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 / 656799 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; ; R2is selected from the group consisting of −H, alkyl, and haloalkyl; R3is selected from the group consisting of: −CH= and −N=; R4is selected from the group consisting of piperazinyl, 2-methylpiperazin-1-yl and ; R5is selected from the group consisting of pyrrolidin-3-yl, 4-methylpyrrolidin-3-yl, 1- (cyanomethyl)cyclobutyl, and ; R6is selected from the group consisting of: −H and halogen; R7is selected from the group consisting of: −H, alkyl, and halogen; R8is selected from the group consisting of: −H, alkyl, and halogen. Further disclosed is a compound selected from a group consisting of: (5R)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[1-(pyrrolidin-3-yl)-1H-indazol-3-yl]-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3- d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; 2-(1-{3-[(5S)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-1H- indazol-1-yl}cyclobutyl)acetonitrile; 2-(1-{3-[(5R)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-1H- indazol-1-yl}cyclobutyl)acetonitrile; (5R)-4-{3-[(2R)-2-methylpiperazin-1-yl]-1H-indazol-1-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; or (5R)-4-(3-{3,8-diazabicyclo[3.2.1]octan-8-yl}-1H-indazol-1-yl)-5-(trifluoromethyl)- 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 C1−4 hydroxyalkyl. 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 at least one compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein, R1is selected from the group consisting of: ; R2is selected from the group consisting of: −H, alkyl, and haloalkyl; R3is selected from the group consisting of: −CH= and −N=; R4is selected from the group consisting of piperazinyl, 2-methylpiperazin-1-yl and ; R5is selected from the group consisting of pyrrolidin-3-yl, 4-methylpyrrolidin-3-yl, 1- (cyanomethyl)cyclobutyl, and ; R6is selected from the group consisting of: −H and halogen; R7is selected from the group consisting of: −H, alkyl, and halogen; R8is selected from the group consisting of: −H, alkyl, and halogen. In one embodiment of the compound of formula I: R2is selected from the group consisting of: −CF2H, −CF2CH3, and −CF3; R3is −N=; R6is selected from the group consisting of: −H and −F; R7is selected from the group consisting of: −H, −CH3, and −F; R8is selected from the group consisting of: −H, −CH3, and −F. In another embodiment of the compound of formula I: R1is ; R2is selected from the group consisting of: −CF2H, −CF2CH3, and −CF3; ; R3is −N=; ; R7is selected from the group consisting of: −H and alkyl; R8is selected from the group consisting of: −H and halogen. In one embodiment of the compound of formula I: R1is ; R3is −N=; R5is selected from the group consisting of 4-methylpyrrolidin-3-yl and ; R7is selected from the group consisting of: −H and halogen. In another embodiment, the compound is selected from the group consisting of: (5R)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[1-(pyrrolidin-3-yl)-1H-indazol-3-yl]-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3- d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; 2-(1-{3-[(5S)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-1H- indazol-1-yl}cyclobutyl)acetonitrile; 2-(1-{3-[(5R)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-1H- indazol-1-yl}cyclobutyl)acetonitrile; (5R)-4-{3-[(2R)-2-methylpiperazin-1-yl]-1H-indazol-1-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; or (5R)-4-(3-{3,8-diazabicyclo[3.2.1]octan-8-yl}-1H-indazol-1-yl)-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one. In one embodiment, the invention provides a pharmaceutical composition comprising the compound of Formula I, and a pharmaceutically acceptable carrier. In one embodiment, the invention provides a method of treating, preventing, or managing a disease or disorder mediated by a protein kinase C theta (PKC-theta), or PKC- theta mutant, in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutical composition comprising formula I. In one embodiment, the invention provides for a method of treating, preventing, or managing a disease or disorder mediated by a protein kinase C theta (PKC-theta) or PKC theta mutant, in a subject, wherein the disease or disorder is an inflammatory disease, an autoimmune disorder, a cancer, an oncologic disease, or an autoimmune infection. 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%) (isomer 1) 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%) (isomer 2) a white solid. LCMS (ESI, m / z): 292; 294 [M+H]+. Example 1 and Example 2 (R)-5-(difluoromethyl)-4-(1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (S)-5-(difluoromethyl)-4-(1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (3R,4S)-4-(3-bromo-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate To a solution of 3-bromo-1H-indazole (200 mg, 1.02 mmol) in toluene (4 mL) were added tert-butyl (3R,4R)-4-hydroxy-3-methylpiperidine-1-carboxylate (218 mg, 1.02 mmol) and (Tributylphosphoranylidene)acetonitrile (491 mg, 2.03 mmol). The resulting mixture was stirred at 85 °C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (1:4) to give tert-butyl (3R,4S)-4-(3-bromo-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate (100 mg, 24%) as an orange solid. LCMS (ESI, m / z): 394, 396 [M+H]+. (1-((3R,4S)-1-(tert-butoxycarbonyl)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)boronic acid To a solution of tert-butyl (3R,4S)-4-(3-bromo-1H-indazol-1-yl)-3-methylpiperidine-1- carboxylate (90 mg, 0.23 mmol) in 1,4-dioxane (2 mL) were added B2pin2(87 mg, 0.34 mmol), KOAc (45 mg, 0.46 mmol) and Pd(dppf)Cl2(18 mg, 0.02 mmol). The resulting mixture was stirred at 90°C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was used in the next step directly without further purification. LCMS (ESI, m / z): 360 [M+H]+. tert-butyl (3R,4S)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin- 4-yl)-1H-indazol-1-yl)-3-methylpiperidine-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 (53 mg, 0.23 mmol), K2CO3(94 mg, 0.68 mmol), water (0.1 mL) and Pd(dppf)Cl2(18 mg, 0.02 mmol). The resulting mixture was stirred at 90°C for 2 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (70 mL) and extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1 / 1) to give tert-butyl (3R,4S)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H- indazol-1-yl)-3-methylpiperidine-1-carboxylate (90 mg, 76%) as a yellow solid. LCMS (ESI, m / z): 513 [M+H]+. 5-(difluoromethyl)-4-(1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of tert-butyl (3R,4S)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate (90 mg, 0.18 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. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (3:1) to give 5-(difluoromethyl)-4-(1- ((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin- 7(6H)-one (70 mg, 96%) as a white solid. LCMS (ESI, m / z): 413 [M+H]+. Example 1 and Example 2 5-(difluoromethyl)-4-(1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (70 mg, 0.17 mmol) was purified by Prep-chiral- HPLC (Column: CHIRALPAK IM, 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 40; Wave Length: 254 / 220 nm; RT1(min): 9.67; RT2(min): 11.23) to afford (R)-5-(difluoromethyl)-4-(1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 19.7 mg, 27%) and (S)-5- (difluoromethyl)-4-(1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 16.1 mg, 22%) both as white solid. Example 1 (first eluting) LCMS (ESI, m / z): 413 [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: 0.578 min.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.93 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.57-6.28 (m, 1H), 5.14-5.08 (m, 1H), 4.85-4.77 (m, 1H), 3.32-3.27 (m, 1H), 3.15-3.05 (m, 2H), 3.05-2.89 (m, 1H), 2.87-2.78 (m, 1H), 2.78-2.73 (m, 1H), 2.45-2.44 (m, 1H), 2.39-2.33 (m, 1H), 1.97-1.94 (m, 1H), 0.70 (d, J = 7.2 Hz, 3H). Example 2 (second eluting) LCMS (ESI, m / z): 413 [M+H]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: Water / 0.05%TFA; Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 40% B in 1.70 min, 40% 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: 1.219 min.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.93 (s, 1H), 8.62 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.53-7.49 (m, 1H), 7.37-7.32 (m, 1H), 6.50-6.36 (m, 1H), 5.06-5.00 (m, 1H), 4.74-4.64 (m, 1H), 3.19-3.01 (m, 3H), 2.88-2.84 (m, 1H), 2.78-2.73 (m, 2H), 2.51- 2.44 (m, 1H), 2.42-2.32 (m, 1H), 1.88-1.86 (m, 1H), 0.72 (d, J = 6.8 Hz, 3H). Example 3 and Example 4 (S)-5-(1,1-difluoroethyl)-4-(6-fluoro-1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-5-(1,1-difluoroethyl)-4-(6-fluoro-1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (3R,4S)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate To a solution of 3-bromo-6-fluoro-1H-indazole (200 mg, 0.93 mmol) in toluene (4 mL) were added tert-butyl (3R,4R)-4-hydroxy-3-methylpiperidine-1-carboxylate (200 mg, 0.93 mmol) and (Tributylphosphoranylidene)acetonitrile (450 mg, 1.86 mmol). The resulting mixture was stirred at 85 °C for 1 d under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with petroleum ether / dichloromethane (0 / 1) to give tert-butyl (3R,4S)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)-3-methylpiperidine-1- carboxylate (200 mg, 52%) as a yellow solid. LCMS (ESI, m / z): 412, 414 [M+H]+. (1-((3R,4S)-1-(tert-butoxycarbonyl)-3-methylpiperidin-4-yl)-6-fluoro-1H-indazol-3- yl)boronic acid To a solution of tert-butyl (3R,4S)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)-3- methylpiperidine-1-carboxylate (200 mg, 0.49 mmol) in 1,4-dioxane (4 mL) were added B2pin2(184 mg, 0.73 mmol), KOAc (95 mg, 0.97 mmol) and Pd(dppf)Cl2(39 mg, 0.05 mmol). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was purified by reverse flash chromatography (water (0.5% TFA) : ACN = 2:3) to afford (1-((3R,4S)-1-(tert- butoxycarbonyl)-3-methylpiperidin-4-yl)-6-fluoro-1H-indazol-3-yl)boronic acid (150 mg, 81%) as an orange solid. LCMS (ESI, m / z): 378 [M+H]+. tert-butyl (3R,4S)-4-(3-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-6-fluoro-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate To a solution of (1-((3R,4S)-1-(tert-butoxycarbonyl)-3-methylpiperidin-4-yl)-6-fluoro-1H- indazol-3-yl)boronic acid (80 mg, 0.21 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) were added 4-chloro-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (50 mg, 0.21 mmol) , K2CO3(87 mg, 0.64 mmol) and Pd(dppf)Cl2(17 mg, 0.02 mmol). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was then quenched with water (70 mL) and extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure and the residue was purified by reverse flash chromatography (water (0.5% TFA) : ACN = 1:1) to afford tert-butyl (3R,4S)-4-(3-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-6-fluoro-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate (70 mg, 60%) as a yellow solid. LCMS (ESI, m / z): 545 [M+H]+. 5-(1,1-difluoroethyl)-4-(6-fluoro-1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of tert-butyl (3R,4S)-4-(3-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-6-fluoro-1H-indazol-1-yl)-3-methylpiperidine-1- carboxylate (70 mg, 0.13 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. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (7:3) to give 5-(1,1- difluoroethyl)-4-(6-fluoro-1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (55 mg, 96%) as a white solid. LCMS (ESI, m / z): 445 [M+H]+. Example 3 and Example 4 5-(1,1-Difluoroethyl)-4-(6-fluoro-1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (55 mg, 0.12 mmol) was separated by chiral- HPLC (Column: CHIRALPAK IE, 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 30; Wave Length: 254 / 220 nm; RT1(min): 14.069; RT2(min): 17.628) to afford (S)-5-(1,1-difluoroethyl)-4-(6-fluoro-1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol- 3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 14.6 mg, 26%) and (R)-5-(1,1-difluoroethyl)-4-(6-fluoro-1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3- yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 15.3 mg, 27%) both as white solid. Example 3 (first eluting) LCMS (ESI, m / z): 445 [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: 0.626 min.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.91 (s, 1H), 8.62 (dd, J = 9.2, 5.6 Hz, 1H), 7.82 (dd, J = 9.6, 2.4 Hz, 1H), 7.22 (td, J = 9.2, 2.4 Hz, 1H), 5.27 (td, J = 16.0, 7.2 Hz, 1H), 5.08-5.04 (m, 1H), 3.31-3.26 (m, 1H), 3.23-3.10 (m, 1H), 3.10-2.99 (m, 1H), 2.99-2.91 (m, 1H), 2.91- 2.86 (m, 1H), 2.83-2.78 (m, 1H), 2.44-2.34 (m, 2H), 1.96-1.93 (m, 1H), 1.49 (t, J = 19.2, 3H), 0.69 (d, J = 6.8 Hz, 3H). Example 4 (second eluting) LCMS (ESI, m / z): 445 [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: 1.186 min.1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.92 (s, 1H), 8.78-8.77 (m, 1H), 8.67- 8.66 (m, 1H), 8.58 (dd, J = 9.2, 5.6 Hz, 1H), 7.82 (dd, J = 10.0, 2.0 Hz, 1H), 7.24 (td, J = 9.2, 2.0 Hz, 1H), 5.24-5.15 (m, 2H), 3.66-3.50 (m, 1H), 3.40-3.36 (m, 1H), 3.36-3.19 (m, 3H), 2.80 (d, J = 16.8 Hz, 1H), 2.63-2.51 (m, 1H), 2.47-2.42(m, 1H), 2.26-2.21 (m, 1H), 1.55 (d, J = 19.2 Hz, 3H), 0.72 (d, J = 7.2 Hz, 3H) Example 5 and Example 6 (R)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (S)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (3R,4S)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate To a solution of 3-bromo-6-fluoro-1H-indazole (400 mg, 1.86 mmol) and tert-butyl (3R,4R)- 3-fluoro-4-hydroxypiperidine-1-carboxylate (408 mg, 1.86 mmol) in toluene (10 mL) was added (Tributylphosphoranylidene)acetonitrile (897 mg, 3.72 mmol). The resulting mixture was stirred at 85 °C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was concentrated under reduce pressure and the residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1:2) to give tert-butyl (3R,4S)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate (550 mg, 71%) as a white solid. LCMS (ESI, m / z): 416; 418 [M+H]+. (1-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-6-fluoro-1H-indazol-3- yl)boronic acid To a solution of tert-butyl (3R,4S)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)-3-fluoropiperidine- 1-carboxylate (100 mg, 0.24 mmol), bis(pinacolato)diboron (91 mg, 0.36 mmol) and KOAc (47 mg, 0.48 mmol) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl2(24 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C overnight 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): 382 [M+H]+. tert-butyl (3R,4S)-3-fluoro-4-(6-fluoro-3-(7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)piperidine-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 (66 mg, 0.26 mmol), K2CO3(108 mg, 0.79 mmol), water (0.3 mL) and Pd(dtbpf)Cl2(17 mg, 0.03 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 diluted with DMF. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1:2) to give tert-butyl (3R,4S)-3-fluoro-4- (6-fluoro-3-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H- indazol-1-yl)piperidine-1-carboxylate (100 mg, 69%) as a yellow solid. LCMS (ESI, m / z): 553 [M+H]+. 4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of tert-butyl (3R,4S)-3-fluoro-4-(6-fluoro-3-(7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (100 mg, 0.18 mmol) in DCM (6 mL) was added drowpwise TFA (2 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 4-(6-fluoro-1-((3R,4S)-3- fluoropiperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (70 mg, 85%) as a white solid. LCMS (ESI, m / z): 453 [M+H]+. Example 5 and Example 6 4-[6-fluoro-1-[(3R,4S)-3-fluoro-4-piperidyl]indazol-3-yl]-5-(trifluoromethyl)-6,8-dihydro- 5H-pyrido[2,3-d]pyrimidin-7-one (70 mg, 0.15 mmol) (racemate) was isolated by Prep- chiral-HPLC(Column: CHIRAL ART Amylose-SA, 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 30; Wave Length: 254 / 220 nm; RT1(min): 8.117; RT2(min): 14.086) to obtain (R)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 10.2 mg, 14%) and (S)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 17.8 mg, 25%) both as white solid. Example 5 (first eluting) LCMS (ESI, m / z): 453 [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: 1.194 min.1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 9.17 (s, 1H), 8.99 (s, 2H), 8.60 (dd, J = 9.2, 5.6 Hz, 1H), 7.83 (dd, J = 9.6, 24 Hz, 1H), 7.29 (td, J = 9.2, 2.4 Hz, 1H), 5.73- 5.68 (m, 1H), 5.40-5.22 (m, 2H), 3.77-3.76 (m, 1H), 3.74-3.60 (m, 1H) 3.55-3.53 (m, 2H), 3.43-3.24 (m, 1H), 2.94-2.81 (m, 1H), 2.75-2.73 (m, 1H), 2.36-2.20 (m, 1H). Example 6 (second eluting) LCMS (ESI, m / z): 453 [M+H]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: Water / 0.05%TFA; Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 40% B in 1.70 min, 40% B to 95% B in 0.60 min; hold at 95% for 0.50 min, 95% B to 5% B in 0.03 min; 254 nm; Rt: 1.331 min.1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.00 (s, 1H), 8.71 (dd, J = 9.2, 5.6 Hz, 1H), 7.85 (dd, J = 9.6, 2.4 Hz, 1H), 7.31 (td, J = 9.2, 2.4 Hz, 1H), 5.73-5.67 (m, 1H), 5.42-5.27 (m, 2H), 3.77-3.76 (m, 1H), 3.74-3.59 (m, 1H) 3.57-3.55 (m, 2H), 3.43-3.21 (m, 1H), 2.94-2.88 (m, 1H), 2.78-2.76 (m, 1H), 2.36-2.22 (m, 1H). Example 7 and Example 8 (S)-5-(difluoromethyl)-4-(5-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-5-(difluoromethyl)-4-(5-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (3R,4S)-4-(3-bromo-5-fluoro-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate To a solution of 3-bromo-5-fluoro-1H-indazole (150 mg, 0.7 mmol) and tert-butyl (3R,4R)- 3-fluoro-4-hydroxy-piperidine-1-carboxylate (229 mg, 1.05 mmol) in toluene (5 mL) was added (Tributylphosphoranylidene)acetonitrile (336 mg, 1.4 mmol). The resulting mixture was stirred at 85 °C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The solvent was removed by distillation under vacuum. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1:2) to give tert-butyl (3R,4S)-4-(3-bromo-5-fluoro-indazol-1-yl)-3-fluoro-piperidine-1-carboxylate (200 mg, 69 % yield) as a light yellow oil. LCMS (ESI, m / z): 416 [M+H]+. (1-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-5-fluoro-1H-indazol-3- yl)boronic acid To a solution of tert-butyl (3R,4S)-4-(3-bromo-5-fluoro-indazol-1-yl)-3-fluoro-piperidine-1- carboxylate (100 mg, 0.24 mmol), B2pin2(122 mg, 0.48 mmol) and KOAc (71 mg, 0.72 mmol) in 1,4-Dioxane (5 mL) was added Pd(dppf)Cl2(20 mg, 0.02 mmol). The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The product was used in the next step directly without further purification. LCMS (ESI, m / z): 382 [M+H]+. tert-butyl (3R,4S)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin- 4-yl)-5-fluoro-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate To the reaction mixture from previous step were added 4-chloro-5-(difluoromethyl)-6,8- dihydro-5H-pyrido[2,3-d]pyrimidin-7-one (67 mg, 0.29 mmol), K2CO3 (109 mg, 0.79 mmol), water (1 mL) and Pd(dppf)Cl2(21 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C for o / n under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was diluted with ethyl acetate. The solid was filtered out and the filtration was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1:2) to give tert-butyl (3R,4S)-4-[3-[5- (difluoromethyl)-7-oxo-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-indazol-1-yl]- 3-fluoro-piperidine-1-carboxylate (90 mg, 64% yield) as a light yellow solid. LCMS (ESI, m / z): 535 [M+H]+. 5-(difluoromethyl)-4-(5-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of tert-butyl (3R,4S)-4-[3-[5-(difluoromethyl)-7-oxo-6,8-dihydro-5H- pyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-indazol-1-yl]-3-fluoro-piperidine-1-carboxylate (90 mg, 0.17 mmol) in DCM (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1)to afford 5-(difluoromethyl)-4-[5- fluoro-1-[(3R,4S)-3-fluoro-4-piperidyl]indazol-3-yl]-6,8-dihydro-5H-pyrido[2,3- d]pyrimidin-7-one (55 mg, 75 % yield) as a yellow solid. LCMS (ESI, m / z): 435 [M+H]+. Example 7 and Example 8 5-(Difluoromethyl)-4-[5-fluoro-1-[(3R,4S)-3-fluoro-4-piperidyl]indazol-3-yl]-6,8-dihydro- 5H-pyrido[2,3-d]pyrimidin-7-one (55 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: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 254 / 220 nm; RT1(min): 7.176; RT2(min): 12.1250.6 mL; Number Of Runs: 5) to obtain (S)-5-(difluoromethyl)-4-(5-fluoro-1-((3R,4S)-3- fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 12.5 mg, 23% yield) and (R)-5-(difluoromethyl)-4-(5-fluoro-1-((3R,4S)-3- fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 13.2 mg, 24% yield) (isomer 2) both as a white solid. Example 7 (first eluting) LCMS (ESI, m / z): 435 [M+H]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: water / 0.05%TFA; Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 40% B in 1.70 min, 40% B to 95% B in 0.60 min, hold at 95% for 0.50 min, 95% B to 5% B in 0.03 min; 254 nm; Rt: 1.250 min.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.93 (s, 1H), 8.34 (dd, J = 9.6, 2.4 Hz, 1H), 8.05 (dd, J = 9.2, 4.4 Hz, 1H), 7.51-7.46 (m, 1H), 6.58-6.30 (m, 1H), 5.26-5.09 (m, 1H), 4.90 (d, J = 51.6 Hz, 1H), 4.77 (dd, J = 29.6, 7.6 Hz, 1H), 3.26-2.93 (m, 4H), 2.84-2.66 (m, 2H), 2.64-2.54 (m, 1H), 1.94-1.92 (m, 1H). Example 8 (second eluting) LCMS (ESI, m / z): 435 [M+H]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: water / 0.05%TFA; Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 40% B in 1.70 min, 40% B to 95% B in 0.60 min, hold at 95% for 0.50 min, 95% B to 5% B in 0.03 min; 254 nm; Rt: 1.260 min.1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.93 (s, 1H), 8.29 (dd, J = 9.6, 2.4 Hz, 1H), 8.05 (dd, J = 9.2, 4.4 Hz, 1H), 7.50-7.46 (m, 1H), 6.57-6.29 (m, 1H), 5.27-5.10 (m, 1H), 4.86 (d, J = 50.8 Hz, 1H), 4.70 (d, J = 30.0 Hz, 1H), 3.26-3.13 (m, 2H), 3.11-2.93 (m, 2H), 2.85-2.72 (m, 2H), 2.64-2.53 (m, 1H), 1.93-1.91 (m, 1H). Example 9 and Example 10 (R)-5-(1,1-difluoroethyl)-4-(5-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (S)-5-(1,1-difluoroethyl)-4-(5-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (3R,4S)-4-(3-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-5-fluoro-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate To a solution of [1-[(3R,4S)-1-tert-butoxycarbonyl-3-fluoro-4-piperidyl]-5-fluoro-indazol-3- yl]boronic acid (90 mg, 0.24 mmol), 4-chloro-5-(1,1-difluoroethyl)-6,8-dihydro-5H- pyrido[2,3-d]pyrimidin-7-one (64 mg, 0.26 mmol), K2CO3 (98 mg, 0.71 mmol) in b was added Pd(dppf)Cl2(19 mg, 0.02 mmol). The resulting mixture was stirred at 90 ℃ for 3 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was diluted with ethyl acetate. The solid was filtered out and the filtration was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1:2) to give tert-butyl (3R,4S)-4-[3-[5- (1,1-difluoroethyl)-7-oxo-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-indazol-1- yl]-3-fluoro-piperidine-1-carboxylate (100 mg, 77 % yield) as a yellow solid. LCMS (ESI, m / z): 549 [M+H]+. 5-(1,1-difluoroethyl)-4-(5-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of tert-butyl (3R,4S)-4-[3-[5-(1,1-difluoroethyl)-7-oxo-6,8-dihydro-5H- pyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-indazol-1-yl]-3-fluoro-piperidine-1-carboxylate (100 mg, 0.18 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 reaction was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1)to afford 5-(1,1-difluoroethyl)-4-[5- fluoro-1-[(3R,4S)-3-fluoro-4-piperidyl]indazol-3-yl]-6,8-dihydro-5H-pyrido[2,3- d]pyrimidin-7-one (60 mg, 73 % yield) as a light yellow solid. LCMS (ESI, m / z): 449 [M+H]+. Example 9 and Example 10 5-(1,1-Difluoroethyl)-4-[5-fluoro-1-[(3R,4S)-3-fluoro-4-piperidyl]indazol-3-yl]-6,8-dihydro- 5H-pyrido[2,3-d]pyrimidin-7-one (60 mg, 0.13 mmol) was isolated by Prep-chiral- HPLC(Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.3% IPAmine)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 40; Wave Length: 254 / 220 nm; RT1(min): 5.211; RT2(min): 6.9270.7 mL; Number Of Runs: 6) to obtain (R)-5-(1,1-difluoroethyl)-4-(5-fluoro-1-((3R,4S)-3- fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 16.4 mg, 27% yield) and (S)-5-(1,1-difluoroethyl)-4-(5-fluoro-1-((3R,4S)- 3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 13.7 mg, 23% yield) (isomer 2) both as a white solid. Example 9 (first eluting) LCMS (ESI, m / z): 449 [M+H]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: water / 0.05%TFA; Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 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: 1.156 min.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.04-9.03 (m, 2H), 8.93 (s, 1H), 8.30 (dd, J = 9.6, 2.4 Hz, 1H), 7.99 (dd, J = 9.6, 4.0 Hz, 1H), 7.57-7.52 (m, 1H), 5.52-5.18 (m, 3H), 3.80-3.74 (m, 1H), 3.62-3.48 (m, 2H), 3.29-3.09 (m, 2H), 2.91-2.84 (m, 2H), 2.34-2.22 (m, 1H), 1.46 (t, J = 19.6 Hz, 3H). Example 10 (second eluting) LCMS (ESI, m / z): 449 [M+H]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: water / 0.05%TFA; Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 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: 1.157 min.1H NMR (400 MHz, Methanol-d4) δ 8.92 (d, J = 1.2 Hz, 1H), 8.40 (dd, J = 9.6, 2.4 Hz, 1H), 7.83 (dd, J = 9.2, 4.0 Hz, 1H), 7.42-7.37 (m, 1H), 5.55-5.26 (m, 3H), 3.90-3.85 (m, 1H), 3.77-3.59 (m, 2H), 3.49-3.42 (m, 1H), 3.21-2.92 (m, 3H), 2.42-2.39 (m, 1H), 1.52 (t, J = 19.2 Hz, 3H). Example 11 and Example 12 (S)-5-(difluoromethyl)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-5-(difluoromethyl)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (1-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-6-fluoro-1H-indazol-3- yl)boronic acid To a stirred solution of tert-butyl (3R,4S)-4-(3-bromo-6-fluoro-1H-indazol-1-yl)-3- fluoropiperidine-1-carboxylate (60 mg, 0.14 mmol) and bis(pinacolato)diboron (55 mg, 0.22 mmol) in 1,4-Dioxane (2 mL) were added KOAc (42 mg, 0.43 mmol) and Pd(dppf)Cl2·DCM (23 mg, 0.03 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 80°C for overnight under a nitrogen atmosphere. LCMS showed the reaction was successful and complete. The mixture was used in the next step directly without further purification. LCMS (ESI, m / z): 382 [M+H]+. tert-butyl (3R,4S)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin- 4-yl)-6-fluoro-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate To a stirred solution of (1-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-6-fluoro- 1H-indazol-3-yl)boronic acid (the crude product of previous step) in 1,4-Dioxane (2 mL) and water (0.4 mL) were added 4-chloro-5-(difluoromethyl)-6,8-dihydro-5H-pyrido[2,3- d]pyrimidin-7-one (47 mg, 0.2 mmol), K2CO3(59.73 mg, 0.43 mmol) and Pd(dppf)Cl2·DCM (23 mg, 0.03 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 90°C for 2 h under a nitrogen atmosphere. LCMS showed the reaction was complete, and the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate =2:1) to obtain tert-butyl (3R,4S)-4-(3-(5- (difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-6-fluoro-1H-indazol- 1-yl)-3-fluoropiperidine-1-carboxylate (70 mg, 90.7%) as a yellow oil. LCMS (ESI, m / z): 535 [M+H]+. 5-(difluoromethyl)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a stirred solution of tert-butyl (3R,4S)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-6-fluoro-1H-indazol-1-yl)-3-fluoropiperidine-1- carboxylate (70 mg, 0.13 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 h. LCMS showed the reaction was complete, and the mixture was concentrated. The residue was purified by reverse phase flash (MeCN in Water (10 mmol / L TFA), 0% to 100% gradient in 20 min; detector, UV 254 nm.) to obtain 5- (difluoromethyl)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (45 mg, 79.1%) as a white solid. LCMS (ESI, m / z): 435 [M+H]+. Example 11 and Example 12 5-(Difluoromethyl)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (45 mg, 0.1 mmol) was separated by Prep-Chiral HPLC (Column: CHIRALPAK IG, 2x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3- MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: isocratic 25; Wave Length: 254 / 220nm). The mobile phase obtained by purification removed solvent by decompression concentration, and the residue was lyophilized to obtain (S)-5- (difluoromethyl)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 16.7 mg, 38.4%) and (S)-5- (difluoromethyl)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 15.1 mg, 34.8%) as a white solid. Example 11 (first eluting) LCMS (ESI, m / z): 435 [M+H]+. Analytic Conditions: Column: CORTECS T3, 30*2.1 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 1.2 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 0.537 min.1H NMR (400 MHz, Methanol-d4) δ 8.99 (s, 1H), 8.74 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.63-7.49 (m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 5.34-4.99 (m, 2H), 3.62-3.52 (m, 1H), 2.94-2.84 (m, 1H), 2.82 (s, 3H), 2.73-2.62 (m, 1H), 2.54-2.45 (m, 1H), 2.38-2.29 (m, 1H), 2.21-2.00 (m, 1H), 1.96- 1.82 (m, 1H). Example 12 (second eluting) LCMS (ESI, m / z): 435 [M+H]+. Analytic Conditions: Column: CORTECS T3, 30*2.1 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 1.2 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 0.531 min.1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.93 (s, 1H), 8.60 (dd, J = 9.2, 5.6 Hz, 1H), 7.90 (d, J = 10.0 Hz, 1H), 7.25 (td, J = 9.2, 2.4 Hz, 1H), 6.44 (t, J = 56.4 Hz, 1H), 5.17-5.01 (m, 1H), 4.95-4.75 (m, 1H), 4.69-4.63 (m, 1H), 3.24-3.14 (m, 2H), 3.09-2.92 (m, 2H), 2.82-2.69 (m, 2H), 2.63- 2.53 (m, 1H), 1.96-1.86 (m, 1H). Example 13 and Example 14 (S)-5-(difluoromethyl)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-5-(difluoromethyl)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (1-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)boronic acid To a stirred solution of tert-butyl (3R,4S)-4-(3-bromo-1H-indazol-1-yl)-3-fluoropiperidine-1- carboxylate (60 mg, 0.15 mmol) and bis(pinacolato)diboron (57 mg, 0.23 mmol) in 1,4- Dioxane (2 mL) were added KOAc (44 mg, 0.45 mmol) and Pd(dppf)Cl2·DCM (25 mg, 0.03 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 80°C for overnight under a nitrogen atmosphere. LCMS showed the reaction was successful and complete. The mixture was used in the next step directly without further purification. LCMS (ESI, m / z): 364 [M+H]+. tert-butyl (3R,4S)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin- 4-yl)-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate To a stirred solution of (1-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H- indazol-3-yl)boronic acid (the crude product of previous step) in 1,4-Dioxane (2 mL) and water (0.4 mL) were added 4-chloro-5-(difluoromethyl)-6,8-dihydro-5H-pyrido[2,3- d]pyrimidin-7-one (49 mg, 0.21 mmol), K2CO3(62.69 mg, 0.45 mmol) and Pd(dppf)Cl2·DCM (24.71 mg, 0.03 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 90°C for 2 h under a nitrogen atmosphere. LCMS showed the reaction was complete, and the mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate =2:1) to obtain tert-butyl (3R,4S)-4-(3-(5- (difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)-3- fluoropiperidine-1-carboxylate (55 mg, 70.3%) as a yellow oil. LCMS (ESI, m / z): 517 [M+H]+5-(difluoromethyl)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a stirred solution of tert-butyl (3R,4S)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate (55 mg, 0.11 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 h. LCMS showed the reaction was complete, and the mixture was concentrated. The residue was purified by reverse phase flash with the following conditions (column, C18 spherical; mobile phase, MeCN in Water (10 mmol / L TFA), 0% to 100% gradient in 20 min; detector, UV 254 nm.) to obtain 5-(difluoromethyl)-4-(1-((3R,4S)-3- fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (35 mg, 78.9%) as a white solid. LCMS (ESI, m / z): 417 [M+H]+. Example 13 and Example 14 5-(Difluoromethyl)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (35 mg, 0.08 mmol) was separated by Prep-Chiral HPLC (Column: CHIRALPAK IG, 2x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3- MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: isocratic 25; Wave Length: 254 / 220nm). The mobile phase obtained by purification removed solvent by decompression concentration, and the residue was lyophilized to obtain (S)-5- (difluoromethyl)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the first eluting peak, 12.1 mg, 33.9%) and (R)-5- (difluoromethyl)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (the second eluting peak, 15.7 mg, 44.4%) as a white solid. Example 13 (first eluting) LCMS (ESI, m / z): 417 [M+H]+. Analytic Conditions: Column: CORTECS T3, 30*2.1 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 1.2 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 0.501 min.1H NMR (400 MHz, Methanol-d4) δ 8.91 (s, 1H), 8.68 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 6.63-6.30 (m, 1H), 5.20-5.06 (m, 1H), 5.05-4.89 (m, 1H), 4.88-4.78 (m, 1H), 3.44-3.35 (m, 2H), 3.21-3.05 (m, 1H), 3.03-2.82 (m, 4H), 2.13-2.01 (m, 1H). Example 14 (second eluting) LCMS (ESI, m / z): 417 [M+H]+. Analytic Conditions: Column: CORTECS T3, 30*2.1 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 1.2 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.02 min; 254 nm; Rt: 0.498 min.1H NMR (400 MHz, Methanol-d4) δ 8.94 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.61-7.57 (m, 1H), 7.43-7.39 (m, 1H), 6.63-6.30 (m, 1H), 5.41-5.24 (m, 2H), 4.81-4.67 (m, 1H), 3.90-3.81 (m, 1H), 3.77-3.61 (m, 2H), 3.52-3.42 (m, 1H), 3.27-3.13 (m, 1H), 3.00-2.96 (m, 2H), 2.49- 2.41 (m, 1H). Example 15 and Example 16 (S)-5-(1,1-difluoroethyl)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-5-(1,1-difluoroethyl)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (3R,4S)-4-(3-bromo-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate To a mixture of 3-bromo-1H-indazole (245 mg, 1.243 mmol) and tert-butyl (3S,4S)-3- fluoro-4-hydroxypiperidine-1-carboxylate (273 mg, 1.243 mmol) in toluene (8 mL) was added 1M (tributylphosphoranylidene)acetonitrile in toluene (2.487 mL, 2.487 mmol). The resulted mixture was sealed and heated at 85 °C overnight. The reaction mixture was cooled to rt, diluted with EtOAc, and poured into water. The separated organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by FCC (40 g silica gel cartridge, eluted with 0~40% EtOAc-Hexanes) to afford the desired product (326 mg). LCMS (ESI, m / z): 398.1 M+H:. tert-butyl (3R,4S)-4-(3-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate To a solution of tert-butyl (3R,4S)-4-(3-bromo-1H-indazol-1-yl)-3-fluoropiperidine-1- carboxylate (100 mg, 0.24 mmol), B2pin2(122 mg, 0.48 mmol) and KOAc (71 mg, 0.72 mmol) in 1,4-Dioxane (5 mL) was added Pd(dppf)Cl2(20 mg, 0.02 mmol). The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. To the reaction mixture was added step 4-chloro-5-(1,1-difluoroethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (67 mg, 0.29 mmol), K2CO3 (109 mg, 0.79 mmol), water (1 mL) and Pd(dppf)Cl2(21 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C for o / n under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was diluted with ethyl acetate. The solid was filtered out and the filtration was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1:2) to give tert-butyl (3R,4S)-4-(3-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate. LCMS (ESI, m / z): 531 [M+H]+. 5-(1,1-difluoroethyl)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of tert-butyl (3R,4S)-4-(3-(5-(1,1-difluoroethyl)-7-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate (90 mg, 0.17 mmol) in DCM (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1)to afford 5-(1,1-difluoroethyl)-4- (1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin- 7(6H)-one. LCMS (ESI, m / z): 431 [M+H]+. Example 15 and Example 16 5-(Difluoromethyl)-4-[5-fluoro-1-[(3R,4S)-3-fluoro-4-piperidyl]indazol-3-yl]-6,8-dihydro- 5H-pyrido[2,3-d]pyrimidin-7-one was isolated by XBridge C18, 19 mm x 200 mm, 5µm particles; Mobile Phase A (ACN / H2O (5:95) with 10mM AA) Mobile Phase B (ACN / H2O (95:5) with 10mM AA); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative SFC with the following conditions: Column: Whelk-O1 (R,R), 21 mm x 250 mm, 5 µm particles; Mobile Phase A (CO2) Mobile Phase B (MeOH with 0.1% Ammonium Hydroxide); Flow Rate: 80 mL / min; Column Temperature: 40 °C. Fraction collection was triggered by UV (254 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain (S)-5-(1,1-difluoroethyl)-4-(1- ((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (7.2 mg) and (R)-5-(1,1-difluoroethyl)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol- 3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (13.2 mg) both as a white solid. Example 15 (first eluting) LCMS (ESI, m / z): 431 [M+H]+. Analytic Conditions: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile Phase A: water / 0.05%TFA; Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 40% B in 1.70 min, 40% B to 95% B in 0.60 min, hold at 95% for 0.50 min, 95% B to 5% B in 0.03 min; 254 nm; Rt: 1.56 min Example 16 (second eluting) LCMS (ESI, m / z): 431 [M+H]+. Analytic Conditions: : Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 % B(0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm) and MS (ESI + / -); Rt: 1.65 min Example 17 and Example 18 (R)-4-(1-((3S,4R)-4-fluoropyrrolidin-3-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one And (R)-4-(1-((3S,4S)-4-fluoropyrrolidin-3-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (3S,4R)-3-(3-bromo-1H-indazol-1-yl)-4-methylpyrrolidine-1-carboxylateBocA solution of 3-bromo-1H-indazole (300 mg, 1.52 mmol), racemic tert-butyl (3R,4R)-3- methyl-4-hydroxy-pyrrolidine-1-carboxylate (312 mg, 1.52 mmol) and CMBP (734 mg, 3.05 mmol) in toluene (3 mL) was stirred at 85 °C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (1:3) to give racemic tert-butyl (3S,4R)-3-(3-bromo-1H-indazol-1-yl)-4-methylpyrrolidine-1-carboxylate (150 mg, 25%) as a yellow solid. LCMS (ESI, m / z): 384, 386 [M+H]+. tert-butyl (3R,4S)-3-methyl-4-(3-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of racemic tert-butyl (3S,4R)-3-(3-bromo-1H-indazol-1-yl)-4- methylpyrrolidine-1-carboxylate (100 mg, 0.24 mmol), B2pin2 (122 mg, 0.48 mmol) and K2OAc (71 mg, 0.72 mmol) in 1,4-Dioxane (5 mL) was added Pd(dppf)Cl2(20 mg, 0.02 mmol). The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. To the reaction mixture was added (R)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (67 mg, 0.29 mmol), K2CO3 (109 mg, 0.79 mmol), water (1 mL) and Pd(dppf)Cl2(21 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C for o / n under a nitrogen atmosphere. The resulting solution was diluted with ethyl acetate. The solid was filtered out and the filtration was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1:2) to give tert- butyl (3R,4S)-3-methyl-4-(3-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate as a mix of diastereomers. LCMS (ESI, m / z): 517 [M+H]+. (R)-4-(1-((3S,4R)-4-methylpyrrolidin-3-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one To a solution of racemic tert-butyl (3R,4S)-3-methyl-4-(3-((R)-7-oxo-5-(trifluoromethyl)- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate (90 mg, 0.17 mmol) in DCM (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (2:1)to afford (R)-4-(1-((3S,4R)-4- methylpyrrolidin-3-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one as a yellow solid. LCMS (ESI, m / z): 417 [M+H]+. Example 17 and Example 18 The diastereomer mixture was separated and purified using XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A (ACN / H2O (5:95) with 0.1% TFA) Mobile Phase B (ACN / H2O (95:5) with 0.1% TFA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R)-4-(1-((3S,4R)-4- fluoropyrrolidin-3-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (30.4 mg) and (R)-4-(1-((3S,4S)-4-fluoropyrrolidin-3-yl)-1H- indazol-3-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (29.7 mg). Stereochemistry was arbitrarily assigned. Example 17 (first eluting) LCMS (ESI, m / z): 417.2 [M+H]+. Analytic Conditions: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0- 100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Rt: 1.44 min. Example 18 (second eluting) LCMS (ESI, m / z): 417.2 [M+H]+. Analytic Conditions: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Rt: 1.48 min. Example 19 and Example 20 (R)-4-(6-fluoro-1-((3R,4R)-4-methylpyrrolidin-3-yl)-1H-indazol-3-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-4-(6-fluoro-1-((3R,4S)-4-methylpyrrolidin-3-yl)-1H-indazol-3-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (3R,4R)-3-(3-bromo-6-fluoro-1H-indazol-1-yl)-4-methylpyrrolidine-1-carboxylate Boc A solution of 3-bromo-6-fluoro-1H-indazole (300 mg, 1.52 mmol), racemic tert-butyl (3R,4R)-3-fluoro-4-hydroxy-pyrrolidine-1-carboxylate (312 mg, 1.52 mmol) and CMBP (734 mg, 3.05 mmol) in toluene (3 mL) was stirred at 85 °C overnight under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.5% TFA) / MeCN (1:3) to give tert-butyl (3R,4R)-3-(3-bromo-6-fluoro-1H-indazol-1-yl)-4- methylpyrrolidine-1-carboxylate as a yellow solid. LCMS (ESI, m / z): 384, 386 [M+H]+. tert-butyl (3R,4R)-3-(6-fluoro-3-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)-4-methylpyrrolidine-1-carboxylate To a solution of racemic tert-butyl (3R,4R)-3-(3-bromo-6-fluoro-1H-indazol-1-yl)-4- methylpyrrolidine-1-carboxylate(100 mg, 0.24 mmol), B2pin2(122 mg, 0.48 mmol) and KOAc (71 mg, 0.72 mmol) in 1,4-Dioxane (5 mL) was added Pd(dppf)Cl2(20 mg, 0.02 mmol). The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction was cooled to room temp and to the reaction mixture was added (R)-4-chloro-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (67 mg, 0.29 mmol), K2CO3 (109 mg, 0.79 mmol), water (1 mL) and Pd(dppf)Cl2(21 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C for overnight under a nitrogen atmosphere. The resulting solution was diluted with ethyl acetate. The solid was filtered out and the filtration was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1:2) to give tert-butyl (3R,4R)-3-(6- fluoro-3-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H- indazol-1-yl)-4-methylpyrrolidine-1-carboxylate. LCMS (ESI, m / z): 535 [M+H]+. Example 19 and Example 20 To a solution of tert-butyl (3R,4R)-3-(6-fluoro-3-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)-4-methylpyrrolidine-1-carboxylate (90 mg, 0.17 mmol) in DCM (3 mL) was added drowpwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. The reaction was concentrated under reduced pressure. The reaction mixture was purified via XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A (ACN / H2O (5:95) with 10mM AA) Mobile Phase B (ACN / H2O (95:5) with 10mM AA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (R)-4-(6-fluoro-1-((3R,4R)-4- methylpyrrolidin-3-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (20.8 mg) and (R)-4-(6-fluoro-1-((3R,4S)-4-methylpyrrolidin-3-yl)- 1H-indazol-3-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (25.6 mg). Stereochemistry was arbitrarily assigned based on biochem data. Example 19 (first eluting) LCMS (ESI, m / z): 435 [M+H]+. Analytic Conditions: 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 20 (second eluting) LCMS (ESI, m / z): 435 [M+H]+. Analytic Conditions: 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: 1.56 min. Example 21 and Example 22 (R)-4-(6-fluoro-1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one And (R)-4-(6-fluoro-1-((3S,4R)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in a similar manner to Example 17 using racemic tert-butyl (3R,4S)-4-(3-bromo-6- fluoro-1H-indazol-1-yl)-3-methylpiperidine-1-carboxylate instead of racemic tert-butyl (3S,4R)-3-(3-bromo-1H-indazol-1-yl)-4-fluoropyrrolidine-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 (ACN / H2O (5:95) with 0.1% TFA) Mobile Phase B (ACN / H2O (95:5) 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 to afford (R)-4-(6-fluoro-1-((3R,4S)-3-methylpiperidin-4-yl)-1H- indazol-3-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (11.9 mg, 32% yield) and (R)-4-(6-fluoro-1-((3S,4R)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (11.5 mg, 31 % yield). Stereochemistry was arbitrarily assigned. Example 21 (first eluting) LCMS (ESI, m / z): 449.1 [M+H]+. Analytic Conditions 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: 1.53 min. Example 22 (second eluting) LCMS (ESI, m / z): 449.1 [M+H]+Analytical Conditions 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 23 (5R)-4-(1-(pyrrolidin-3-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one tert-butyl 3-(3-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylate A mixture of 3-bromo-1H-indazole (400 mg, 2.030 mmol), racemic tert-butyl 3- bromopyrrolidine-1-carboxylate (609 mg, 2.436 mmol) and cesium carbonate (992 mg, 3.05 mmol) in DMF (15 mL) was sealed and heated at 85 °C for 12 h. The reaction mixture was cooled to rt, poured into water, and extracted with ethyl acetate (25 mL). The separated organic layer was washed with 5% citric acid and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography purification using an ISCO system (80 g silica gel column, gradient elution from 0 to 20% of ethyl acetate in hexanes) afforded tert-butyl 3-(3-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylate (300 mg, 0.819 mmol, 40.3 % yield) as the third eluting peak. LCMS (ESI, m / z): 365.8, 367.7 [M+H]+Retention time: 1.12 min tert-butyl 3-(3-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate To a solution of racemic tert-butyl 3-(3-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylate (100 mg, 0.24 mmol), B2pin2 (122 mg, 0.48 mmol) and KOAc (71 mg, 0.72 mmol) in 1,4- Dioxane (5 mL) was added Pd(dppf)Cl2(20 mg, 0.02 mmol). The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction wasa cooled to room temp and to the reaction mixture was added (R)-4-chloro-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (67 mg, 0.29 mmol), K2CO3 (109 mg, 0.79 mmol), water (1 mL) and Pd(dppf)Cl2(21 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C for overnight under a nitrogen atmosphere. The resulting solution was diluted with ethyl acetate. The solid was filtered out and the filtration was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with water (0.05% TFA) / MeCN (1:2) to give tert-butyl (3R,4R)-3-(6-fluoro-3-((R)-7-oxo-5-(trifluoromethyl)- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)-4-methylpyrrolidine-1- carboxylate. LCMS (ESI, m / z): 503 [M+H]+. Example 23 To a solution of tert-butyl 3-(3-((R)-7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate (90 mg, 0.17 mmol) in DCM (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. The reaction was concentrated under reduced pressure and purified using XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A (ACN / H2O (5:95) with 0.1% TFA) Mobile Phase B (ACN / H2O (95:5) with 0.1% TFA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (5.5 mg, 8% yield). Example 23 LCMS (ESI, m / z): 403.2 [M+H]+. Analytic Conditions: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -); Rt: 1.49 min Example 24 and Example 25 (S)-5-(1,1-difluoroethyl)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-5-(1,1-difluoroethyl)-4-(6-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in a similar manner to Example 17 using tert-butyl (3R,4S)-4-(3-bromo-6-fluoro- 1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate instead of tert-butyl (3R,4R)-3-(3-bromo- 1H-indazol-1-yl)-4-methylpyrrolidine-1-carboxylate and 4-bromo-5-(1,1-difluoroethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one instead of (R)-4-chloro-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 (ACN / H2O (5:95) with 10mM AA) Mobile Phase B (ACN / H2O (95:5) with 10mM AA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative SFC with the following conditions: Column: Whelk-O1 (R,R), 21 mm x 250 mm, 5 µm particles; Mobile Phase A (CO2) Mobile Phase B (MeOH with 0.1% Ammonium Hydroxide) Flow Rate: 75 mL / min; Column Temperature: 40 °C. Fraction collection was triggered by UV (254 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (S)-5-(1,1-difluoroethyl)-4-(6- fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (4.7 mg, 18% yield) and (R)-5-(1,1-difluoroethyl)-4-(6-fluoro-1- ((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (4.8 mg, 19% yield). Example 24 (first eluting) LCMS (ESI, m / z): 449.1 [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- 3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm) and MS (ESI + / -); Rt: 1.44 min. Example 25 (second eluting) LCMS (ESI, m / z): 449.1 [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- 3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm) and MS (ESI + / -); Rt: 1.45 min. Example 26 and Example 27 (S)-4-(1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one and (R)-4-(1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in a similar manner to Example 17 using tert-butyl (3R,4S)-4-(3-bromo-1H-indazol- 1-yl)-3-methylpiperidine-1-carboxylate instead of tert-butyl (3R,4R)-3-(3-bromo-1H-indazol- 1-yl)-4-methylpyrrolidine-1-carboxylate and 4-bromo-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one instead of (R)-4-chloro-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one to afford the title compound. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 µm particles; Mobile Phase A (ACN / H2O (5:95) with 0.1% TFA) Mobile Phase B (ACN / H2O (95:5) with 0.1% TFA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 4-(1-((3R,4S)-3-methylpiperidin-4-yl)-1H-indazol-3-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: Whelk-O1 (R,R), 21 mm x 250 mm, 5 µm particles; Mobile Phase A (CO2) Mobile Phase B (MeOH with 0.1% Ammonium Hydroxide) Flow Rate: 75 mL / min; Column Temperature: 40 °C. Fraction collection was triggered by UV (235 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (S)-4-(1-((3R,4S)-3- methylpiperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (11.7 mg, 34% yield) and (R)-4-(1-((3R,4S)-3-methylpiperidin-4-yl)- 1H-indazol-3-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. (8.5 mg, 24% yield) Example 26 (first eluting) LCMS (ESI, m / z): 431 [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 27 (second eluting) LCMS (ESI, m / z): 431 [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: 1.46 min. Example 28 (R)-4-(1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in a similar manner as Example 17 using tert-butyl (3R,4S)-4-(3-bromo-1H-indazol- 1-yl)-3-fluoropiperidine-1-carboxylate instead of tert-butyl (3R,4R)-3-(3-bromo-1H-indazol- 1-yl)-4-methylpyrrolidine-1-carboxylate and (R)-4-bromo-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one instead of (R)-4-chloro-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 (ACN / H2O (5:95) with 10 mM AA) Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (17.9 mg, 40% yield). LCMS (ESI, m / z): 435.1 [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 + / -); Rt: 1.38 min. Example 29 (R)-4-(5-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in a similar manner as Example 17 using tert-butyl (3R,4S)-4-(3-bromo-5-fluoro- 1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylate instead of tert-butyl (3R,4R)-3-(3-bromo- 1H-indazol-1-yl)-4-methylpyrrolidine-1-carboxylate and (R)-4-bromo-5-(trifluoromethyl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one instead of (R)-4-chloro-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 (ACN / H2O (5:95) with 10 mM AA) Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (R)-4-(5-fluoro-1-((3R,4S)-3-fluoropiperidin-4-yl)-1H-indazol-3-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (19.2mg, 42% yield). LCMS (ESI, m / z): 453.1 [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 + / -); Rt: 1.47 min. Example 30 (R)-5-(difluoromethyl)-4-(6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl 4-(3-bromo-6-methyl-1H-indazol-1-yl)piperidine-1-carboxylate 3-bromo-6-methyl-1H-indazole (0.32 g, 1.516 mmol) was mixed with tert-butyl 4- (tosyloxy)piperidine-1-carboxylate (0.539 g, 1.516 mmol) in DMF (10.11 ml). Added Cs2CO3 (0.741 g, 2.274 mmol). The reaction was heated in microwave synthesizer at 85°C for 30 hours. The rmixture was concentrated as oily residue. The residue was purfied by Si chromatography (Si-40g, 10-30%EtOAc-Hex). Fractions with product mixture were combined, and dried by vacuum to obtaine mixture separable by 50-80% AA buffer. The above residue was dissolved in 6ml DMF, then purified by Prep-HPLC AA buffer. The major isomer was the desired regioisomer and was collected and dried by vacuum (300 mg). LCMS (ESI, m / z): 337 [M+H]+. tert-butyl (R)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4- yl)-6-methyl-1H-indazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(3-bromo-6-methyl-1H-indazol-1-yl)piperidine-1-carboxylate (100 mg, 0.24 mmol), B2pin2(122 mg, 0.48 mmol) and KOAc (71 mg, 0.72 mmol) in 1,4- Dioxane (5 mL) was added Pd(dppf)Cl2(20 mg, 0.02 mmol). The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction was cooled to room temp and to the reaction mixture was added (R)-4-chloro-5-(difluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (67 mg, 0.29 mmol), K2CO3 (109 mg, 0.79 mmol), water (1 mL) and Pd(dppf)Cl2(21 mg, 0.03 mmol). The resulting mixture was stirred at 90 °C for overnight under a nitrogen atmosphere. The resulting solution was diluted with ethyl acetate. The solid was filtered out and the filtration was concentrated under reduced pressure to give tert-butyl (R)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-6-methyl-1H-indazol-1-yl)piperidine-1-carboxylate. LCMS (ESI, m / z): 513 [M+H]+. Example 30 To a solution of tert-butyl (R)-4-(3-(5-(difluoromethyl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-6-methyl-1H-indazol-1-yl)piperidine-1-carboxylate (90 mg, 0.17 mmol) in DCM (3 mL) was added drowpwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. The reaction was concentrated under reduced pressure. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Mobile Phase A (ACN / H2O (5:95) with 10 mM AA) Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +) Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (18.5 mg, 55% yield). LCMS (ESI, m / z): 413.1 [M+H]+. Analytic Conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -).; Rt: 1.47 min. Example 31 (R)-4-(6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in a similar manner as Example 17 using tert-butyl 4-(3-bromo-6-methyl-1H- indazol-1-yl)piperidine-1-carboxylate instead of tert-butyl (3R,4R)-3-(3-bromo-1H-indazol- 1-yl)-4-methylpyrrolidine-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 (ACN / H2O (5:95) with 10 mM AA) Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (17 mg, 50% yield). LCMS (ESI, m / z): 431 [M+H]+. Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -).; Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -).; Rt: 1.47 min. Example 32 (R)-4-(6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl 4-(3-bromo-6-fluoro-1H-indazol-1-yl)piperidine-1-carboxylate 3-bromo-6-fluoro-1H-indazole (0.32 g, 1.516 mmol) was mixed with tert-butyl 4- (tosyloxy)piperidine-1-carboxylate (0.539 g, 1.516 mmol) in DMF (10.11 ml). Added Cs2CO3 (0.741 g, 2.274 mmol). The reaction was heated in microwave synthesizer at 85°C for 30 hours. The mixture was concentrated as oily residue. The residue was purified by Si chromatography (Si-40g, 10-30%EtOAc-Hex). Fractions with product mixture were combined and dried by vacuum to obtain mixture separable by 50-80% AA buffer. The above residue was dissolved in 6ml DMF, then purified by Prep-HPLC AA buffer. The major isomer was the desired regioisomer and was collected and dried by vacuum (300 mg). LCMS (ESI, m / z): 398 [M+H]+. tert-butyl (R)-4-(6-fluoro-3-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-1H-indazol-1-yl)piperidine-1-carboxylate To a solution tert-butyl 4-(3-bromo-6-fluoro-1H-indazol-1-yl)piperidine-1-carboxylate (32 mg, 0.08 mmol), B2pin2(24 mg, 0.096 mmol) and KOAc (71 mg, 0.72 mmol) in 1,4- Dioxane (5 mL) was added Pd(dppf)Cl2(8.5 mg, 0.01 mmol). The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction was cooled to room temp and to the reaction mixture was added (R)-4-chloro-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (20 mg, 0.08 mmol), K2CO3 (29 mg, 0.296 mmol), water (1 mL) and Pd(dppf)Cl2(8 mg, 0.01 mmol). The resulting mixture was stirred at 90 °C for overnight under a nitrogen atmosphere. The resulting solution was diluted with ethyl acetate. The solid was filtered out and the filtration was concentrated under reduced pressure to give tert-butyl (R)-4-(6-fluoro-3-(7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)piperidine-1-carboxylate. LCMS (ESI, m / z): 535 [M+H]+. Example 32 To a solution of tert-butyl (R)-4-(6-fluoro-3-(7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (34 mg, 0.08 mmol) in DCM (3 mL) was added dropwise TFA (1 mL). The resulting solution was stirred for 1 h at room temperature. The reaction was concentrated under reduced pressure. The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Mobile Phase A (ACN / H2O (5:95) with 10 mM AA) Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +) Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R)-4-(6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl)-5- (trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (17 mg, 48%). LCMS (ESI, m / z): 435 [M+H]+. Analytic Conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; 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: 1.5 min. Example 33 (R)-5-(difluoromethyl)-4-(6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one Prepared in a similar way to Example 32 but using (R)-4-chloro-5-(difluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one instead of (R)-4-chloro-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 (ACN / H2O (5:95) with 10 mM AA) Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (R)-5- (difluoromethyl)-4-(6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (14.6 mg, 44% yield) LCMS (ESI, m / z): 417.2 [M+H]+. 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 + / -).: UV (220 nm) and MS (ESI + / -).; Rt: 1.37 min. Example 34 and Example 35 (R)-2-(1-(3-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H- indazol-1-yl)cyclobutyl)acetonitrile and (S)-2-(1-(3-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H- indazol-1-yl)cyclobutyl)acetonitrile Prepared in a similar manner as Example 17 using 2-(1-(3-bromo-1H-indazol-1- yl)cyclobutyl)acetonitrile instead of tert-butyl (3R,4R)-3-(3-bromo-1H-indazol-1-yl)-4- methylpyrrolidine-1-carboxylate and 4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one instead of (R)-4-chloro-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 (ACN / H2O (5:95) with 10 mM AA) Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-(1-(3-(7- oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-1- yl)cyclobutyl)acetonitrile. 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; Mobile Phase A (CO2) Mobile Phase B (MeOH with 0.1% Ammoniu Hydroxide) Flow Rate: 75 mL / min; Column Temperature: 40 °C. Fraction collection was triggered by UV (215 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (R)-2-(1-(3-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-4-yl)-1H-indazol-1-yl)cyclobutyl)acetonitrile (12.6 mg, 10% yield) and (S)-2- (1-(3-(7-oxo-5-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol- 1-yl)cyclobutyl)acetonitrile (13.5 mg, 11% yield). Example 34 (first eluting) LCMS (ESI, m / z): 427.2 [M+H]+. XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -).; Rt: 1.95 min. Example 35 (second eluting) LCMS (ESI, m / z): 427.2 [M+H]+. XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -).; Rt: 1.95 min. Example 36 (R)-4-(3-((R)-2-methylpiperazin-1-yl)-1H-indazol-1-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl (3R)-3-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)piperazine-1- carboxylate To a vial containing 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.0 g, 3.6 mmol), tert-butyl (R)-3-methylpiperazine-1-carboxylate (3.6 g, 17.8 mmol), and sodium trimethylsilanolate (0.42 g, 3.7 mmol) was vacuumed and filled with nitrogen 3x, and then 4.6 mL of anhydrous THF was added. To another vial containing GPhos Pd G6 TES (0.17 g, 0.18 mmol) was vacuumed and filled with nitrogen twice, 4.6 mL of anhydrous THF was added, and then this solution was transferred to the other vial. The reaction was sealed and heated at 90 °C for 5 h. The crude reaction was concentrated and purified by FCC (0 to 100% EtOAc / hexanes) to afford tert-butyl (3R)-3-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-3-yl)piperazine-1-carboxylate as a colorless oil (1.27 g, 89% yield). LCMS (ESI, m / z): 401.1 M+H. (R)-3-(2-methylpiperazin-1-yl)-1H-indazole A solution of tert-butyl (3R)-3-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3- yl)piperazine-1-carboxylate (1.27 g, 3.17 mmol) and 4 M HCl in dioxane (15.8 mL, 63.4 mmol) was stirred at 30 °C overnight. The reaction was filtered and the solids were washed with dioxane to afford (R)-3-(2-methylpiperazin-1-yl)-1H-indazole, which was taken forward without further purification. LCMS (ESI, m / z): 217.0 M+H. tert-butyl (3R)-3-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)piperazine-1- carboxylate To a mixture of (R)-3-(2-methylpiperazin-1-yl)-1H-indazole (686 mg, 3.17 mmol) in DCM (26.4 mL) was added triethylamine (1.8 mL, 12.7 mmol), Boc anhydride (590 mg, 2.70 mmol), and 4-dimethylaminopyridine (38.7 mg, 0.317 mmol). The resulted mixture was stirred at room temperature for 20 minutes. The reaction was diluted with water and extracted with DCM 3x. The combined organic layers were dried over Na2SO4, concentrated, and purified by FCC (0 to 100% EtOAc / hexanes) to afford tert-butyl (3R)-3-methyl-4-(1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)piperazine-1-carboxylate. LCMS (ESI, m / z): 316.8 M+H. tert-butyl (R)-4-(1-((R)-8-(4-methoxybenzyl)-7-oxo-5-(trifluoromethyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-3-yl)-3-methylpiperazine-1-carboxylate A solution of (R)-4-chloro-8-(4-methoxybenzyl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one (50 mg, 0.14 mmol), tert-butyl (3R)-3-methyl-4-(1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-3-yl)piperazine-1-carboxylate (51 mg, 0.16 mmol), and Cs2CO3(88 mg, 0.27 mmol) in DMF (1.3 mL) was sealed and heated at 50 °C for 3 h. The reaction was diluted with 10% LiCl in water and DCM. The organic layer was washed once more with 10% LiCl in water and dried over Na2SO4. The crude material was purified by FCC (0 to 30% EtOAc / hexanes) to afford tert-butyl (R)-4-(1-((R)-8-(4-methoxybenzyl)-7-oxo-5- (trifluoromethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-3-yl)-3- methylpiperazine-1-carboxylate. LCMS (ESI, m / z): 652.1 M+H. Example 36 To a solution of tert-butyl (R)-4-(1-((R)-8-(4-methoxybenzyl)-7-oxo-5-(trifluoromethyl)- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H-indazol-3-yl)-3-methylpiperazine-1- carboxylate (35 mg, 0.054 mmol) in DCM (0.25 mL) at 0 °C was added TFA (0.25 mL, 3.2 mmol) and TfOH (0.025 mL, 0.28 mmol). The reaction was stirred at 0 °C for 30 minutes, and then saturated sodium bicarbonate was slowly added dropwise. The reaction was then extracted with DCM 1x and EtOAc 2x. (R)-4-(3-((R)-2-methylpiperazin-1-yl)-1H-indazol-1- yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one was isolated by XBridge C18, 19 mm x 200 mm, 5µm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain (R)-4-(3-((R)-2-methylpiperazin-1-yl)-1H-indazol-1-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (9.6 mg). LCMS (ESI, m / z): 432.1 [M+H]+. Analytic Conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H20 (5:95) with 10 mM AA; Mobile Phase B: ACN / H20 (95:5) with 10 mM AA; Flow rate: 1.0 mL / min; Gradient: 0-100 %B 0.0-3.0 min, 100 %B 3.0-3.5 min; 220 nm; RT 1.48 min. Example 37 (5R)-4-(3-(3,8-diazabicyclo[3.2.1]octan-8-yl)-1H-indazol-1-yl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one tert-butyl 8-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3,8-diazabicyclo[3.2.1]octane- 3-carboxylate A vial containing 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 0.711 mmol), 3-Boc-3,8-diazabicyclo[3.2.1]octane (755 mg, 3.56 mmol), Sodium trimethylsilanolate (160 mg, 1.423 mmol), GPhos Pd G6 TES (67.2 mg, 0.071 mmol), and THF (2 mL) was sparged with nitrogen for 5 minutes. The vial was sealed and heated at 90 °C overnight. The crude reaction was concentrated and purified by flash chromatography (0 to 100% EtOAc / hexanes) to afford tert-butyl 8-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3- yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (290 mg, 0.703 mmol, 99 % yield) as an oil. LCMS (ESI, m / z): 413 [M+H]+. (R)-3-(2-methylpiperazin-1-yl)-1H-indazole Tert-butyl 8-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3,8-diazabicyclo[3.2.1]octane- 3-carboxylate (290 mg, 0.703 mmol) was dissolved in 4 M HCl in dioxane (1582 µl, 6.33 mmol) and stirred at RT for 2 hours.3-(3,8-diazabicyclo[3.2.1]octan-8-yl)-1H-indazole (160 mg, 0.701 mmol) was concentrated in vacuo as an oily solid, which was taken forward without further purification. LCMS (ESI, m / z): 229 [M+H]+.100 % conversion assumed. tert-butyl (3R)-3-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)piperazine-1- carboxylate A mixture of 3-(3,8-diazabicyclo[3.2.1]octan-8-yl)-1H-indazole (160 mg, 0.701 mmol), dmap (8.56 mg, 0.070 mmol), TEA (488 µl, 3.50 mmol), and boc2o (163 µl, 0.701 mmol) in DCM (3.5 mL) was stirred at room temperature for 2 hours. The crude reaction mixture was purified directly by flash chromatography (0-100% ethyl acetate in hexanes) to give tert- butyl 8-(1H-indazol-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (62 mg, 0.189 mmol, 26.9 % yield). LCMS (ESI, m / z): 329 [M+H]+. (R)-4-chloro-8-(4-methoxybenzyl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin- 7(6H)-one A suspension of (R)-4-chloro-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)- one (200 mg, 0.795 mmol), 4-Methoxybenzyl chloride (129 µl, 0.954 mmol), and Cs2CO3 (389 mg, 1.192 mmol) in Acetonitrile (3975 µl) was sealed and heated at 40 °C overnight. The resulting suspension was filtered to remove excess cesium carbonate. The solvent was removed in vacuo. The crude product was purified by flash chromatography (0-100% ethyl acetate in hexanes) to afford (R)-4-chloro-8-(4-methoxybenzyl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (228 mg, 0.613 mmol, 77 % yield). LCMS (ESI, m / z): 372 [M+H]+. Example 37 A suspension of tert-butyl 8-(1H-indazol-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (21 mg, 0.064 mmol), (R)-4-chloro-8-(4-methoxybenzyl)-5-(trifluoromethyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one (23.77 mg, 0.064 mmol), and Cs2CO3 (41.7 mg, 0.128 mmol) in DMF (320 µl) was heated to 40 °C overnight. The solvent was removed in vacuo to give crude product as oil. The protected product was dissolved in a fresh solution of DCM (0.25 mL), TFA (0.25 mL, 3.2 mmol), and TfOH (0.025 mL, 0.28 mmol). The reaction was stirred at room temperature for 1 hour, and then quenched with solid sodium bicarbonate while on an ice bath. 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. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. to obtain (5R)-4-(3-(3,8-diazabicyclo[3.2.1]octan-8-yl)-1H- indazol-1-yl)-5-(trifluoromethyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (8.7 mg, 0.019 mmol, 29.1 % yield). LCMS (ESI, m / z): 444.2 [M+H]+. Analytic Conditions: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H20 (5:95) with 10 mM AA; Mobile Phase B: ACN / H20 (95:5) with 10 mM AA; Flow rate: 1.0 mL / min; Gradient: 0-100 %B 0.0-3.0 min, 100 %B 3.0-3.5 min; 220 nm; RT 1.35 min.1H NMR (500 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.75 (s, 1H), 8.72 (br d, J=8.7 Hz, 1H), 8.08 (br d, J=7.8 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.38 (br t, J=7.2 Hz, 1H), 5.89 (br s, 1H), 4.70 (br d, J=17.3 Hz, 2H), 3.24 (br d, J=11.6 Hz, 1H), 2.73 (br d, J=18.3 Hz, 1H), 2.23 - 2.06 (m, 1H)5 protons obscured by water suppression. 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. Example Number pIC50 1 8.6 2 6.7 3 6.7 4 8.6 5 8.6 6 6.6 7 5.8 8 8.1 9 8.0 10 5.8 11 6.2 12 8.5 13 6.3 14 8.4 15 5.5 16 8.0 17 8.6 18 8.3 19 8.6 8.3 8.4 8.4 8.3 4.9 8.1 8.6 8.6 8.5 8.4 7.9 NA 8.5 NA 5.4 8.3 8.5 NA

Claims

14576 - US - PSP CLAIMS What is claimed is:

1. A compound of Formula I:(I) or a pharmaceutically acceptable salt thereof, wherein, R1is selected from the group consisting of; R4R5;alkyl, and haloalkyl; R3is selected from the group consisting of: −CH= and −N=;14576 - US - PSP R4is selected from the group consisting of piperazinyl, 2-methylpiperazin-1-yl and ;R5is selected from the group consisting of pyrrolidin-3-yl, 4-methylpyrrolidin-3-yl, 1- (cyanomethyl)cyclobutyl, and ;R6is selected from the group consisting of: −H and halogen; R7is selected from the group consisting of: −H, alkyl, and halogen; R8is selected from the group consisting of: −H, alkyl, and halogen.

2. The compound according to Claim 1, wherein: R2is selected from the group consisting of: −CF2H, −CF2CH3, and −CF3; R3is −N=; R6is selected from the group consisting of: −H and −F; R7is selected from the group consisting of: −H, −CH3, and −F; R8is selected from the group consisting of: −H, −CH3, and −F.

3. The compound according to Claim 1, wherein:14576 - US - PSP R1is R5N R7;R2is selected from the group consisting of: −CF2H, −CF2CH3, and −CF3; R3is −N=; R5is ;R7is selected from the group consisting of: −H and alkyl; R8is selected from the group consisting of: −H and halogen.

4. The compound according to Claim 1, wherein: R1is R514576 - US - PSP R3is −N=; R5is selected from the group consisting of 4-methylpyrrolidin-3-yl and R8;R7is selected from the group consisting of: −H and halogen.

5. The compound of claim 1 wherein the compound is selected from the group consisting of: (5R)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one;14576 - US - PSP (5S)-5-(difluoromethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one;14576 - US - PSP (5R)-4-{1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4R)-4-methylpyrrolidin-3-yl]-1H-indazol-3-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{6-fluoro-1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[1-(pyrrolidin-3-yl)-1H-indazol-3-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5S)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(1,1-difluoroethyl)-4-{6-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3- yl}-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4S)-3-methylpiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-4-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one;14576 - US - PSP (5R)-4-{5-fluoro-1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-indazol-3-yl}-5- (trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-methyl-1-(piperidin-4-yl)-1H-indazol-3-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-4-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-5-(trifluoromethyl)-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; (5R)-5-(difluoromethyl)-4-[6-fluoro-1-(piperidin-4-yl)-1H-indazol-3-yl]-5H,6H,7H,8H- pyrido[2,3-d]pyrimidin-7-one; 2-(1-{3-[(5S)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-1H- indazol-1-yl}cyclobutyl)acetonitrile; 2-(1-{3-[(5R)-7-oxo-5-(trifluoromethyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-yl]-1H- indazol-1-yl}cyclobutyl)acetonitrile; (5R)-4-{3-[(2R)-2-methylpiperazin-1-yl]-1H-indazol-1-yl}-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one; or (5R)-4-(3-{3,8-diazabicyclo[3.2.1]octan-8-yl}-1H-indazol-1-yl)-5-(trifluoromethyl)- 5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-7-one.

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

7. A method of treating, preventing, or managing a disease or disorder mediated by a protein kinase C theta (PKC-theta) mutant in a subject, comprising administering a14576 - US - PSP therapeutically or prophylactically effective amount of a compound of any one of claims 1-5 or a pharmaceutical composition of claim 6 to the subject.

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

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

Images