 g, 9.24 mmol) in THF (30 mL) was added NaH (0.44 g, 11.09 mmol) at 0 °C under nitrogen atmosphere. After 30 min, methyl 2-dimethoxyphosphorylacetate (2.02 g, 11.09 mmol) was added the mixture. The reaction mixture was stirred for 2 h at 0°C and was allowed to warm to room temperature. LCMS showed the reaction was completed. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3:2) to give methyl (Z)-3-[2-(tert- butoxycarbonylamino)-4-chloro-3-pyridyl]-4,4,4-trifluoro-but-2-enoate (1.7 g, 48.3%) as a yellow solid. LCMS (ESI, m / z): 381, 383 [M+H]+. tert-butyl (S)-4-(2'-((tert-butoxycarbonyl)amino)-3'-(1,1,1-trifluoro-4-methoxy-4-oxobut-2- en-2-yl)-4-(trifluoromethyl)-[2,4'-bipyridin]-6-yl)-2-methylpiperazine-1-carboxylate mmol), cesium carbonate (1287 mg, 3.95 mmol), methyl 3-(2-((tert-butoxycarbonyl)amino)- methyl (S)-3-(2'-amino-6-(3-methylpiperazin-1-yl)-4-(trifluoromethyl)-[2,4'-bipyridin]-3'-yl)- 4,4,4-trifluorobut-2-enoate To a solution of tert-butyl (S)-4-(2'-((tert-butoxycarbonyl)amino)-3'-(1,1,1-trifluoro-4- methoxy-4-oxobut-2-en-2-yl)-4-(trifluoromethyl)-[2,4'-bipyridin]-6-yl)-2-methylpiperazine- 1-carboxylate (280 mg, 0.406 mmol) in MeOH (2 mL) was added TFA (0.2 mL). The resulting solution was stirred for 2 h at room temperature. LCMS showed the reaction was completed. The mixture was concentrated under reduce pressure to give methyl (S)-3-(2'-amino-6-(3- methylpiperazin-1-yl)-4-(trifluoromethyl)-[2,4'-bipyridin]-3'-yl)-4,4,4-trifluorobut-2-enoate (130 mg, 65%). The product was used in the next step directly without further purification. LCMS (ESI, m / z): 490 [M+H]+. 5-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-4-(trifluoromethyl)-3,4- dihydro-1,8-naphthyridin-2(1H)-one To a solution of methyl (S)-3-(2'-amino-6-(3-methylpiperazin-1-yl)-4-(trifluoromethyl)-[2,4'- bipyridin]-3'-yl)-4,4,4-trifluorobut-2-enoate (130 mg, 0.266 mmol) in MeOH (3 mL) was added Pd-C (0.057 g, 0.531 mmol).The reaction mixture was filled with N2, then the reaction was purged with H2ballon. The resulting solution was stirred for 2 h at room temperature. LCMS showed the reaction was completed. The mixture was concentrated under reduce pressure and The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: Waters X-Bridge Phenyl, 19 mm x 200 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 5-(6-((S)-3-methylpiperazin-1-yl)- 4-(trifluoromethyl)pyridin-2-yl)-4-(trifluoromethyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (19.2 mg, 16% ). LCMS (ESI, m / z): 460 [M+H]+. Example 21 and Example 22 5-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-4-(trifluoromethyl)-3,4- dihydro-1,8-naphthyridin-2(1H)-one (19.2 mg, 0.042 mmol) was purified by preparative SFC with the following conditions: Column: Chiralpak IH, 21 mm x 250 mm, 5 μm particles; Flow Rate: 75 mL / min; Column Temperature: 40 °C. Mobile Phase A: CO2, Mobile Phase B: MeOH with 0.1% ammonium hydroxide; RT1(min): 13.09; RT2(min): 16.54) to afford (S)-4-(6-((S)- 3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8 dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 3.9 mg, 20%) and (R)-4-(6- ((S) 3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 3.3 mg, 17%). Example 21 LCMS (ESI, m / z): 460 [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; 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: 1.35 min. Example 22 LCMS (ESI, m / z): 460[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; 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: 1.47 min. Example 23 (S)-4-(6-(3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one To a solution of bis(pinacolato)diboron (36.8 mg, 0.145 mmol), tert-butyl (S)-4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.132 mmol) and KOAc (38.8 mg, 0.395 mmol) in dioxane (1.5 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (21.5 mg, 0.026 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): 390 [M+H]+. The resulting reaction mixture was allowed to cooled down to rt. To the crude reaction mixture was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (8.58 mg, 0.013 mmol), cesium carbonate (129 mg, 0.395 mmol) and 4-chloro-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (24.17 mg, 0.132 mmol). The resulting mixture was stirred at 90 °C overnight under nitrogen atmosphere. The reaction mixture was filtered and concentrated. To the crude mixture was added 2mL 5.0-6.0 M HCl in IPA and the resulting mixture was stirred for 1 hour at 80 °C. The reaction mixture was concentrated under reduced pressure and 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (S)-4-(6-(3- methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin- 7(6H)-one (25.1 mg, 48%). LCMS (ESI, m / z): 393 [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; 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 + / -). Rt: 1.13 min. Example 24 (S)-4-(6-(3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 23 using tert-butyl (R)-4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-3-ethylpiperazine-1-carboxylate as a starting material instead of tert-butyl (S)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate. 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: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 (S)-4-(6-(3-methylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (30.9 mg, 59%). LCMS (ESI, m / z): 407 [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; 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 + / -). Rt: 1.18 min. Example 25 and Example 26 (S)-5-methyl-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-5-methyl-4-(6-((S)-3-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of bis(pinacolato)diboron (73.5 mg, 0.290 mmol), tert-butyl (S)-4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.263 mmol) and KOAc (78 mg, 0.79 mmol) in dioxane (3 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (43 mg, 0.053 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): 390 [M+H]+. The resulting reaction mixture was allowed to cooled down to rt. To the crude reaction mixture was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (17.16 mg, 0.026 mmol), cesium carbonate (257 mg, 0.79 mmol) and 4-chloro-5-methyl-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (52.0 mg, 0.263 mmol). The resulting mixture was stirred at 90 °C overnight under nitrogen atmosphere. The reaction mixture was filtered and concentrated. To the crude mixture was added 2mL 5.0-6.0 M HCl in IPA and the resulting mixture was stirred for 1 hour at 80 °C. The reaction mixture was concentrated under reduced pressure and 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 5-methyl-4-(6-((S)-3- methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin- 7(6H)-one (51.9 mg, 48.5%). LCMS (ESI, m / z): 407. The material was further purified via preparative SFC with the following conditions: Column: Chiralpak IH, 21 mm x 250 mm, 5 μm particles; Flow Rate: 75 mL / min; Column Temperature: 40 °C. Mobile Phase A: CO2, Mobile Phase B: MeOH with 0.1% ammonium hydroxide; RT1(min): 2.41; RT2(min): 4.10) to afford (S)-5-methyl-4-(6-((S)-3-methylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 19.6 mg, 38%) and (R)-5-methyl-4-(6-((S)-3-methylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 17.8 mg, 34%). Example 25 LCMS (ESI, m / z): 407 [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; 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 26 LCMS (ESI, m / z): 407[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; 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 27 and Example 28 (S)-4-(6-((R)-2-ethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-methyl-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)- 4-(6-((R)-2-ethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-methyl-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 25 and Example-26 using tert-butyl (R)-4-(6-chloro- 4-(trifluoromethyl)pyridin-2-yl)-3-ethylpiperazine-1-carboxylate as a starting material instead of tert-butyl (S)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine-1- carboxylate. 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: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 4-(6-((R)-2- ethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-methyl-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (68.3 mg, 64%). LCMS (ESI, m / z): 421. The material was further purified via preparative SFC with the following conditions: Column: Chiralpak IH, 21 mm x 250 mm, 5 μm particles; Flow Rate: 75 mL / min; Column Temperature: 40 °C. Mobile Phase A: CO2, Mobile Phase B: MeOH with 0.1% ammonium hydroxide; RT1(min): 11.26; RT2(min): 18.63) to afford (S)-4-(6-((R)-2-ethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 10.5 mg, 15%) and (R)- 4-(6-((R)-2-ethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 9.7 mg, 14%). Example 27 LCMS (ESI, m / z): 421 [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; 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: 1.28 min. Example 28 LCMS (ESI, m / z): 407[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; 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: 1.28 min. Example 29 (R)-5-(difluoromethyl)-4-(4-methyl-6-(piperazin-1-yl)pyridin-2-yl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one To a solution of bis(pinacolato)diboron (98.0 mg, 0.385 mmol), tert-butyl 4-(6-chloro-4- methylpyridin-2-yl)piperazine-1-carboxylate (100 mg, 0.321 mmol) and KOAc (63.0 mg, 0.642 mmol) in dioxane (1.5 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (26.2 mg, 0.032 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 3h. Bronic acid intermediate was observed on LCMS. The resulting reaction mixture was allowed to cooled down to rt. To the crude reaction mixture was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (17.5 mg, 0.021 mmol), potassium phosphate, tribasic (214 µl, 3 M, 0.642 mmol) and (R)-4-chloro- 5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (50 mg, 0.214 mmol). The resulting mixture was stirred at 90 °C overnight under nitrogen atmosphere. The reaction mixture was filtered and concentrated. To the crude mixture was added 2mL 5.0-6.0 M HCl in IPA and the resulting mixture was stirred for 1 hour at 80 °C. The reaction mixture was concentrated under reduced pressure and 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-5-(difluoromethyl)-4-(4-methyl-6-(piperazin-1- yl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (27 mg, 34%). 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 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 + / -). Rt: 1.15 min. Example 30 (R)-5-(difluoromethyl)-4-(4-methyl-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in a similar manner as Example 29 using tert-butyl (S)-4-(6-chloro-4-methylpyridin- 2-yl)-2-methylpiperazine-1-carboxylate as a starting material instead of tert-butyl 4-(6-chloro- 4-methylpyridin-2-yl)piperazine-1-carboxylate. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-5-(difluoromethyl)-4-(4-methyl-6-((S)-3- methylpiperazin-1-yl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (46.9 mg, 57%). LCMS (ESI, m / z): 389 [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; 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 + / -). Rt: 1.17 min. Example 31 (R)-4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one To a solution of bis(pinacolato)diboron (40.4 mg, 0.159 mmol), tert-butyl 4-(6-bromo-4- chloropyridin-2-yl)piperazine-1-carboxylate (50 mg, 0.133 mmol) and KOAc (39.1 mg, 0.398 mmol) in dioxane (2.0 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (21.7 mg, 0.027 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 3h. Bronic acid intermediate was observed on LCMS. The resulting reaction mixture was allowed to be cooled down to rt. To the crude reaction mixture was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (21.7 mg, 0.027 mmol), potassium phosphate, tribasic (0.199 mL, 2 M, 0.398 mmol) and (R)-4- bromo-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (39.3 mg, 0.133 mmol). The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. The reaction mixture was filtered and concentrated. To the crude mixture was added 2mL 5.0-6.0 M HCl in IPA and the resulting mixture was stirred for 1 hour at 80 °C. The reaction mixture was concentrated under reduced pressure and 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (9.6 mg, 18%). LCMS (ESI, m / z): 413 [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; 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 + / -). Rt: 1.4 min. Example 32 (R)-4-(4-methyl-6-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl 4-(6-chloro-4-methylpyridin-2- yl)piperazine-1-carboxylate as a starting material instead of tert-butyl 4-(6-bromo-4- chloropyridin-2-yl)piperazine-1-carboxylate. 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: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 (R)-4-(4-methyl-6-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (56 mg, 89%). LCMS (ESI, m / z): 393 [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; 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 + / -). Rt: 1.05 min. Example 33 (R)-4-(4-chloro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(difluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 29 using tert-butyl (S)-4-(6-bromo-4-chloropyridin- 2-yl)-2-methylpiperazine-1-carboxylate and (R)-4-bromo-5-(difluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one as a starting material instead of tert-butyl 4-(6- chloro-4-methylpyridin-2-yl)piperazine-1-carboxylate and (R)-4-chloro-5-(difluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 (R)-4-(4-chloro-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(difluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (2.1 mg, 4.8%). LCMS (ESI, m / z): 409 [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; 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 + / -). Rt: 1.27 min. Example 34 (R)-4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(difluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 29 using tert-butyl 4-(6-bromo-4-chloropyridin-2- yl)piperazine-1-carboxylate and (R)-4-bromo-5-(difluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one as a starting material instead of tert-butyl 4-(6-chloro-4- methylpyridin-2-yl)piperazine-1-carboxylate and (R)-4-chloro-5-(difluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5- (difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (3.1 mg, 7.4%). LCMS (ESI, m / z): 395 [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; 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 + / -). Rt: 1.21 min. Example 35 and Example 36 (S)-5-(1,1-difluoroethyl)-4-(4-methyl-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)- 5-(1,1-difluoroethyl)-4-(4-methyl-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl (S)-4-(6-chloro-4-methylpyridin- 2-yl)-2-methylpiperazine-1-carboxylate and 4-chloro-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one as starting material instead of tert-butyl 4-(6- bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate and (R)-4-bromo-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 5-(1,1-difluoroethyl)-4-(4-methyl-6-((S)-3- methylpiperazin-1-yl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. The material was further purified via preparative SFC with the following conditions: Column: Chiralpak IG, 21 mm x 250 mm, 5 μm particles; Flow Rate: 75 mL / min; Column Temperature: 40 °C. Mobile Phase A: CO2, Mobile Phase B: MeOH with 0.1% ammonium hydroxide; RT1(min): 12.6; RT2(min): 16.3) to afford (S)-5-(1,1-difluoroethyl)-4-(4-methyl-6-((S)-3- methylpiperazin-1-yl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 16.2 mg, 19%) and (R)- 5-(1,1-difluoroethyl)-4-(4-methyl-6-((S)-3- methylpiperazin-1-yl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 18.5 mg, 22%). Example 35 LCMS (ESI, m / z): 403 [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; 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: 1.36 min. Example 36 LCMS (ESI, m / z): 403 [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; 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: 1.23 min. Example 37 and Example 38 (S)- 4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one and (R)-4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using 4-bromo-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one as starting material instead of (R)-4-bromo-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one The material was further purified via preparative SFC with the following conditions: Column: Chiralpak IG, 21 mm x 250 mm, 5 μm particles; Flow Rate: 75 mL / min; Column Temperature: 40 °C. Mobile Phase A: CO2, Mobile Phase B: MeOH with 0.1% ammonium hydroxide; RT1(min): 21.76; RT2(min): 28.47) to afford (S)- 4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)- 5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 7.6 mg, 13%) and (R)- 4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 7.3 mg, 13%). Example 37 LCMS (ESI, m / z): 409 [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; 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: 1.32 min. Example 38 LCMS (ESI, m / z): 409 [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; 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: 1.33 min. Example 39 and Example 40 (S)-4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one and (R)-4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl (S)-4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-2-isopropylpiperazine-1-carboxylate and 4-chloro-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one as starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate and (R)-4-bromo-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (61.9 mg, 64%) The material was further purified via preparative SFC with the following conditions: Column: Whelk-O1 (R,R), 21 mm x 250 mm, 5 μm particles; Flow Rate: 75 mL / min; Column Temperature: 40 °C. Mobile Phase A: CO2, Mobile Phase B: MeOH with 0.1% ammonium hydroxide; RT1(min): 12.07; RT2(min): 13.64) to afford (S)- 4-(4-chloro-6-(piperazin-1- yl)pyridin-2-yl)-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 21.5 mg, 22%) and (R)- 4-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(1,1- difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 19 mg, 19%). Example 39 LCMS (ESI, m / z): 489 [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; 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: 1.59 min. Example 40 LCMS (ESI, m / z): 409 [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; 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: 1.83 min. Example 41 and Example 42 (S)-4-(6-((S)-3-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)- 4-(6-((S)-3-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl (S)-4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate and 4-chloro-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one as starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate and (R)-4-bromo-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 4-(6-((S)-3-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. The material was further purified via preparative SFC with the following conditions: Column: Chiralpak IG, 21 mm x 250 mm, 5 μm particles; Flow Rate: 75 mL / min; Column Temperature: 40 °C. Mobile Phase A: CO2, Mobile Phase B: MeOH with 0.1% ammonium hydroxide; RT1(min): 8.15; RT2(min): 10.42) to afford (S)-4-(6-((S)-3-cyclopropylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (the first eluting peak, 21 mg, 26%) and (R)- 4-(6-((S)-3-cyclopropylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (the second eluting peak, 21.9 mg, 18%). Example 41 LCMS (ESI, m / z): 487 [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; 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: 1.71 min. Example 42 LCMS (ESI, m / z): 487 [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; 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: 1.57 min. Example 43 (R)-4-(4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl 4-(6-chloro-4-(1,1- difluoroethyl)pyridin-2-yl)piperazine-1-carboxylate as a starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-4-(4-(1,1-difluoroethyl)-6-(piperazin-1- yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (25.4 mg, 58%). LCMS (ESI, m / z): 443 [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; 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 + / -). Rt: 1.44 min. Example 44 and Example 45 (S)-4-(6-((S)-2-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-4-(6-((S)-2-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl (S)-4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate and 4-chloro-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one as starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate and (R)-4-bromo-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 4-(6-((S)-2-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. The material was further purified via preparative SFC with the following conditions: Column: Chiralpak IG, 21 mm x 250 mm, 5 μm particles; Flow Rate: 75 mL / min; Column Temperature: 40 °C. Mobile Phase A: CO2, Mobile Phase B: MeOH with 0.1% ammonium hydroxide; RT1(min): 8.11; RT2(min): 14.89) to afford (S)-4-(6-((S)-2-methylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (the first eluting peak, 23.6 mg, 25%) and (R)-4-(6-((S)-2-methylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (the second eluting peak, 23.3 mg, 25%). Example 44 LCMS (ESI, m / z): 461 [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; 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 45 LCMS (ESI, m / z): 461 [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; 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: 1.63 min. Example 46 (R)-4-(4-(1,1-difluoroethyl)-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl (S)-4-(6-chloro-4-(1,1- difluoroethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate as a starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-4-(4-(1,1-difluoroethyl)-6-((S)- 3-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (23 mg, 58%). LCMS (ESI, m / z): 457 [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; 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 + / -). Rt: 1.51 min. Example 47 (R)-4-(6-(4-(fluoromethyl)piperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl 4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-4-(fluoromethyl)piperidine-1-carboxylate and (R)-4-chloro-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one as a starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate and (R)-4-bromo-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 (R)-4-(6-(4-(fluoromethyl)piperidin-4-yl)-4- (trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (10.2 mg, 27%). LCMS (ESI, m / z): 478 [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; 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 + / -). Rt: 1.47 min. Example 48 (R)-4-(6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl 4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and (R)-4-chloro-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one as a starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate and (R)-4-bromo-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.1% TFA; 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 (R)-4-(6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2- yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (30 mg, 66%). LCMS (ESI, m / z): 461 [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; 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 + / -). Rt: 1.52 min. Example 49 (R)-4-(4-(difluoromethyl)-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl (S)-4-(6-chloro-4- (difluoromethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate as a starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-4-(4-(difluoromethyl)-6-((S)- 3-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (30.3 mg, 87%). LCMS (ESI, m / z): 443 [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; 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 + / -). Rt: 1.47 min. Example 50 (R)-4-(6-((R)-2-methylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl (R)-4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate and (R)-4-chloro-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one as a starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate and (R)-4-bromo-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-4-(6-((R)-2-methylpiperazin-1- yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin- 7(6H)-one (21.3 mg, 58%). LCMS (ESI, m / z): 461 [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; 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 + / -). Rt: 1.6 min. Example 51 (R)-4-(4-(1,1-difluoroethyl)-6-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)-5-(difluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl (S)-4-(6-chloro-4-(1,1- difluoroethyl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate and (R)-4-chloro-5- (difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one as a starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate and (R)-4-bromo-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-4-(4-(1,1-difluoroethyl)-6-((S)- 3-methylpiperazin-1-yl)pyridin-2-yl)-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin- 7(6H)-one (29.9 mg, 78%). LCMS (ESI, m / z): 439 [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; 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 + / -). Rt: 1.35 min. Example 52 (R)-4-(4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl)-5-(difluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl 4-(6-chloro-4-(1,1- difluoroethyl)pyridin-2-yl)piperazine-1-carboxylate and (R)-4-chloro-5-(difluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one as a starting material instead of tert-butyl 4-(6- bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate and (R)-4-bromo-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-4-(4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin- 2-yl)-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (41.1 mg, >90%). LCMS (ESI, m / z): 425 [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; 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 + / -). Rt: 1.49 min. Example 53 4-(6-(4-methylpiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in an similar manner as Example 31 using tert-butyl 4-(6-bromo-4- (trifluoromethyl)pyridin-2-yl)-4-methylpiperidine-1-carboxylate and 4-chloro-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one as a starting material instead of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1-carboxylate and (R)-4-bromo-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 4-(6-(4-methylpiperidin-4-yl)-4- (trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (2.1 mg, 6%). LCMS (ESI, m / z): 460 [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; 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 + / -). Rt: 1.36 min. Example 54 (R)-5-(difluoromethyl)-4-(6-((S)-3-methyl-5-oxopiperazin-1-yl)-4-(trifluoromethyl)pyridin- 2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of bis(pinacolato)diboron (51.9 mg, 0.204 mmol), (S)-4-(6-chloro-4- (trifluoromethyl)pyridin-2-yl)-6-methylpiperazin-2-one (50 mg, 0.170 mmol) and KOAc (33.4 mg, 0.341 mmol) in dioxane (1.0 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (13.9 mg, 0.017 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2h. Bronic acid intermediate was observed on LCMS. The resulting reaction mixture was allowed to cooled down to rt. To the crude reaction mixture was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (9.27 mg, 0.011 mmol), potassium phosphate, tribasic (0.114 mL, 3 M, 0.341 mmol) and (R)-4- bromo-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (31.6 mg, 0.114 mmol). The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. The reaction mixture was filtered and concentrated. 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: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; 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 (R)-5-(difluoromethyl)-4-(6-((S)-3-methyl-5-oxopiperazin- 1-yl)-4-(trifluoromethyl)pyridin-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (10.2 mg, 14%). LCMS (ESI, m / z): 457 [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; 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 + / -). Rt: 1.6 min. Example 55 (S)-4-(6-((S)-3-methylpiperazin-1-yl)pyrazin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- methylpiperazine-1-carboxylate (21.90 mg, 0.07 mmol), and potassium acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for one and half hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-2-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2- yl)piperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 322.7 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (S)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (17.6 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 8 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-2-methyl-4-(6-((S)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)pyrazin-2-yl)piperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 494.0 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 60%A-40%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (11.5 mg, 42%), with estimated purity >99% by Reverse Phase analysis. LCMS (ESI, m / z): 394.2 [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 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 + / -); Retention time: 1.29 min. Example 56 (S)-4-(6-((S)-3-ethylpiperazin-1-yl)pyrazin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- ethylpiperazine-1-carboxylate (22.88 mg, 0.07 mmol), and potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for two hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-2-ethyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperazine-1- carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 336.9 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (S)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (17.6 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 6 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-2-ethyl-4-(6-((S)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)pyrazin-2-yl)piperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 507.9 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 70%A-30%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (8.8 mg, 31%), with estimated purity >99% by Reverse Phase analysis. LCMS (ESI, m / z): 408.1 [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; 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 + / -); Retention time: 1.33 min. Example 57 (S)-4-(6-((S)-3-cyclopropylpiperazin-1-yl)pyrazin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- cyclopropylpiperazine-1-carboxylate (23.72 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for two hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-2-cyclopropyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2- yl)piperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 348.9 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (S)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (17.6 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 6 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-2-cyclopropyl-4-(6-((S)-7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)pyrazin-2-yl)piperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 520.0 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 60%A-40%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (21.8 mg, 74%), with estimated purity >99% by Reverse Phase analysis. LCMS (ESI, m / z): 420.1 [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; 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 + / -); Retention time: 1.39 min. Example 58 2-((S)-3-methylpiperazin-1-yl)-6-((S)-7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)isonicotinonitrile In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloro-4-cyanopyridin-2- yl)-2-methylpiperazine-1-carboxylate (23.6 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for one and half hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-4-(4-cyano-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)-2-methylpiperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 346.8 [M+H]+. In another reaction vial was charged with PdCl2 dppf-dcm adduct (5.7 mg, 0.007 mmol) and (S)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (17.6 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 12 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-4-(4-cyano-6-((S)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 518.0 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 96%A-4%B to 66%A-34%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (16.3 mg, 56%), with estimated purity >99% by Reverse Phase analysis. 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; 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 + / -); Retention time: 1.46 min. Example 59 (R)-4-(6-((S)-3-cyclopropylpiperazin-1-yl)pyrazin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- cyclopropylpiperazine-1-carboxylate (23.72 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for two hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-2-cyclopropyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2- yl)piperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 348.7 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (R)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (17.6 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 10 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-2-cyclopropyl-4-(6-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)pyrazin-2-yl)piperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 520.0 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 72%A-38%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (8.4 mg, 26%), with estimated purity 92.3% by Reverse Phase analysis. LCMS (ESI, m / z): 420.2 [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 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 + / -); Retention time: 1.40 min. Example 60 (R)-4-(6-((S)-3-ethylpiperazin-1-yl)pyrazin-2-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- ethylpiperazine-1-carboxylate (22.88 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for two hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-2-ethyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperazine-1- carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 336.7 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (R)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (17.6 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 10 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-2-ethyl-4-(6-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)pyrazin-2-yl)piperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 508.0 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 72%A-28%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (12.7 mg, 42%), with estimated purity 93.7% by Reverse Phase analysis. LCMS (ESI, m / z): 408.1 [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; 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 + / -); Retention time: 1.35 min. Example 61 (R)-4-(6-((S)-3-methylpiperazin-1-yl)pyrazin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- methylpiperazine-1-carboxylate (21.90 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for one and half hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-2-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2- yl)piperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 322.7 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (R)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (17.6 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 8 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-2-methyl-4-(6-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)pyrazin-2-yl)piperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 493.9 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 70%A-30%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (27 mg, 97%), with estimated purity 98.5% by Reverse Phase analysis. LCMS (ESI, m / z): 394.1 [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; 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 + / -); Retention time: 1.41 min. Example 62 2-((S)-3-methylpiperazin-1-yl)-6-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)isonicotinonitrile In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloro-4-cyanopyridin-2- yl)-2-methylpiperazine-1-carboxylate (23.6 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for two hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-4-(4-cyano-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2- methylpiperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 346.8 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (R)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (17.6 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 12 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-4-(4-cyano-6-((S)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 518.0 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 97%A-3%B to 67%A-33%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (8.3 mg, 28%), with estimated purity 97.6% by Reverse Phase analysis. LCMS (ESI, m / z): 418.2 [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 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 + / -); Retention time: 1.44 min. Example 63 (R)-4-(6-((S)-3-cyclopropylpiperazin-1-yl)pyrazin-2-yl)-5-(difluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- cyclopropylpiperazine-1-carboxylate (23.72 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for two hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-2-cyclopropyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2- yl)piperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 348.7 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (R)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (16.35 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 10 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-2-cyclopropyl-4-(6-((R)-5-(difluoromethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)pyrazin-2-yl)piperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 501.9 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 70%A-30%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (17.4 mg, 58%), with estimated purity 94% by Reverse Phase analysis. LCMS (ESI, m / z): 402.2 [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 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 + / -); Retention time: 1.37 min. Example 64 (R)-5-(difluoromethyl)-4-(6-((S)-3-ethylpiperazin-1-yl)pyrazin-2-yl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- ethylpiperazine-1-carboxylate (22.88 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for two hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-2-ethyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperazine-1- carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 336.7 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (R)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (16.35 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 10 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-4-(6-((R)-5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin- 4-yl)pyrazin-2-yl)-2-ethylpiperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 489.9 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 65%A-35%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (16.6 mg, 60%), with estimated purity 99% by Reverse Phase analysis. LCMS (ESI, m / z): 390.1 [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; 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 + / -); Retention time: 1.35 min. Example 65 (R)-5-(difluoromethyl)-4-(6-((S)-3-methylpiperazin-1-yl)pyrazin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- methylpiperazine-1-carboxylate (21.90 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for one and half hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-2-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2- yl)piperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 322.7 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (R)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (16.35 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 8 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-4-(6-((R)-5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin- 4-yl)pyrazin-2-yl)-2-methylpiperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 475.9 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 72%A-28%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (10.3 mg, 37%), with estimated purity 94% by Reverse Phase analysis. LCMS (ESI, m / z): 376.2 [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 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 + / -); Retention time: 1.13 min. Example 66 2-((R)-5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-6-((S)-3- methylpiperazin-1-yl)isonicotinonitrile In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloro-4-cyanopyridin-2- yl)-2-methylpiperazine-1-carboxylate (23.6 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for two hours. Analysis by LCMS showed Borylation product, tert-butyl (S)-4-(4-cyano-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2- methylpiperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 346.8 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (R)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (16.35 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 12 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (S)-4-(4-cyano-6-((R)-5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 499.9 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 72%A-28%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (14.5 mg, 51%), with estimated purity 98.3% by Reverse Phase analysis. LCMS (ESI, m / z): 400.2 [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 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 + / -); Retention time: 1.43 min. Example 67 (R)-4-(6-((R)-2-methylpiperazin-1-yl)pyrazin-2-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2 dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- methylpiperazine-1-carboxylate (21.90 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for two hours. Analysis by LCMS showed Borylation product, tert-butyl (R)-3-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2- yl)piperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 323.1 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (R)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (17.6 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 10 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (R)-3-methyl-4-(6-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)pyrazin-2-yl)piperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 494.2 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 72%A-28%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (21.4 mg, 78%), with estimated purity >99% by Reverse Phase analysis. LCMS (ESI, m / z): 394.1 [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; 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 + / -); Retention time: 0.95 min. Example 68 (R)-5-(difluoromethyl)-4-(6-((R)-2-methylpiperazin-1-yl)pyrazin-2-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one In a microwave vial was added PdCl2dppf-dcm adduct (7.4 mg, 0.0091 mmol), Bis(pinacolato)diboron (23.1 mg, 0.091 mmol), tert-butyl (S)-4-(6-chloropyrazin-2-yl)-2- methylpiperazine-1-carboxylate (21.90 mg, 0.07 mmol), and Potassium Acetate (25.4 mg, 0.26 mmol). The vial was sealed and purged with N2. Dioxane (0.7 ml) was added, and the reaction was heated to 90 °C for two hours. Analysis by LCMS showed Borylation product, tert-butyl (R)-3-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2- yl)piperazine-1-carboxylate, as predominant peak. The crude slurry from borylation was then filtered by 0.45 µm PTFE filter and the filtrate was used as boronic ester in dioxane solution with no purification. LCMS (ESI, m / z) as boronic acid: 323.1 [M+H]+. In another reaction vial was charged with PdCl2dppf-dcm adduct (5.7 mg, 0.007 mmol) and (R)-4-chloro-5-(difluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (16.35 mg, 0.070 mmol). Then the filtrate of the above borylation product (~0.07 mmol) in Dioxane (~0.7 ml) was added to the reaction mixture, followed by addition of Potassium phosphate, 3M aq. solution (0.070 mL, 0.21 mmol). The resultant suspension was degassed by sparging with nitrogen for 10 minutes. Reaction mixture was heated in microwave synthesizer at 95oC for 10 hours. The crude mixture was diluted by EtOAc, filtered through a layer of silica gel with rinse of EtOAc (3x3ml) and the filtrate was concentrated to afford crude Boc-protected product, tert-butyl (R)-4-(6-((R)-5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin- 4-yl)pyrazin-2-yl)-3-methylpiperazine-1-carboxylate, that was used at next step without further purification. LCMS (ESI, m / z): 476.1 [M+H]+. The above crude sample was mixed withiPrOH (~1.4 mL) and 4M HCl aqueous solution (~0.7 mL). The reaction mixture was heated at 65oC for one hour. The reaction solution was then neutralized by excess Na2CO3powder. The mixture was extracted by EtOAc-brine, 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 100%A to 72%A-28%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 UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (13.2 mg, 50%), with estimated purity >99% by Reverse Phase analysis. LCMS (ESI, m / z): 376.1 [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; 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 + / -); Retention time: 0.86 min. PKC-theta HTRF: A solution was prepared containing 0.8 nM Anti-GST-Terbium (Cisbio, 61GSTTLB), 7.5 nM designed-probe and 1.5 nM PKC theta (Carna Biosciences #01-140) in FRET Buffer (20 mM HEPES, 10 mM MgC12, 0.015% Brij-35, 4mM DTT, 0.05 mg / mL BSA). Using Formulatrix Tempest for liquid handling, the detection antibody / enzyme / probe solution (2 uL per well) was dispensed into wells of a 1536 plate (Black Low Binding Polystyrene 1536 Plate (Corning, 3724) containing 10 nL of compounds of interest at appropriate concentration in DMSO. The plate was incubated at room temperature for 1 h. FRET was measured using the EnVision plate reader (Excitation: 340 nM, Emission: 520 nM / 495 nM). Total signal (0% inhibition) was calculated from wells containing 10 nL DMSO only. Blank signal (100% inhibition) calculated from wells containing 10 nL of 15 nM staurosporine and internal controls. IC50 values were determined from 11-point concentration-response curves and are reported as pIC50 values. 14575–US-PSP Example Number pIC50 Example Number pIC50 1 6.2 21 5.6 2 8.6 22 8.6 3 8.5 23 6.9 4 5.4 24 6.8 5 6.4 25 6.0 6 8.9 26 8.7 7 5.7 27 6.5 8 9.0 28 8.4 9 5.4 29 8.3 10 8.5 30 8.7 11 7.8 31 8.3 12 5.9 32 8.0 13 5.6 33 8.2 14 8.5 34 8.2 15 6.1 35 4.9 16 8.8 36 8.1 17 6.0 37 5.2 18 8.7 38 7.8 19 8.2 39 5.7 20 6.4 40 8.7 14575–US-PSP Example Number pIC50 Example Number pIC50 41 6.2 61 7.8 42 8.7 62 8.3 43 8.3 63 8.3 44 6.5 64 8.3 45 8.1 65 7.9 46 8.6 66 8.3 47 7.9 67 NA 48 8.4 68 NA 49 8.7 50 8.4 51 8.6 52 8.1 53 NA 54 NA 55 5.8 56 5.0 57 5.0 58 4.9 59 8.2 60 8.1

Claims

14575–US-PSP CLAIMS What is claimed is:

1. A compound of Formula I: orsalt thereof, wherein: R1is selected from the group consisting of: −CH= and −N=; R2is selected from the group consisting of: −N= and −C(R5)=; R3is selected from the group consisting of: 1,4-diazepan-1-yl, ;R4is group alkyl, haloalkyl;14575–US-PSP R5is selected from the group consisting of: alkyl, halogen, −CN, −CHF2, −CF2CH3, and −CF3; R6is selected from the group consisting of: alkyl and haloalkyl; R7is selected from the group consisting of: −CH2− and −CO−; R8is selected from the group consisting of: −H and alkyl; R9is selected from the group consisting of: −H, alkyl, branched alkyl, and cyclyl.

2. The compound according to Claim 1, wherein: R4is selected from the group consisting of: −H, −CH3, −CHF2, −CF2CH3and −CF3; R5is selected from the group consisting of: −CH3, −F, −Cl, −CN, −CHF2, −CF2CH3, and −CF3; R6is selected from the group consisting of: −CH3 and −CH2F; R8is selected from the group consisting of: −H, −CH3, and −CH2CH3; R9is selected from the group consisting of: −H, −CH3, −CH2CH3, −CH(CH3)2, and cyclopropyl.

3. The compound according to Claim 1, wherein: R2is −C(R5)=; R4is selected from the group consisting of: −H, alkyl, haloalkyl, and −CF3; R5is selected from the group consisting of: alkyl, halogen, −CHF2, −CCH3F2, and −CF3; R9is selected from the group consisting of: −H, alkyl, and cyclyl.

4. The compound according to Claim 1, wherein: R1is −N=; R2is −C(R5)=;14575–US-PSP R3is ;R5is −CF3; R7is −CH2−; R8is −H; R9is alkyl.

5. The compound according to Claim 1, wherein: R1is −N=; R2is −C(R5)=; R3is ;R4is selected from the group consisting of: −H and haloalkyl; R5is selected from the group consisting of halogen and −CF3; R7is −CH2−; R8is −H; R9is selected from the group consisting of: −H and alkyl.14575–US-PSP 6. The compound of claim 1 wherein the compound is selected from the group consisting of: (5S)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one (5R)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]-4- (trifluoromethyl)pyridin-2-yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one;14575–US-PSP (5R)-5-(1,1-difluoroethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-[6-(piperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{4-fluoro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-fluoro-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-[4-fluoro-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (4S)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-one;14575–US-PSP (4R)-5-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-4- (trifluoromethyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-one; 4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; 4-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-5-methyl-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-methyl-4-{6-[(3S)-3-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5-methyl- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(2R)-2-ethylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5-methyl- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-methyl-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one;14575–US-PSP (5R)-4-{4-chloro-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}-5-(difluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(difluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{4-methyl-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(1,1-difluoroethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-chloro-6-(piperazin-1-yl)pyridin-2-yl]-5-(1,1-difluoroethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(3S)-3-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one;14575–US-PSP (5S)-4-{6-[(2S)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(2S)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[4-(fluoromethyl)piperidin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-(1,4-diazepan-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(difluoromethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-[(2R)-2-methylpiperazin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-[(3S)-3-methylpiperazin-1-yl]pyridin-2-yl]-5- (difluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[4-(1,1-difluoroethyl)-6-(piperazin-1-yl)pyridin-2-yl]-5-(difluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; 4-[6-(4-methylpiperidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (6S)-4-{6-[(5R)-5-(difluoromethyl)-7-oxo-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-4- (trifluoromethyl)pyridin-2-yl}-6-methylpiperazin-2-one;14575–US-PSP (5S)-4-{6-[(3S)-3-methylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-ethylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; 2-[(3S)-3-methylpiperazin-1-yl]-6-[(5S)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-4-yl]pyridine-4-carbonitrile; (5R)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one (5R)-4-{6-[(3S)-3-ethylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one (5R)-4-{6-[(3S)-3-methylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one 2-[(3S)-3-methylpiperazin-1-yl]-6-[(5R)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-4-yl]pyridine-4-carbonitrile; (5R)-4-{6-[(3S)-3-cyclopropylpiperazin-1-yl]pyrazin-2-yl}-5-(difluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one (5R)-5-(difluoromethyl)-4-{6-[(3S)-3-ethylpiperazin-1-yl]pyrazin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{6-[(3S)-3-methylpiperazin-1-yl]pyrazin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one;14575–US-PSP 2-[(5R)-5-(difluoromethyl)-7-oxo-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-6-[(3S)-3- methylpiperazin-1-yl]pyridine-4-carbonitrile; (5R)-4-{6-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; or (5R)-5-(difluoromethyl)-4-{6-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one.

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

8. 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.

9. 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.

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

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