Dgk targeting compounds and uses thereof

Abstract

Disclosed herein are compounds of Formula (A), or a pharmaceutically acceptable salt thereof, which inhibit the activity of one or both of diacylglycerol kinase alpha (DGKα). These compounds are useful in the treatment of proliferative diseases (e.g., cancer) and viral infections.

Description

[0001] DGK TARGETING COMPOUNDS AND USES THEREOF RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 305,668, filed February 1, 2022, the entire contents of which are incorporated herein by reference. BACKGROUND Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al. (2006) Science 314:268–74). The adaptive immune system, comprised of T and B lymphocytes, has powerful anti-cancer potential, with a broad capacity and exquisite specificity to respond to diverse tumor antigens. Further, the immune system demonstrates considerable plasticity and a memory component. The successful harnessing of all these attributes of the adaptive immune system would make immunotherapy unique among all cancer treatment modalities. However, although an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, and established cancers are viewed as “self” and tolerated by the immune system. Contributing to this state of tolerance, tumors may exploit several distinct mechanisms to actively subvert anti-tumor immunity. These mechanisms include dysfunctional T-cell signaling (Mizoguchi et al. (1992) Science 258:1795–98), suppressive regulatory cells (Facciabene et al. (2012) Cancer Res.72:2162–71), and the co- opting of endogenous “immune checkpoints,” which serve to down-modulate the intensity of adaptive immune responses and protect normal tissues from collateral damage, by tumors to evade immune destruction (Topalian et al. (2012) Curr. Opin. Immunol.24:1–6; Mellman et al. (2011) Nature 480:480–89). Accordingly, new and novel anticancer agents that are safe and effective in restoring T-cell activation, lowering antigen threshold, enhancing antitumor functionality, and / or overcoming the suppressive effects of one or more endogenous immune checkpoints are needed in the art for the treatment of cancer. SUMMARY Disclosed herein are compounds that have activity as inhibitors of diacylglycerol kinase alpha (DGKα). Additionally, in embodiments, the disclosed compounds cause the degradation of DGKα. In embodiments, compounds described herein have desirable efficacy, stability, bioavailability, therapeutic index, and toxicity values that are important to their use as pharmaceuticals. In aspects, provided herein are compounds of having the structure of Formula (A): (A) or a pharmaceutically acceptable salt thereof, wherein: Ring A is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic ring fused to ring B; Ring C is a heterocyclic ring, which may be further substituted in addition to R3and R4; R1is C1–C4alkyl; R2is H or an electron withdrawing functional group; each R3is independently NR5R6; each R4is independently C1–C4alkyl or C1–C4alkoxy, or one R3and one R4, together with the atoms of ring C to which they are attached, form a substituted or unsubstituted ring; R5and R6are each independently H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R5and R6, together with the nitrogen to which they are attached, form a substituted or unsubstituted ring; m and n are each independently 0, 1, 2, 3, or 4. In embodiments, disclosed herein are compounds having the structure of Formula (A): (A) or a pharmaceutically acceptable salt thereof, wherein Ring A is a substituted or unsubstituted heteroaromatic ring fused to ring B. In embodiments of the compound of Formula (I), the compound has the structure of Formula (II): (II) or a pharmaceutically acceptable salt thereof, wherein R9is H or C1–C4alkyl. In embodiments of Formula II, R9is straight or branched C1–C4alkyl. In embodiments of Formula II, R9is methyl. In embodiments of the compound of Formula (I), the compound has the structure of Formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein R10is C1–C4alkyl or an electron withdrawing functional group. In embodiments of Formula (III), R10is straight or branched C1–C4alkyl. In embodiments of the compound of Formula (III), the compound has the structure of Formula (IIIa): (IIIa) or a pharmaceutically acceptable salt thereof. In embodiments of the compound of Formula (III) or Formula (IIIa), R10is selected from halogen, -CH3, -SO2CF3, -N(R11)2, -NO2, -SO2R12, -C≡N, -C(R13)3, -COR14, -CO2R16, - CON(R17)2, and -N=O, wherein: each of R11, R12, R14, R15, R16, and R17is independently H or C1–C4alkyl (e.g., straight or branched C1–C4alkyl); and each R13is halogen. In embodiments of the compound of Formulae (III) and (IIIa), R10is -Cl. In embodiments of the compound of Formula (III) and (IIIa), R10is -C≡N. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), R1is straight or branched C1–C4alkyl. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), R1is methyl. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), R2is selected from H, halogen, -SO2CF3, -N(R32)2, -NO2, -SO2R26, -C≡N, -C(R27)3, -COR28, - CO2R30, -CON(R31)2, and -N=O, wherein: each of R32, R26, R28, R30, and R31is independently H or C1–C4alkyl (e.g., straight or branched C1–C4alkyl); and each R33is halogen. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), R2is H. In embodiments of the compounds of Formula (I), (II), (III), and (IIIa), R2is -C≡N. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), R4is C1– C4 alkyl (e.g., straight or branched C1–C4alkyl). In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), R4is C1– C4alkoxy. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is further substituted by one or more substituents selected from R15, R18, R19, R20, R21, and R22. In embodiments any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is selected from ; ; ; and , wherein: R18and R19are each, independently H, OH, C1–C4alkoxy, C1–C4alkyl (e.g., straight or branched C1–C4alkyl), or -NR23R24, or R18and R19, together with the carbon atom to which they are attached, form a substituted or unsubstituted ring; R20is H or C1–C4alkyl (e.g., straight or branched C1–C4alkyl), or R18and R20, or R19and R20, together with the carbon atoms to which they are attached, form a substituted or unsubstituted ring; R21is H, C1–C4alkyl (e.g., straight or branched C1–C4alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl R22is C1–C4alkyl (e.g., straight or branched C1–C4alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R23and R24are each, independently H, C1–C4alkyl (e.g., straight or branched C1–C4alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R15is C1–C4alkyl (e.g., straight or branched C1–C4alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and indicates the point of attachment of ring C to ring B. In embodiments of Ring C, R21is straight or branched C1–C4alkyl. In embodiments, R22is straight or branched C1–C4alkyl. In embodiments of Ring C, R23and R24are each, independently H, straight or branched C1–C4alkyl, aryl, or heteroaryl. In embodiments of Ring C, R15is straight or branched C1–C4alkyl. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is , wherein R18and R19, together with the carbon atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted carbocyclic ring or a 5- or 6- membered substituted or unsubstituted heterocyclic ring. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is , wherein R18and R20, or R19and R20, together with the carbon atoms to which they are attached form a substituted or unsubstituted 5-, 6-, or 7-membered carbocyclic ring or a substituted or unsubstituted 5-, 6-, or 7-membered heterocyclic ring. In embodiments of Ring C, R20is straight or branched C1–C4alkyl. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is selected from ; ; ; ; ; ; ; ; and In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is wherein R21is , wherein: R25is selected from OH, halogen, C1–C4alkyl (e.g., straight or branched C1–C4alkyl), C1–C4alkoxy, C1–C4haloalkyl, C1–C4haloalkoxy, aryl, and heteroaryl; t is 0, 1, or 2; and indicates the point of attachment of R21to N. In embodiments of any one of the compounds of Formula (I), (II), (III), and (IIIa), ring C is , wherein R is , wherein: R25is selected from OH, halogen, C1–C4alkyl (e.g., straight or branched C1–C4alkyl), C1–C4alkoxy, C1–C4haloalkyl, C1–C4haloalkoxy, aryl, and heteroaryl; t is 0, 1, or 2; and indicates the point of attachment of R21to N. In embodiments of Ring C, each R25is independently selected from OH, halogen, C1–C4alkyl (e.g., straight or branched C1–C4alkyl), C1–C4alkoxy, C1–C4haloalkyl, C1–C4haloalkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is , wherein R21is selected from In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is w21 herein R is selected from ; ; ; ; ; ; and In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is selected from ; ; ; ; ; ; ; and In embodiments of Ring C, R22is C1–C4alkyl (e.g., straight or branched C1–C4alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments of Ring C, R22is straight or branched C1–C4alkyl. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is , wherein R18and R19are each independently selected from -H, -OH, C1 – C4 alkoxy, C1–C4alkyl (straight or branched C1–C4alkyl), and , wherein: R26is H, C1–C4alkyl (straight or branched C1–C4alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R27is -OH, C1–C4alkyl (straight or branched C1–C4alkyl), halogen, C1–C4alkoxy, or C1–C4haloalkoxy, or two adjacent R27groups, and the carbon atoms two which they are attached, form a substituted or unsubstituted 5- or 6-membered ring; q is 0, 1, or 2; and indicates the point of attachment of one or both of R18and R19to ring C. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is selected from and , wherein R18and R19are each independently selected from -H, -OH, C1–C4alkyl, and , wherein: R26is H, C1–C4alkyl (straight or branched C1–C4alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R27is -OH, C1–C4alkyl (straight or branched C1–C4alkyl), halogen, C1–C4alkoxy, or C1–C4haloalkoxy, or two adjacent R27groups, and the carbon atoms two which they are attached, form a substituted or unsubstituted 5- or 6-membered ring; q is 0, 1, or 2; and indicates the point of attachment of one or both of R18and R19to ring C. In embodiments of Ring C, R26is straight or branched C1–C4alkyl. In embodiments of Ring C, each R27is -OH, straight or branched C1–C4alkyl, C1–C4alkoxy, or C1–C4haloalkoxy. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is selected from ; ; ; ; ; ; ; ; ; In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is selected from . In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is ; ; ; ; , wherein18 19 R and R , together with the carbon atom to which they are attached, for m , wherein: X and Y are each, independently CH2, NR29, O, or C=O; R28is -OH, halogen, C1–C4alkyl (straight or branched C1–C4alkyl), C1–C4haloalkyl, C1–C4alkoxy, or C1–C4haloalkoxy; R29is H or C1–C4alkyl (straight or branched C1–C4alkyl); and w is 0, 1, or 2. In embodiments of Ring C, each R28is independently selected from -OH, halogen, straight or branched C1–C4alkyl, C1–C4haloalkyl, C1–C4alkoxy, and C1–C4haloalkoxy. In embodiments of Ring C, R29is straight or branched C1–C4alkyl. In embodiments of any one of the compounds of Formula (I), (II), (III), and (IIIa), ring C is selected from ; ; ; ; ; ; ; and In embodiments of any one of the compounds of Formula (I), (II), (III), and (IIIa), ring C is selected from ; and wherein R34is C1–C4alkyl. In embodiments of Ring C, R34is straight or branched C1–C4alkyl. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is , wherein R32is In embodiments of the compounds of Formula (I), (II), (III), and (IIIa), ring C is ; ; ; ; ; ; o , wherein R22is C1–C4alkyl (e.g., straight or branched C1–C4alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is selected from

[0002] ; ; ; ; and . In embodiments, ring C is or . In embodiments, disclosed herein are compounds selected from:

[0003]  

[0004] 

[0005] 

[0006] 

[0007] ;

[0008] ;

[0009] or a pharmaceutically acceptable salt thereof. In embodiments, disclosed herein are compounds selected from:

[0010] ;

[0011] 

[0012] or a pharmaceutically acceptable salt thereof, wherein: X is CH2, O, or NR29; and R29is H or C1–C4alkyl (e.g., straight or branched C1–C4alkyl). In embodiments, disclosed herein are compounds selected from:

[0013] or a pharmaceutically acceptable salt thereof. Also disclosed herein are pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient. In embodiments, the pharmaceutical compositions further comprise one or more additional anti-cancer agents. In embodiments, at least one of the additional anti- cancer agents is an immune checkpoint inhibitor. In aspects, disclosed herein are methods treating cancer, comprising administering a therapeutically effective amount of one or more compounds disclosed herein, or a pharmaceutical composition thereof, to a subject in need thereof. In embodiments, the cancer is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and / or neck cancer, lymphoma, lymphoma, leukemia, and melanoma. In aspects, disclosed herein are methods of inhibiting the activity of diacylglycerol kinase alpha (DGKα), comprising administering a therapeutically effective amount one or more compounds disclosed herein, or a pharmaceutical composition thereof, to a subject in need thereof. DETAILED DESCRIPTION Diacylglycerol kinases (DGKs) are lipid kinases that mediate the conversion of diacylglycerol to phosphatidic acid thereby terminating T-cell functions propagated through the TCR signaling pathway. Thus, DGKs serve as intracellular checkpoints, and inhibition of DGKs is expected to enhance T-cell signaling pathways and T-cell activation. Knock-out mouse models of DGKα have shown a hyper-responsive T-cell phenotype and improved anti- tumor immune activity (Zha Y et al. Nature Immunology, (2006) 12:1343; Olenchock B. A. et al., Nature (2006) 11: 1174–81). Furthermore, tumor infiltrating lymphocytes isolated from human renal cell carcinoma patients were observed to overexpress DGKα that resulted in inhibited T-cell function (Prinz, P. U. et al. J Immunology (2012) 12:5990–6000). Thus, DGKα may be viewed as a target for cancer immunotherapy (Riese M. J. et al. Front Cell Dev Biol. (2016) 4: 108; Chen, S. S. et al. Front Cell Dev Biol. (2016) 4: 130; Avila-Flores, A. et al. Immunology and Cell Biology (2017) 95: 549-563; Noessner, E. Front Cell Dev Biol. (2017) 5: 16; Krishna, S., et al. Front Immunology (2013) 4:178; Jing, W. et al. Cancer Research (2017) 77: 5676–86). There remains a need for compounds useful as inhibitors of DGKα. Accordingly, disclosed herein are compounds that have activity as inhibitors of DGKα. In embodiments, the disclosed compounds selectively inhibit DGKα. In embodiments, the disclosed compounds are selective inhibitors for DGKα over other diacylglycerol kinases (e.g., DGKζ). In embodiments, the disclosed compounds cause the degradation of DGKα. In embodiments, the disclosed compounds cause the selective degradation of DGKα. In embodiments, the disclosed compounds cause the selective degradation of DGKα over other diacylglycerol kinases (e.g., DGKζ). The disclosed compounds can be used to treat certain diseases or disorders. In embodiments, the disclosed compounds can be used for the treatment of certain cancers (e.g., colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and / or neck cancer, lymphoma, lymphoma, leukemia, and melanoma). Definitions Unless otherwise defined herein, scientific, and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art. The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well-known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g., “Principles of Neural Science,” McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al. “Molecular Cell Biology, 4th ed.,” W. H. Freeman & Co., New York (2000); Griffiths et al. “Introduction to Genetic Analysis, 7th ed. ,” W. H. Freeman & Co., N.Y. (1999); and Gilbert et al. “Developmental Biology, 6th ed.,” Sinauer Associates, Inc., Sunderland, M A (2000). Chemistry terms used herein are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms,” Parker S., Ed., McGraw- Hill, San Francisco, Calif. (1985). All the above, and all other publications, patents, and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In embodiments, an in vitro cell can be a cell in a cell culture. In embodiments, an in vivo cell is a cell living in an organism such as a mammal. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” the DGKα enzyme with a compound of the invention includes the administration of a compound of the present invention to a subject, such as a human, having DGKα, as well as, for example, introducing a of compound the invention into a sample containing a cellular or purified preparation containing the DGKα enzyme. The term “DGKα degrader” refers to an agent that targets the DGKα enzyme resulting in its degradation. The term “DGKα inhibitor” refers to an agent capable of inhibiting the enzymatic activity of diacylglycerol kinase alpha (DGKα) in T-cells resulting in enhanced T-cell stimulation. The DGKα inhibitor can be a reversible DGKα inhibitor. “A reversible DGKα inhibitor” is a compound that reversibly inhibits DGKα enzyme activity either at the catalytic site or at a non-catalytic site. The terms “patient,” “subject,” and “individual” are used interchangeably herein and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). In embodiments, the subject is a human. As used herein, the term “selective inhibitors of DGKα” refers to a compound’s to selectively inhibit the activity of DGKα as compared to other diacylglycerol kinases (e.g., DGKζ). As used herein, the term “selective degraders of DGKα” refers to a compound’s to selectively degrade DGKα as compared to other diacylglycerol kinases (e.g., DGKζ). “Treating” a condition or patient, and “treatment” refer to taking steps to obtain beneficial or desired results, including clinical results, via administration of a compound or composition of the present invention. Beneficial or desired results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total. “Treatment” also can mean prolonging survival as compared to expected survival if not receiving treatment. “Administering” or “administration of” a compound or a composition of the invention to a subject can be carried out using any of a variety of routes and methods known to those skilled in the art based on the directions of an attending healthcare provider. For example, a compound or pharmaceutical composition of the invention can be administered to a subject in need of such treatment by any of the following routes: intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, buccally, orally (by ingestion), intranasally (by inhalation), intravaginally, intraspinally, intrathecally, intracerebrally, and transdermally (by absorption through the skin). A compound or composition of the present invention can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow, delayed, or controlled release of the compound or composition. Administering also can be performed, for example, once, a plurality of times, and / or over one or more extended periods. Appropriate methods of administering a compound or pharmaceutical composition of the invention to the subject will also depend on a variety of factors such as, for example, age, weight, gender, and physical condition of the subject, as well as the chemical and biological properties of the compound or pharmaceutical composition (e.g., solubility, absorption, bioavailability, metabolism, stability, and toxicity). In embodiments, a compound or pharmaceutical composition of present invention is administered orally, e.g., to a subject by ingestion. In embodiments, the orally administered compound or pharmaceutical composition is in a controlled release (e.g., a delayed release, extended release, or slow release) formulation. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either simultaneously or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents. A “therapeutically effective amount” or a “therapeutically effective dose” of a compound or pharmaceutical composition of the invention is an amount of the drug or composition that, when administered to a subject, will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The effective amount needed for a subject will depend, for example, upon the subject’s age, weight, health, gender, and the nature and extent of the condition (e.g., cancer) being treated. The attending healthcare provider will generally determine the effective amount for a given situation according to these and other factors. The term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., C1–C6for straight chains, C3–C6for branched chains), and more preferably four or less carbons in its backbone. The term “alkoxy” refers to an alkyl group having an oxygen attached thereto, represented by -O-alkyl. For example, “C1–C4alkoxy” includes methoxy, ethoxy, propoxy, isopropoxy, and butoxy. The term “Cx–Cy,” when used in conjunction with a chemical moiety (e.g, alkyl, alkenyl, alkoxy) is meant to include groups that contain from x to y carbons in the chain. A C1–C6alkyl group, for example, contains from one to six carbon atoms in the chain; a C1–C4-alkyl contains from one to four carbon atoms in the chain. The term “aryl,” as used herein, includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings and wherein at least one of the rings is aromatic, i.e., the other cyclic rings can be selected from cycloalkyls, cycloalkenyls, aryls, heteroaryls, heterocyclyls, and combinations thereof. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. The term “carbocyclic ring,” as used herein, refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon that is substituted or unsubstituted. Preferably, a carbocycle ring contains from 3 to 10 atoms, more preferably from 3 to 8 atoms, including 5 to 7 atoms, such as, for example, 5 or 6 atoms. The term “electron withdrawing group,” as used herein, means an atom or functional group that draws electron density from neighboring atoms towards itself, typically by resonance or inductive effects. Exemplary electron withdrawing groups include, but are not limited to, trifluoromethylsulfonyl groups (-SO2CF3), substituted or unsubstituted ammonium groups (-NR3+, wherein each R is H or alkyl), nitro groups (-NO2), sulfonic acid groups (-SO3H), sulfonyl groups (SO2R, wherein R is alkyl), cyano groups (-C≡N), haloformyl groups (-COX, wherein X is Cl, Br, or I), formyl groups (-CHO), acyl groups (-COR, wherein R is alkyl), carboxyl groups (-CO2H), alkoxycarboxyl groups (-CO2R, wherein R is alkyl), substituted or unsubstituted amino carbonyl groups (-CONH2, -CONHR, -CONR2, wherein R is alkyl), halogen groups, and nitroso groups (-N=O). The terms “halo,” “halogen,” and “halogen groups,” as used herein, refer to a substituent group from Group 17 of the periodic table of the elements and includes fluoro (-F), chloro (- Cl), bromo(-Br), and iodo (-I) substituent groups. The terms “haloalkyl” and “haloalkoxy” mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms. The term “heteroaryl” or “heteroaromatic” includes substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be selected from cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur. The term “heterocyclic ring” refers to substituted or unsubstituted non-aromatic ring structure, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term “heterocyclic ring” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be selected from cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and heterocyclyls. Heterocyclyl groups include, for example, diazinane, imidazolidine, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, octahydropyrrolo[3,4-c]pyrrole, and the like. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. The term “aromatic ring” includes aryl and heteroaryl rings. The term “ring” includes aryl, cycloalkyl, heterocyclic, carbocyclic, and heteroaryl, ring systems. Certain compounds described herein may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. When a disclosed compound is named or depicted by structure with or without indicating stereochemistry, it is understood that the name or structure encompasses all possible stereoisomers, geometric isomers, including essentially pure stereo or geometric isomers, as well as combination thereof. When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all the compounds with the same or opposite stereochemical configuration in a mixture. When the stereochemical configuration at a chiral center in a compound having two or more chiral centers is depicted by its structure (e.g., the configuration is indicated by “wedge” bonds), and the configuration about the two or more chiral centers is labelled as “or1”, this means that compound comprises a mixture of stereoisomers and the stereochemistry is relative in the depicted configuration between the two or more stereocenters. For example, means that the compound comprises a mixture of and . When the stereochemical configuration at a chiral center in a compound having two or more chiral centers is depicted by its structure (e.g., the configuration is indicated by “wedge” bonds), and the configuration about the two or more chiral centers is labelled as “abs”, this means that the compound is stereochemically enriched as the drawn stereochemistry or as the opposite, i.e., is absolute of one or the other stereoisomers. For example,

[0014] means that the compound is or at an enrichment of the indicated configuration relative to the opposite configuration of greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that contain two or more asymmetrically substituted carbon atoms. “Geometric isomers” are stereoisomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a carbocyclyl ring, or to a bridged bicyclic system. Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral- phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods. Compounds of the Invention Disclosed herein are compounds that have activity as inhibitors of DGKα. In preferred embodiments, the disclosed compounds selectively inhibit DGKα. In embodiments, the disclosed compounds are selective inhibitors of DGKα over other diacylglycerol kinases (e.g., DGKζ). In embodiments, the disclosed compounds cause the degradation of DGKα. In embodiments, the disclosed compounds cause the selective degradation of DGKα. In embodiments, the disclosed compounds cause the selective degradation of DGKα over other diacylglycerol kinases (e.g., DGKζ). In embodiments, the disclosed compounds have desirable efficacy, stability, bioavailability, therapeutic index, and toxicity values that are important to their use as pharmaceuticals. In embodiments, disclosed herein is a compound of having a structure according to Formula (A): (A) or a pharmaceutically acceptable salt thereof, wherein: Ring A is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic ring fused to ring B; Ring C is a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring; R1is alkyl (e.g., straight or branched C1–C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, pentyl, hexyl)); R2is H or an electron withdrawing functional group; each R3is independently NR5R6; each R4is independently alkyl (e.g., straight or branched C1–C6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, pentyl, hexyl)) or alkoxy (e.g., C1–C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, neopentoxy, pentoxyl, hexoxy)), or one R3and one R4, together with the atoms of ring C to which they are attached, form a substituted or unsubstituted ring; R5and R6are each, independently H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R5and R6, together with the nitrogen to which they are attached, form a substituted or unsubstituted ring; and m and n are each, independently 0 or an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In embodiments of Formula (A), disclosed herein are compounds having the structure according to Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is a substituted or unsubstituted heteroaromatic ring fused to ring B Ring C is a substituted or unsubstituted heterocyclic ring; R1is C1–C4alkyl (e.g., straight or branched C1–C4alkyl); R2is H or an electron withdrawing functional group; each R3is independently NR5R6; each R4is independently C1–C4alkyl (e.g., straight or branched C1–C4alkyl) or C1–C4alkoxy, or one R3and one R4, together with the atoms of ring C to which they are attached, form a substituted or unsubstituted ring; R5and R6are each independently H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R5and R6, together with the nitrogen to which they are attached, form a substituted or unsubstituted ring; m and n are each independently 0, 1, 2, 3, or 4. In embodiments, disclosed herein is a compound of having the structure according to Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5- or 6-membered substituted or unsubstituted heteroaromatic ring fused to ring B; Ring C is a 5- to 8-membered substituted or unsubstituted heterocyclic ring; R1is C1–C4alkyl (e.g., straight or branched C1–C4alkyl); R2is H or an electron withdrawing functional group; each R3is independently NR5R6; each R4is independently C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl) or C1–C4alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), or one R3and one R4, together with the atoms of ring C to which they are attached, form a substituted or unsubstituted ring; R5and R6are each independently H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R5and R6, together with the nitrogen to which they are attached, form a substituted or unsubstituted ring; and m and n are each independently 0, 1, 2, 3, or 4. In embodiments, disclosed herein is a compound of Formula (A) or Formula (I), wherein Ring A is selected from pyridine, imidazole, thiazole, oxazole, pyrazole, and isoxazole. In embodiments, disclosed herein is a compound of Formula (A) or Formula (I), wherein Ring A is selected from piperidine, diazinane, octahydropyrrolo[3,4-c]pyrrole, imidazolidine, and pyrrolidine. In embodiments, disclosed herein is a compound of Formula (A) or Formula (I), having a structure according to Formula (IIa): (IIa) or a pharmaceutically acceptable salt thereof, wherein Y is S or CH or CR33; R9is H, halogen, cyano (-CN), C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), C1–C4haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloropropyl, dichloropropyl, trichloropropyl), C1–C4alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), or NR9a, wherein R9ais C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl); and R33is C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), C1–C4haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloropropyl, dichloropropyl, trichloropropyl), or C1–C4alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy),. In certain embodiments, R9is straight or branched C1–C4alkyl. For example, in particular embodiments, R9is methyl, ethyl, propyl, or butyl. In specific embodiments, R9is methyl. In embodiments, disclosed herein is a compound of Formula (A) or Formula (I), having a structure according to Formula (II): (II) or a pharmaceutically acceptable salt thereof, wherein R9is H, halogen, cyano (-CN), C1–C4alkyl (e.g., straight or branched C1–C4alkyl such as methyl, ethyl, propyl, isopropyl, butyl), C1–C4haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloropropyl, dichloropropyl, trichloropropyl), C1–C4alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), or NR9a, wherein R9ais C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl). In embodiments, R9is straight or branched C1–C4alkyl. For example, in particular embodiments, R9is methyl, ethyl, propyl, or butyl. In embodiments of Formula (II), R9is methyl. In embodiments, disclosed herein is a compound of Formula (A) or Formula (I), having the structure according to Formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein R10is H, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), carbocycle (e.g., C3– C7-cycloalkyl), or an electron withdrawing functional group; and q is 1 or 2. In embodiments of Formula (III), R10is C1–C4alkyl (e.g., straight or branched C1–C4alkyl) or an electron withdrawing functional group. In embodiments, R10is methyl, ethyl, propyl, isopropyl, butyl. In embodiments of Formula III), R10is methyl. In embodiments, disclosed herein is a compound of Formula (III), having the structure of Formula (IIIa): (IIIa) or a pharmaceutically acceptable salt thereof. In embodiments of Formula (IIIa), R10is C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl). In embodiments of Formula (IIIa), R10is straight or branched C1–C4alkyl. In embodiments of Formula (IIIa), R10is methyl (-CH3). In embodiments, R10is selected from halogen (e.g., -F, -Cl), -CH3, -SO2CF3, -N(R11)2, -NO2, -SO2R12, -C≡N, -C(R13)3, -COR14, -CSR15, -CO2R16, -CON(R17)2, and -N=O, wherein: each of R11, R12, R14, R15, R16, and R17is independently H or C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl); and each R13is halogen (e.g., -F, -Cl). In embodiments, R10is -Cl. Alternatively, R10is -F. In embodiments, R10is -C≡N. In embodiments, R10is -N(R11)2, -SO2R12, or -C(R13)3, -CSR15, wherein each of R11, R12, and R15is independently H or methyl. In embodiments, R10is -COR14, wherein R14is H or methyl. In embodiments, R10is -CHO. In embodiments, R10is -CO(CH3). In embodiments, R10is -CO2(R16), wherein R16is H or methyl. In embodiments, R10is CO2(CH3) In embodiments, R10is -CON(R17)2, wherein each R17is independently H or methyl. In embodiments, R10is -CONH(CH3). In embodiments, R10is -CON(CH3)2. In embodiments, R10is -N=O. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein R1is straight or branched C1–C4alkyl. In embodiments of any one of Formulae (A), (I), (II), (III), or (IIIa), R1is methyl, ethyl, propyl, or butyl. In embodiments of Formulae (A), (I), (II), (III), or (IIIa), wherein R1is methyl. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein R2is selected from H, halogen, -SO2CF3, - N(R32)2, -NO2, -SO2R26, -C≡N, -C(R27)3, -COR28, -CSR29, -CO2R30, -CON(R31)2, and -N=O, wherein: each of R32, R26, R28, R29, R30, and R31is independently H or C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl); and each R33is halogen (e.g., -F, -Cl). In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein R2is H. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein R2is -C≡N. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein R2is -N(R32)2, -SO2R26, -C(R33)3, -COR28, - CSR29, -CO2R30, or -CON(R31)2, wherein each of R32, R26, R28, R29, R30, and R31is independently H or methyl; and each R33is halogen. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is further substituted by one or more substituents selected from R15, R18, R19, R20, R21, and R22. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), ring C is further substituted by one or more substituents selected from R15, R18, R19, R20, R21, and R22wherein: R15is straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R18and R19are each, independently C1–C4alkoxy, C1–C4alkyl, or -NR23R24, or R18and R19, together with the carbon atom to which they are attached, form a substituted or unsubstituted ring; R20is straight or branched C1–C4alkyl, or an electron withdrawing group, or R18and R20, or R19and R20, together with the carbon atoms to which they are attached, form a substituted or unsubstituted ring; R21is straight or branched C1–C4alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R22is straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R23and R24are each, independently straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), R4is straight or branched C1–C4alkyl. In embodiments of any one of the compounds of Formulae (I), (II), (III), and (IIIa), R4is C1– C4alkoxy. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is selected from and , wherein: R15is straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R18and R19are each, independently H, OH, C1–C4alkoxy, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), or -NR23R24, or R18and R19, together with the carbon atom to which they are attached, form a substituted or unsubstituted ring (e.g., a 5- or 6-membered substituted or unsubstituted carbocyclic ring or a 5- or 6-membered substituted or unsubstituted heterocyclic ring); R20is H, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), or C1–C4alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), or R18and R20, or R19and R20, together with the carbon atoms to which they are attached, form a ring (e.g., 5-, 6-, or 7-membered substituted or unsubstituted carbocyclic ring or a 5-, 6-, or 7-membered substituted or unsubstituted heterocyclic ring); R21is H or C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R22is C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R23and R24are each, independently H, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and indicates the point of attachment of ring C to ring B. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is selected from ; ; ; and , wherein: R15is straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R18and R19are each, independently OH, C1–C4alkoxy, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), or -NR23R24, or R18and R19, together with the carbon atom to which they are attached, form a substituted or unsubstituted ring (e.g., a 5- or 6-membered substituted or unsubstituted carbocyclic ring or a 5- or 6-membered substituted or unsubstituted heterocyclic ring); R20is C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), or C1–C4alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), or R18and R20, or R19and R20, together with the carbon atoms to which they are attached, form a ring (e.g., 5-, 6-, or 7-membered substituted or unsubstituted carbocyclic ring or a 5-, 6-, or 7-membered substituted or unsubstituted heterocyclic ring); R21is C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R22is C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R23and R24are each, independently H, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and indicates the point of attachment of ring C to ring B. In embodiments of Ring C, any one of R32, R26, R28, R29, R30, or R31is straight or branched C1–C4alkyl. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is selected from ; and , wherein: R18and R19are each, independently H, OH, C1–C4alkoxy, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), or -NR23R24, or R18and R19, together with the carbon atom to which they are attached, form a substituted or unsubstituted ring (e.g., a 5- or 6-membered substituted or unsubstituted carbocyclic ring or a 5- or 6-membered substituted or unsubstituted heterocyclic ring); R20is H or C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), or R18and R20, or R19and R20, together with the carbon atoms to which they are attached, form a ring (e.g., 5-, 6-, or 7-membered substituted or unsubstituted carbocyclic ring or a 5-, 6-, or 7-membered substituted or unsubstituted heterocyclic ring); R21is H or C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), aryl, or heteroaryl; R22is C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R23and R24are each, independently H, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R15is C1–C4alkyl e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and indicates the point of attachment of ring C to ring B. In embodiments of Ring C, R21is straight or branched C1–C4alkyl. In embodiments of Ring C, R22is straight or branched C1–C4alkyl. In embodiments of Ring C, R15is unsubstituted C1–C4alkyl. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is18 , wherein R and R19, together with the carbon atom to which they are attached, form a substituted or unsubstituted 5- or 6-membered carbocyclic ring or a substituted or unsubstituted 5- or 6- membered heterocyclic ring. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is18 , wherein R and R20, or R19and R20, together with the carbon atoms to which they are attached form a substituted or unsubstituted 5-, 6-, or 7-membered carbocyclic ring or a substituted or unsubstituted 5-, 6-, or 7-membered heterocyclic ring. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is selected from ; ; ; ; ; ; ; ; and . In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is , wherein R21is , wherein R25is selected from OH, halogen (-Cl, -F), C1–C4alkyl (e.g., straight or branched C1– C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), C1–C4alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), C1–C4haloalkyl (e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, -CH2CF3, -(CH2)2CH2F, -(CH2)2CHF2, -(CH2)2CF3, -(CH2)3CH2F, -(CH2)3CHF2, -(CH2)3CF3), C1–C4haloalkoxy (e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -O(CH2)2CH2F, -O(CH2)2CHF2, -O(CH2)2CF3, -O(CH2)3CH2F, -O(CH2)3CHF2, -O(CH2)3CF3), substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; t is 0, 1, or 2; and indicates the point of attachment of R21to N. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is R, wherein R21is , wherein Each R25is independently selected from OH, halogen (-Cl, -F), C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), C1–C4alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), C1–C4haloalkyl (e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -(CH2)2CH2F, -(CH2)2CHF2, -(CH2)2CF3, -(CH2)3CH2F, -(CH2)3CHF2, -(CH2)3CF3), C1–C4haloalkoxy (e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -O(CH2)2CH2F, -O(CH2)2CHF2, -O(CH2)2CF3, -O(CH2)3CH2F, -O(CH2)3CHF2, -O(CH2)3CF3), substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; t is 0, 1, or 2; and indicates the point of attachment of R21to N. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is , wherein R21is selected from ; ; ; ; ; ; and In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is21 , wherein R is selected from ; ; ; ; ; ; and .

[0015] In embodiments, disclosed herein is a compound having the structure according to any one of Formula (A), (I), (II), (III), or (IIIa), wherein ring C is selected from ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and . In embodiments of Ring C, R22is straight or branched C1–C4alkyl. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is , wherein R18and R19are each independently selected from -H, -OH, alkyl (e.g., straight or branched C1–C4alkyl) and , wherein: R26is H, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R27is -OH, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such methyl, ethyl, propyl, isopropyl, butyl), halogen (-Cl, -F), C1–C4alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), or C1–C4haloalkyl (e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, -CH2CF3, -(CH2)2CH2F, -(CH2)2CHF2, -(CH2)2CF3, -(CH2)3CH2F, - (CH2)3CHF2, -(CH2)3CF3), C1–C4haloalkoxy (e.g., -OCH2F, -OCHF2, -OCF3, - OCH2CH2F, -OCH2CHF2, -OCH2CF3, -O(CH2)2CH2F, -O(CH2)2CHF2, -O(CH2)2CF3, -O(CH2)3CH2F, -O(CH2)3CHF2, -O(CH2)3CF3), or two adjacent R27groups, and the carbon atoms two which they are attached, form a 5- or 6-membered substituted or unsubstituted ring; q is 0, 1, or 2; and indicates the point of attachment of one or both of R18and R19to ring C. In embodiments, disclosed herein is a compound having the structure according to any one of N Formulae (A), (I), (II), (III), or (IIIa), wherein ring C isR18 R19; ; ; ; ; ; ; ; ; ; ; ; or , wherein R18and R19are each independently selected from -H, -OH, alkyl (e.g., straight or branched C1–C4alkyl), and , wherein: R26is H, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R27is -OH, C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), halogen (-Cl, -F), C1–C4alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), or C1–C4haloalkyl (e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, -CH2CF3, -(CH2)2CH2F, -(CH2)2CHF2, -(CH2)2CF3, -(CH2)3CH2F, - (CH2)3CHF2, -(CH2)3CF3), C1–C4haloalkoxy (e.g., -OCH2F, -OCHF2, -OCF3, - OCH2CH2F, -OCH2CHF2, -OCH2CF3, -O(CH2)2CH2F, -O(CH2)2CHF2, -O(CH2)2CF3, -O(CH2)3CH2F, -O(CH2)3CHF2, -O(CH2)3CF3), or two adjacent R27groups, and the carbon atoms two which they are attached, form a 5- or 6-membered substituted or unsubstituted ring; and q is 0, 1, or 2. In embodiments of Ring C, R26is straight or branched C1–C4alkyl. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is selected from ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is selected from ; ; ; In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is ; ; or , wherein R18and R19, together with the carbon atom to which they are attached, form , wherein: X and Y are each, independently CH2, NR29, O, or C=O; R28is -OH, halogen (-Cl, -F), C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), C1–C4haloalkyl (e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -(CH2)2CH2F, -(CH2)2CHF2, -(CH2)2CF3, - (CH2)3CH2F, -(CH2)3CHF2, -(CH2)3CF3), C1–C4alkyoxy (e.g., methoxy, ethoxy, propoxy, butoxy), or C1–C4haloalkoxy (e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -O(CH2)2CH2F, -O(CH2)2CHF2, -O(CH2)2CF3, - O(CH2)3CH2F, -O(CH2)3CHF2, -O(CH2)3CF3); or R29is H or C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl); and w is 0, 1, or 2. In embodiments of Ring C, R29is straight or branched C1–C4alkyl.

[0016] In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is selected from ; and . In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is selected from ; ; ; ; and , wherein R34is C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl). In embodiments of Ring C, R34is straight or branched C1–C4alkyl. In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is ,32 wherein R is ; ; ; or . In embodiments, the disclosed herein is a compound having the structure of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is ; ; ; ; ; ; ; ; ; ; ; ; or , wherein R22is C1–C4alkyl (e.g., straight or branched C1–C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments of Ring C, R22is straight or branched C1–C4alkyl. In embodiments, the disclosed herein is a compound having the structure of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C selected from ; ; ; ; ; ; ; ; ; ; ; ;

[0017] ; ; ; ; ; and . In embodiments, disclosed herein is a compound having the structure according to any one of Formulae (A), (I), (II), (III), or (IIIa), wherein ring C is or In embodiments, disclosed herein is a compound having a chemical formula according to any one of Compounds 1–234, as shown in Table 1. Table 1. 176 177 178

[0018]

[0019] or a pharmaceutically acceptable salt thereof. In embodiments, disclosed herein is a compound having a chemical formula according to any one of Compounds 235–311, as shown in Table 2. Table 2.

[0020] or a pharmaceutical salt thereof.

[0021] Example 312: Exemplary Synthesis of 4-[(3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]- 3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-1-yl]-6-chloro-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile Step 1: Preparation of tert-butyl 5-[5-(trifluoromethoxy)- 2-pyridyl]-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-1-carboxylate To a solution of 2-bromo-5-(trifluoromethoxy)pyridine (2.67 g, 11.05 mmol, 1 eq) and tert- butyl 2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridine-1-carboxylate (2.50 g, 11.05 mmol, 1 eq) in dioxane (25 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H- imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (1.07 g, 1.10 mmol, 0.1 eq) and cesium carbonate (10.80 g, 33.14 mmol, 3 eq). The mixture was stirred at 100 °C for 3 h. To the reaction mixture was added water (30 mL) and extracted with ethyl acetate 60 mL (30 mL x 2). The combined organic layers were washed with saturated sodium chloride (30 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate=100 / 1 to 5 / 1) to give tert-butyl 5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridine-1-carboxylate (3.74 g, 9.65 mmol, 87% yield) as a yellow oil. LC / MS: (ESI) m / z: 388.1 [M+1]+.

[0022] Step 2: Preparation of tert-butyl (3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]- 3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-1-carboxylate and tert-butyl (3aS,7aR)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2- c]pyridine-1-carboxylate Racemic tert-butyl (3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a-hexahydro- 2H-pyrrolo[3,2-c]pyridine-1-carboxylate (1.9 g, 4.90 mmol, 1 eq) was purified by SFC (column: REGIS(S,S)WHELK-O1(250mm x 25mm,10um); mobile phase: [neutral-ethyl alcohol]; 15%-15%, 200min) to afford tert-butyl (3aR,7aS)-5-[5-(trifluoromethoxy)-2- pyridyl]-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-1-carboxylate (870 mg, 2.25 mmol, 45% yield) as a green oil (SFC:Rt=1.061 min) and tert-butyl (3aS,7aR)-5-[5- (trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-1- carboxylate (830 mg, 2.14 mmol, 43% yield)) as a green oil (SFC: Rt = 1.209 min). The absolute stereochemical configuration was tentatively assigned. Step 3: Preparation of WC-ARV-JM-047-A-2a, (3aR,7aS)-5-[5-(trifluoromethoxy)-2- pyridyl]-1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridine To a solution of tert-butyl (3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridine-1-carboxylate (500 mg, 1.29 mmol, 1 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (7.70 g, 67.53 mmol, 5.00 mL, 52.32 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give (3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-1,2,3,3a,4,6,7,7a- octahydropyrrolo[3,2-c]pyridine (517 mg, crude, trifluoroacetic acid) as a yellow solid. LC / MS: MS (ESI) m / z: 288.3 [M+1]+. Step 4: Preparation of 4-[(3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridin-1-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine- 3-carbonitrile To a solution of (3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]-1,2,3,3a,4,6,7,7a- octahydropyrrolo[3,2-c]pyridine (517 mg, 1.29 mmol, 1 eq, trifluoroacetic acid) and 4,6- dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (327 mg, 1.29 mmol, 1 eq) in acetonitrile (5 mL) was added diisopropylethylamine (833 mg, 6.44 mmol, 1.12 mL, 5 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [water (formic acid)- acetonitrile]; 58%-88%, 58min) to give 4-[(3aR,7aS)-5-[5-(trifluoromethoxy)-2-pyridyl]- 3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-1-yl]-6-chloro-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (465.7 mg, 0.89 mmol, 69% yield, 96% purity) as a yellow solid. LC / MS: (ESI) m / z: 505.2507.3, 505.3 [M+1]+.1H NMR: (400 MHz, DMSO-d6) δ: 8.13 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.58 (dd, J = 2.4, 9.2 Hz, 1H), 6.88 (d, J = 9.6 Hz, 1H), 5.54 - 5.42 (m, 1H), 4.46 - 4.34 (m, 1H), 3.99 - 3.89 (m, 2H), 3.84 - 3.75 (m, 1H), 3.63 (dd, J = 4.4, 13.6 Hz, 1H), 3.50 (s, 3H), 3.21 - 3.13 (m, 1H), 2.57 (d, J = 6.4 Hz, 1H), 2.24 - 2.15 (m, 1H), 2.08 - 1.99 (m, 1H), 1.96 - 1.86 (m, 1H), 1.81 - 1.71 (m, 1H) In embodiments, disclosed herein is a compound having a chemical formula according to any one of Compounds 312–390, as shown in Table 3. These compounds were made using a similar synthesis as is described for Compound 312, which is discussed in more detail below. In embodiments, disclosed herein is a compound having a chemical formula according to any one of Compounds 391-449, as shown in Table 4. These compounds were made using a similar synthesis as is desribed for Compounds 397, 416, and 429, which is discussed in more detail below. Pharmaceutical Compositions Disclosed herein are pharmaceutical composition comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipients. The compositions of the invention may be in a form suitable for oral use (for example, as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), for topical use (for example, as creams, ointments, gels, or aqueous or oily solutions, suspensions, or transdermal patches), for administration by inhalation (for example, as a finely divided powder or a liquid aerosol), for administration by insufflation (for example, as a finely divided powder), or for parenteral administration (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or as a suppository for rectal or intravaginal dosing). The pharmaceutical compositions of the invention can be obtained by conventional procedures in view of this disclosure using conventional pharmaceutical excipients well- known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring, and / or preservative agents. Pharmaceutically acceptable excipients that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-alpha-tocopherol, polyethyleneglycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., tweens), polyethoxylated castor oil (e.g., CREMOPHOR surfactant (BASF)) or other similar polymeric delivery matrices, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins (e.g., alpha-, beta-, and gamma-cyclodextrin), chemically modified derivatives thereof (e.g., hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins), or other solubilized derivatives also may be advantageously used to enhance delivery of compounds of the compounds described herein. The amount of the compound(s) that can be administered and the dosage regimen for treating a disease condition with the compounds and / or compositions of this invention depends on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen can vary widely, but may be routinely determined using standard methods. The daily dose can be administered in one to four doses divided per day. Other dosing schedules include one dose per week and one dose per two-day cycle. Methods of Treatment The compounds of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, are useful for the treatment of cancer. In embodiments, disclosed herein the compounds of the invention, or a pharmaceutically acceptable salt thereof, can be used in the treatment of diseases or disorders associated with DGK target inhibition in T-cells. In some such embodiments, the compound of the invention is prepared in combination with one or more additional therapeutic agents for conjoint administration for treating diseases or disorders associated with DGK target inhibition in T- cells. Also provided herein are methods for treating a subject suffering from or susceptible to a medical condition that is associated with DGK target inhibition in T-cells. For example, the compounds described herein may be used to treat or prevent viral infections and proliferative diseases such as cancer. More specifically, disease or conditions that are associated with DGK target inhibition in T cells include viral and other infections (e.g., skin infections, GI infection, urinary tract infections, genito-urinary infections, systemic infections), and proliferative diseases (e.g., cancer). In embodiments, the subject is being treated for cancer. Types of cancers that may be treated with a compound of the invention include, but are not limited to, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers. Examples of such cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma. In preferred embodiments, the compounds of the invention treat colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and / or neck cancer, lymphoma, lymphoma, leukemia, and melanoma. In embodiments, the compounds of the invention can inhibit activity of the diacylglycerol kinase alpha (DGKα). For example, the compounds of the invention can be used to inhibit activity of DGKα in a cell or in a subject in need of modulation of DGKα by administering a therapeutically effective amount of a compound of the invention or a salt thereof. In embodiments, the compounds of the invention can cause the degradation of DGKα. For example, the compounds of the invention can be used to degrade DGKα in a cell or in a subject in need of said treatment by administering a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. Also disclosed herein are methods of treating diseases or conditions associated with activity or expression, including abnormal activity and / or overexpression, of DGKαin a subject by administering to the subject in need of such treatment a therapeutically effective amount or dose of any one or more compounds of the invention or a pharmaceutical composition thereof. Exemplary diseases can include any disease, disorder, or condition that is directly or indirectly linked to expression or activity of the DGKαenzyme, such as over expression or abnormal activity. A DGKα-associated disease can also include any disease, disorder, or condition that can be prevented, ameliorated, or cured by modulating the DGKα enzyme activity. Examples of DGKα associated diseases include cancer and viral infections such as HIV infection, hepatitis B, and hepatitis C. Combination Therapies In embodiments, the compounds of the invention may be conjointly administered with an additional anticancer, such as an immuno-oncology agent. In certain embodiments, the compounds of the invention are administered concurrently with the additional anticancer agent. Alternatively, the compounds of the invention may be co-formulated with the anticancer agent. Exemplary anticancer agents include, but are not limited to, a small molecule drugs, antibodies, or other biologics or small molecules. Exemplary biologics include, but are not limited to, cancer vaccines, antibodies, and cytokines. In embodiments, the antibody is a monoclonal antibody. In some such embodiments, the monoclonal antibody is humanized or human. In embodiments, the anticancer agent is an immuno-oncology agent. In some such embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including a co- stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T-cell responses (often referred to as immune checkpoint regulators). Certain stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7- DC (PD-L2), B7-H2(ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD4OL, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4- IBB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DRS, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTOR, LIGHT, DcR3, HVEM, VEGUTL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin a 1β2, FAS, FASL, RELT, DR6, TROY, NGFR. In embodiments, T-cell responses can be stimulated by a combination of a compound of the invention and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-IBB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX4OL, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H. Other agents that can be combined with the compounds of the invention for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds of the invention can be combined with antagonists of KIR, such as lirilumab. Yet other agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (e.g., International Patent Publication Nos. WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (e.g., International Patent Publication Nos. WO11 / 140249; WO13169264; WO14 / 036357). In embodiments, the compounds of the invention can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1 / PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse / prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and / or inflammation at tumor sites. In embodiments, the additional anticancer agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab), or tremelimumab. In embodiments, the additional anticancer agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; e.g., International Patent Publication No. WO2012 / 145493). The immuno-oncology agent may also include pidilizumab (CT-011), though its specificity for PD-1 binding has been questioned. Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224. In embodiments, the additional anticancer agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; e.g., International Patent Publication No. WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (e.g., International Patent Publication No. WO2007 / 005874), and MSB0010718C (e.g., International Patent Publication No. WO2013 / 79174). In embodiments, the additional anticancer agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (e.g., International Patent Publication Nos. WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (e.g., International Patent Publication Nos. WO08 / 132601, WO09 / 44273). In embodiments, the additional anticancer agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab, and PF-05082566 (e.g., International Patent Publication No. WO12 / 32433). In embodiments, the additional anticancer agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX- 518 (e.g., International Patent Publication Nos. WO06 / 105021, WO09 / 009116), and MK- 4166 (e.g., International Patent Publication No. WO11 / 028683). In embodiments, the additional anticancer agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 e.g., International Patent Publication Nos. (WO2006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, BMS-986205, or NLG-919 (e.g., International Patent Publication No. WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237). In embodiments, the additional anticancer agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In embodiments, the additional anticancer agent is an OX4OL antagonist, such as an antagonistic OX40 antibody. Suitable OX4OL antagonists include, for example, RG-7888 (e.g., International Patent Publication No. WO06 / 029879). In embodiments, the additional anticancer agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the anticancer agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab. In embodiments, the additional anticancer agent agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab. In embodiments, the additional anticancer agent is MGA271 (to B7H3) (e.g., International Patent Publication No. WO11 / 109400). Combination therapies, as disclosed herein, are intended to embrace conjoint administration of these therapeutic agents; for example, administration of said therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be affected by any appropriate route including, but not limited to, oral routes, parental routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or both therapeutic agents may be administered by parentally, e.g., by intravenous injection. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks. One or more additional pharmaceutical agents or treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors can be optionally used in combination with the compounds of the invention for treatment of DGKα associated diseases, disorders, or conditions. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. Suitable additional anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. In embodiments, in the treatment of cancer (e.g., melanoma) suitable additional agents for use in combination with the compounds of the invention include: dacarbazine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the “Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOYTM. The compounds of the invention also can be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF). In embodiments, the compounds of the invention also can be used in combination with vaccine therapy in the treatment of cancer (e.g., melanoma). Antimelanoma vaccines are, in some ways, similar to the anti-virus vaccines that are used to prevent diseases caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body’s immune system to destroy melanoma cells. Suitable additional anti-cancer agents also include, for example, anti-metabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6- mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine. Suitable additional anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN- a), etoposide, and teniposide. Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, and droloxafine. Also suitable are cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors. Other additional anti-cancer agent(s) include antibody therapeutics such as trastuzumab (HERCEPTIN®), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10 or TGF-β). Other additional anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4. Other additional anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T-cell transfer. Additional anti-cancer agents also include anti-cancer vaccines, such as, for example, dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. The treatment methods of the invention may optionally include conjointly administering at least one signal transduction inhibitor (STI). A “signal transduction inhibitor” is an agent that selectively inhibits one or more vital steps in signaling pathways, in the normal function of cancer cells, thereby leading to apoptosis. Suitable STIs include, but are not limited to: (i) bcr / abl kinase inhibitors such as, for example, STI 571 (GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors ORES SA®, SSI-774) and antibodies (Imclone: C225 [Goldstein et al. Clin. Cancer Res., 1:1311–18 (1995)], and Abgenix: ABX-EGF); (iii) her-2 / neu receptor inhibitors such as farnesyl transferase inhibitors (FTI) such as, for example, L-744,832 (Kohl et al. Nat. Med., 1(8):792–97 (1995)); (iv) inhibitors of Akt family kinases or the Akt pathway, such as, for example, rapamycin (see, for example, Sekulic et al. Cancer Res., 60:3504–13 (2000)); (v) cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-01 (see, for example, Sausville Curr. Med. Chem. Anti-Canc. Agents, 3:47–56 (2003)); and (vi) phosphatidyl inositol kinase inhibitors such as, for example, LY294002 (see, for example, Vlahos et al. J. Biol. Chem., 269:5241–48 (1994)). Alternatively, at least one STI and at least one compound of Formula (I) may be in separate pharmaceutical compositions. In specific embodiments of the present invention, at least one compound of the invention and at least one STI may be administered to the patient conjointly. In other words, at least one compound of the invention may be administered first or at least one STI may be administered first and the other is administered next; or at least one compound of the invention and at least one STI may be administered at the same time. Additionally, when more than one compound of invention and / or STI is used, the compounds may be administered in any order. Also disclosed herein are pharmaceutical compositions for the treatment of a chronic viral infections in a subject comprising administering a therapeutically effective amount of at least one compound of the invention, optionally, at least one chemotherapeutic drug, and, optionally, at least one antiviral agent, in a pharmaceutically acceptable carrier. In embodiments, one or more compounds of the invention, one or more chemotherapeutic drugs, and / or one or more antiviral agents are administered conjointly. For example, in embodiments, at least one compound of the invention may be administered first or at least one chemotherapeutic agent may be administered first. Alternatively, at least one compound of the invention and the at least one STI may be administered at the same time. Additionally, when more than one compound of the invention and / or chemotherapeutic agent is used, the compounds may be administered in any order. Similarly, any antiviral agent or STI may also be administered at any point in relation to the administration of the compound of the invention. Chronic viral infections that may be treated using the present combinatorial treatment include, but are not limited to, diseases caused by hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV). Notably, parasitic infections (e.g., malaria) may also be treated by the above methods wherein compounds known to treat the parasitic conditions are optionally added in place of the antiviral agents. Suitable antiviral agents contemplated for use in combination with the compound of Formula (I) can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non- nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs. Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(P0M)- PMEA]; lobucavir; BCH-I0652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L- D4C and named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD, ((−)-beta-D-2,6-diamino- purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI- RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)- pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir; DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607. Also disclosed herein are pharmaceutical kits useful, for example, in the treatment or prevention of DGKα-associated diseases or disorders referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. Methods of Preparation The compounds of the present invention may be synthesized by many methods available to those skilled in the art in view of the present disclosure. General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Examples of compounds of the present invention prepared by methods described in the general schemes are given in the Examples section set out hereinafter. Preparation of homochiral examples may be carried out by techniques known to one skilled in the art. For example, homochiral compounds may be prepared by separation of racemic products or diastereomers by chiral phase preparative HPLC. Alternatively, the example compounds may be prepared by methods known to give enantiomerically or diastereomerically enriched products. The reactions and techniques described in this section are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods given below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work-up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art, with alternatives required when incompatible substituents are present. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of a protecting group used for protection of reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Wuts and Greene, Greene’s Protective Groups in Organic Synthesis, Fourth Edition, Wiley and Sons (2007).

[0023] EXEMPLIFICATION Synthetic Preparation of Compound Embodiments Synthesis of Compound 1 Preparation of 7-[(3aR,6aR)-2-[4-(trifluoromethoxy)phenyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-2,4-dimethyl-5-oxo-thiazolo[5,4-b]pyridine-6- carbonitrile (Compound 1) The title compound was prepared in an analogous manner to 2,4-dimethyl-5-oxo-7-spiro[3H- benzofuran-2,4'-piperidine]-1'-yl-thiazolo[5,4-b]pyridine-6-carbonitrile starting from (3aS,6aS)-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole. (off-white solid). LC / MS (ESI) m / z: 476.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.16 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 4.22 - 4.14 (m, 2H), 4.11 - 4.02 (m, 2H), 3.54 - 3.49 (m, 2H), 3.47 (s, 3H), 3.30 - 3.29 (m, 2H), 3.19 (t, J = 9.2 Hz, 2H), 2.69 (s, 3H).

[0024] Synthesis of Compound 2 Preparation of 7-[(3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methyl-1-piperidyl]-2,4- dimethyl-5-oxo-thiazolo[5,4-b]pyridine-6-carbonitrile (Compound 2) The title compound was prepared in an analogous manner to 2,4-dimethyl-5-oxo-7-spiro[3H- benzofuran-2,4'-piperidine]-1'-yl-thiazolo[5,4-b]pyridine-6-carbonitrile starting from (3S,4R)-N-(4-fluorophenyl)-N,3-dimethyl-piperidin-4-amine. (white solid). LC / MS (ESI) m / z: 426.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.03 (t, J = 8.8 Hz, 2H), 6.87 - 6.81 (m, 2H), 4.50 (d, J = 12.4 Hz, 1H), 4.32 (d, J = 13.6 Hz, 1H), 3.96 (td, J = 4.0, 12.4 Hz, 1H), 3.73 (dd, J = 2.4, 13.2 Hz, 1H), 3.48 (s, 3H), 3.42 - 3.38 (m, 1H), 2.79 (s, 3H), 2.71 (s, 3H), 2.41 (dd, J = 4.0, 12.4 Hz, 1H), 2.35 - 2.27 (m, 1H), 1.76 - 1.68 (m, 1H), 0.82 (d, J = 6.8 Hz, 3H). Synthesis of Compound 3

[0025] Step 1: Preparation of tert-butyl 4-[(2,5-difluorophenyl)methyl]-4-hydroxy- piperidine-1-carboxylate To isopropyl magnesium chloride (2 M, 6.72 mL, 1.43 eq) in tetrahydrofuran was added a solution of 2-bromo-1,4-difluoro-benzene (1.81 g, 9.38 mmol, 1 eq) in tetrahydrofuran, and the resulting mixture was stirred at 25°C for 6 h. Bromocopper;methylsulfanylmethane (193 mg, 0.9 mmol, 0.1 eq) was added then added, and the resulting mixture was stirred for 10 minutes at 25°C. A solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2 g, 9.38 mmol, 1 eq) in tetrahydrofuran was then added over a period of 5 min, maintaining the temperature at 25°C, and the reaction mixture was stirred at 25°C for 12 h. Saturated aqueous NH4Cl (20 ml) was added, and the resulting mixture was extracted with ethyl acetate (20 mL*2). The combined organic extracts were washed with brine (40 mL), dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give the tert-butyl 4-[(2,5-difluorophenyl)methyl]-4-hydroxy-piperidine-1-carboxylate (2.23 g, 6.80 mmol, 73% yield) as a yellow oil. LC / MS (ESI) m / z: 254.0 [M -73]+. Step 2: Preparation of 5-fluorospiro[3H-benzofuran-2,4'-piperidine] A mixture of tert-butyl 4-[(2,5-difluorophenyl)methyl]-4-hydroxy-piperidine-1-carboxylate (1 g, 3.05 mmol, 1 eq) and potassium tert-butoxide (1 g, 9.16 mmol, 3 eq) in 1,2- dimethoxyethane (15 mL) was stirred at 60 °C for 12 h. The material was collected by filtration and then treated with concentrated hydrochloric acid. The resulting mixture was concentrated, and the resulting residue was purified by prep-HPLC (column: YMC Triart C18250*50 mm*7 µm; mobile phase: [1-35% CH3CN in water (HCl)]) to afford 5- fluorospiro[3H-benzofuran-2,4'-piperidine] (50 mg, 0.2 mmol, 7% yield, HCl salt) as a white solid. LC / MS (ESI) m / z: 208.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 9.84 - 9.44 (m, 2H), 6.92 - 6.80 (m, 2H), 6.68 (dd, J = 4.0, 8.8 Hz, 1H), 3.48 - 3.36 (m, 4H), 3.08 (s, 2H), 2.32 - 2.2 (m, 2H), 2.16 - 2.12 (m, 2H). Step 3: Preparation of 7-(5-fluorospiro[3H-benzofuran-2,4'-piperidine]-1'-yl)-2,4- dimethyl-5-oxo-thiazolo[5,4-b]pyridine-6-carbonitrile (Compound 3) The title compound was prepared in an analogous manner to 2,4-dimethyl-5-oxo-7-spiro[3H- benzofuran-2,4'-piperidine]-1'-yl-thiazolo[5,4-b]pyridine-6-carbonitrile starting from 5- fluorospiro[3H-benzofuran-2,4'-piperidine]. (off-white solid). LC / MS (ESI) m / z: 411.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.08 (dd, J = 2.8, 8.4 Hz, 1H), 6.92 (dt, J = 2.8, 9.2 Hz, 1H), 6.76 (dd, J = 4.4, 8.8 Hz, 1H), 4.12 - 4.04 (m, 2H), 3.96 - 3.88 (m, 2H), 3.48 (s, 3H), 3.12 (s, 2H), 2.72 (s, 3H), 2.04 - 1.96 (m, 4H).

[0026] Synthesis of Compound 4 Preparation of 7-[(3aR,6aR)-2-(4-fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2,4-dimethyl-5-oxo-thiazolo[5,4-b]pyridine-6-carbonitrile (Compound 4) Compound 4 racemic The title compound was prepared in an analogous manner to 2,4-dimethyl-5-oxo-7-spiro[3H- benzofuran-2,4'-piperidine]-1'-yl-thiazolo[5,4-b]pyridine-6-carbonitrile starting from 5-(4- fluorophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole. (white solid). LC / MS (ESI) m / z: 410.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.01 (t, J = 8.8 Hz, 2H), 6.49 (dd, J = 4.4, 9.2 Hz, 2H), 4.18 (dd, J = 5.6, 9.2 Hz, 2H), 4.11 - 4.01 (m, 2H), 3.50 - 3.44 (m, 5H), 3.20 - 3.12 (m, 2H), 2.69 (s, 3H), 2.48 - 2.39 (m, 2H).

[0027] Synthesis of Compound 6 Step 1: Preparation of tert-butyl (3S,4R)-4-(4-chloro-N-methyl-anilino)-3-methyl- piperidine-1-carboxylate To a mixture of tert-butyl (3S,4R)-4-(4-chloroanilino)-3-methyl-piperidine-1-carboxylate (120 mg, 0.37 mmol, 1 eq), formaldehyde (149.89 mg, 1.85 mmol, 0.14 mL, 37% purity, 5 eq), and sodium cyanoborohydride (70 mg, 1.11 mmol, 3 eq) in methanol (1 mL) and tetrahydrofuran (1 mL) was added acetic acid (53 mg, 0.88 mmol, 0.05 mL, 2.37 eq), and the reaction mixture was stirred at 40 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give tert-butyl (3S,4R)-4-(4-chloro- N-methyl-anilino)-3-methyl-piperidine-1-carboxylate (100 mg, 0.30 mmol, 80% yield) as colorless oil. LC / MS (ESI) m / z: 339.0 [M+H]+.1H NMR (400MHz, DMSO-d6) δ 7.22 - 7.13 (m, 2H), 6.80 - 6.69 (m, 2H), 4.10 (d, J = 2.4 Hz, 1H), 3.89 - 3.81 (m, 1H), 3.81 - 3.65 (m, 1H), 3.17 - 2.96 (m, 1H), 2.95 - 2.78 (m, 1H), 2.77 (s, 3H), 2.12 (s, 1H), 2.04 - 1.96 (m, 1H), 1.49 (dd, J = 2.4, 12.4 Hz, 1H), 1.40 (s, 9H), 0.80 (d, J = 7.2 Hz, 3H). Step 2: Preparation of (3S,4R)-N-(4-chlorophenyl)-N,3-dimethyl-piperidin-4-amine A mixture of tert-butyl (3S,4R)-4-(4-chloro-N-methyl-anilino)-3-methyl-piperidine-1- carboxylate (100 mg, 0.30 mmol, 1 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 45.77 eq) in dichloromethane (1 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give (3S,4R)-N-(4-chlorophenyl)-N,3-dimethyl- piperidin-4-amine (100 mg, crude, TFA salt) as a colorless oil. LC / MS (ESI) m / z: 239.0 [M+H]+. Step 3: Preparation of 6-chloro-4-[(3S,4R)-4-(4-chloro-N-methyl-anilino)-3-methyl- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 6) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3S,4R)-N-(4- chlorophenyl)-N,3-dimethyl-piperidin-4-amine. (yellow solid). LC / MS (ESI) m / z: 456.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 9.2 Hz, 2H), 4.34 (d, J = 12.4 Hz, 1H), 4.14 (td, J = 3.2, 12.4 Hz, 1H), 4.04 - 3.95 (m, 1H), 3.91 - 3.83 (m, 1H), 3.53 (s, 3H), 3.45 (t, J = 11.6 Hz, 1H), 2.85 (s, 3H), 2.78 - 2.69 (m, 1H), 2.33 (d, J = 3.6 Hz, 1H), 1.82 - 1.72 (m, 1H), 0.87 (d, J = 6.8 Hz, 3H). Synthesis of Compound 7 Step 1: Preparation of tert-butyl (3aR,4R,6aS)-4-methyl-2-[4- (trifluoromethoxy)phenyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5- carboxylate To a mixture of tert-butyl (3aR,4R,6aS)-4-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4- c]pyrrole-5-carboxylate (257 mg, 1.14 mmol, 1 eq) ,1-bromo-4-(trifluoromethoxy)benzene (274 mg, 1.14 mmol, 0.2 mL, 1 eq), and Cs2CO3(1.11 g, 3.41 mmol, 3 eq) in N,N- dimethylacetamide (2.5 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro- 2H-imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (55 mg, 0.06 mmol, 0.05 eq) under nitrogen atmosphere, and the suspension was degassed and purged with nitrogen (3X). The reaction mixture was stirred at 80°C for 3 h under N2. The mixture was diluted with water (6 mL) and extracted with ethyl acetate (6 mL*2). The combined organic extracts were washed with brine (12 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography(gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give tert-butyl (3aR,4R,6aS)-4-methyl-2-[4- (trifluoromethoxy)phenyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (181 mg, 0.55 mmol, 41% yield) as a yellow oil. LC / MS (ESI) m / z: 387.2 [M+H]+. Step 2: Preparation of (3R,3aR,6aR)-3-methyl-5-[4-(trifluoromethoxy)phenyl]- 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole A mixture of tert-butyl (3aR,4R,6aS)-4-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (90 mg, 0.23 mmol, 1 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 57.99 eq) in dichloromethane (1 mL) was stirred at 25°C for 15 minutes. The mixture was concentrated under vacuum to give (3R,3aR,6aR)-3-methyl-5- [4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (100 mg, crude, TFA salt) as a red oil. LC / MS (ESI) m / z: 287.3 [M+H]+.

[0028] Step 3: Preparation of 4-[(3aR,4R,6aS)-4-methyl-2-[[4- (trifluoromethoxy)phenyl]methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]- 6-chloro-1-methyl-1,5-naphthyridin-2-one The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3R,3aR,6aR)-3- methyl-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole and (6-chloro-1-methyl-2-oxo-1,5-naphthyridin-4-yl) trifluoromethanesulfonate. (off-white solid). LC / MS (ESI) m / z: 479.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.61 - 6.53 (m, 2H), 5.63 (s, 1H), 5.06 - 4.90 (m, 1H), 4.00 (dd, J = 8.4, 11.2 Hz, 1H), 3.56 (dd, J = 8.8, 9.6 Hz, 1H), 3.50 - 3.40 (m, 5H), 3.27 - 3.23 (m, 1H), 3.21 (d, J = 4.0 Hz, 1H), 3.13 (dd, J = 6.0, 10.0 Hz, 1H), 2.90 - 2.80 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H). Synthesis of Compound 8

[0029] Step 1: Preparation of tert-butyl (3aS,6aR)-2-[4-(trifluoromethoxy)phenyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate To a solution of tert-butyl (3aS,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5- carboxylate (150 mg, 0.71 mmol, 1 eq) and 1-bromo-4-(trifluoromethoxy)benzene (255 mg, 1.06 mmol, 0.16 mL, 1.5 eq) in dioxane (3 mL) were added Cs2CO3(690 mg, 2.12 mmol, 3 eq) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (34 mg, 0.035 mmol, 0.05 eq), and the reaction mixture was stirred at 100 °C for 4 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to afford tert-butyl (3aS,6aR)-2-[4-(trifluoromethoxy)phenyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (270 mg, crude) as a green oil. LC / MS (ESI) m / z: 372.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 8.8 Hz, 2H), 6.51 - 6.46 (m, 2H), 3.65 (dd, J = 7.2, 11.2 Hz, 2H), 3.51 (d, J = 2.8 Hz, 2H), 3.37 (d, J = 10.4 Hz, 1H), 3.31 - 3.23 (m, 1H), 3.20 (dd, J = 3.2, 9.2 Hz, 2H), 3.00 (s, 2H), 1.46 (s, 9H). Step 2: Preparation of (3aR,6aS)-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole

[0030] To a solution of tert-butyl (3aS,6aR)-2-[4-(trifluoromethoxy)phenyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (120 mg, 0.32 mmol, 1 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 21 eq), and the reaction mixture was stirred at 25 °C for 0.25 h. The mixture was concentrated under reduced pressure to give (3aR,6aS)-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4- c]pyrrole (120 mg, crude, TFA salt) as a brown oil. LC / MS (ESI) m / z: 273.3 [M+H]+. Step 3: 4-[(3aS,6aR)-2-[4-(trifluoromethoxy)phenyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (Compound 8) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3aR,6aS)-5-[4- (trifluoromethoxy)phenyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole. (yellow solid). LC / MS (ESI) m / z: 490.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.61 - 6.54 (m, 2H), 4.51 (dd, J = 6.8, 12.4 Hz, 2H), 4.09 (s, 2H), 3.55 - 3.50 (m, 2H), 3.48 (s, 3H), 3.29 - 3.24 (m, 2H), 3.20 - 3.13 (m, 2H). Synthesis of Compound 9 Step 1: Preparation of WC-ARV-JM-027-C-1, tert-butyl (3aS,6aR)-3a,6a-dimethyl-2- [4-(trifluoromethoxy)phenyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate To a solution of tert-butyl (3aR,6aS)-3a,6a-dimethyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4- c]pyrrole-5-carboxylate (150 mg, 0.62 mmol, 1 eq) and 1-bromo-4- (trifluoromethoxy)benzene (225 mg, 0.93 mmol, 0.14 mL, 1.5 eq) in dioxane (3 mL) were added Cs2CO3(610 mg, 1.87 mmol, 3 eq) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5- dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (30 mg, 0.03 mmol, 0.05 eq), and the reaction mixture was stirred at 100 °C for 4 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to afford tert-butyl (3aS,6aR)-3a,6a-dimethyl-2-[4-(trifluoromethoxy)phenyl]-1,3,4,6-tetrahydropyrrolo[3,4- c]pyrrole-5-carboxylate (85 mg, 0.21 mmol, 34% yield) as a brown oil. LC / MS (ESI) m / z: 401.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 8.8 Hz, 2H), 6.45 - 6.39 (m, 2H), 3.43 - 3.34 (m, 4H), 3.31 - 3.26 (m, 2H), 3.22 (d, J = 9.6 Hz, 2H), 1.44 (s, 9H), 1.13 (s, 6H). Step 2: Preparation of (3aR,6aS)-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole To a solution of tert-butyl (3aS,6aR)-3a,6a-dimethyl-2-[4-(trifluoromethoxy)phenyl]-1,3,4,6- tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate (85 mg, 0.21 mmol, 1 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (77 mg, 6.8 mmol, 0.5 mL, 31.8 eq), and the reaction mixture was stirred at 25 °C for 0.25 h. The mixture was concentrated under reduced pressure to give (3aR,6aS)-3a,6a-dimethyl-5-[4-(trifluoromethoxy)phenyl]-2,3,4,6- tetrahydro-1H-pyrrolo[3,4-c]pyrrole (85 mg, crude, TFA salt) as a brown oil. LC / MS (ESI) m / z: 301.2 [M+H]+. Step 3: Preparation of 4-[(3aS,6aR)-3a,6a-dimethyl-2-[4-(trifluoromethoxy)phenyl]- 1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (Compound 9) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3aR,6aS)-3a,6a- dimethyl-5-[4-(trifluoromethoxy)phenyl]-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole. (yellow solid). LC / MS (ESI) m / z: 518.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 9.2 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.55 - 6.49 (m, 2H), 4.35 - 4.30 (m, 2H), 4.24 - 4.17 (m, 2H), 3.50 (s, 1H), 3.49 - 3.46 (m, 4H), 3.26 (d, J = 10.4 Hz, 2H), 1.17 (s, 6H). Synthesis of Compound 10 Step 1: Preparation of ethyl 2-methyl-5-(methylamino)thiazole-4-carboxylate To a mixture of ethyl 5-amino-2-methyl-thiazole-4-carboxylate (15 g, 80.55 mmol, 1 eq) in tetrahydrofuran (150 mL) was added sodium hydride (4.19 g, 104.71 mmol, 60% purity, 1.3 eq) in portions, and the mixture was stirred at 0°C for 0.5 h. Iodomethane (19.44 g, 136.93 mmol, 8.52 mL, 1.7 eq) was then added, and the reaction mixture was stirred at 20°C for 12 h under nitrogen. The mixture was diluted with saturated aqueous NH4Cl (300 mL), then extracted with ethyl acetate (3 × 300 mL). The combined organic extract was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 3:1 petroleum ether / ethyl acetate) to give ethyl 2-methyl-5-(methylamino)thiazole-4-carboxylate (18 g, 89.88 mmol, 56% yield) as a yellow solid. LC / MS (ESI) m / z: 200.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.31 - 7.15 (m, 1H), 4.48 - 4.33 (m, 2H), 3.03 - 3.00 (m, 3H), 2.63 - 2.50 (m, 3H), 1.46 - 1.34 (m, 3H). Step 2: Preparation of ethyl 5-[(2-cyanoacetyl)-methyl-amino]-2-methyl-thiazole-4- carboxylate A mixture of 2-cyanoacetic acid (3.06 g, 35.95 mmol, 1.2 eq) in acetic anhydride (32.70 g, 320.31 mmol, 30.00 mL, 10.69 eq) was stirred at 80 °C for 0.5 h. Ethyl 2-methyl-5- (methylamino)thiazole-4-carboxylate (6 g, 29.96 mmol, 1 eq) was then added, and the reaction mixture was stirred at 80 °C for 0.5 h under nitrogen. The mixture was concentrated, and the resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give ethyl 5-[(2-cyanoacetyl)-methyl-amino]-2-methyl- thiazole-4-carboxylate (2.5 g, 9.35 mmol, 31% yield) as a yellow solid. LC / MS (ESI) m / z: 268.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 4.47 - 4.40 (m, 2H), 3.43 (d, J = 15.2 Hz, 2H), 3.28 (s, 3H), 2.81 - 2.74 (m, 3H), 1.42 - 1.37 (m, 3H). Step 3: Preparation of 7-hydroxy-2,4-dimethyl-5-oxo-thiazolo[5,4-b]pyridine-6- carbonitrile A mixture of ethyl 5-[(2-cyanoacetyl)-methyl-amino]-2-methyl-thiazole-4-carboxylate (2.5 g, 9.35 mmol, 1 eq) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (1.71 g, 11.22 mmol, 1.69 mL, 1.2 eq) in ethanol (20 mL) was stirred at 20 °C for 0.5 h under nitrogen. The mixture was concentrated, and the resulting residue was purified by prep-HPLC (column: Welch Xtimate C18250*70mm#10µm; mobile phase: [0-30% CH3CN in water (0.225% formic acid)]) to give 7-hydroxy-2,4-dimethyl-5-oxo-thiazolo[5,4-b]pyridine-6-carbonitrile (1.1 g, 4.97 mmol, 53% yield) as a white solid. LC / MS (ESI) m / z: 221.9 [M+1]+.1H NMR (400 MHz, DMSO-d6) δ 3.50 (s, 3H), 2.74 (s, 3H). Step 4: Preparation of (6-cyano-2,4-dimethyl-5-oxo-thiazolo[5,4-b]pyridin-7-yl) trifluoromethanesulfonate To a mixture of 7-hydroxy-2,4-dimethyl-5-oxo-thiazolo[5,4-b]pyridine-6-carbonitrile (1.1 g, 4.97 mmol, 1 eq), triethylamine (1.51 g, 14.92 mmol, 2.08 mL, 3 eq), and 4- dimethylaminopyridine (61 mg, 0.50 mmol, 0.1 eq) in dichloromethane (10 mL) at 0°C was added trifluoromethylsulfonyl trifluoromethanesulfonate (2.81 g, 9.94 mmol, 1.64 mL, 2 eq), and the reaction mixture was stirred at 0°C for 1 h under nitrogen. The mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL*2). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: 10 / 1 to 1:1 etroleum ether / ethyl acetate) to give (6-cyano-2,4-dimethyl-5-oxo-thiazolo[5,4- b]pyridin-7-yl) trifluoromethanesulfonate (1.2 g, 3.40 mmol, 68% yield) as a yellow solid. LC / MS(ESI) m / z: 354.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 3.50 (s, 3H), 2.74 (s, 3H). Step 5: Preparation of 2,4-dimethyl-5-oxo-7-spiro[3H-benzofuran-2,4'-piperidine]-1'- yl-thiazolo[5,4-b]pyridine-6-carbonitrile (Compound 10) A mixture of (6-cyano-2,4-dimethyl-5-oxo-thiazolo[5,4-b]pyridin-7-yl) trifluoromethanesulfonate (80 mg, 0.23 mmol, 1 eq), spiro[3H-benzofuran-2,4'-piperidine] (51 mg, 0.23mmol, 1 eq, hydrogen chloride), and diisopropylethylamine (88 mg, 0.68 mmol, 0.12 mL, 3 eq) in acetonitrile (2 mL) was degassed and purged with nitrogen (3X), then stirred at 40 °C for 4 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with DMF (0.1 mL) and acetonitrile (0.2 mL) at 25°C, then collected by filtration to afford 2,4-dimethyl-5- oxo-7-spiro[3H-benzofuran-2,4'-piperidine]-1'-yl-thiazolo[5,4-b]pyridine-6-carbonitrile (33 mg, 0.082 mmol, 36% yield) as a white solid. LC / MS (ESI) m / z: 393.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.21 (d, J = 7.2 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 6.86 - 6.77 (m, 2H), 4.13 - 4.04 (m, 2H), 3.97 - 3.88 (m, 2H), 3.49 (s, 3H), 3.11 (s, 2H), 2.70 (s, 3H), 2.03 - 1.95 (m, 4H). Synthesis of Compound 11 Compound 11 Step 1: Preparation of tert-butyl (3R,4R)-4-(4-chloro-2-methyl-anilino)-3-methyl- piperidine-1-carboxylate and tert-butyl (3S,4R)-4-(4-chloro-2-methyl-anilino)-3- methyl-piperidine-1-carboxylate To a mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (3 g, 14.07 mmol, 1 eq) and 4-chloro-2-methyl-aniline (2.39 g, 16.88 mmol, 1.2 eq) in methanol (15 mL) and acetic acid (15 mL) was added borane 2-methylpyridine (3.01 g, 28.13 mmol, 2 eq), and the reaction mixture was stirred at 25 °C for 12 h under nitrogen. The mixture was concentrated under vacuum, and the resulting residue was purified by prep-HPLC (column: Welch Xtimate C18250*70mm#10um; mobile phase: [53-88% CH3CN in water (NH4HCO3)]) followed by prep-SFC (column: DAICEL CHIRALPAK AD-H(250mm*30mm,5um); mobile phase: 20% isopropanol (0.1% NH4OH) in CO2) to afford the two diastereomers. Compound tert-butyl (3R,4R)-4-(4-chloro-2-methyl-anilino)-3-methyl-piperidine-1- carboxylate (600 mg, 1.77 mmol, 21% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.02 - 6.97 (m, 2H), 6.61 (d, J = 8.4 Hz, 1H), 4.35 - 4.31 (m, 1H), 3.94 - 3.78 (m, 1H), 3.70 - 3.56 (m, 2H), 3.13 - 2.83 (m, 2H), 2.09 (s, 3H), 2.06 (d, J = 3.6 Hz, 1H), 1.74 - 1.62 (m, 1H), 1.54 (d, J = 3.6 Hz, 1H), 1.39 (s, 9H), 0.76 (d, J = 7.2 Hz, 3H). tert-Butyl (3S,4R)-4-(4-chloro-2-methyl-anilino)-3-methyl-piperidine-1-carboxylate (1.2 g, 3.54 mmol, 43% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.01 - 6.91 (m, 2H), 6.58 (d, J = 9.2 Hz, 1H), 4.54 (d, J = 9.2 Hz, 1H), 3.91 (d, J = 11.6 Hz, 2H), 3.12 – 3.08 (m, 1H), 2.85 (d, J = 1.6 Hz, 1H), 2.06 (s, 3H), 1.88 (dd, J = 3.2, 13.2 Hz, 1H), 1.75 - 1.59 (m, 1H), 1.40 (s, 9H), 1.26 - 1.15 (m, 1H), 0.88 (d, J = 6.4 Hz, 3H). Step 2: Preparation of tert-butyl (3S,4R)-4-(4-chloro-2-methyl-anilino)-3-methyl- piperidine-1-carboxylate and tert-butyl (3R,4S)-4-(4-chloro-2-methyl-anilino)-3- methyl-piperidine-1-carboxylate The enantiomers were separated by prep-SFC(column: DAICEL CHIRALCEL OD(250mm*30mm,10um); mobile phase: 20% isopropanol (0.1% NH4OH) in CO2). Absolute configuration was arbitrarily assigned. tert-Butyl (3S,4R)-4-(4-chloro-2-methyl-anilino)-3-methyl-piperidine-1-carboxylate (780 mg) was obtained as a white solid. LC / MS (ESI) m / z: 339.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.03 - 6.97 (m, 2H), 6.61 (d, J = 8.4 Hz, 1H), 4.38 - 4.32 (m, 1H), 3.92 - 3.75 (m, 1H), 3.71 - 3.56 (m, 2H), 3.34 (s, 3H), 3.17 (d, J = 5.2 Hz, 1H), 3.10 (d, J = 12.0 Hz, 1H), 3.04 - 2.79 (m, 1H), 1.76 - 1.63 (m, 1H), 1.57 - 1.50 (m, 1H), 1.42 - 1.38 (m, 9H), 0.76 (d, J = 7.2 Hz, 3H). tert-Butyl (3R,4S)-4-(4-chloro-2-methyl-anilino)-3-methyl-piperidine-1-carboxylate (630 mg) was obtained as a white solid. LC / MS (ESI) m / z: 339.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.03 - 6.97 (m, 2H), 6.61 (d, J = 8.4 Hz, 1H), 4.34 (d, J = 7.6 Hz, 1H), 3.93 - 3.73 (m, 1H), 3.70 - 3.57 (m, 2H), 3.34 (s, 3H), 3.17 (d, J = 4.8 Hz, 1H), 3.10 (d, J = 12.0 Hz, 1H), 2.89 (s, 1H), 1.74 - 1.62 (m, 1H), 1.57 - 1.49 (m, 1H), 1.39 (s, 9H), 0.76 (d, J = 7.2 Hz, 3H). Step 3: Preparation of (3S,4R)-N-(4-chloro-2-methyl-phenyl)-3-methyl-piperidin-4- amine To a solution of tert-butyl (3S,4R)-4-(4-chloro-2-methyl-anilino)-3-methyl-piperidine-1- carboxylate (100 mg, 0.29 mmol, 1 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 23 eq), and the reaction mixture was stirred at 25 °C for 0.25 h. The mixture was concentrated under vacuum to afford (3S,4R)-N-(4-chloro-2- methyl-phenyl)-3-methyl-piperidin-4-amine (100 mg, crude, TFA salt) as a colorless oil. LC / MS (ESI) m / z: 239.0 [M+H]+. Step 4: Preparation of 6-chloro-4-[(3S,4R)-4-(4-chloro-2-methyl-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 11)

[0031] The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile. (yellow solid). LC / MS (ESI) m / z: 456.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.04 - 6.99 (m, 2H), 6.72 (d, J = 9.2 Hz, 1H), 4.55 (d, J = 8.0 Hz, 1H), 4.18 (d, J = 13.8 Hz, 1H), 4.00 - 3.93 (m, 1H), 3.89 - 3.81 (m, 2H), 3.63 - 3.54 (m, 1H), 3.53 (s, 3H), 2.28 - 2.18 (m, 1H), 2.15 (s, 3H), 2.07 (s, 1H), 1.89 - 1.79 (m, 1H), 0.86 (d, J = 6.8 Hz, 3H). Synthesis of Compound 12 Synthesis of 6-chloro-4-[(3S,4S)-4-(4-chloro-2-methyl-anilino)-3-methyl-1-piperidyl]- 1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 12) The title compound was prepared in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4- chloro-2-methyl-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile starting from tert-butyl (3S,4S)-4-(4-chloro-2-methyl-anilino)-3-methyl- piperidine-1-carboxylate. (yellow solid). LC / MS (ESI) m / z: 456.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.05 - 6.93 (m, 2H), 6.75 - 6.65 (m, 1H), 4.75 (d, J = 9.2 Hz, 1H), 4.37 - 4.20 (m, 2H), 3.66 - 3.55 (m, 1H), 3.53 (s, 3H), 3.19 - 3.11 (m, 1H), 2.26 - 2.16 (m, 1H), 2.13 - 2.06 (m, 4H), 1.69 - 1.55 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H). Synthesis of Compound 13 Preparation of 6-chloro-4-[(3S,4S)-4-(4-chloro-2-methoxy-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 13) The title compound was prepared in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4- chloro-2-methoxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile starting from tert-butyl (3S,4S)-4-(4-chloro-2-methoxy-anilino)-3-methyl- piperidine-1-carboxylate. (yellow solid). LC / MS (ESI) m / z: 472.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.8 (d, J = 9.2 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.80 - 6.76 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.76 (d, J = 9.6 Hz, 1H), 4.32 - 4.2 (m, 2H), 3.80 (s, 3H), 3.64 - 3.56 (m, 1H), 3.52 (s, 3H), 3.4 - 3.32 (m, 1H), 3.16 (dd, J = 11.2, 12.8 Hz, 1H), 2.16 - 2.04 (m, 2H), 1.64 - 1.52 (m, 1H), 0.96 (d, J = 6.4 Hz, 3H). Synthesis of Compound 14 Preparation of 6-chloro-4-[(3R,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 14)

[0032] The title compound was prepared in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4- chloro-2-methoxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile starting from tert-butyl (3R,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl- piperidine-1-carboxylate. (yellow solid). LC / MS (ESI) m / z: 472.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.80 - 6.76 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.76 (d, J = 9.6 Hz, 1H), 4.24 (t, J = 13.6 Hz, 2H), 3.80 (s, 3H), 3.6 - 3.56 (m, 1H), 3.52 (s, 3H), 3.4 - 3.36 (m, 1H), 3.16 (t, J = 12.0 Hz, 1H), 2.16 - 2.04 (m, 2H), 1.64 - 1.52 (m, 1H), 0.96 (d, J = 6.4 Hz, 3H). Synthesis of Compound 15 Preparation of 2,4-dimethyl-5-oxo-7-spiro[indane-2,4'-piperidine]-1'-yl-thiazolo[5,4- b]pyridine-6-carbonitrile (Compound 15) The title compound was prepared in an analogous manner to 2,4-dimethyl-5-oxo-7-spiro[3H- benzofuran-2,4'-piperidine]-1'-yl-thiazolo[5,4-b]pyridine-6-carbonitrile starting from 1,3- dihydrospiro[indene-2,4'-piperidine] and (6-cyano-2,4-dimethyl-5-oxo-thiazolo[5,4- b]pyridin-7-yl) trifluoromethanesulfonate. (off-white solid). LC / MS (ESI) m / z: 391.1 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 7.24 - 7.17 (m, 2H), 7.15 - 7.09 (m, 2H), 3.94 (s, 4H), 3.48 (s, 3H), 2.88 (s, 4H), 2.69 (s, 3H), 1.78 - 1.72 (m, 4H). Synthesis of Compound 16 Preparation of 6-chloro-4-[(3R,4R)-4-(4-chloro-2-methyl-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 16) The title compound was prepared in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4- chloro-2-methyl-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile starting from tert-butyl (3R,4R)-4-(4-chloro-2-methyl-anilino)-3-methyl- piperidine-1-carboxylate. (yellow solid). LC / MS (ESI) m / z: 456.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.06 - 6.92 (m, 2H), 6.73 - 6.67 (m, 1H), 4.75 (d, J = 9.2 Hz, 1H), 4.35 - 4.21 (m, 2H), 3.64 - 3.56 (m, 1H), 3.53 (s, 3H), 3.15 (dd, J = 11.2, 12.8 Hz, 1H), 2.28 - 2.17 (m, 1H), 2.16 - 2.10 (m, 1H), 2.09 (s, 3H), 1.67 - 1.55 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H). Synthesis of Compound 17 Preparation of 6-chloro-4-[(3R,4S)-4-(4-chloro-2-methoxy-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 17)

[0033] The title compound was prepared in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4- chloro-2-methoxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile starting from tert-butyl (3R,4S)-4-(4-chloro-2-methoxy-anilino)-3-methyl- piperidine-1-carboxylate. (off-white solid). LC / MS (ESI) m / z: 472.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.84 - 6.76 (m, 1H), 6.76 - 6.68 (m, 1H), 4.6 (d, J = 8.8 Hz, 1H), 4.16 - 4.04 (m, 1H), 3.92 - 3.8 (m, 6H), 3.6 (t, J = 10 Hz, 1H), 3.52 (s, 3H), 2.32 (dd, J = 1.6, 3.6 Hz, 1H), 2.08 (d, J = 2.8 Hz, 1H), 1.88 (td, J = 4.4, 8.8 Hz, 1H), 0.76 (s, 3H). Synthesis of Compound 18 Preparation of 6-chloro-4-[(3S,4R)-4-(4-chloro-2-methyl-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 18) C Compound 18 The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile. (yellow solid). LC / MS (ESI) m / z: 456.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.04 - 6.99 (m, 2H), 6.72 (d, J = 9.2 Hz, 1H), 4.55 (d, J = 8.0 Hz, 1H), 4.18 (d, J = 13.8 Hz, 1H), 4.00 - 3.93 (m, 1H), 3.89 - 3.81 (m, 2H), 3.63 - 3.54 (m, 1H), 3.53 (s, 3H), 2.28 - 2.18 (m, 1H), 2.15 (s, 3H), 2.07 (s, 1H), 1.89 - 1.79 (m, 1H), 0.86 (d, J = 6.8 Hz, 3H). Synthesis of Compound 19 Step 1: Preparation of tert-butyl (3S,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl- piperidine-1-carboxylate and tert-butyl (3R,4R)-4-(4-chloro-2-methoxy-anilino)-3- methyl-piperidine-1-carboxylate A mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (3 g, 14.07 mmol, 1 eq), 4- chloro-2-methoxy-aniline (2.22 g, 14.07 mmol, 1 eq), and borane 2-methylpyridine (3 g, 28.13 mmol, 2 eq) in methanol (15 mL) and acetic acid (15 mL) and stirred at 25 °C for 12 h. The mixture was concentrated under vacuum, and the crude product was diluted with water (40 mL) and extracted with ethyl acetate (40 mL*2). The combined organic extracts were washed with brine (80 mL), dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: YMC Triart C18 70*250 mm*7 µm; mobile phase: [51-81% CH3CN in water (NH4HCO3)]) followed by SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm,5 um); mobile phase: 20% isopropanol (0.1% NH4OH) in CO2) to afford the diastereomers. tert-Butyl (3S,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl-piperidine-1-carboxylate (1.57 g, 4.42 mmol, 31% yield) was obtained as an off-white oil.1H NMR (400 MHz, DMSO-d6) δ 6.88 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 2.4, 8.4 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 4.48 (d, J = 8.8 Hz, 1H), 3.8 (s, 3H), 3.68 - 3.52 (m, 2H), 3.32 (s, 1H), 3.16 - 3.08 (m, 1H), 3 - 2.84 (m, 1H), 2.12 - 2.0 (m, 1H), 1.68 - 1.48 (m, 2H), 1.40 (s, 9H), 0.76 (d, J = 7.2 Hz, 3H). tert-Butyl (3R,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl-piperidine-1-carboxylate (624 mg, 1.76 mmol, 13% yield) was obtained as an off-white oil.1H NMR (400 MHz, DMSO- d6) δ 6.84 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 2.4, 8.4 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.68 (d, J = 9.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 2H), 3.80 (s, 3H), 3.12 - 3.00 (m, 1H), 2.88 - 2.76 (m, 1H), 1.88 - 1.8 (m, 1H), 1.68 - 1.52 (m, 1H), 1.40 (s, 9H), 1.24 - 1.08 (m, 2H), 0.84 (d, J = 6.4 Hz, 3H). Step 2: Preparation of tert-butyl (3S,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl- piperidine-1-carboxylate tert-butyl (3R,4S)-4-(4-chloro-2-methoxy-anilino)-3-methyl- piperidine-1-carboxylate The enantiomers were separated by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm,10 um); mobile phase: 20% isopropanol in CO2). Absolute configuration was arbitrarily assigned. tert-Butyl (3S,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl-piperidine-1-carboxylate (731 mg, 2.06 mmol, 46% yield) was obtained as an off-white oil. LC / MS (ESI) m / z: 299.0 [M- 55]+. tert-Butyl (3R,4S)-4-(4-chloro-2-methoxy-anilino)-3-methyl-piperidine-1-carboxylate (758 mg, 2.14 mmol, 48% yield) was obtained as an off-white oil. LC / MS (ESI) m / z: 299.0 [M- 55]+. Step 3: Preparation of (3S,4R)-N-(4-chloro-2-methoxy-phenyl)-3-methyl-piperidin-4- amine A mixture of tert-butyl (3S,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl-piperidine-1- carboxylate (100 mg, 0.28 mmol, 1 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 47.93 eq) in dichloromethane (1 mL) was stirred at 25°C for 15 minutes. The mixture was concentrated under vacuum to give (3S,4R)-N-(4-chloro-2-methoxy-phenyl)-3-methyl- piperidin-4-amine (120 mg, crude, TFA salt) as a red oil. LC / MS (ESI) m / z: 255.1 [M+H]+Step 4: Preparation of 6-chloro-4-[(3S,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 19) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3S,4R)-N-(4- chloro-2-methoxy-phenyl)-3-methyl-piperidin-4-amine. (white solid). LC / MS (ESI) m / z: 472.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.8 (d, J = 9.2 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.84 - 6.76 (m, 1H), 6.76 - 6.72 (m, 1H), 4.6 (d, J = 8.8 Hz, 1H), 4.08 (d, J = 12.4 Hz, 1H), 3.88 - 3.8 (m, 6H), 3.64 - 3.56 (m, 1H), 3.52 (s, 3H), 2.32 (s, 1H), 2.2 - 2.08 (m, 1H), 1.92 - 1.80 (m, 1H), 0.84 (d, J = 7.2 Hz, 3H). Synthesis of Compounds 21 and 20

[0034] Step 1: Preparation of tert-butyl (3S,4R)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl- piperidine-1-carboxylate and tert-butyl (3R,4R)-4-(4-fluoro-2-hydroxy-anilino)-3- methyl-piperidine-1-carboxylate A mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (3 g, 14.1 mmol, 1 eq) , 2- amino-5-fluoro-phenol (2.68 g, 21 mmol, 1.5 eq), and acetic acid (84.47 mg, 1.41 mmol, 0.08 mL, 0.1 eq) in CH3OH (30 mL) was stirred at 50 °C for 0.5 h. Sodium cyanoborohydride (2.65 g, 42 mmol, 3 eq) was then added, and the reaction mixture was stirred at 50 °C for 12 h. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL*4). The combined organic extracts were washed with brine (300 mL*2), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: YMC Triart C18250*50mm*7um; mobile phase: [37-67% CH3CN in water (NH4HCO3)]) to afford the desired products. tert-Butyl (3S,4R)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl-piperidine-1-carboxylate (1 g, 3 mmol, 22% yield) was obtained as a brown oil.1H NMR (400 MHz, DMSO-d6) δ 9.84 (d, J = 2.0 Hz, 1H), 6.56 - 6.49 (m, 2H), 6.47 - 6.40 (m, 1H), 4.12 - 4.01 (m, 2H), 3.63 - 3.50 (m, 2H), 3.09 (d, J = 12.0 Hz, 1H), 2.08 - 2.00 (m, 1H), 1.60 - 1.49 (m, 2H), 1.39 (s, 9H), 0.75 (d, J = 6.8 Hz, 3H). tert-Butyl (3R,4R)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl-piperidine-1-carboxylate (480 mg, 1.48 mmol, 11% yield) was obtained as a brown oil. LC / MS (ESI) m / z: 269.0 (M-55)+.1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 6.52 - 6.46 (m, 2H), 6.45 - 6.39 (m, 1H), 4.11 (d, J = 9.2 Hz, 1H), 3.88 (d, J = 12.4 Hz, 2H), 3.04 - 2.92 (m, 1H), 2.90 - 2.73 (m, 1H), 1.88 (dd, J = 3.2, 13.2 Hz, 1H), 1.59 - 1.52 (m, 1H), 1.40 (s, 9H), 1.14 - 1.06 (m, 1H), 0.89 (d, J = 6.4 Hz, 3H). Step 2: Preparation of 5-fluoro-2-[[(3S,4R)-3-methyl-4-piperidyl]amino]phenol To a solution of tert-butyl (3S,4R)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl-piperidine-1- carboxylate (400 mg, 1.23 mmol, 1 eq) in dichloromethane (4 mL) was added trifluoroacetic acid (3.08 g, 27 mmol, 2 mL, 22 eq), and the reaction mixture was stirred at 25 °C for 0.25 h. The mixture was concentrated under reduced pressure to give 5-fluoro-2-[[(3S,4R)-3-methyl- 4-piperidyl]amino]phenol (400 mg, crude, TFA salt) as a brown oil. LC / MS (ESI) m / z: 225.1 [M+H]+.

[0035] Step 3: Preparation of 6-chloro-4-[(3S,4R)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile. (yellow solid). LC / MS MS (ESI) m / z: 442.0 [M+H]+. Step 4: Preparation of 6-chloro-4-[(3S,4R)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 21) and 6- chloro-4-[(3R,4S)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2- oxo-1,5-naphthyridine-3-carbonitrile (Compound 20) The enantiomers were separated by prep-HPLC (column: DAICEL CHIRALPAK AD(250mm*30mm, 10 µm); mobile phase: [0.1% NH4OH in ethanol]; B%: 50%-50%, 3.2; 30 min). The enantiomers were further purified by prep-HPLC(column: Phenomenex luna C18150*25mm* 10um; mobile phase: [31-61% CH3CN in water (0.225% formic acid)]). Absolute configuration was arbitrarily assigned. 6-Chloro-4-[(3S,4R)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (30 mg, 0.07 mmol, 29% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 442.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.04 - 9.64 (m, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 6.64 (d, J = 6.0, 8.8 Hz, 1H), 6.57 - 6.51 (m, 1H), 6.47 (t, J = 2.8, 8.8 Hz, 1H), 4.18 (d, J = 9.2 Hz, 1H), 4.11 - 4.00 (m, 1H), 3.92 - 3.74 (m, 3H), 3.63 - 3.55 (m, 1H), 3.52 (s, 3H), 2.30 (s, 1H), 2.12 - 2.02 (m, 1H), 1.90 - 1.82 (m, 1H), 0.84 (d, J = 7.2 Hz, 3H). 6-Chloro-4-[(3R,4S)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (40 mg, 0.09 umol, 39% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 442.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.2 (dd, J = 2.4, 12.0 Hz, 1H), 7.0 (dd, J = 1.2, 8.8 Hz, 1H), 6.8 (t, J = 9.2 Hz, 1H), 5.2 (d, J = 7.2 Hz, 1H), 3.72 - 3.56 (m, 2H), 3.2 - 3.00 (m, 1H), 2.96 - 2.8 (m, 1H), 2.08 - 2.00 (m, 1H), 1.76 - 1.60 (m, 1H), 1.56 - 1.48 (m, 2H), 1.40 (s, 9H), 0.76 (d, J = 6.8 Hz, 3H). Synthesis of Compound 22 Preparation of 6-chloro-4-[(3R,4S)-4-(4-chloro-2-fluoro-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 22) The title compound was made in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4-chloro-2- fluoro-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from tert-butyl (3R,4S)-4-(4-chloro-2-fluoro-anilino)-3-methyl-piperidine-1- carboxylate. (off-white solid). LC / MS (ESI) m / z: 460 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.20 (dd, J = 2.4, 11.6 Hz, 1H), 7.00 (dd, J = 1.6, 8.8 Hz, 1H), 6.96 - 6.88 (m, 1H), 5.52 - 5.44 (m, 1H), 4.20 - 4.08 (m, 1H), 3.96 (dd, J = 5.2, 13.2 Hz, 1H), 3.92 - 3.76 (m, 2H), 3.60 (t, J = 10.4 Hz, 1H), 3.52 (s, 3H), 2.32 (d, J = 2.0 Hz, 1H), 2.28 - 2.16 (m, 1H), 1.92 - 1.76 (m, 1H), 0.84 (d, J = 6.8 Hz, 3H). Synthesis of Compound 23 Step 1: Preparation of tert-butyl (3S,4R)-4-(4-chloro-2-fluoro-anilino)-3-methyl- piperidine-1-carboxylate, tert-butyl (3R,4S)-4-(4-chloro-2-fluoro-anilino)-3-methyl- piperidine-1-carboxylate, tert-butyl (3R,4R)-4-(4-chloro-2-fluoro-anilino)-3-methyl- piperidine-1-carboxylate, tert-butyl (3S,4S)-4-(4-chloro-2-fluoro-anilino)-3-methyl- piperidine-1-carboxylate A mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (3 g, 14.07 mmol, 1 eq), 4- chloro-2-fluoro-aniline (2 g, 14.07 mmol, 1 eq), and borane 2-methylpyridine (3 g, 28.13 mmol, 2 eq) in acetic acid (15 mL) and methanol (15 mL) was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum, and the crude product was diluted with water (40 mL) and extracted with ethyl acetate (40 mL*2). The combined organic extracts were washed with brine (80 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: YMC Triart C1870*250mm*7µm; mobile phase: [51-81% CH3CN in water (NH4HCO3)]) followed by SFC (column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5µm); mobile phase: 20% methanol (0.1% NH4OH) in CO2) to afford the desired four isomers. tert-Butyl (3R,4S)-4-(4-chloro-2-fluoro-anilino)-3- methyl-piperidine-1-carboxylate was further purified by SFC (column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5µm); mobile phase: 20% methanol (0.1% NH4OH) in CO2). tert-Butyl (3S,4S)-4-(4-chloro-2-fluoro-anilino)-3-methyl-piperidine-1-carboxylate was purified by SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 µm); mobile phase: 25% methanol (0.1% NH4OH) in CO2). Absolute configuration was arbitrarily assigned. tert-Butyl (3S,4R)-4-(4-chloro-2-fluoro-anilino)-3-methyl-piperidine-1-carboxylate (333 mg, 0.97 mmol, 7% yield) was obtained as an off-white oil.1H NMR (400 MHz, DMSO-d6) δ 7.2 (dd, J = 2.4, 11.6 Hz, 1H), 7.20 (td, J = 1.2, 8.8 Hz, 1H), 6.80 (t, J = 9.2 Hz, 1H), 5.20 (d, J = 7.2 Hz, 1H), 3.92 - 3.76 (m, 1H), 3.68 (dd, J = 2.8, 13.2 Hz, 1H), 3.64 - 3.56 (m, 1H), 3.08 (d, J = 12.0 Hz, 1H), 2.96 - 2.76 (m, 1H), 2.04 (dd, J = 3.6, 6.8 Hz, 1H), 1.76 - 1.6 (m, 1H), 1.52 - 1.48 (m, 1H), 1.40 (s, 9H), 0.76 (d, J = 7.2 Hz, 3H). tert-Butyl (3R,4S)-4-(4-chloro-2-fluoro-anilino)-3-methyl-piperidine-1-carboxylate (260 mg, 0.76 mmol, 5% yield) was obtained as an off-white oil.1H NMR (400 MHz, DMSO-d6) δ 7.2 (dd, J = 2.4, 11.8 Hz, 1H), 7.0 (dd, J = 1.2, 8.8 Hz, 1H), 6.8 (t, J = 9.2 Hz, 1H), 5.2 (d, J = 7.2 Hz, 1H), 3.72 - 3.56 (m, 2H), 3.2 - 3.00 (m, 1H), 2.96 - 2.8 (m, 1H), 2.08 - 2.00 (m, 1H), 1.76 - 1.60 (m, 1H), 1.56 - 1.48 (m, 2H), 1.40 (s, 9H), 0.76 (d, J = 6.8 Hz, 3H). tert-Butyl (3R,4R)-4-(4-chloro-2-fluoro-anilino)-3-methyl-piperidine-1-carboxylate (107 mg, 0.31 mmol, 2% yield) was obtained as an off-white oil.1H NMR (400 MHz, DMSO-d6) δ 7.2 (dd, J = 2.4, 12.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.8 (t, J = 9.2 Hz, 1H), 5.4 (dd, J = 2.2, 9.2 Hz, 1H), 4.0 - 3.84 (m, 2H), 3.12 (dq, J = 3.6, 9.9 Hz, 1H), 2.92 - 2.72 (m, 1H), 1.84 (dd, J = 3.2, 13.2 Hz, 1H), 1.68 - 1.56 (m, 1H), 1.40 (s, 9H), 1.32 - 1.2 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H). tert-Butyl (3S,4S)-4-(4-chloro-2-fluoro-anilino)-3-methyl-piperidine-1-carboxylate (88 mg, 0.26 mmol, 2% yield) was obtained as an off-white oil.1H NMR (400 MHz, DMSO-d6) δ 7.2 (dd, J = 2.4, 12.0 Hz, 1H), 6.96 (td, J = 1.2, 8.8 Hz, 1H), 6.80 - 6.72 (m, 1H), 5.36 (dd, J = 2.0, 9.2 Hz, 1H), 3.96 - 3.80 (m, 2H), 3.12 (dq, J = 4.0, 9.92 Hz, 1H), 2.92 - 2.72 (m, 1H), 1.84 (dd, J = 3.2, 12.8 Hz, 1H), 1.72 - 1.6 (m, 1H), 1.40 (s, 9H), 1.28 - 1.20 (m, 1H), 0.84 (d, J = 6.4 Hz, 3H) Step 2: Preparation of (3S,4R)-N-(4-chloro-2-fluoro-phenyl)-3-methyl-piperidin-4- amine A mixture of tert-butyl (3S,4R)-4-(4-chloro-2-fluoro-anilino)-3-methyl-piperidine-1- carboxylate (100 mg, 0.29 mmol, 1 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 46.30 eq) in dichloromethane (1 mL) and stirred at 25 °C for 15 minutes. The mixture was concentrated under vacuum to give (3S,4R)-N-(4-chloro-2-fluoro-phenyl)-3-methyl- piperidin-4-amine (120 mg, crude, TFA salt) as a red oil. LC / MS (ESI) m / z: 243.1 [M+H]+. Step 3: Preparation of 6-chloro-4-[(3S,4R)-4-(4-chloro-2-fluoro-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 23)

[0036] A mixture of (3S,4R)-N-(4-chloro-2-fluoro-phenyl)-3-methyl-piperidin-4-amine (120 mg, 0.34 mmol, 1 eq, trifluoroacetic acid), 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (70 mg, 0.28 mmol, 8.19e-1 eq), and diisopropylethylamine (371.00 mg, 2.87 mmol, 0.5 mL, 8.53 eq) in acetonitrile (1.5 mL) was stirred at 40 °C for 3 h. The mixture was concentrated, and the crude product was triturated in DMF, (1 mL) washed with acetonitrile (1 mL*2), and collected by filtration to afford 6-chloro-4-[(3S,4R)-4-(4-chloro-2-fluoro- anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (90.1 mg, 0.19 mmol, 57% yield) as a white solid. LC / MS (ESI) m / z: 460.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.20 (dd, J = 2.4, 11.6 Hz, 1H), 7.2 (dd, J = 2.0, 8.8 Hz, 1H), 6.96 - 6.88 (m, 1H), 5.48 (dd, J = 2.0, 8.4 Hz, 1H), 4.20 - 4.08 (m, 1H), 4.00 - 3.92 (m, 1H), 3.88 - 3.76 (m, 2H), 3.60 - 3.56 (m, 1H), 3.52 (s, 3H), 2.32 - 2.28 (m, 1H), 2.28 - 2.16 (m, 1H), 1.88 - 1.76 (m, 1H), 0.84 (d, J = 6.8 Hz, 3H). Synthesis of Compound 24 Preparation of 1,6-dimethyl-2-oxo-4-spiro[3H-benzofuran-2,4'-piperidine]-1'-yl-1,5- naphthyridine-3-carbonitrile (Compound 24) The title compound was made in an analogous manner to 1,6-dimethyl-2-oxo-4-spiro[indane- 2,4'-piperidine]-1'-yl-1,5-naphthyridine-3-carbonitrile starting from 6-chloro-1-methyl-2-oxo- 4-spiro[3H-benzofuran-2,4'-piperidine]-1'-yl-1,5-naphthyridine-3-carbonitrile. (brown solid). LC / MS (ESI) m / z: 387.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.88 - 6.76 (m, 2H), 4.04 - 3.88 (m, 4H), 3.52 (s, 3H), 3.16 (s, 2H), 2.56 (s, 3H), 2.08 (t, J = 5.6 Hz, 4H). Synthesis of Compound 25 Preparation of 6-chloro-4-[(3S,4R)-4-(4-fluoroanilino)-3-methoxy-1-piperidyl]-1- methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 25) Step 1: Preparation of (3S,4R)-N-(4-fluorophenyl)-3-methoxy-piperidin-4-amine A mixture of tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1-carboxylate (100 mg, 0.31 mmol, 1 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 43.81 eq) in dichloromethane (1 mL) was stirred at 25°C for 15 minutes. The mixture was concentrated under vacuum to give (3S,4R)-N-(4-fluorophenyl)-3-methoxy-piperidin-4-amine (125 mg, crude, TFA salt) as a red oil. LC / MS (ESI) m / z: 255.1 [M+H]+.

[0037] Step 2: Preparation of 6-chloro-4-[(3S,4R)-4-(4-fluoroanilino)-3-methoxy-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 25) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3S,4R)-N-(4- fluorophenyl)-3-methoxy-piperidin-4-amine. (off-white solid). LC / MS (ESI) m / z: 442.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 6.92 (t, J = 8.8 Hz, 2H), 6.80 - 6.64 (m, 2H), 5.44 (d, J = 8.8 Hz, 1H), 4.32 - 4.12 (m, 2H), 3.84 (d, J = 12.4 Hz, 2H), 3.64 (s, 1H), 3.52 (s, 3H), 3.52 - 3.48 (m, 1H), 3.20 (s, 3H), 2.28 - 2.16 (m, 1H), 1.88 - 1.76 (m, 1H). Synthesis of Compound 26 Preparation of 1,6-dimethyl-2-oxo-4-spiro[indane-2,4'-piperidine]-1'-yl-1,5- naphthyridine-3-carbonitrile (Compound 26)

[0038] To a mixture of 6-chloro-1-methyl-2-oxo-4-spiro[indane-2,4'-piperidine]-1'-yl-1,5- naphthyridine-3-carbonitrile (200 mg, 0.49 mmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (372 mg, 1.48 mmol, 0.41 mL, 50% purity, 3 eq) and potassium carbonate (137 mg, 0.99 mmol, 2 eq) in dioxane (2 mL) and water (0.4 mL) was added cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (36 mg, 0.05 mmol, 0.1 eq) under nitrogen. The suspension was degassed under vacuum and purged with nitrogen 3 times. The mixture was then stirred under nitrogen at 90 °C for 12 h. The mixture was collected by filtration, and the residue was purified by prep-HPLC (column: Phenomenex C18 150*25mm*10um; mobile phase: [49-79% CH3CN in water (NH4HCO3)]) to give 1,6- dimethyl-2-oxo-4-spiro[indane-2,4'-piperidine]-1'-yl-1,5-naphthyridine-3-carbonitrile (17.9 mg, 0.05 mmol, 9% yield) as an off-white solid. LC / MS (ESI) m / z: 385.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.24 - 7.20 (m, 2H), 7.16 - 7.12 (m, 2H), 3.92 (s, 4H), 3.52 (s, 3H), 2.92 (s, 4H), 2.54 (s, 3H), 1.84 (t, J = 5.2 Hz, 4H). Synthesis of Compounds 27 Compound 27 Step 1: Preparation of 6-chloro-4-[(3R,4R)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile The title compound was made in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4-fluoro-2- hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from tert-butyl (3R,4R)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl-piperidine-1- carboxylate. (yellow solid). LC / MS (ESI) m / z: 441.9 [M+H]+. Step 2: Preparation of 6-chloro-4-[(3R,4R)-4-(4-fluoro-2-hydroxy-anilino)-3-methyl- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile The enantiomer was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm, 10 um); mobile phase: 50% ethanol (0.1% NH4OH) in CO2) followed by prep-HPLC (column: Welch Ultimate C18150*25mm*5µm; mobile phase: [32-62% CH3CN in water (0.225% formic acid)]) to give 6-chloro-4-[(3R,4R)-4-(4-fluoro-2-hydroxy-anilino)-3- methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (48 mg, 0.11 mmol, 40% yield) as a yellow solid. Absolute configuration was arbitrarily assigned. LC / MS (ESI) m / z: 442.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 6.63 - 6.41 (m, 3H), 4.30 - 4.12 (m, 3H), 3.61 - 3.50 (m, 4H), 3.21 - 3.12 (m, 1H), 2.16 - 2.00 (m, 2H), 1.59 - 1.43 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). Synthesis of Compounds 29 and 28 Preparation of 6-chloro-4-[(3R,4R)-4-(4-chloroanilino)-3-methyl-1-piperidyl]-1- methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 29) and 6-chloro-4- [(3S,4S)-4-(4-chloroanilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (Compound 28) The title compounds were made in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4- chloroanilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile and 6- chloro-4-[(3R,4S)-4-(4-chloroanilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile starting from tert-butyl (3R,4R)-4-(4-chloroanilino)-3-methyl- piperidine-1-carboxylate. 6-Chloro-4-[(3R,4R)-4-(4-chloroanilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (53.7 mg, 0.121 mmol, 27% yield) (Compound 29). (yellow solid). LC / MS (ESI) m / z: 442.1[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.17 - 6.97 (m, 2H), 6.78 - 6.55 (m, 2H), 5.80 (d, J = 8.8 Hz, 1H), 4.33 - 4.15 (m, 2H), 3.62 - 3.54 (m, 1H), 3.52 (s, 3H), 3.29 - 3.23 (m, 1H), 3.21 - 3.10 (m, 1H), 2.17 - 2.09 (m, 1H), 2.06 - 1.96 (m, 1H), 1.57 - 1.43 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H). 6-Chloro-4-[(3S,4S)-4-(4-chloroanilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (50.2 mg, 0.112 mmol, 25% yield, 98% purity) (Compound 28). (yellow solid). LC / MS (ESI) m / z: 442.1[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 5.80 (d, J = 9.2 Hz, 1H), 4.33 - 4.14 (m, 2H), 3.62 - 3.54 (m, 1H), 3.52 (s, 3H), 3.30 - 3.23 (m, 1H), 3.16 (dd, J = 10.8, 12.8 Hz, 1H), 2.18 - 2.08 (m, 1H), 2.07 - 1.92 (m, 1H), 1.55 - 1.44 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H). Synthesis of Compound 30 Preparation of 6-chloro-4-[(3S,4S)-4-(4-chloro-2-fluoro-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 30) The title compound was made in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4-chloro-2- fluoro-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from tert-butyl (3S,4S)-4-(4-chloro-2-fluoro-anilino)-3-methyl-piperidine-1- carboxylate. (yellow solid). LC / MS (ESI) m / z: 460.0 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ 8.04 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.16 (dd, J = 2.4, 11.6 Hz, 1H), 7.00 (dd, J = 2.0, 8.8 Hz, 1H), 6.92 - 6.84 (m, 1H), 5.56 (dd, J = 2.0, 9.2 Hz, 1H), 4.32 - 4.16 (m, 2H), 3.60 - 3.56 (m, 1H), 3.52 (s, 3H), 3.44 - 3.36 (m, 1H), 3.20 - 3.12 (m, 1H), 2.24 - 2.12 (m, 1H), 2.08 - 2.00 (m, 1H), 1.64 (dq, J = 4.0, 12.0 Hz, 1H), 0.96 (d, J = 6.8 Hz, 3H). Synthesis of Compound 31 Step 1: Preparation of tert-butyl 3,4,4-trimethoxypiperidine-1-carboxylate To tert-butyl 3-hydroxy-4,4-dimethoxy-piperidine-1-carboxylate (500 mg, 1.91 mmol, 1 eq) in tetrahydrofuran (6 mL) at 0 °C was added sodium hydride (115 mg, 2.87 mmol, 60% purity, 1.5 eq), and the resulting mixture was stirred at 0 °C for 0.5 h. Iodomethane (543 mg, 3.83 mmol, 0.24 mL, 2 eq) was then added, and the reaction mixture was stirred at 0°C for 1 h under nitrogen. The mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 3:1 petroleum ether / ethyl acetate) to give tert-butyl 3,4,4-trimethoxypiperidine-1-carboxylate (480 mg, 1.74 mmol, 91% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 4.11 (d, J = 14.0 Hz, 1H), 3.88 - 3.66 (m, 1H), 3.31 (s, 3H), 3.29 - 3.19 (m, 2H), 3.10 – 3.08 (m, 6H), 2.90 - 2.69 (m, 1H), 1.68 (d, J = 14.0 Hz, 1H), 1.57 - 1.45 (m, 1H), 1.39 (s, 9H). Step 2: Preparation of tert-butyl 3-methoxy-4-oxo-piperidine-1-carboxylate A mixture of tert-butyl 3,4,4-trimethoxypiperidine-1-carboxylate (330 mg, 1.20 mmol, 1 eq) and 4-methylbenzenesulfonic acid (41 mg, 0.24 mmol, 0.2 eq) in acetone (10 mL) and water (1 mL), was stirred at 80 °C for 1 h. The mixture was concentrated under vacuum to give tert- butyl 3-methoxy-4-oxo-piperidine-1-carboxylate (280 mg, crude) as an off-white oil. Step 3: Preparation of tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1- carboxylate A mixture of tert-butyl 3-methoxy-4-oxo-piperidine-1-carboxylate (280 mg, 1.22 mmol, 1 eq), 4-fluoroaniline (135.70 mg, 1.22 mmol, 0.12 mL, 1 eq), and borane 2-methylpyridine (261 mg, 2.44 mmol, 2 eq) in methanol (1.5 mL) and acetic acid (1.5 mL) was stirred at 25 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (column: Phenomenex luna C18150*25mm* 10µm; mobile phase: [39-69% CH3CN in water (0.225% formic acid)]) to afford tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methoxy- piperidine-1-carboxylate (95 mg, 0.29 mmol, 24% yield) as a gray solid. LC / MS (ESI) m / z: 268.9 (M-55)+.1H NMR (400 MHz, DMSO-d6) δ 6.96 - 6.84 (m, 2H), 6.72 - 6.64 (m, 2H), 5.12 (d, J = 9.2 Hz, 1H), 4.16 (d, J = 13.2 Hz, 1H), 3.96 - 3.76 (m, 1H), 3.56 - 3.44 (m, 1H), 3.40 - 3.36 (m, 1H), 3.28 (s, 3H), 3.00 - 2.72 (m, 2H), 1.60 - 1.48 (m, 2H), 1.40 (s, 9H). Step 4: Preparation of tert-butyl (3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy- piperidine-1-carboxylate A mixture of tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1-carboxylate (90 mg, 0.28 mmol, 1 eq), formaldehyde (68 mg, 0.83 mmol, 0.06 mL, 37% purity, 3 eq), and sodium cyanoborohydride (52 mg, 0.83 mmol, 3 eq) in methanol (1 mL) was stirred at 25°C for 12 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*2). The combined organic extracts were washed with brine (10 mL), dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give tert-butyl (3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy-piperidine-1-carboxylate (89 mg, 0.26 mmol, 95% yield) as a colorless oil. LC / MS (ESI) m / z: 339.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.04 - 6.96 (m, 2H), 6.84 - 6.76 (m, 2H), 4.32 - 4.04 (m, 2H), 3.80 (d, J = 12.0 Hz, 1H), 3.52 - 3.36 (m, 1H), 3.20 (s, 3H), 2.92 (q, J = 13.6 Hz, 1H), 2.80 (s, 3H), 2.04 (d, J = 12.0 Hz, 1H), 1.40 (s, 11H). Step 5: Preparation of (3S,4R)-N-(4-fluorophenyl)-3-methoxy-N-methyl-piperidin-4- amine A mixture of tert-butyl (3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy-piperidine-1- carboxylate (89 mg, 0.26 mmol, 1 eq) and trifluoroacetic acid (2 g, 13.51 mmol, 1 mL, 51.36 eq) in dichloromethane (1 mL) and stirred at 25 C for 15 minutes. The mixture was concentrated under vacuum to give (3S,4R)-N-(4-fluorophenyl)-3-methoxy-N-methyl- piperidin-4-amine (100 mg, crude, TFA salt) as a red oil. LC / MS (ESI) m / z: 239.1 [M+H]+. Step 6: Preparation of 6-chloro-4-[(3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 31) A mixture of (3S,4R)-N-(4-fluorophenyl)-3-methoxy-N-methyl-piperidin-4-amine (100 mg, 0.28 mmol, 1 eq, TFA salt), 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (50 mg, 196.79 µmol, 6.93e-1 eq), and diisopropylethylamine (371.00 mg, 2.87 mmol, 0.5 mL, 10.11 eq) in acetonitrile (1 mL) was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum, and the crude product was triturated in DMF (0.5 mL), washed with acetonitrile (1.5 mL), and collected by filtration to afford 6-chloro-4-[(3S,4R)-4-(4- fluoro-N-methyl-anilino)-3-methoxy-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (60.8 mg, 0.13 mmol, 46% yield) as a yellow solid. LC / MS (ESI) m / z: 456.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.08 - 7.00 (m, 2H), 6.88 (dd, J = 4.4, 9.2 Hz, 2H), 4.48 (dd, J = 2.4, 13.2 Hz, 1H), 4.36 (d, J = 13.6 Hz, 1H), 4.12 (d, J = 11.6 Hz, 1H), 3.80 (d, J = 13.6 Hz, 1H), 3.64 (s, 1H), 3.52 (s, 3H), 3.48 (t, J = 11.6 Hz, 1H), 3.04 (s, 3H), 2.88 (s, 3H), 2.84 - 2.80 (m, 1H), 1.68 (d, J = 9.6 Hz, 1H). Synthesis of Compound 32 Step 1: Preparation of tert-butyl (3S,4R)-3-methyl-4-[4-(trifluoromethoxy) anilino]piperidine-1-carboxylate. A mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (2 g, 9.38 mmol, 1 eq) ,4- (trifluoromethoxy)aniline (1.66 g, 9.38 mmol, 1 mL, 1 eq), sodium cyanoborohydride (884 mg, 14.07 mmol, 1.5 eq), and acetic acid (56 mg, 0.938 mmol, 0.05 mL, 0.1 eq) in methanol (20 mL) was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum, and the crude product was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Welch Xtimate C18250*50mm*10 µm; mobile phase: [35-70% CH3CN in water (TFA)]) to give tert-butyl (3S,4R)-3-methyl-4-[4-(trifluoromethoxy)anilino]piperidine-1- carboxylate (140 mg, 0.374 mmol, 4% yield) as a yellow solid. LC / MS (ESI) m / z: 319.2 (M- 55)+.1H NMR (400 MHz, DMSO-d6) δ 7.04 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 9.2 Hz, 2H), 5.72 (d, J = 8.4 Hz, 1H), 3.52 (dt, J = 4.4, 8.4 Hz, 2H), 3.32 (s, 1H), 3.2 (dd, J = 3.2, 13.2 Hz, 1H), 2.04 - 1.96 (m, 1H), 1.6 - 1.48 (m, 2H), 1.40 (s, 9H), 1.32 - 1.16 (m, 1H), 0.8 (d, J = 6.8 Hz, 3H). Step 2: Preparation of tert-butyl (3S,4R)-3-methyl-4-[N-methyl-4-(trifluoromethoxy) anilino]piperidine-1-carboxylate. A mixture of tert-butyl (3S,4R)-3-methyl-4-[4-(trifluoromethoxy)anilino]piperidine-1- carboxylate (140 mg, 0.37 mmol, 1 eq), formaldehyde (91 mg, 1.12 mmol, 0.084 mL, 37% purity, 3 eq), and sodium cyanoborohydride (71 mg, 1.12 mmol, 3 eq) in methanol (1.5 mL) was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum, and the resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give tert-butyl (3S,4R)-3-methyl-4-[N-methyl-4- (trifluoromethoxy)anilino]piperidine-1-carboxylate (99 mg, 255 mmol, 68% yield) as a white solid. LC / MS (ESI) m / z: 333.1 (M-55)+.1H NMR (400 MHz, DMSO-d6) δ 7.12 (d, J = 8.4 Hz, 2H), 6.8 (d, J = 7.6 Hz, 2H), 4.16 - 3.96 (m, 1H), 3.92 - 3.68 (m, 2H), 3.16 - 3.00 (m, 1H), 2.80 (s, 3H), 2.16 - 1.96 (m, 2H), 1.52 - 1.48 (m, 1H), 1.40 (s, 9H), 1.28 - 1.12 (m, 1H), 0.80 (d, J = 6.0 Hz, 3H). Step 3: Preparation of (3S,4R)-N,3-dimethyl-N-[4- (trifluoromethoxy)phenyl]piperidin-4-amine. A mixture of tert-butyl (3S,4R)-3-methyl-4-[N-methyl-4- (trifluoromethoxy)anilino]piperidine-1-carboxylate (99 mg, 0.26 mmol, 1 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 52.99 eq) in dichloromethane (1 mL) was stirred at 25 °C for 15 minutes. The mixture was concentrated under vacuum to give (3S,4R)- N,3-dimethyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine (110 mg, crude, TFA salt) as a red oil. LC / MS (ESI) m / z: 289.1 [M+H]+. Step 4: Preparation of 6-chloro-1-methyl-4-[(3S,4R)-3-methyl-4-[N-methyl-4- (trifluoromethoxy)anilino]-1-piperidyl]-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 32) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3S,4R)-N,3- dimethyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. (yellow solid). LC / MS (ESI) m / z: 506.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.8 (d, J = 8.8 Hz, 1H), 7.2 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 9.2 Hz, 2H), 4.4 - 4.28 (m, 1H), 4.16 (td, J = 3.6, 12.0 Hz, 1H), 4.04 - 3.96 (m, 1H), 3.92 - 3.84 (m, 1H), 3.52 (s, 3H), 3.48 - 3.44 (m, 1H), 2.88 (s, 3H), 2.76 - 2.64 (m, 1H), 2.4 - 2.28 (m, 1H), 1.80 - 1.72 (m, 1H), 0.88 (d, J = 7.2 Hz, 3H). Synthesis of Compounds 33 and 34

[0039] Step 1: Preparation of tert-butyl (3S,4R)-4-(4-chloroanilino)-3-methyl-piperidine-1- carboxylate and tert-butyl (3R,4R)-4-(4-chloroanilino)-3-methyl-piperidine-1- carboxylate To a mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (2 g, 9.38 mmol, 1 eq) and 4-chloroaniline (1.20 g, 9.38 mmol, 1 eq) in methanol (20 mL) was added sodium cyanoborohydride (1.47 g, 23.44 mmol, 2.5 eq), and the reaction mixture was stirred at 40 °C for 12 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by prep-HPLC (column: Welch Xtimate C18250*50mm*10 µm; mobile phase: [40- 75% CH3CN in water (0.225% formic acid)]) to give the desired products. tert-Butyl (3S,4R)-4-(4-chloroanilino)-3-methyl-piperidine-1-carboxylate (223 mg, 0.69 mmol, 7.3% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.08 - 7.03 (m, 2H), 6.66 - 6.61 (m, 2H), 5.63 (d, J = 8.4 Hz, 1H), 3.79 - 3.60 (m, 1H), 3.57 - 3.47 (m, 2H), 3.30 - 3.27 (m, 1H), 3.16 (dd, J = 3.6, 13.6 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.57 - 1.47 (m, 2H), 1.39 (s, 9H), 0.77 (d, J = 6.8 Hz, 3H). tert-Butyl (3R,4R)-4-(4-chloroanilino)-3-methyl-piperidine-1-carboxylate (153 mg, 0.48 mmol, 5.0% yield) was obtained as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 7.09 - 7.00 (m, 2H), 6.61 - 6.53 (m, 2H), 5.80 - 5.45 (m, 1H), 3.87 (d, J = 13.2 Hz, 2H), 3.08 - 2.96 (m, 1H), 2.86 (s, 1H), 2.63 - 2.52 (m, 1H), 1.93 - 1.84 (m, 1H), 1.51 - 1.43 (m, 1H), 1.40 (s, 9H), 1.15 - 1.02 (m, 1H), 0.89 (d, J = 6.4 Hz, 3H). Step 2: Preparation of (3S,4R)-N-(4-chlorophenyl)-3-methyl-piperidin-4-amine To a solution of tert-butyl (3S,4R)-4-(4-chloroanilino)-3-methyl-piperidine-1-carboxylate (100 mg, 0.31 mmol, 1 eq) in dichloromethane (1 mL) was added dropwise trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 43.87 eq), and the resulting mixture was stirred at 25 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure to give (3S,4R)- N-(4-chlorophenyl)-3-methyl-piperidin-4-amine (100 mg, crude, TFA salt) as a brown oil. Step 3: Preparation of 6-chloro-4-[(3S,4R)-4-(4-chloroanilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile. (yellow solid).1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.10 - 7.05 (m, 2H), 6.75 - 6.70 (m, 2H), 5.90 (d, J = 8.4 Hz, 1H), 4.08 - 3.97 (m, 1H), 3.85 (d, J = 4.4 Hz, 2H), 3.81 - 3.72 (m, 1H), 3.70 - 3.61 (m, 1H), 3.52 (s, 3H), 2.33 - 2.26 (m, 1H), 2.14 - 2.01 (m, 1H), 1.87 - 1.82 (m, 1H), 0.86 (d, J = 7.2 Hz, 3H). Step 4: Preparation of 6-chloro-4-[(3S,4R)-4-(4-chloroanilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 33) and 6- chloro-4-[(3R,4S)-4-(4-chloroanilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (Compound 34) The enantiomers were separated by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10µm); mobile phase: 40% methanol (0.1%NH4OH) in CO2) followed by prep-HPLC (column: Phenomenex luna C18150*25mm* 10µm; mobile phase: [50-80% CH3CN in water (0.225% formic acid)]). Absolute configuration was arbitrarily assigned. 6-Chloro-4-[(3S,4R)-4-(4-chloroanilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (33.8 mg, 0.076 mmol, 39% yield) (Compound 33). (yellow solid). LC / MS (ESI) m / z: 442.1 [M+1]+.1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 8.8 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.80 - 6.63 (m, 2H), 5.94 - 5.86 (m, 1H), 4.06 - 3.96 (m, 1H), 3.85 (d, J = 4.8 Hz, 2H), 3.80 - 3.74 (m, 1H), 3.70 - 3.63 (m, 1H), 3.52 (s, 3H), 2.32 - 2.26 (m, 1H), 2.14 - 2.00 (m, 1H), 1.90 - 1.79 (m, 1H), 0.86 (d, J = 7.2 Hz, 3H). 6-Chloro-4-[(3R,4S)-4-(4-chloroanilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (31.1 mg, 68.37 umol, 35% yield) (Compound 34). (yellow solid). LC / MS (ESI) m / z: 442.1 [M+1]+.1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.72 (d, J = 8.8 Hz, 2H), 5.94 - 5.86 (m, 1H), 4.11 - 3.96 (m, 1H), 3.85 (d, J = 4.8 Hz, 2H), 3.79 - 3.74 (m, 1H), 3.69 - 3.63 (m, 1H), 3.52 (s, 3H), 2.31 - 2.26 (m, 1H), 2.14 - 2.01 (m, 1H), 1.89 - 1.79 (m, 1H), 0.86 (d, J = 7.2 Hz, 3H). Synthesis of Compound 35 Preparation of 6-chloro-4-[(3R,4R)-4-(4-chloro-2-fluoro-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 35) The title compound was made in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4-chloro-2- fluoro-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from tert-butyl (3R,4R)-4-(4-chloro-2-fluoro-anilino)-3-methyl-piperidine-1- carboxylate. (yellow solid). LC / MS (ESI) m / z: 460.0 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ 8.04 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.2 (dd, J = 2.4, 12.0 Hz, 1H), 7.00 (dd, J = 2.0, 8.8 Hz, 1H), 6.92 - 6.84 (m, 1H), 5.56 (dd, J = 2.0, 9.2 Hz, 1H), 4.32 - 4.20 (m, 2H), 3.60 - 3.56 (m, 1H), 3.52 (s, 3H), 3.44 - 3.36 (m, 1H), 3.16 - 3.08 (m, 1H), 2.20 - 2.12 (m, 1H), 2.04 (dd, J = 3.2, 13.2 Hz, 1H), 1.72 - 1.60 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H).

[0040] Synthesis of Compound 36 Step 1: Preparation of tert-butyl 4-(4-chloro-N-methyl-anilino) piperidine-1- carboxylate A mixture of tert-butyl 4-(4-chloroanilino)piperidine-1-carboxylate (200 mg, 0.64 mmol, 1 eq), sodium cyanoborohydride (61 mg, 0.97 mmol, 1.5 eq), and formaldehyde (57 mg, 0.71 mmol, 0.05 mL, 37% purity, 1.1 eq) in methanol (2 mL) was stirred at 25 °C for 12 hours. The mixture was concentrated under vacuum, and the resulting residue was purified by prep- HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [56-86% CH3CN in water (NH4HCO3)]) to give tert-butyl 4-(4-chloro-N-methyl-anilino) piperidine-1-carboxylate (114 mg, 0.351 mmol, 55% yield) as a white solid. LC / MS (ESI) m / z: 268.9 [M-55]+. Step 2: Preparation of (3R,4R)-N-(4-fluorophenyl)-3-methoxy-piperidin-4-amine A mixture of tert-butyl 4-(4-chloro-N-methyl-anilino)piperidine-1-carboxylate (114 mg, 0.35 mmol, 1 eq) and trifluoroacetic acid (80 mg, 0.7 mmol, 0.05 mL, 2 eq) in dichloromethane (1 mL) was stirred at 25°C for 15 minutes. The mixture was concentrated under vacuum to give N-(4-chlorophenyl)-N-methyl-piperidin-4-amine (190 mg, crude, trifluoroacetic acid) as a red oil. LC / MS (ESI) m / z: 225.2 [M+H]+. Step 3: Preparation of 6-chloro-4-[4-(4-chloro-N-methyl-anilino)-1-piperidyl]-2-oxo- 1H-1,5-naphthyridine-3-carbonitrile The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from N-(4- chlorophenyl)-N-methyl-piperidin-4-amine. (yellow solid). LC / MS (ESI) m / z: 442.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 9.2 Hz, 2H), 6.8 (d, J = 9.2 Hz, 2H), 4.28 (d, J = 12.4 Hz, 2H), 4.16 - 4.04 (m, 1H), 3.6 - 3.52 (m, 2H), 3.53 (s, 3H), 2.72 (s, 3H), 2.04 – 2.0 (m, 2H), 1.76 (d, J = 12.4 Hz, 2H). Synthesis of Compound 37 Step 1: Preparation of tert-butyl (3S,4R)-4-(4-fluoro-2-methyl-anilino)-3-methyl- piperidine-1-carboxylate To a solution of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (2 g, 9.38 mmol, 1 eq) and 4-fluoro-2-methyl-aniline (1.17 g, 9.38 mmol, 1.0 eq) in methanol (20 mL) was added sodium cyanoborohydride (1.47 g, 23.44 mmol, 2.5 eq), and the reaction mixture was stirred at 40 °C for 12 hr. The mixture concentrated under reduced pressure, and the resulting residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 µm); mobile phase: [30-95% CH3CN in water (0.225% formic acid)]) to give tert-butyl (3S,4R)-4- (4-fluoro-2-methyl-anilino)-3-methyl-piperidine-1-carboxylate (250 mg, 0.78 mmol, 8% yield) as a brown solid. LC / MS (ESI) m / z: 267.0 [M-55]+.1H NMR (400 MHz, DMSO-d6) δ 6.90 - 6.74 (m, 2H), 6.64 - 6.52 (m, 1H), 4.13 - 4.02 (m, 1H), 3.93 - 3.77 (m, 1H), 3.70 - 3.62 (m, 1H), 3.57 (td, J = 4.4, 8.4 Hz, 1H), 3.29 (s, 1H), 3.13 - 3.05 (m, 1H), 2.98 - 2.84 (m, 1H), 2.11 - 2.07 (m, 3H), 1.70 - 1.62 (m, 1H), 1.58 - 1.51 (m, 1H), 1.40 (s, 9H), 0.77 (d, J = 6.8 Hz, 3H). Step 2: Preparation of tert-butyl (3S,4R)-4-(4-fluoro-N,2-dimethyl-anilino)-3-methyl- piperidine-1-carboxylate To a mixture of tert-butyl (3S,4R)-4-(4-fluoro-2-methyl-anilino)-3-methyl-piperidine-1- carboxylate (150 mg, 0.47 mmol, 1 eq), sodium cyanoborohydride (88 mg, 1.40 mmol, 3 eq), and formaldehyde (189 mg, 2.33 mmol, 0.17 mL, 37% purity, 5 eq) in methanol (1 mL) and tetrahydrofuran (1 mL) was added acetic acid (105 mg, 1.75 mmol, 0.1 mL, 3.76 eq), and the reaction mixture was stirred at 40 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (gradient: 100:1 to 1:1 petroleum ether / ethyl acetate) to give tert-butyl (3S,4R)-4-(4-fluoro- N,2-dimethyl-anilino)-3-methyl-piperidine-1-carboxylate (87 mg, 0.26 mmol, 56 % yield) as a colorless oil. LC / MS (ESI) m / z: 337.1 [M+H]+.1H NMR (400MHz, DMSO-d6) δ 7.23 (dd, J = 5.6, 8.4 Hz, 1H), 7.08 - 6.92 (m, 2H), 4.17 - 3.67 (m, 2H), 3.56 - 3.39 (m, 1H), 2.98 (td, J = 4.0, 11.6 Hz, 1H), 2.93 - 2.74 (m, 1H), 2.41 (s, 3H), 2.23 (s, 3H), 2.14 - 2.00 (m, 1H), 1.37 (s, 9H), 1.31 - 1.23 (m, 1H), 1.21 - 1.11 (m, 1H), 0.83 - 0.74 (m, 3H). Step 3: Preparation of (3S,4R)-N-(4-fluoro-2-methyl-phenyl)-N,3-dimethyl-piperidin- 4-amine A mixture of tert-butyl (3S,4R)-4-(4-fluoro-N,2-dimethyl-anilino)-3-methyl-piperidine-1- carboxylate (90 mg, 0.27 mmol, 1 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1.00 mL, 50.49 eq) in dichloromethane (1 mL) was stirred at 25 °C for 30 min under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give (3S,4R)-N-(4-fluoro- 2-methyl-phenyl)-N,3-dimethyl-piperidin-4-amine (90 mg, crude, TFA salt) as a colorless oil. LC / MS (ESI) m / z: 237.0 [M+H]+. Step 4: Preparation of 6-chloro-4-[(3S,4R)-4-(4-fluoro-N,2-dimethyl-anilino)-3- methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 37) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3S,4R)-N-(4- fluoro-2-methyl-phenyl)-N,3-dimethyl-piperidin-4-amine. (yellow solid). LC / MS (ESI) m / z: 454.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 5.6, 8.8 Hz, 1H), 7.10 - 6.97 (m, 2H), 4.27 - 4.01 (m, 2H), 3.70 - 3.59 (m, 1H), 3.51 (s, 3H), 3.28 - 3.19 (m, 2H), 2.47 (s, 3H), 2.27 (s, 4H), 1.99 - 1.85 (m, 1H), 1.56 - 1.46 (m, 1H), 0.87 (d, J = 6.8 Hz, 3H). Synthesis of Compound 38

[0041] Step 1: Preparation of O2-benzyl O5-tert-butyl (3aR,6aR)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-2,5-dicarboxylate To a mixture of tert-butyl (3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5- carboxylate (500 mg, 2.36 mmol, 1 eq) and triethylamine (715 mg, 7.07 mmol, 0.98 mL, 3 eq) in dichloromethane (10 mL) was added benzyl chloroformate (482 mg, 2.83 mmol, 0.4 mL, 1.2 eq), and the reaction mixture was stirred at 25°C for 12 h under N2. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic extracts were washed with brine (20 mL), dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex C18250*50mm*10 um; mobile phase: [40-70% CH3CN in water (NH4HCO3)]) to afford O2-benzyl O5-tert-butyl (3aR,6aR)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-2,5-dicarboxylate (95 mg, 0.27 mmol, 12% yield) as a colorless oil. LC / MS (ESI) m / z: 291.1 [M-55]+. Step 2: Preparation of benzyl (3aS,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4- c]pyrrole-5-carboxylate To a solution of O2-benzyl O5-tert-butyl (3aR,6aR)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrole-2,5-dicarboxylate (95 mg, 0.27 µmol, 1 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 24.6 eq), and the reaction mixture was stirred at 25 °C for 0.25 h. The mixture was concentrated under reduced pressure to give benzyl (3aS,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (90 mg, crude, TFA salt) as a brown oil. LC / MS (ESI) m / z: 247.0 [M+H]+. Step 3: Preparation of benzyl (3aR,6aR)-2-(4-fluoro-2-methyl-phenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate A mixture of benzyl (3aS,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5- carboxylate (250 mg, 0.69 mmol, 1 eq, trifluoroacetic acid) , 4-fluoro-1-iodo-2-methyl- benzene (245 mg, 1.04 mmol, 1.5 eq), Cs2CO3(1.13 g, 3.47 mmol, 5 eq), and 1,3-bis[2,6- bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (34 mg, 0.03 mmol, 0.05 eq) in dioxane (3 mL) was degassed and purged with nitrogen (3X), and the reaction mixture was stirred at 100 °C for 4 hours under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic extracts were washed with brine (25 mL), dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give benzyl (3aR,6aR)-2-(4-fluoro-2-methyl-phenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (200 mg, crude) as a yellow oil. LC / MS (ESI) m / z: 355.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.42 - 7.30 (m, 5H), 6.87 - 6.76 (m, 3H), 5.21 - 5.13 (m, 2H), 3.82 - 3.73 (m, 2H), 3.39 - 3.31 (m, 2H), 3.21 - 3.13 (m, 4H), 2.42 - 2.31 (m, 2H), 2.28 (s, 3H). Step 4: Preparation of (3aS,6aS)-5-(4-fluoro-2-methyl-phenyl)-2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole To a solution of benzyl (3aR,6aR)-2-(4-fluoro-2-methyl-phenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (200 mg, 564.31 umol, 1 eq) in CH3OH (5 mL) was added palladium on activated carbon catalyst (50 mg, 10% purity) under nitrogen, and the resulting suspension was degassed under vacuum and purged with hydrogen several times. The mixture was then stirred under hydrogen (15 psi) at 30°C for 12 hours. The mixture was concentrated to give (3aS,6aS)-5-(4-fluoro-2-methyl-phenyl)-2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole (120 mg, crude) as a colorless oil. LC / MS (ESI) m / z: 221.1 [M+H]+. Step 5: Preparation of 4-[(3aR,6aR)-2-(4-fluoro-2-methyl-phenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (Compound 38) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3aS,6aS)-5-(4- fluoro-2-methyl-phenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole. (yellow solid). LC / MS (ESI) m / z: 438.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 9.6 Hz, 1H), 6.88 - 6.82 (m, 2H), 4.26 - 4.14 (m, 4H), 3.50 (s, 3H), 3.46 (d, J = 10.0 Hz, 2H), 3.23 - 3.17 (m, 2H), 2.46 - 2.39 (m, 2H), 2.27 (s, 3H). Synthesis of Compound 39

[0042] Step 1: Preparation of tert-butyl 4-[(4-chloro-2-hydroxy-phenyl)methyl]piperazine-1- carboxylate A mixture of tert-butyl piperazine-1-carboxylate (357 mg, 1.92 mmol, 1 eq), 4-chloro-2- hydroxy-benzaldehyde (300 mg, 1.92 mmol, 1 eq), and sodium cyanoborohydride (241 mg, 3.83 mmol, 2 eq) in methanol (3 mL) was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum, and the resulting crude product was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex C18250*50mm*10 µm; mobile phase: [49-79% CH3CN in water (NH4HCO3)]) to give tert-butyl 4-[(4-chloro-2- hydroxy-phenyl)methyl]piperazine-1-carboxylate (530 mg, 1.62 mmol, 85% yield) as a yellow oil. LC / MS (ESI) m / z: 327.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 6.88 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.8 - 6.8 (m, 1H), 3.68 (s, 2H), 3.6 - 3.2 (m, 4H), 2.52 (s, 4H), 1.48 (s, 9H). Step 2: Preparation of 5-chloro-2-(piperazin-1-ylmethyl)phenol A mixture of tert-butyl 4-[(4-chloro-2-hydroxy-phenyl)methyl]piperazine-1-carboxylate (20 mg, 0.06 mmol, 1 eq) and trifluoroacetic acid (154 mg, 1.35 mmol, 0.1 mL, 22.07 eq) in dichloromethane (0.2 mL) was stirred at 20 °C for 0.5 h. The mixture was concentrated to give 5-chloro-2-(piperazin-1-ylmethyl)phenol (21 mg, crude, TFSA salt) as a yellow oil. LC / MS (ESI) m / z: 227.2 [M+H]+. Step 3: Preparation of 7-{4-[(4-chloro-2-hydroxyphenyl)methyl]piperazin-1-yl}-2,4- dimethyl-5-oxo-4H,5H-[1,3]thiazolo[5,4-b]pyridine-6-carbonitrile (Compound 39) The title compound was prepared in an analogous manner to 2,4-dimethyl-5-oxo-7-spiro[3H- benzofuran-2,4'-piperidine]-1'-yl-thiazolo[5,4-b]pyridine-6-carbonitrile starting from 5- chloro-2-(piperazin-1-ylmethyl)phenol. (white solid). LC / MS (ESI) m / z: 430.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.21 (d, J=8.8 Hz, 1H), 6.87 - 6.79 (m, 2H), 3.93 (s, 4H), 3.61 (s, 2H), 3.48 (s, 3H), 2.68 (s, 3H), 2.61 (s, 4H).

[0043] Synthesis of Compound 40 Step 1: Preparation of tert-butyl (3aS,6aR)-2-(4-fluoro-2-methyl-phenyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate To a mixture of tert-butyl (3aS,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5- carboxylate (400 mg, 1.88 mmol, 1 eq), 1-bromo-4-fluoro-2-methyl-benzene (392 mg, 2.07 mmol, 1.1 eq), and potassium carbonate (781 mg, 5.65 mmol, 3 eq) in dioxane (4 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (91 mg, 0.94 mmol, 0.05 eq) under nitrogen atmosphere, and the reaction mixture was degassed, purged with nitrogen (3X), and then stirred at 100 °C for 4 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give tert-butyl (3aS,6aR)-2-(4-fluoro-2-methyl-phenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5- carboxylate (117 mg, 0.37 mmol, 19% yield) as a white solid. LC / MS (ESI) m / z: 265.0 [M- 55]+.1H NMR (400 MHz, CDCl3) δ 6.8 - 6.8 (m, 3H), 3.68 (s, 2H), 3.32 (s, 2H), 3.12 (s, 2H), 2.92 (s, 4H), 2.28 (s, 3H), 1.44 (s, 9H). Step 2: Preparation of (3aR,6aS)-5-(4-fluoro-2-methyl-phenyl)-2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole A mixture of tert-butyl (3aS,6aR)-2-(4-fluoro-2-methyl-phenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (110 mg, 0.34 mmol, 1 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 1 eq) in dichloromethane (1 mL) was stirred at 25℃ for 15 minutes. The mixture was concentrated under vacuum to give (3aR,6aS)-5-(4-fluoro-2- methyl-phenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (190 mg, crude, TFA salt) as a red oil. LC / MS (ESI) m / z: 221.0 (M+H)+. Step 3 Preparation of 6-chloro-4-((3aR,6aS)-5-(4-fluoro-2- methylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-methyl-2-oxo-1,2-dihydro- 1,5-naphthyridine-3-carbonitrile (Compound 40) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3aR,6aS)-5-(4- fluoro-2-methyl-phenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole. (yellow solid). LC / MS (ESI) m / z: 438.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.0 (d, J = 8.4 Hz, 1H), 7.8 (d, J = 8.8 Hz, 1H), 7.2 - 6.8 (m, 3H), 4.48 - 4.36 (m, 2H), 4.28 (d, J = 12.0 Hz, 2H), 3.52 (s, 3H), 3.16 (d, J = 6.0 Hz, 2H), 3.08 (d, J = 9.2 Hz, 4H), 2.16 (s, 3H).

[0044] Synthesis of Compound 41 Step 1: Preparation of O5-benzyl O1-tert-butyl 3,3a,4,6,7,7a-hexahydro-2H- pyrrolo[3,2-c]pyridine-1,5-dicarboxylate To a mixture of tert-butyl 2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridine-1-carboxylate (250 mg, 1.10 mmol, 1 eq) and triethylamine (223 mg, 2.21 mmol, 0.31 mL, 2 eq) in dichloromethane (5 mL) was added benzyl chloroformate (226 mg, 1.33 mmol, 0.19 mL, 1.2 eq) dropwise, and the reaction mixture stirred at 20 °C for 12 h under N2. The mixture was concentrated, and the resulting residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [42-72% CH3CN in water (NaHCO3)]) to give O5-benzyl O1-tert-butyl 3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-1,5-dicarboxylate (170 mg, 0.47 mmol, 43% yield) as a yellow solid. LC / MS (ESI) m / z: 383.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.38 - 7.29 (m, 5H), 5.14 (d, J=3.2 Hz, 2H), 3.93 (s, 3H), 3.47 - 3.27 (m, 3H), 3.02 - 2.75 (m, 1H), 2.40 - 2.19 (m, 1H), 2.05 - 1.92 (m, 1H), 1.91 - 1.75 (m, 2H), 1.66 - 1.58 (m, 1H), 1.46 (s, 9H). Step 2: Preparation of benzyl 1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridine-5- carboxylate A mixture of O5-benzyl O1-tert-butyl 3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine- 1,5-dicarboxylate (170 mg, 0.47 mmol, 1 eq) and trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 57.27 eq) in dichloromethane (2 mL) was stirred at 25 °C for 15 minutes. The mixture was concentrated under vacuum to give benzyl 1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2- c]pyridine-5-carboxylate (200 mg, crude, TFA salt) as a red oil. LC / MS (ESI) m / z: 261.0 [M+H]+. Step 3: Preparation of benzyl 1-(4-fluorophenyl)-3,3a,4,6,7,7a-hexahydro-2H- pyrrolo[3,2-c]pyridine-5-carboxylate

[0045] To a mixture of benzyl 1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridine-5-carboxylate (200 mg, 0.53 mmol, 1 eq, trifluoroacetic acid) ,1-fluoro-4-iodo-benzene (296 mg, 1.34 mmol, 0.15 mL, 2.5 eq), and Cs2CO3(522 mg, 1.60 mmol, 3 eq) in DMF (2 mL) was added 1,3- bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine; dichloropalladium (26 mg, 0.027 mmol, 0.05 eq) was added under nitrogen atmosphere, and the reaction mixture was stirred at 80 °C for 3 h. The mixture was diluted with water (8 mL) and extracted with ethyl acetate (8 mL*2). The combined organic extracts were washed with brine (16 mL), dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give benzyl 1-(4-fluorophenyl)-3,3a,4,6,7,7a-hexahydro-2H- pyrrolo[3,2-c]pyridine-5-carboxylate (110 mg, 0.31 mmol, 58% yield) as a white solid. LC / MS (ESI) m / z: 355.2 [M+H]+. Step 4: Preparation of 1-(4-fluorophenyl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2- c]pyridine To a solution of benzyl 1-(4-fluorophenyl)-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2- c]pyridine-5-carboxylate (108 mg, 0.31 mmol, 1 eq) in CH3OH (3 mL) was added palladium on activated carbon catalyst (30 mg, 10% purity) under nitrogen, and the resulting suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25°C for 12 hours. The mixture was filtered, and the filtrate was concentrated to give 1-(4-fluorophenyl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2- c]pyridine (70 mg, crude) as a colorless oil. LC / MS (ESI) m / z: 221.0 [M+H]+. Step 5: Preparation of 4-[(3aR,7aS)-1-(4-fluorophenyl)-3,3a,4,6,7,7a-hexahydro-2H- pyrrolo[3,2-c]pyridin-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (Compound 41) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from 1-(4- fluorophenyl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridine. (yellow solid). LC / MS (ESI) m / z: 438.1 [M+H]+.1H NMR (400 MHz, DMSO) δ 8.08 (d, J = 9.2 Hz, 1H), 7.8 (d, J = 9.2 Hz, 1H), 7.00 (t, J = 8.8 Hz, 2H), 6.56 (dd, J = 4.4, 8.8 Hz, 2H), 4.24 - 4.08 (m, 2H), 4.04 - 3.88 (m, 2H), 3.52 (s, 3H), 3.49 - 3.4 (m, 1H), 3.24 - 3.16 (m, 1H), 2.6 (d, J = 6.8 Hz, 2H), 2.24 - 2.12 (m, 1H), 2.12 - 2.04 (m, 2H), 1.84 - 1.72 (m, 1H). Synthesis of Compound 43

[0046] Step 1: Preparation of tert-butyl 4-(4-chloroanilino)piperidine-1-carboxylate A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (600 mg, 3.01 mmol, 1 eq), 4- chloroaniline (384 mg, 3.01 mmol, 1 eq), sodium cyanoborohydride (473.10 mg, 7.53 mmol, 2.5 eq), and acetic acid (18 mg, 0.30 mmol, 0.017 mL, 0.1 eq) in methanol (6 mL) was stirred at 25°C for 12 h. The mixture was concentrated under vacuum, and the crude product was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*2). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: 100:1 to 1:1 petroleum ether / ethyl acetate) to give tert-butyl 4-(4-chloroanilino)piperidine-1- carboxylate (250 mg, 0.80 mmol, 27% yield) as a white solid. LC / MS (ESI) m / z: 255.1 [M- 55]+.1H NMR (400 MHz, CDCl3) δ 7.18 - 7.05 (m, 2H), 6.58 - 6.50 (m, 2H), 4.05 (d, J = 8.0 Hz, 2H), 2.92 (t, J = 12.0 Hz, 2H), 2.05 - 1.98 (m, 2H), 1.47 (s, 11H), 1.32 (d, J = 10.8 Hz, 2H). Step 2: Preparation of N-(4-chlorophenyl)piperidin-4-amine A mixture of tert-butyl 4-(4-chloroanilino)piperidine-1-carboxylate (62 mg, 0.20 mmol, 1 eq) and trifluoroacetic acid (924 mg, 8.10 mmol, 0.6 mL, 83.96 eq) in dichloromethane (0.6 mL) was stirred at 25 °C for 15 minutes. The mixture was concentrated under vacuum to give N- (4-chlorophenyl)piperidin-4-amine (100 mg, crude, trifluoroacetic acid) as a red oil. LC / MS (ESI) m / z: 211.0 [M+H]+. Step 3: Preparation of 6-chloro-4-[4-(4-chloroanilino)-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile A mixture of N-(4-chlorophenyl)piperidin-4-amine (41 mg, 0.13 mmol, 6.49e-1 eq, trifluoroacetic acid), 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (50 mg, 0.2 mmol, 1 eq) and diisopropylethylamine (76 mg, 0.59 mmol, 0.10 mL, 3 eq) in acetonitrile (0.6 mL) was stirred at 40 °C for 12 hours. The mixture was concentrated under vacuum, and the resulting precipitate was triturated in dimethylformamide (1.5 mL), washed with acetonitrile (1.5 mL), and collected by filtration to afford 6-chloro-4-[4-(4-chloroanilino)-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (30.4 mg, 0.07 mmol, 35% yield) as a yellow solid. LC / MS (ESI) m / z: 428.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 5.88 (d, J = 8.0 Hz, 1H), 4.20 (br d, J = 12.8 Hz, 2H), 3.64 - 3.56 (m, 2H), 3.53 (s, 3H), 3.30 (s, 1H), 2.10 (d, J = 10.8 Hz, 2H), 1.77 - 1.55 (m, 2H).

[0047] Synthesis of Compound 44

[0048] Step 1: Preparation of ethyl 3-acetamido-6-chloro-pyridine-2-carboxylate A mixture of ethyl 3-amino-6-chloro-pyridine-2-carboxylate (4 g, 19.94 mmol, 1 eq), and acetic anhydride (2.04 g, 19.94 mmol, 1.87 mL, 1 eq) in dioxane (40 mL) was stirred at 110°C for 12 h. The mixture was concentrated under vacuum, and the resulting residue was purified by silica gel flash chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give ethyl 3-acetamido-6-chloro-pyridine-2-carboxylate (5 g, crude) as a yellow solid. LC / MS (ESI) m / z: 243.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 9.12 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 2.28 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H). Step 2: Preparation of ethyl 3-[acetyl(methyl)amino]-6-chloro-pyridine-2-carboxylate A mixture of ethyl 3-acetamido-6-chloro-pyridine-2-carboxylate (200 mg, 0.82 mmol, 1 eq), methyl iodide (234 mg, 1.65 mmol, 0.1 mL, 2 eq), and Cs2CO3(671 mg, 2.06 mmol, 2.5 eq) in DMF (2 mL) was stirred at 25 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic layers were washed with brine (20 mL), dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatograph on silica gel (gradient: 0 to 1:1 petroleum ether / ethyl acetate) followed by prep-HPLC (column: Waters xbridge 150*25mm 10µm; mobile phase: [10-40% CH3CN in water (NH4HCO3)]) to give ethyl 3- [acetyl(methyl)amino]-6-chloro-pyridine-2-carboxylate (110 mg, 0.43 mmol, 52% yield) as a white solid. LC / MS (ESI) m / z: 257.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.6 (s, 1H), 4.48 - 4.4 (m, 2H), 3.08 (s, 3H), 1.92 - 1.84 (m, 3H), 1.40 (t, J = 7.2 Hz, 3H). Step 3: Preparation of 6-chloro-4-hydroxy-1-methyl-1,5-naphthyridin-2-one To a solution of ethyl 3-[acetyl(methyl)amino]-6-chloro-pyridine-2-carboxylate (110 mg, 0.43 mmol, 1 eq) in tetrahydrofuran (1 mL) at 0°C was added dropwise potassium bis(trimethylsilyl)amide (1 M, 0.64 mL, 1.5 eq), and the reaction mixture was stirred at 0 °C for 2 hr. The pH of the mixture was adjusted to 5 by addition of 1 M hydrochloric acid. The mixture was filtered, and the residue was washed with acetonitrile (2 mL) to give 6-chloro-4- hydroxy-1-methyl-1,5-naphthyridin-2-one (32 mg, 0.15 mmol, 35% yield) as a white solid. LC / MS (ESI) m / z: 210.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 6.10 (s, 1H), 3.52 (s, 3H) Step 4: Preparation of (6-chloro-1-methyl-2-oxo-1,5-naphthyridin-4-yl) trifluoromethanesulfonate A mixture of 6-chloro-4-hydroxy-1-methyl-1,5-naphthyridin-2-one (32 mg, 0.15 mmol, 1 eq), trifluoromethanesulfonic anhydride (107 mg, 0.38 mmol, 0.062 mL, 2.5 eq), triethylamine (77 mg, 0.76 mmol, 0.11 mL, 5 eq), and 4-dimethylaminopyridine (2 mg, 0.015 mmol, 0.1 eq) in dichloromethane (1 mL) was stirred at 0 °C for 2 hr under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give (6-chloro-1-methyl-2-oxo-1,5-naphthyridin-4-yl) trifluoromethanesulfonate (33 mg, 0.095 mmol, 63% yield) as a yellow solid. LC / MS (ESI) m / z: 342.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H), 3.63 (s, 3H). Step 5: Preparation of tert-butyl 2-(4-fluorophenyl)-4-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate A mixture of tert-butyl 4-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5- carboxylate (200 mg, 0.88 mmol, 1 eq), 1-bromo-4-fluoro-benzene (185 mg, 1.06 mmol, 0.12 mL, 1.2 eq), Cs2CO3(864 mg, 2.65 mmol, 3 eq), and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]- 4,5-dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (43 mg, 0.044 mmol, 0.05 eq) in dioxane (5 mL) was stirred at 100°C for 3 h under N2. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL*2). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 5:1 petroleum ether / ethyl acetate) to give tert-butyl 2-(4- fluorophenyl)-4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (150 mg, 0.47 mmol, 53% yield) as a yellow solid. LC / MS (ESI) m / z: 321.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 6.99 - 6.90 (m, 2H), 6.50 - 6.42 (m, 2H), 3.82 (s, 1H), 3.66 (dd, J=8.0, 11.6 Hz, 1H), 3.56 - 3.42 (m, 2H), 3.37 (d, J=14.8 Hz, 1H), 3.19 - 3.11 (m, 2H), 3.04 (s, 1H), 2.67 - 2.57 (m, 1H), 1.46 (s, 9H), 1.27 (d, J=6.4 Hz, 3H). Step 6: Preparation of (3S,3aS,6aS)-5-(4-fluorophenyl)-3-methyl-2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole A mixture of tert-butyl (3aS,4S,6aR)-2-(4-fluorophenyl)-4-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (80 mg, 0.25 mmol, 1 eq) and trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 27.05 eq) in dichloromethane (1 mL) was stirred at 20 °C for 0.5 h. The mixture was concentrated to give (3S,3aS,6aS)-5-(4-fluorophenyl)-3-methyl- 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (85 mg, crude, TFA salt) as a brown oil. LC / MS (ESI) m / z: 221.0 [M+H]+. Step 7: Preparation of 4-[(3aS,4S,6aR)-2-(4-fluorophenyl)-4-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-1,5-naphthyridin-2-one The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3S,3aS,6aS)-5- (4-fluorophenyl)-3-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole and (6-chloro- 1-methyl-2-oxo-1,5-naphthyridin-4-yl) trifluoromethanesulfonate. (yellow solid). LC / MS (ESI) m / z: 413.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 6.99 (t, J=8.8 Hz, 2H), 6.56 - 6.47 (m, 2H), 5.63 (s, 1H), 5.00 (s, 1H), 3.97 (dd, J=8.4, 11.6 Hz, 1H), 3.54 - 3.49 (m, 1H), 3.48 (s, 3H), 3.46 - 3.39 (m, 2H), 3.20 (d, J=7.6 Hz, 2H), 3.10 (dd, J=6.0, 9.6 Hz, 1H), 2.88 - 2.79 (m, 1H), 1.20 (d, J=6.4 Hz, 3H).

[0049] Synthesis of Compound 45 Step 1: Preparation of (3aR,6aS)-5-(4-fluorophenyl)-2,3,3a,4,6,6a-hexahydro-1H- pyrrolo[3,4-c]pyrrole To a solution of tert-butyl (3aS,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5- carboxylate (200 mg, 0.94 mmol, 1 eq) and 1-bromo-4-fluoro-benzene (247 mg, 1.41 mmol, 0.15 mL, 1.5 eq) in dioxane (4 mL) were added Cs2CO3(921 mg, 2.83 mmol, 3 eq) and 1,3- bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (46 mg, 0.047 mmol, 0.05 eq), and the reaction mixture was stirred at 100 °C for 4 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL*2). The combined organic extracts were washed with brine (100 mL), dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate). To the product was added trifluoroacetic acid (2 mL), and the resulting mixture was stirred at 20°C for 1 h. The mixture was concentrated to give (3aR,6aS)-5-(4- fluorophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (200 mg, crude, TFA salt) as a red oil. LC / MS (ESI) m / z: 207.2 [M+H]+. Step 2: Preparation of 6-chloro-4-((3aR,6aS)-5-(4- fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-methyl-2-oxo-1,2-dihydro- 1,5-naphthyridine-3-carbonitrile (Compound 45) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3aR,6aS)-5-(4- fluorophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole. (yellow solid). LC / MS (ESI) m / z: 424.1 [M+H]+.1H NMR (400MHz, DMSO-d6) δ 8.00 (d, J = 9.2 Hz, 1H), 7.82 - 7.74 (m, 1H), 7.01 (t, J = 8.4 Hz, 2H), 6.53 (dd, J = 2.4, 4.8 Hz, 2H), 4.50 (dd, J = 6.4, 12.4 Hz, 2H), 4.14 (d, J = 12.4 Hz, 2H), 3.50 - 3.43 (m, 5H), 3.25 (d, J = 10.4 Hz, 2H), 3.15 (s, 2H). Synthesis of Compound 46 Step 1: Preparation of tert-butyl 4-(4-fluoro-N-(4-fluorophenyl)anilino)piperidine-1- carboxylate A mixture of tert-butyl 4-(4-fluoroanilino)piperidine-1-carboxylate (200 mg, 0.68 mmol, 1 eq), 1-fluoro-4-iodo-benzene (151 mg, 0.68 mmol, 0.078 mL, 1 eq), tert-butyl phosphorus (6 mg, 0.03 mmol, 0.007 mL, 4.42e-2 eq), diacetoxypalladium (7 mg, 0.03 mmol, 4.42e-2 eq), and potassium;2-methylpropan-2-olate (229 mg, 2.04 mmol, 3 eq) in toluene (10 mL) was stirred at 100 °C for 6 hours. The reaction mixture was filtered, then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 10:1 petroleum ether / ethyl acetate) to give compound tert-butyl 4-(4-fluoro-N-(4- fluorophenyl)anilino)piperidine-1-carboxylate (188 mg, 0.48 mmol, 71% yield) as a white solid. LC / MS (ESI) m / z: 333.0 [M-55]+.1H NMR (400 MHz, DMSO-d6) δ 7.11 (t, J = 8.8 Hz, 4H), 6.82 (dd, J = 4.8, 8.8 Hz, 4H), 3.99 - 3.89 (m, 2H), 2.99 - 2.77 (m, 2H), 1.88 (d, J = 12.0 Hz, 2H), 1.33 (s, 9H), 1.10 - 0.99 (m, 2H), 0.89 - 0.77 (m, 1H). Step 2: Preparation of N,N-bis(4-fluorophenyl)piperidin-4-amine To a solution of tert-butyl 4-(4-fluoro-N-(4-fluorophenyl)anilino)piperidine-1-carboxylate (70 mg, 0.18 mmol, 1 eq) in dichloromethane (1 mL) was added dropwise trifluoroacetic acid (1.20 g, 10.50 mmol, 0.78 mL, 58.29 eq), and the resulting mixture was stirred at 25 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure to give compound N,N-bis(4-fluorophenyl)piperidin-4-amine (60 mg, crude, TFA salt) as a green oil. LC / MS (ESI) m / z: 289.1 [M+H]+. Step 3: Preparation of 6-chloro-4-[4-(4-fluoro-N-(4-fluorophenyl)anilino)-1-piperidyl]-1- methyl-2-oxo-1,5-naphthyridine-3-carbonitrile The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from N,N-bis(4- fluorophenyl)piperidin-4-amine. (yellow solid). LC / MS (ESI) m / z: 506.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.13 (t, J = 8.8 Hz, 4H), 6.88 (dd, J = 4.8, 8.8 Hz, 4H), 4.37 - 4.26 (m, 1H), 4.25 - 4.17 (m, 2H), 3.64 - 3.54 (m, 2H), 3.49 (s, 3H), 2.11 - 2.02 (m, 2H), 1.67 - 1.51 (m, 2H). Synthesis of Compound 48

[0050] Step 1: Preparation of tert-butyl (3aR,6aR)-2-[4-(trifluoromethoxy)phenyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate To a mixture of 1-bromo-4-(trifluoromethoxy)benzene (50 mg, 0.21 mmol, 0.030 mL, 1 eq), tert-butyl (3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (48 mg, 0.23 mmol, 1.1 eq) and Cs2CO3(203 mg, 0.62 mmol, 3 eq) in dioxane (1 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (10 mg, 0.01 mmol, 0.05 eq), and the reaction mixture was stirred at 100 °C for 3 hours. The mixture was filtered, and the filtrate was diluted with water (2 mL) and extracted with ethyl acetate (2 mL*2). The combined organic extracts were concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 10:1 petroleum ether / ethyl acetate) to give tert-butyl (3aR,6aR)-2-[4-(trifluoromethoxy)phenyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5- carboxylate (20 mg, 0.054 mmol, 26% yield) as a yellow solid. LC / MS (ESI) m / z: 373.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 8.4 Hz, 2H), 6.50 - 6.40 (m, 2H), 3.81 - 3.63 (m, 2H), 3.55 - 3.39 (m, 2H), 3.17 - 3.03 (m, 4H), 2.42 - 2.26 (m, 2H), 1.49 (s, 9H).

[0051] Step 2: Preparation of (3aS,6aS)-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole To a solution of tert-butyl (3aR,6aR)-2-[4-(trifluoromethoxy)phenyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (110 mg, 0.30 mmol, 1 eq) in dichloromethane (1 mL) was added dropwise trifluoroacetic acid (1.69 g, 14.86 mmol, 1.1 mL, 50.29 eq), and the resulting mixture was stirred at 25 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure to give (3aS,6aS)-5-[4-(trifluoromethoxy)phenyl]- 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (120 mg, crude, TFA) as a yellow oil. LC / MS (ESI) m / z: 272.9 [M+H]+. Step 3: Preparation of 4-[(3aR,6aR)-2-[4-(trifluoromethoxy)phenyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile

[0052] The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3aS,6aS)-5-[4- (trifluoromethoxy)phenyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole. (yellow solid). LC / MS (ESI) m / z: 490.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.99 (m, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 4.27 - 4.14 (m, 4H), 3.58 - 3.51 (m, 2H), 3.50 (s, 3H), 3.25 - 3.16 (m, 2H), 2.52 (s, 2H). Synthesis of Compound 49 Compound 49

[0053] Step 1: Preparation of tert-butyl (3aR,6aS)-2-(4-fluoro-2-methyl-phenyl)-3a,6a- dimethyl-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate To a solution of 1-bromo-4-fluoro-2-methyl-benzene (300 mg, 1.59 mmol, 1 eq) and tert- butyl (3aR,6aS)-3a,6a-dimethyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (343 mg, 1.43 mmol, 0.9 eq) in dioxane (6 mL) was added K2CO3(658 mg, 4.76 mmol, 3 eq) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (77 mg, 0.079 mmol, 0.05 eq), and the reaction mixture was stirred at 100 °C for 4 hr. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL*2). The combined organic extracts were washed with brine (100 mL), dried with sodium sulfate, and concentrated. The resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to give tert-butyl (3aR,6aS)-2-(4-fluoro-2-methyl-phenyl)-3a,6a-dimethyl-1,3,4,6-tetrahydropyrrolo[3,4- c]pyrrole-5-carboxylate (50 mg, crude) as a white solid. LC / MS (ESI) m / z: 349.1 [M+H]+. Step 2: Preparation of (3aS,6aR)-5-(4-fluoro-2-methyl-phenyl)-3a,6a-dimethyl- 2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole To a solution of tert-butyl (3aR,6aS)-2-(4-fluoro-2-methyl-phenyl)-3a,6a-dimethyl-1,3,4,6- tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate (60 mg, 0.17 mmol, 1 eq) in dichloromethane (0.6 mL) was added trifluoroacetic acid (19 mg, 0.17 mmol, 0.013 mL, 1 eq), and the reaction mixture was stirred at 25 °C for 0.25 h. The mixture was concentrated under reduced pressure to give (3aS,6aR)-5-(4-fluoro-2-methyl-phenyl)-3a,6a-dimethyl-2,3,4,6-tetrahydro- 1H-pyrrolo[3,4-c]pyrrole (65 mg, crude, trifluoroacetic acid salt) as a green solid. LC / MS (ESI) m / z: 249.0 [M+H]+. Step 3: Preparation of 4-[(3aS,6aR)-2-(4-fluoro-2-methyl-phenyl)-3a,6a-dimethyl- 1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (Compound 49) Compound 49 The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3aS,6aR)-5-(4- fluoro-2-methyl-phenyl)-3a,6a-dimethyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole. (white solid). LC / MS (ESI) m / z: 466.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.64 - 7.57 (m, 1H), 7.49 (d, J = 8.8 Hz, 1H), 6.87 - 6.75 (m, 3H), 4.62 (d, J = 12.8 Hz, 2H), 4.24 (d, J = 12.8 Hz, 2H), 3.61 (s, 3H), 3.39 (d, J = 9.2 Hz, 2H), 3.10 (d, J = 9.2 Hz, 2H), 2.23 (s, 3H), 1.24 (s, 6H).

[0054] Synthesis of Compound 50 Step 1: Preparation of tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-hydroxy-piperidine-1- carboxylate To a mixture of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (3 g, 15.06 mmol, 1 eq) and 4-fluoroaniline (1.67 g, 15.06 mmol, 1.44 mL, 1 eq) in dichloroethane (30 mL) was added scandium(3+); trifluoromethanesulfonate (1.48 g, 3.01 mmol, 0.2 eq), and the reaction mixture stirred at 80 °C for 8 h under the N2. The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated, and the aqueous phase was further extracted with ethyl acetate (100 mL x 2). The combined organic extract was dried over sodium sulfate and concentrated. The crude product was purified by prep-HPLC (column: Phenomenex luna C18250*50mm*10 µm; mobile phase: [20-50% CH3CN in water (0.225% formic acid)]) to give tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-hydroxy-piperidine- 1-carboxylate (1.7 g, 5.48 mmol, 36% yield) as a yellow solid. LC / MS (ESI) m / z: 255.2 (M- 55)+.1H NMR (400 MHz, CDCl3) δ 6.92 - 6.68 (m, 2H), 6.64 - 6.52 (m, 2H), 4.32 - 4.16 (m, 1H), 4.12 - 3.92 (m, 1H), 3.36 (d, J = 4.0 Hz, 1H), 3.16 - 3.08 (m, 1H), 2.80 - 2.48 (m, 3H), 2.04 - 1.96 (m, 1H), 1.40 (s, 9H), 1.24 - 1.16 (m, 1H). Step 2: Preparation of tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1- carboxylate To a mixture of tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-hydroxy-piperidine-1-carboxylate (400 mg, 1.29 mmol, 1 eq) in tetrahydrofuran (5 mL) at 0°C was added sodium hydride (129 mg, 3.22 mmol, 60% purity, 2.5 eq), and the resulting mixture was stirred at 0 °C for 0.5 h. Iodomethane (549 mg, 3.87 mmol, 0.024 mL, 3 eq) was then added, and the reaction mixture was stirred at 20°C for 1 h under N2. The mixture was diluted with saturated aqueous ammonium chloride (20 mL), then extracted with ethyl acetate (3 × 20 mL). The combined organic extract was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (gradient: 30 / 1 to 3:1 petroleum ether / ethyl acetate) to give tert-butyl (3R,4R)-4-(4- fluoroanilino)-3-methoxy-piperidine-1-carboxylate (390 mg, 1.20 mmol, 93% yield) as a yellow oil. LC / MS (ESI) m / z: 347.0 (M+Na)+.1H NMR (400 MHz, CDCl3) δ 6.94 - 6.83 (m, 2H), 6.68 - 6.56 (m, 2H), 4.25 - 4.04 (m, 1H), 3.89 - 3.75 (m, 1H), 3.45 (s, 3H), 3.26 (d, J=4.4 Hz, 1H), 3.17 - 2.75 (m, 3H), 2.20 - 2.08 (m, 1H), 1.48 (s, 9H), 1.43 - 1.32 (m, 1H). Step 3: Preparation of (3R,4R)-N-(4-fluorophenyl)-3-methoxy-piperidin-4-amine A mixture of tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1-carboxylate (150 mg, 0.46 mmol, 1 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 29.21 eq) in dichloromethane (1 mL) and stirred at 25°C for 0.5 h. The reaction mixture was concentrated under vacuum to give (3R,4R)-N-(4-fluorophenyl)-3-methoxy-piperidin-4-amine (1.1 g, crude, trifluoroacetic) as a white solid. LC / MS (ESI) m / z: 225.2 [M+H]+. Step 4: Preparation of 6-chloro-4-[(3R,4R)-4-(4-fluoroanilino)-3-methoxy-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 50) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3R,4R)-N-(4- fluorophenyl)-3-methoxy-piperidin-4-amine. (yellow solid). LC / MS (ESI) m / z: 442.2 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ 8.08 - 9.2 (m, 1H), 7.84 - 9.2 (m, 1H), 6.92 - 8.8 (m, 2H), 6.68 - 4.4, 8.8 (m, 2H), 5.6 - 7.6 (m, 1H), 4.52 - 12.0 (m, 1H), 4.04 - 3.88 (m, 1H), 3.76 - 3.56 (m, 2H), 3.52 (s, 3H), 3.4 (s, 3H), 3.24 - 3.16 (m, 1H), 2.24 - 2.16 (m, 1H), 1.56 - 1.44 (m, 1H), 1.35 - 1.12 (m, 1H). Synthesis of Compound 51 Compound 51 Step 1: Preparation of tert-butyl (3R,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy- piperidine-1-carboxylate To a solution of tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1-carboxylate (140 mg, 0.43 mmol, 1 eq) and formaldehyde (162 mg, 2.16 mmol, 0.15 mL, 40% purity, 5 eq) in methanol (1 mL) and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (81 mg, 1.29 mmol, 3 eq), and the reaction mixture was stirred at 40 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic extracts were concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 10:1 petroleum ether / ethyl acetate) to give tert-butyl (3R,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy-piperidine-1-carboxylate (50 mg, 147.75 µmol, 34% yield) as a yellow oil. LC / MS (ESI) m / z: 339.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.00 - 6.87 (m, 2H), 6.81 (dd, J = 4.4, 8.8 Hz, 2H), 4.71 - 4.29 (m, 1H), 4.23 - 3.91 (m, 1H), 3.56 - 3.46 (m, 1H), 3.41 (s, 3H), 3.29 (dt, J = 4.8, 9.6 Hz, 1H), 2.78 (s, 3H), 2.74 - 2.63 (m, 1H), 2.58 - 2.46 (m, 1H), 1.73 - 1.61 (m, 2H), 1.49 (s, 9H). Step 2: Preparation of (3R,4R)-N-(4-fluorophenyl)-3-methoxy-N-methylpiperidin-4- amine To a solution of tert-butyl (3R,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy-piperidine-1- carboxylate (120 mg, 0.35 mmol, 1 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (1.85 g, 16.21 mmol, 1.20 mL, 45.71 eq), and the resulting mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give (3R,4R)- N-(4-fluorophenyl)-3-methoxy-N-methyl-piperidin-4-amine (125 mg, crude, TFA salt) as a yellow oil. LC / MS (ESI) m / z: 239.1 [M+H]+. Step 3: Preparation of 6-chloro-4-[(3R,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 51)

[0055] The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3R,4R)-N-(4- fluorophenyl)-3-methoxy-N-methyl-piperidin-4-amine. (yellow solid). LC / MS (ESI) m / z: 456.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.04 - 6.95 (m, 2H), 6.89 - 6.82 (m, 2H), 4.66 (d, J = 12.0 Hz, 1H), 4.06 (d, J = 12.0 Hz, 1H), 3.95 - 3.79 (m, 2H), 3.62 (dt, J = 2.8, 12.4 Hz, 1H), 3.54 (s, 3H), 3.38 (s, 3H), 3.07 (dd, J = 9.6, 12.4 Hz, 1H), 2.76 (s, 3H), 1.95 - 1.76 (m, 2H).

[0056] Synthesis of Compounds 52 and 53 Step 1: Preparation of tert-butyl 2,5-dimethyl-4-oxo-piperidine-1-carboxylate To a solution of tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate (2.0 g, 9.38 mmol, 1.00 eq) in tetrahydrofuran (70 mL) at -78 °C was added dropwise lithium diisopropylamide in tetrahydrofuran (2 M, 5.16 mL, 1.10 eq), and the reaction mixture was stirred at -78 °C for 2 h. Iodomethane (1.73 g, 12.19 mmol, 1.30 eq) was then added, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition saturated ammonium chloride solution (100 mL), and the resulting aqueous mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 2,5-dimethyl-4- oxo-piperidine-1-carboxylate (2.1 g, crude) as a colorless oil. LC / MS (ESI) m / z: 172.2 [M- C4H9+H]+. Step 2: Preparation of benzyl (2S,5R)-2,5-dimethyl-4-oxo-piperidine-1-carboxylate To a solution of tert-butyl 2,5-dimethyl-4-oxo-piperidine-1-carboxylate (2.1 g, 9.24 mmol, 1.00 eq) in dichloromethane (10 mL) was added hydrogen chloride in dioxane (4 M, 10 mL, 4.33 eq), and the resulting mixture was stirred at 25 °C for 0.5 hours. The mixture was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (20 mL) and water (10 mL), then treated with NaHCO3(3.85 g, 45.83 mmol, 5.00 eq) and benzyl chloroformate (3.13 g, 18.33 mmol, 2.00 eq). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (100 / 1 to 30 / 1 petroleum ether / ethyl acetate) followed by semi- preparative reverse phase HPLC (32-62% acetonitrile + 0.1% formic acid in water, 11 min) to afford benzyl 2,5-dimethyl-4-oxo-piperidine-1-carboxylate (600 mg, 2.30 mmol, 25% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.44 - 7.29 (m, 5H), 5.28 - 5.07 (m, 2H), 4.64 -4.60 and 3.46 - 3.31 (m, 1H), 4.43 - 4.22 (m, 1H), 3.86 - 3.65 (m, 1H), 2.88 - 2.60 (m, 1H), 2.57 - 2.36 (m, 1H), 2.32 - 2.22 (m, 1H), 1.26 (dd, J = 5.6, 6.8 Hz, 3H), 1.18 (dd, J = 7.2, 9.6 Hz, 3H). This material was further purified by SFC [method: (column: DAICEL CHIRALPAK AY-H(250mm * 30mm,10um); mobile phase: 15% CH3OH in CO2] to afford benzyl (2S,5R)-2,5-dimethyl-4-oxo-piperidine-1-carboxylate (350 mg, 1.34 mmol, 58% yield) as a yellow oil.1H NMR δ 7.45 - 7.31 (m, 5H), 5.28 - 5.12 (m, 2H), 4.65 (dt, J = 3.1, 6.6 Hz, 1H), 3.90 - 3.78 (m, 1H), 3.75 - 3.65 (m, 1H), 2.84 (dd, J = 6.8, 15.4 Hz, 1H), 2.60 - 2.47 (m, 1H), 2.28 (dd, J = 3.3, 15.4 Hz, 1H), 1.26 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 7.1 Hz, 3H). Step 3: Preparation of benzyl (2S,5R)-4-(4-fluoroanilino)-2,5-dimethyl-piperidine-1- carboxylate To a solution of benzyl (2S,5R)-2,5-dimethyl-4-oxo-piperidine-1-carboxylate (100 mg, 0.38 mmol, 1.00 eq) and 4-fluoroaniline (63 mg, 0.57 mmol, 1.50 eq) in methanol (2 mL) were added sodium cyanoborohydride (48 mg, 0.76 mmol, 2.00 eq) and acetic acid (2 mg, 38.27 umol, 0.10 eq), and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water 10 mL and extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by semi-preparative reverse phase HPLC (70-80% acetonitrile + 0.225% formic acid in water, 7 min) to afford benzyl (2S,5R)- 4-(4-fluoroanilino)-2,5-dimethyl-piperidine-1-carboxylate (60 mg, 0.16 mmol, 43% yield) as a colorless oil.1H NMR (400MHz, CDCl3) δ 7.41 - 7.29 (m, 5H), 6.96 - 6.83 (m, 2H), 6.61 - 6.45 (m, 2H), 5.24 - 5.07 (m, 2H), 4.17 (t, J = 6.8 Hz, 1H), 3.78 - 3.61 (m, 1H), 3.40 (dd, J = 4.8, 14.0 Hz, 1H), 3.21 - 3.04 (m, 1H), 2.27 - 2.09 (m, 1H), 1.81 - 1.68 (m, 1H), 1.44 - 1.32 (m, 1H), 1.29 - 1.21 (m, 3H), 1.18 - 0.96 (m, 2H). Step 4: Preparation of benzyl (2S,5R)-4-(4-fluoro-N-methyl-anilino)-2,5-dimethyl- piperidine-1-carboxylate To a solution of benzyl (2S,5R)-4-(4-fluoroanilino)-2,5-dimethyl-piperidine-1-carboxylate (60 mg, 0.16 mmol, 1.00 eq) in methanol (2 mL) were added sodium cyanoborohydride (15 mg, 0.25 mmol, 1.50 eq) and formaldehyde (136 mg, 1.68 mmol, 37% purity in water, 10.00 eq), and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give benzyl (2S,5R)-4-(4-fluoro-N-methyl-anilino)-2,5-dimethyl-piperidine-1- carboxylate (62 mg, crude) as a white solid. LC / MS (ESI) m / z: 370.9 [M+H]+. Step 5: Preparation of (2S,5R)-N-(4-fluorophenyl)-N,2,5-trimethyl-piperidin-4-amine To a solution of benzyl (2S,5R)-4-(4-fluoro-N-methyl-anilino)-2,5-dimethyl-piperidine-1- carboxylate (62 mg, 0.16 mmol, 1.00 eq) in methanol (4 mL) was added palladium on activated carbon catalyst (20 mg, 10% purity) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen (3X), and the reaction mixture was stirred under hydrogen (15 Psi) at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give (2S,5R)-N-(4-fluorophenyl)-N,2,5-trimethyl-piperidin-4-amine (40 mg, crude) as a white solid. Step 6: Preparation of 8-[(2S,4R,5R)-4-(4-fluoro-N-methyl-anilino)-2,5-dimethyl-1- piperidyl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (Compound 52) and 8- [(2S,4S,5R)-4-(4-fluoro-N-methyl-anilino)-2,5-dimethyl-1-piperidyl]-5-methyl-6-oxo- 1,5-naphthyridine-2-carbonitrile (Compound 53) To a solution of (2S,5R)-N-(4-fluorophenyl)-N,2,5-trimethyl-piperidin-4-amine (40 mg, 0.16 mmol, 1.00 eq) and (6-cyano-1-methyl-2-oxo-1,5-naphthyridin-4-yl) trifluoromethanesulfonate (62 mg, 0.18 mmol, 1.10 eq) in propan-2-ol (2 mL) was added N,N-diisopropylethylamine (43 mg, 0.33 mmol, 2.00 eq), and the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by semi-preparative reverse phase HPLC (48-78% CH3CN in water (0.225% formic acid)) to afford the desired products. 8-[(2S,4R,5R)-4-(4-fluoro-N-methyl-anilino)-2,5-dimethyl-1-piperidyl]-5-methyl-6-oxo-1,5- naphthyridine-2-carbonitrile (Compound 52) (8.4 mg, 0.02 mol, 11% yield, yellow solid). LC / MS (ESI) m / z: 420.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.86 - 7.79 (m, 1H), 7.77 - 7.70 (m, 1H), 6.98 (t, J = 8.4 Hz, 2H), 6.83 (s, 2H), 6.38 (s, 1H), 3.97 (dd, J = 3.6, 12.0 Hz, 1H), 3.68 (s, 3H), 3.52 - 3.26 (m, 2H), 2.84 (s, 3H), 2.63 - 2.46 (m, 1H), 2.43 - 2.29 (m, 1H), 1.89 (d, J = 6.8 Hz, 2H), 1.20 (d, J = 5.6 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H). 8-[(2S,4S,5R)-4-(4-fluoro-N-methyl-anilino)-2,5-dimethyl-1-piperidyl]-5-methyl-6-oxo-1,5- naphthyridine-2-carbonitrile (Compound 53) (5.4 mg, 0.01 mmol, 7% yield, yellow solid). LC / MS (ESI) m / z: 420.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.8 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.00 (t, J = 8.8 Hz, 2H), 6.81 (dd, J = 4.4, 9.2 Hz, 2H), 6.16 (s, 1H), 5.02 (d, J = 6.0 Hz, 1H), 4.04 - 3.92 (m, 1H), 3.76 - 3.61 (m, 4H), 3.50 (dd, J = 2.4, 12.8 Hz, 1H), 2.87 (s, 3H), 2.57 (m, 1H), 2.42 (d, J = 2.4 Hz, 1H), 1.57 (d, J = 12.4 Hz, 1H), 1.24 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 7.2 Hz, 3H). Synthesis of Compound 54

[0057] Step 1: Preparation of (3aR,6aR)-5-benzyl-3-methyl-2,3,3a,4,6,6a-hexahydro-1H- pyrrolo[3,4-c]pyrrole A mixture of tert-butyl (3aR,6aS)-2-benzyl-4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrole-5-carboxylate (200 mg, 0.63 mmol, 1 eq) and HCl / dioxane (4 M, 1 mL, 6.33 eq) in dichloromethane (1 mL) was stirred at 20 °C for 1 h. The mixture was concentrated to give (3aR,6aR)-5-benzyl-3-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (200 mg, crude, HCl) as a white solid. LC / MS(ESI) m / z: 217.3 [M+H]+. Step 2: Preparation of (3aR,6aS)-2-benzyl-5-(4-fluorophenyl)-4-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole To a mixture of (3aR,6aR)-5-benzyl-3-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4- c]pyrrole (160.00 mg, 0.63 mmol, 1 eq, HCl), 1-bromo-4-fluoro-benzene (122 mg, 0.69 mmol, 0.076 mL, 1.1 eq), and Cs2CO3(619 mg, 1.90 mmol, 3 eq) in dioxane (3 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (30.79 mg, 31.65 µmol, 0.05 eq), and the reaction mixture was stirred at 100°C for 3 h under N2. The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (gradient: 40 / 1 to 5:1 petroleum ether / ethyl acetate) to give (3aR,6aS)-2-benzyl-5-(4-fluorophenyl)-4- methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole (140 mg, 451.02 µmol, 71% yield) as a yellow oil. LC / MS (ESI) m / z: 311.2 [M+H]+. Step 3: Preparation of (3aR,6aS)-5-(4-fluorophenyl)-4-methyl-2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole To a solution of (3aR,6aS)-2-benzyl-5-(4-fluorophenyl)-4-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole (140.00 mg, 0.45 mmol, 1 eq) in ethanol (3 mL) was added palladium on activated carbon catalyst (30 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(50psi) at 50°C for 12 h. The mixture was filtered, and filtrate was concentrated to give (3aR,6aS)-5-(4-fluorophenyl)-4-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (70 mg, crude) as a yellow oil. LC / MS (ESI) m / z: 220.8 [M+H]+. Step 4: Preparation of 4-[(3aR,6aS)-5-(4-fluorophenyl)-4-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile

[0058] The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3aR,6aS)-5-(4- fluorophenyl)-4-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole. (off-white solid). LC / MS (ESI) m / z: 438.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J=9.2 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 7.03 - 6.98 (m, 2H), 6.53 (dd, J=4.0, 8.8 Hz, 2H), 4.53 - 4.44 (m, 2H), 4.20 (d, J=12.8 Hz, 1H), 3.97 - 3.86 (m, 2H), 3.61 - 3.55 (m, 1H), 3.47 (s, 3H), 3.10 - 3.04 (m, 1H), 2.81 - 2.74 (m, 1H), 2.52 (s, 1H), 1.16 (d, J=6.4 Hz, 3H). Synthesis of Compounds 55 and 56

[0059] Step 1: Preparation of tert-butyl (1R,3aS,6aR)-5-(6-chloro-3-cyano-1-methyl-2-oxo- 1,2-dihydro-1,5-naphthyridin-4-yl)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate To a mixture of tert-butyl (3aR,6aS)-4-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c] pyrrole-5-carboxylate (0.10 g, 0.44 mmol, 1 eq) and 4,6-dichloro-1-methyl-2-oxo -1,5- naphthyridine-3-carbonitrile (112 mg, 0.44 mmol, 1 eq) in acetonitrile (3 mL) was added diisopropylethylamine (171 mg, 1.33 mmol, 3 eq), and the reaction mixture was stirred at 40 °C for 12 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (5:1 to 1:0 petroleum ether: ethyl acetate) to give tert-butyl (1R,3aS,6aR)-5-(6-chloro-3-cyano-1-methyl-2-oxo-1,2-dihydro-1,5- naphthyridin-4-yl)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (50 mg, 0.11 mmol, 25% yield) as a yellow oil. LC / MS (ESI) m / z: 388.3 [M-56+H]+.1H NMR (400MHz, CDCl3) δ 7.54 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 4.57 - 4.45 (m, 2H), 4.16 - 4.07 (m, 2H), 3.87 - 3.78 (m, 1H), 3.68 - 3.58 (m, 1H), 3.51 (s, 3H), 3.27 - 3.19 (m, 1H), 3.06 - 2.95 (m, 1H), 2.60 - 2.50 (m, 1H), 1.39 (s, 9H), 1.26 - 1.21 (m, 3H). Step 2: Preparation of 6-chloro-1-methyl-4-((3aR,4R,6aR)-4- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-oxo-1,2-dihydro-1,5- naphthyridine-3-carbonitrile To a mixture of tert-butyl (1R,3aS,6aR)-5-(6-chloro-3-cyano-1-methyl-2-oxo-1,2-dihydro- 1,5-naphthyridin-4-yl)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (50 mg, 0.11 mmol, 1 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL), and the reaction mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure to give 6-chloro-1-methyl-4-((3aR,4R,6aR)-4-methylhexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (50 mg, 0.11 mmol, 96% yield, trifluoroacetate) as a yellow oil. LC / MS (ESI) m / z: 344.2 [M+H]+. Step 3: Preparation of 4-[(3aR,4R,6aR)-5-[(4-chloro-2-hydroxy-phenyl) methyl]-4- methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]-6-chloro-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile To a mixture of 6-chloro-1-methyl-4-((3aR,4R,6aR)-4-methylhexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (50 mg, 0.11 mmol, 1 eq, trifluoroacetate) and 4-chloro-2-hydroxy-benzaldehyde (34 mg, 0.22 mmol, 2 eq) in 1,2- dichloroethane (3 mL) were added sodium triacetoxyborohydride (69 mg, 0.32 mmol, 3 eq) and triethylamine (33 mg, 0.32 mmol, 3 eq), and the reaction mixture was stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by semi-preparative reverse phase (column: Phenomenex Synergi Polar-RP 100*25mm*4um; mobile phase: [32-52% CH3CN in water (TFA)]) to give 4-[(3aR,4R,6aR)- 5-[(4-chloro-2-hydroxy-phenyl) methyl]-4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile. LC / MS (ESI) m / z: 484.2 [M+H]+. Step 4: Preparation of 4-[(3aR,4R,6aR)-5-[(4-chloro-2-hydroxy-phenyl) methyl]-4- methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]-6-chloro-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (Compound 55) and 4-[(3aS,4S,6aS)-5 -[(4-chloro- 2-hydroxy-phenyl)methyl]-4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2- yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 56) The mixture of enantiomers (40 mg, 0.08 mmol, 1 eq) was separated by supercritical fluid chromatography (Column: DAICEL CHIRALCEL OD(250mm*30mm,10um); mobile phase: [0.1%NH3OH in CH3OH]; B%: 60%-60%, 3.4 min; 40 min). 4-[(3aR,4R,6aR)-5-[(4-chloro-2-hydroxy-phenyl) methyl]-4-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (14.6 mg, 0.03 mmol, 36% yield) (Compound 55) as an off-white solid. LC / MS (ESI) m / z: 484.1 [M+H]+.1H NMR (400MHz, CDCl3) δ 7.60 - 7.52 (m, 1H), 7.48 - 7.41 (m, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.75 - 6.70 (m, 1H), 6.69 - 6.63 (m, 1H), 4.60 (d, J = 12.4 Hz, 1H), 4.40 (dd, J = 2.0, 12.4 Hz, 1H), 4.10 (d, J = 13.6 Hz, 1H), 4.01 - 3.89 (m, 2H), 3.54 (s, 3H), 3.35 - 3.25 (m, 2H), 2.96 - 2.85 (m, 1H), 2.61 - 2.48 (m, 2H), 2.30 - 2.19 (m, 1H), 1.27 (d, J = 5.6 Hz, 3H). The second peak was purified by semi-preparative reverse phase (column: Unisil 3-100 C18 Ultra 150*50mm*3 um; mobile phase: [5-35% CH3CN in water (0.225% formic acid)]) to give 4-[(3aS,4S,6aS)-5-[(4-chloro-2-hydroxy-phenyl)methyl]-4-methyl-1,3,3a,4,6,6a - hexahydropyrrolo[3,4-c]pyrrol-2-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (9.6 mg, 0.02 mmol, 23% yield) (Compound 56) as a white solid. LC / MS (ESI) m / z: 484.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.69 - 7.62 (m, 1H), 7.57 - 7.51 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 - 6.80 (m, 1H), 6.79 - 6.74 (m, 1H), 4.75 - 4.59 (m, 1H), 4.55 - 4.41 (m, 1H), 4.19 (d, J = 13.6 Hz, 1H), 4.11 - 3.99 (m, 2H), 3.68 - 3.61 (m, 3H), 3.44 - 3.33 (m, 2H), 3.06 - 2.95 (m, 1H), 2.69 - 2.58 (m, 2H), 2.37 - 2.28 (m, 1H), 1.37 (d, J = 5.6 Hz, 3H). Synthesis of Compounds 57 and 58

[0060] Step 1: Preparation of tert-butyl (1S,3aR,6aS)-5-(4-chloro-2-hydroxybenzyl)-1- methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate To a mixture of tert-butyl (1R,3aS,6aR)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (0.50 g, 2.21 mmol, 1 eq) and 4-chloro-2-hydroxy-benzaldehyde (371 mg, 2.37 mmol, 1.07 eq) in 1,2-dichloroethane (10 mL) were added sodium triacetoxyborohydride (1.40 g, 6.63 mmol, 3 eq) and triethylamine (447 mg, 4.42 mmol, 2 eq), and the reaction mixture was stirred at 60 °C for 12 h. The mixture was diluted with water (5 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 0:1) to give tert-butyl (1S,3aR,6aS)-5-(4-chloro-2-hydroxybenzyl)-1- methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.70 g, 1.91 mmol, 86% yield) as a yellow solid. LC / MS (ESI) m / z: 367.3 [M+H]+. Step 2: Preparation of 5-chloro-2-(((3aS,4S,6aS)-4-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)methyl)phenol To a mixture of tert-butyl (1S,3aR,6aS)-5-(4-chloro-2-hydroxybenzyl)-1- methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.30 g, 0.81 mmol, 1 eq) in dichloromethane (6 mL) was added trifluoroacetic acid (3 mL), and the reaction mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure to give 5- chloro-2-(((3aS,4S,6aS)-4-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)phenol (0.30 g, 0.78 mmol, 96% yield, TFA salt) as a yellow oil. Step 3: Preparation of 4-[(3aS,4S,6aR)-2-[(4-chloro-2-hydroxy-phenyl) methyl]-4- methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile To a mixture of 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (0.10 g, 0.39 mmol, 1 eq) and 5-chloro-2-(((3aS,4S,6aS)-4-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)methyl)phenol (0.30 g, 0.78 mmol, 2.00 eq, trifluoroacetate) in tetrahydrofuran (5 mL) was added diisopropylethylamine (152 mg, 1.18 mmol, 3 eq), and the reaction mixture was stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by semi-preparative reverse phase (column: Phenomenex Synergi Polar- RP 100*25mm*4 µm; mobile phase: [32-52% CH3CN in water (TFA)]) to give 4- [(3aS,4S,6aR)-2-[(4-chloro-2-hydroxy-phenyl) methyl]-4-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (0.15 g, 0.30 mmol, 78% yield) as an off-white solid. LC / MS (ESI) m / z: 484.2 [M+H]+.

[0061] Step 4: Preparation of 4-[(3aS,4S,6aR)-2-[(4-chloro-2-hydroxy-phenyl) methyl]-4- methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (Compound 57) and 4-[(3aR,4R,6aS)-2 -[(4-chloro- 2-hydroxy-phenyl)methyl]-4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 58) The mixture of enantiomers (0.15 g, 0.30 mmol, 1 eq) was separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250mm*30mm,10µm); mobile phase: [0.1%NH4OH in isopropanol]; B%: 40%-40%, 3.2 min; 60 min). Absolute configuration was arbitrarily assigned. The first peak was purified further by semi-preparative reverse phase (column: Waters Xbridge 150*25mm* 5um; mobile phase: [45-75% CH3CN in water (NH4OH)]) to give 4- [(3aS,4S,6aR)-2-[(4-chloro-2-hydroxy-phenyl) methyl]-4-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (22.6 mg, 0.04 mmol, 14% yield) (Compound 57) as a yellow solid. LC / MS (ESI) m / z: 484.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 9.2 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.64 (dd, J = 2.0, 8.0 Hz, 1H), 6.60 - 6.55 (m, 1H), 6.00 - 5.86 (m, 1H), 4.44 - 4.34 (m, 1H), 3.79 (br d, J = 12.4 Hz, 1H), 3.65 - 3.47 (m, 7H), 3.11 - 3.00 (m, 1H), 2.78 - 2.59 (m, 4H), 1.21 (d, J = 6.4 Hz, 3H). The second peak was purified further by semi-preparative reverse phase (column: Phenomenex C1875*30mm*3µm; mobile phase: [12-42% CH3CN in water (formic acid)]) to give 4-[(3aR,4R,6aS)-2-[(4-chloro-2-hydroxy-phenyl)methyl]-4-methyl-1,3,3a,4,6,6a - hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (30.9 mg, 0.06 mmol, 77% yield) (Compound 58) as an off-white solid. LC / MS (ESI) m / z: 484.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.07 (br d, J = 8.0 Hz, 1H), 6.77 - 6.56 (m, 2H), 5.97 - 5.81 (m, 1H), 4.43 - 4.30 (m, 1H), 3.86 - 3.54 (m, 4H), 3.52 (s, 3H), 3.13 - 3.03 (m, 1H), 2.94 - 2.70 (m, 3H), 2.69 - 2.57 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H). Synthesis of Compound 61 Preparation of 8-[(3aR,6aR)-2-[(4-chloro-2-hydroxy-phenyl)methyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-5-methyl-6-oxo-1,5-naphthyridine-2- carbonitrile (Compound 61) A solution of 2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-ylmethyl)-5-chloro- phenol (65 mg, 0.22 mmol, 1 eq, hydrochloride), triethylamine (113 mg, 1.12 mmol, 0.15 mL, 5.0 eq), and (6-cyano-1-methyl-2-oxo-1,5-naphthyridin-4-yl) trifluoromethanesulfonate (74 mg, 0.22 mmol, 1 eq) in dichloromethane (5 mL) and DMF (1 mL) was stirred at 20 °C for 15 h. The reaction mixture was concentrated under reduced pressure. The product was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 µm; mobile phase: [35-65% CH3CN in water (NH4HCO3)]) followed by lyophilization to afford 8-[(3aR,6aR)-2-[(4- chloro-2-hydroxy-phenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-5- methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (36.1 mg, 82.82 µmol, 37% yield) as a white solid. LC / MS (ESI) m / z: 436.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.17 - 8.10 (m, 1H), 8.05 - 7.98 (m, 1H), 7.16 - 7.08 (m, 1H), 6.82 - 6.73 (m, 2H), 5.65 - 5.59 (m, 1H), 3.98 - 3.93 (m, 2H), 3.50 (br s, 5H), 2.97 - 2.90 (m, 2H), 2.71 - 2.64 (m, 4H), 2.40 - 2.35 (m, 2H). Synthesis of Compound 62 Step 1: Preparation of 1-benzyl-4-(2-bromoanilino)piperidine-4-carbonitrile To a stirred solution of 1-benzylpiperidin-4-one (10.0 g, 52.8 mmol, 9.8 mL, 1 eq) and 2- bromoaniline (9.10 g, 52.8 mmol, 1 eq) in AcOH (40 mL) was added TMSCN (5.5 g, 56.0 mmol, 7.0 mL, 1.06 eq), and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was neutralized by addition of 8 N aqueous NaOH (120 mL) at 0 °C, and the resulting mixture was extracted with ethyl acetate (100 mL ×3). The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (gradient: of 0~10% ethyl acetate in petroleum ether) to give 1-benzyl-4-(2-bromoanilino) piperidine-4-carbonitrile (10.0 g, 27.0 mmol, 51% yield) as a white solid. LC / MS (ESI) m / z: 370.2 [M+H]+. Step 2: Preparation of 1'-benzylspiro[indoline-2,4'-piperidine]-3-imine To a stirred solution of 1-benzyl-4-(2-bromoanilino)piperidine-4-carbonitrile (7.4 g, 19.98 mmol, 1 eq) in toluene (200 mL) were added AIBN (328 mg, 2.00 mmol, 0.1 eq) and Bu3SnH (6.4 g, 21.98 mmol, 5.8 mL, 1.1 eq), and the reaction mixture was stirred at 110 °C under N2for 16 hours. After cooling to 25°C, the reaction mixture was quenched by addition of saturated KF (200 mL) and extracted with ethyl acetate (200 mL ×2). The combined organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1'-benzylspiro[indoline-2,4'-piperidine]-3-imine (7.7 g, crude) as a yellow gum. LC / MS (ESI) m / z: 292.3 [M+H]+. Step 3: Preparation of 1'-benzylspiro[indoline-2,4'-piperidine]-3-one A mixture of 1'-benzylspiro[indoline-2,4'-piperidine]-3-imine (7.70 g, 26.4 mmol, 1 eq) in aqueous HCl (1 M, 232 mL, 8.8 eq) was stirred at 100 °C for 1 hour. After cooling to 25°C, the mixture was basified with saturated aqueous NaHCO3to pH = 8 and then extracted with CH2Cl2(200 mL ×3). The combined organic layer was washed with brine (100 mL ×2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (gradient: 0~1% CH3OH in CH2Cl2) to give 1'-benzylspiro[indoline-2,4'-piperidine]-3-one (3.00 g, 10.3 mmol, 38.83% yield) as a yellow solid. LC / MS (ESI) m / z: 293.3 [M+H]+. Step 4: Preparation of 1'-benzylspiro[indoline-2,4'-piperidine]-3-ol To a solution of 1'-benzylspiro[indoline-2,4'-piperidine]-3-one (500 mg, 1.71 mmol, 1 eq) in THF (5 mL) was added LiAlH4 (1 M, 1.8 mL, 1.1 eq) at 0°C, and the reaction mixture was stirred at 25°C for 1 hour. The reaction quenched by sequential addition of water (0.3 mL), 15% aq. NaOH (0.3 mL), and water (0.6 mL). The resulting suspension was dried over anhydrous Na2SO4and then filtered. The filtrate was concentrated in vacuo to give 1'- benzylspiro[indoline-2,4'-piperidine]-3-ol (500 mg, crude) as a white solid. LC / MS (ESI) m / z: 295.3 [M+H]+. Step 5: Preparation of 1'-benzylspiro[indoline-2,4'-piperidine] A solution of 1'-benzylspiro[indoline-2,4'-piperidine]-3-ol (500 mg, 1.70 mmol, 1 eq) and Et3SiH (987 mg, 8.49 mmol, 1.3 mL, 5 eq) in CH2Cl2(10 mL) was treated with TFA (1.9 g, 16.9 mmol, 1.3 mL, 10 eq) at 25°C for 1 hour. The mixture was basified with sat. aq. NaHCO3to pH = 8, and the suspension was extracted with CH2Cl2(20 mL ×3). The combined organic extract was washed with brine (15 mL ×3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (gradient: 0~50 % ethyl acetate in petroleum ether) to give 1'- benzylspiro[indoline-2,4'-piperidine] (370 mg, 1.33 mmol, 86.95% yield) as a white solid. LC / MS (ESI) m / z: 279.3 [M+H]+. Step 6: Preparation of 1'-benzyl-1-methyl-spiro[indoline-2,4'-piperidine] To a mixture of 1'-benzylspiro[indoline-2,4'-piperidine] (450 mg, 1.62 mmol, 1 eq) and formaldehyde (655 mg, 8.08 mmol, 601 µL, 37% purity, 5 eq) in CH3OH (10 mL) were added AcOH (970 mg, 16.1 mmol, 924 µL, 10 eq) and borane 2-methylpyridine (864 mg, 8.08 mmol, 5 eq), and the reaction mixture was stirred at 25 °C for 10 hours. The mixture was basified with triethylamine to pH = 8, and then concentrated. The crude product was purified by flash silica gel chromatography (gradient: 0~50 % ethyl acetate in petroleum ether) to give 1'-benzyl-1-methyl-spiro[indoline-2,4'-piperidine] (300 mg, 1.03 mmol, 63% yield) as a yellow oil. LC / MS (ESI) m / z: 293.1 [M+H]+. Step 7: Preparation of spiro[indoline-2,4'-piperidine] To a solution of 1'-benzyl-1-methyl-spiro[indoline-2,4'-piperidine] (150 mg, 0.513 mmol, 1 eq) in CH3OH (5 mL) were added Pd(OH)2(62 mg, 0.442 mmol, 20% purity, 0.8 eq) and AcOH (61 mg, 1.03 mmol, 58 µL, 2 eq) under N2, and the resulting mixture was degassed and purged with H2(3X), then stirred at 50 °C for 2 hours under H2(50 Psi). The reaction mixture was filtered, the filter cake was washed with CH3OH (200 mL), and the filtrate concentrated under reduced pressure to give 1-methylspiro[indoline-2,4'-piperidine] (100 mg, crude) as a white solid. LC / MS (ESI) m / z: 203.1 [M+H]+. Step 8: Preparation of 6-chloro-1-methyl-4-(1-methylspiro[indoline-2,4'-piperidine]- 1'-yl)-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 62) To a solution of 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (87 mg, 0.346 mol, 1 eq) in CH3CN (3 mL) were added 1-methylspiro[indoline-2,4'-piperidine] (70 mg, 0.346 mmol, 1 eq) and diisopropylethylamine (223 mg, 1.73 mmol, 305 µL, 5 eq), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated, and the crude product was purified by prep-HPLC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 µm); mobile phase: [0.1% NH4OH in EtOH]; B%: 45%-45%, 5 min). Pure fraction was concentrated and lyophilized to give 6-chloro-1-methyl-4-(1- methylspiro[indoline-2,4'-piperidine]-1'-yl)-2-oxo-1,5-naphthyridine-3-carbonitrile (21.6 mg, 0.0506 mmol, 15% yield) as a yellow solid. LC / MS (ESI) m / z: 419.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.10-6.94 (m, 2H), 6.55 (t, J = 7.2 Hz, 1H), 6.37 (d, J = 7.6 Hz, 1H), 4.26 ( d, J = 12.8 Hz, 2H), 3.54 (s, 3H), 3.49 (s, 2H), 3.07 (s, 2H), 2.63 (s, 3H), 2.18-2.15 (m, 2H), 1.60 (d, J = 12.8 Hz, 2H). Synthesis of Compound 63 Preparation of 6-chloro-1-methyl-2-oxo-4-spiro[3H-benzofuran-2,4'-piperidine]-1'- yl-1,5-naphthyridine-3-carbonitrile (Compound 63) A mixture of spiro[3H-benzofuran-2,4'-piperidine] (250 mg, 1.32 mmol, 1 eq) ,4,6-dichloro- 1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (336 mg, 1.32 mmol, 1 eq), and diisopropylethylamine (371.00 mg, 2.87 mmol, 0.5 mL, 2.17 eq) in acetonitrile (3 mL) was stirred at 25°C for 12 h. The mixture was concentrated under vacuum, and the crude product was triturated in dimethylformamide (1mL), washed with acetonitrile, and collected by filtration to afford 6-chloro-1-methyl-2-oxo-4-spiro[3H-benzofuran-2,4'-piperidine]-1'-yl-1,5- naphthyridine-3-carbonitrile (475 mg, 1.15 mmol, 87% yield) as a white solid. LC / MS (ESI) m / z: 407.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.2 (d, J = 7.2 Hz, 1H), 7.12 - 7.08 (m, 1H), 6.88 - 6.8 (m, 2H), 4.00 - 3.84 (m, 4H), 3.52 (s, 3H), 3.12 (s, 2H), 2.08 (t, J = 5.6 Hz, 4H). Synthesis of Compound 64 Step 1: Preparation of tert-butyl 2-(4-fluorophenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate To a solution of tert-butyl 3,4-bis(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate (2.0 g, 5.16 mmol, 1.0 eq) and potassium carbonate (7.13 g, 51.62 mmol, 10.0 eq) in acetonitrile (50 mL) was added 4-fluoroaniline (1.72 g, 15.49 mmol, 1.48 mL, 3.0 eq), and the reaction mixture was stirred at 90 °C for 15 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (200 mL) and water (30 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (gradient: 10 / 1 to 2 / 1 petroleum ether / ethyl acetate) followed by prep-TLC (SiO2, petroleum ether / ethyl acetate=2 / 1) to afford tert-butyl 2-(4-fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (0.3 g, 979.19 umol, 19% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 6.98 - 6.92 (m, 2H), 6.45 - 6.38 (m, 2H), 3.78 - 3.66 (m, 2H), 3.46 - 3.40 (m, 2H), 3.15 - 3.03 (m, 4H), 2.41 - 2.24 (m, 2H), 1.49 (s, 9H). Step 2: Preparation of 5-(4-fluorophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4- c]pyrrole To a solution of tert-butyl 2-(4-fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole- 5-carboxylate (0.3 g, 0.98 mmol, 1 eq) in methanol (3 mL) and dichloromethane (5 mL) was added hydrochloric acid / dioxane (4 M, 10 mL), and the reaction mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to afford 5-(4-fluorophenyl)-2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole (0.23 g, 947.60 umol, 97% yield, HCl salt) as a yellow solid. LC / MS (ESI) m / z: 207.5 [M+H]+. Step 3: Preparation of 4-[(3aR,6aR)-2-(4-fluorophenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (Compound 64)

[0062] To a solution of 5-(4-fluorophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (71 mg, 0.29 mmol, 1.5 eq, hydrochloride) and N,N-diisopropylethylamine (152 mg, 1.18 mmol, 0.2 mL, 6.00 eq) in dichloromethane (10 mL) and DMF (1 mL) was added 4,6-dichloro-1- methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (50 mg, 0.2 mmol, 1.0 eq), and the reaction mixture was stirred at 20 °C for 15 h. Water (20 mL) and ethyl acetate (20 mL) were added, and the resulting mixture was stirred at 20 °C for 10 minutes. The precipitate was filtered, and the product was washed with water (5 mL) and ethyl acetate (5 mL x 2), then concentrated at 40 °C to afford 4-[(3aR,6aR)-2-(4-fluorophenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (48.9 mg, 115.37 umol, 59% yield) as a yellow solid. LC / MS (ESI) m / z: 424.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.07 - 7.97 (m, 1H), 7.85 - 7.75 (m, 1H), 7.08 - 6.93 (m, 2H), 6.55 - 6.44 (m, 2H), 4.28 - 4.15 (m, 4H), 3.54 - 3.45 (m, 5H), 3.31 - 3.28 (m, 2H), 3.21 - 3.15 (m, 2H). Synthesis of Compounds 65, 66, 67, and 60 Step 1: Preparation of 5-chloro-2-[(3-methyl-4-piperidyl)amino]phenol To a solution of tert-butyl 4-(4-chloro-2-hydroxy-anilino)-3-methyl-piperidine-1-carboxylate (100 mg, 0.29 mmol, 1.00 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (33 mg, 0.29 mmol, 1.00 eq), and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 5-chloro-2-[(3-methyl-4- piperidyl)amino]phenol (100 mg, 0.28 mmol, 96% yield, trifluoroacetic acid salt) as a brown oil. Step 2: Preparation of 6-chloro-4-[4-(4-chloro-2-hydroxy-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile To a solution of 5-chloro-2-[(3-methyl-4-piperidyl)amino]phenol (100 mg, 0.28 mmol, 1.00 eq, trifluoroacetate) in acetonitrile (5 mL) were added 4,6-dichloro-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (71 mg, 0.28 mmol, 1.00 eq) and N,N-diisopropylethylamine (36 mg, 0.28 mmol, 1.00 eq), and the reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 µm; mobile phase: [45-75% CH3CN in water (0.225% formic acid)]) to afford 6-chloro-4-[4-(4-chloro-2-hydroxy- anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (100 mg, 0.21 mmol, 77% yield) as a yellow solid. LC / MS (ESI) m / z: 458.1[M+H]+.

[0063] Step 3: Preparation of 6-chloro-4-[(3S,4R)-4-(4-chloro-2-hydroxy-anilino)-3-methyl- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 65), 6- chloro-4-[(3R,4S)-4-(4-chloro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2- oxo-1,5-naphthyridine-3-carbonitrile (Compound 66), 6-chloro-4-[(3R,4R)-4-(4- chloro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine- 3-carbonitrile (Compound 67), and 6-chloro-4-[(3S,4S)-4-(4-chloro-2-hydroxy- anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 60) The isomers (100 mg, 0.21 mmol) were separated by SFC. First SFC method (column: DAICEL CHIRALPAK AD (250mm*30 mm, 10 µm); mobile phase: 60% ethanol (0.1% NH4OH) in CO2) to give a mixture of 6-chloro-4-[(3S,4R)-4-(4-chloro-2-hydroxy-anilino)-3- methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile and 6-chloro-4- [(3R,4R)-4-(4-chloro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile, and mixture of 6-chloro-4-[(3R,4S)-4-(4-chloro-2-hydroxy- anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile and 6- chloro-4-[(3S,4S)-4-(4-chloro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile. Further purification of each mixture as shown below afforded the individual isomers. SFC method (column: Daicel ChiralPak IG (250*30 mm, 10 um); mobile phase: 45% ethanol (0.1% NH4OH) in CO2) gave 6-chloro-4-[(3S,4R)-4-(4-chloro-2-hydroxy-anilino)-3-methyl- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (4.4 mg, 0.009 mmol, 14% yield) as a yellow solid, and 6-chloro-4-[(3R,4R)-4-(4-chloro-2-hydroxy-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (5.1 mg, 0.01 mmol, 16% yield) as a yellow solid. SFC method (column: DAICEL CHIRALPAK IC (250mm*30 mm,10 um); mobile phase: 50% methanol (0.1% NH4OH) in CO2) gave 6-chloro-4-[(3R,4S)-4-(4-chloro-2-hydroxy- anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (7.4 mg, 0.01 mmol, 23% yield) as a yellow solid, and 6-chloro-4-[(3S,4S)-4-(4-chloro-2-hydroxy- anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (9.3 mg, 0.02 mmol, 29% yield) as a yellow solid. Absolute configuration was arbitrarily assigned. 6-Chloro-4-[(3S,4R)-4-(4-chloro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (Compound 65). LC / MS (ESI) m / z: 458.1 [M+H]+.1HNMR (400 MHz, CD3OD) δ 8.01 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 6.72-6.66 (m, 3H), 4.18 - 3.93 (m, 1H), 3.85-3.82 (m, 2H), 3.80 - 3.73 (m, 1H), 3.72 - 3.70 (m, 1H), 3.63 (s, 3H), 2.46 - 2.45 (m, 1H), 2.25 - 2.22 (m, 1H), 2.05 - 2.01 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H). 6-Chloro-4-[(3R,4S)-4-(4-chloro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (Compound 66). LC / MS (ESI) m / z: 458.1 [M+H]+.1HNMR (400 MHz, CD3OD) δ 8.02 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 6.72 - 6.66 (m, 3H), 4.18 - 4.17(m, 1H), 3.96 - 3.93(m, 2H), 3.84 - 3.82(m, 1H), 3.81 - 3.73(m, 1H), 3.63 (s, 3H), 2.45 - 2.43(m, 1H), 2.24 - 2.21(m, 1H), 2.01 - 2.00 (m, 1H),0.97 (d, J = 7.2 Hz, 3H) 6-Chloro-4-[(3R,4R)-4-(4-chloro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (Compound 67). LC / MS (ESI) m / z: 458.1 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 6.70 - 6.63 (m, 3H), 4.44 - 4.36 (m, 2H), 3.67 - 3.61 (m, 4H), 3.31 - 3.19 (m, 1H), 2.29 - 2.15 (m, 1H), 2.14 -2.11 (m, 1H), 1.66 -1.63 (m, 1H), 1.32 - 1.29 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H). 6-Chloro-4-[(3S,4S)-4-(4-chloro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (Compound 60). LC / MS (ESI) m / z: 458.0 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 6.74 - 6.58 (m, 3H), 4.48 - 4.33 (m, 2H), 3.69 - 3.61 (m, 4H), 3.27 - 3.19 (m, 1H), 2.66 (s, 1H), 2.33 - 2.23 (m, 1H), 2.20 - 2.07 (m, 1H), 1.73 - 1.56 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H). Synthesis of Compound 68 Compound 68 Step 1: Preparation of spiro[indoline-2,4'-piperidine]-3-one To a solution of 1'-benzylspiro[indoline-2,4'-piperidine]-3-one (150 mg, 0.513 mmol, 1 eq) in CH2Cl2(3 mL) was added 1-chloroethyl carbonochloridate (733 mg, 5.13 mmol, 10 eq), and the reaction mixture was stirred at 45 °C for 10 hours. The reaction mixture was concentrated to give a residue. A mixture of the residue in CH3OH (5 mL) was stirred at 60 °C for 1 hour. The mixture was concentrated to give spiro[indoline-2,4'-piperidine]-3-one (100 mg, crude) as a yellow solid. LC / MS (ESI) m / z: 203.3 [M+H]+.

[0064] Step 2: Preparation of 6-chloro-1-methyl-2-oxo-4-(3-oxospiro[indoline-2,4'- piperidine]-1'-yl)-1,5-naphthyridine-3-carbonitrile The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-fluoro-N- methyl-anilino)-1-piperidyl]-1-methyl-2-oxo-1, 5-naphthyridine-3-carbonitrile starting from spiro[indoline-2,4'-piperidine]-3-one. LC / MS (ESI) m / z: 419.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.57-7.38 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 4.27 (d, J = 13.6 Hz, 2H), 3.79 (t, J = 11.6 Hz, 2H), 3.55 (s, 3H), 2.10-2.09 (m, 2H), 1.51-1.50 (m, 2H).

[0065] Synthesis of Compounds 69 and 43

[0066] Step 1: Preparation of tert-butyl (3aR,6aR)-2-(4-fluorophenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate and tert-butyl (3aS,6aS)-2-(4- fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate The enantiomers were separated by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um); mobile phase: 10% CH3OH (0.1% NH4OH) in CO2). Absolute configuration was arbitrarily assigned. tert-butyl (3aR,6aR)-2-(4-fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5- carboxylate (43 mg, 0.14 mmol, 43% yield, white solid) (Rt = 1.14 min). tert-butyl (3aS,6aS)-2-(4-fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5- carboxylate (42 mg, 0.14 mmol, 42% yield, white solid) (Rt = 1.23 min).

[0067] Step 2: Preparation of 4-[(3aR,6aR)-2-(4-fluorophenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (Compound 69) and 4-[(3aS,6aS)-2-(4-fluorophenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (Compound 43) The title compounds were prepared in an analogous manner to 4-[(3aR,6aR)-2-(4- fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile. 4-[(3aR,6aR)-2-(4-fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro- 1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (yellow solid) (Compound 69). LC / MS (ESI) m / z: 424.0 [M+H]+.1H NMR (400MHz, DMSO-d6) δ 8.02 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.01 (t, J = 8.8 Hz, 2H), 6.60 - 6.43 (m, 2H), 4.28 - 4.17 (m, 4H), 3.52 - 3.46 (m, 5H), 3.39 (dd, J = 2.4, 3.6 Hz, 2H), 3.18 (t, J = 9.2 Hz, 2H). 4-[(3aS,6aS)-2-(4-fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro- 1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (yellow solid) (Compound 43). LC / MS (ESI) m / z: 424.0 [M+H]+.1H NMR (400MHz, DMSO-d6) δ 8.08 - 7.98 (m, 1H), 7.85 - 7.74 (m, 1H), 7.08 - 6.94 (m, 2H), 6.66 - 6.38 (m, 2H), 4.31 - 4.16 (m, 4H), 3.54 - 3.45 (m, 5H), 3.37 (s, 2H), 3.18 (t, J = 8.8 Hz, 2H). MS (ESI) m / z: 424.0 [M+1]+1H NMR: (400MHz, DMSO-d6) δ = 8.02 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.01 (t, J = 8.8 Hz, 2H), 6.60 - 6.43 (m, 2H), 4.28 - 4.17 (m, 4H), 3.52 - 3.46 (m, 5H), 3.39 (dd, J = 2.4, 3.6 Hz, 2H), 3.18 (t, J = 9.2 Hz, 2H) Synthesis of Compound 71 Step 1: Preparation of ethyl 3-amino-6-chloro-pyridine-2- carboxylate To a solution of 3-amino-6-chloro-pyridine-2-carboxylic acid (10.0 g, 58.0 mmol, 1 eq) in EtOH (100 mL) was added SOCl2 (8.96 g, 75.3 mmol, 1.3 eq), and the reaction mixture was stirred at 85 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give ethyl 3-amino-6-chloro-pyridine-2-carboxylate (13.5 g, 56.9 mmol, 98% yield, HCl) as a yellow solid. LC / MS (ESI) m / z: 201.2 [M+H]+. Step 2: Preparation of ethyl 6-chloro-3-[(2-cyanoacetyl)amino] pyridine-2- carboxylate To a solution of ethyl 3-amino-6-chloro-pyridine-2-carboxylate (8.00 g, 33.7 mmol, 1 eq, HCl) in DMF (50 mL) were added triethylamine (17.1 g, 169 mmol, 5 eq), 2-cyanoacetic acid (8.61 g, 101 mmol, 3 eq) and 1-propanephosphonic anhydride (34.4 g, 54.0 mmol, 50% purity, 1.6 eq), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL ×3). The combined organic extract was washed with brine (80 mL ×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give ethyl 6-chloro-3-[(2- cyanoacetyl)amino]pyridine-2-carboxylate (8.71 g, 24.1 mmol, 71% yield) as a yellow solid. LC / MS (ESI) m / z: 268.1 [M+H]+. Step 3: Preparation of 6-chloro-4-hydroxy-2-oxo-1H-1,5 –naphthyridine-3- carbonitrile To a solution of ethyl 6-chloro-3-[(2-cyanoacetyl)amino]pyridine-2-carboxylate (8.71 g, 32.5 mmol, 1 eq) in THF (90 mL) was added potassium bis(trimethylsilyl)amide (1 M, 39.05 mL, 1.2 eq) at -78 °C, and the reaction mixture was stirred at -78°C under N2for 1 hour. The reaction mixture was quenched by addition of 1M aqueous HCl to adjust pH=3, then concentrated under reduced pressure. The resulting residue was suspended in water (150 mL), and the suspension was cooled in an ice bath, then filtered. The solid was dried in vacuo to give 6-chloro-4-hydroxy-2-oxo-1H-1,5-naphthyridine-3-carbonitrile (5.33 g, 20.9 mmol, 64% yield) as a yellow solid. LC / MS (ESI) m / z: 221.9 [M+H]+. Step 4: Preparation of 6-chloro-4-hydroxy-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile To a solution of 6-chloro-4-hydroxy-2-oxo-1H-1,5-naphthyridine-3-carbonitrile (5.33 g, 20.9 mmol, 87% purity, 1 eq) in DMF (80 mL) was added NaH (4.81 g, 120 mmol, 60% purity, 5.74 eq) at 0 °C, and the reaction mixture was stirred at 0 °C under N2for 0.5 hour. Iodomethane (10.2 g, 72.2 mmol, 3.45 eq) was then added, and the reaction mixture was stirred at 25 °C under N2for 16 hours. The mixture was slowly poured into water (100 mL), and the pH of the resulting mixture was adjusted to pH=3 with 1N aqueous HCl. The resulting suspension was filtered, and the filter cake was collected and dried under vacuum to give 6-chloro-4-hydroxy-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (5.14 g, 21.8 mmol, 91% yield) as a yellow solid. LC / MS (ESI) m / z: 235.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 3.54 (s, 3H). Step 5: Preparation of 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile To a solution of 6-chloro-4-hydroxy-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (5.14 g, 21.8 mmol, 1 eq) and N,N-diisopropylethylamine (16.9 g, 131 mmol, 6 eq) in CH3CN (100 mL) were added benzyl(triethyl)ammonium chloride (9.94 g, 43.6 mmol, 2 eq) and POCl3 (16.7 g, 109 mmol, 5 eq) at 0 °C, and the reaction mixture was stirred at 25 °C under N2for 16 hours. The mixture was concentrated under reduced pressure. The resulting residue was poured into ice and saturated NaHCO3solution (30 mL), and the mixture was extracted with CH2Cl2(30 mL ×3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography (gradient: 0~3% THF / CH2Cl2) to give 4,6-dichloro-1- methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (3.03 g, 11.9 mmol, 55% yield) as a yellow solid. LC / MS (ESI) m / z: 253.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 3.65 (s, 3H). Step 6: Preparation of 6-chloro-1-methyl-2-oxo-4-spiro[indane-2,4'-piperidine]-1'-yl- 1,5-naphthyridine-3-carbonitrile A mixture of spiro[indane-2,4'-piperidine] (300 mg, 1.34 mmol, 1 eq, hydrochloric acid), 4,6- dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (341 mg, 1.34 mmol, 1 eq), and diisopropylethylamine (693 mg, 5.36 mmol, 0.934 mL, 4 eq) in acetonitrile (3 mL) was stirred at 40 °C for 3 h. The mixture was concentrated under vacuum, and the resulting precipitate was triturated in dimethylformamide (1 mL), washed with acetonitrile (5 mL), and collected by filtration to afford 6-chloro-1-methyl-2-oxo-4-spiro[indane-2,4'-piperidine]-1'- yl-1,5-naphthyridine-3-carbonitrile (471 mg, 1.15 mmol, 86% yield) as a yellow solid. LC / MS (ESI) m / z: 405.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 9.2 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.24 - 7.2 (m, 2H), 7.12 (dd, J = 3.2, 5.6 Hz, 2H), 3.84 (d, J = 4.8 Hz, 4H), 3.52 (s, 3H), 2.92 (s, 4H), 1.88 - 1.76 (m, 4H).

[0068] Synthesis of Compound 72 Compound 72 Step 1: Preparation of tert-butyl 2-[(4-chlorophenyl)methyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate To a solution of tert-butyl 3,4-bis(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate (2.0 g, 5.16 mmol, 1 eq) and (4-chlorophenyl)methanamine (2.19 g, 15.49 mmol, 1.89 mL, 3.0 eq) in acetonitrile (50 mL) was added potassium carbonate (7.13 g, 51.62 mmol, 10.0 eq), and the reaction mixture was stirred at 90 °C for 15 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=10 / 1, 1 / 1, 0 / 1) to give the crude product (2.0 g). The crude product was purified by prep-TLC (dichloromethane / Ethyl acetate / methanol = 2 / 10 / 1) to afford tert-butyl 2-[(4- chlorophenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (0.77 g, 2.29 mmol, 44% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.34 (m, 4H), 3.90 - 3.77 (m, 2H), 3.64 - 3.45 (m, 2H), 3.00 - 2.77 (m, 4H), 2.65 - 2.51 (m, 2H), 2.35 - 2.14 (m, 2H), 1.47 - 1.45 (m, 9H). Step 2: Preparation of 5-[(4-chlorophenyl)methyl]-2,3,3a,4,6,6a-hexahydro-1H- pyrrolo[3,4-c]pyrrole To a solution of tert-butyl 2-[(4-chlorophenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrole-5-carboxylate (0.1 g, 0.3 mol, 1 eq) in methanol (5 mL) was added hydrochloric acid / dioxane (4 M, 10 mL) and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to afford 5-[(4-chlorophenyl)methyl]-2,3,3a,4,6,6a-hexahydro-1H- pyrrolo[3,4-c]pyrrole (81 mg, 296.49 µmol, hydrochloride) as a yellow solid. LC / MS (ESI) m / z: 237.1 [M+H]+.

[0069] Step 3: Preparation of 6-chloro-4-[2-[(4-chlorophenyl)methyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (Compound 72) To a solution of 5-[(4-chlorophenyl)methyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4- c]pyrrole (81 mg, 0.3 mmol, 1.51 eq, hydrochloride) and N,N-diisopropylethylamine (152 mg, 1.18 mmol, 0.2 mL, 6.00 eq) in dichloromethane (10 mL) and DMF (1 mL) was added 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (50 mg, 0.2 mmol, 1.0 eq), and the reaction mixture was stirred at 20 °C for 15 h. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The mixture was stirred at 20 °C for 10 min. The precipitate was filtered, and the product was washed with water (5 mL) and ethyl acetate (5 mL x 2), then concentrated at 40 °C to afford 6-chloro-4-[2-[(4- chlorophenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (34.1 mg, 72.91 µmol, 37% yield) as an off-white solid. LC / MS (ESI) m / z: 470.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.03 - 7.96 (m, 1H), 7.81 - 7.74 (m, 1H), 7.41 - 7.31 (m, 4H), 4.11 - 4.01 (m, 4H), 3.91 - 3.78 (m, 2H), 3.51 - 3.47 (m, 3H), 2.94 - 2.84 (m, 2H), 2.69 - 2.64 (m, 2H), 2.38 - 2.31 (m, 2H).

[0070] Synthesis of Compound 73 Preparation of 8-[(3aR,6aR)-2-(4-fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (Compound 73) To a solution of 5-(4-fluorophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (87.40 mg, 0.36 mmol, 1.5 eq, hydrochloride) and N,N-diisopropylethylamine (186 mg, 1.44 mmol, 0.25 mL, 6.00 eq) in dichloromethane (10 mL) and DMF (1 mL) was added (6-cyano-1- methyl-2-oxo-1,5-naphthyridin-4-yl) trifluoromethanesulfonate (80 mg, 0.24 mmol, 1.0 eq), and the reaction mixture was stirred at 20 °C for 15 h. Water (20 mL) and ethyl acetate (20 mL) were added, and the mixture was stirred at 20 °C for 10 minutes. The precipitate was filtered, and the product was washed with water (5 mL) and ethyl acetate (5 mL x 2), then concentrated at 40 °C to afford 8-[(3aR,6aR)-2-(4-fluorophenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (40.8 mg, 100.83 umol, 42% yield) as a yellow solid. LC / MS (ESI) m / z: 390.1 [M+H]+.1H NMR (400MHz, DMSO-d6) δ 8.20 (s, 1H), 8.06 - 7.98 (m, 1H), 7.07 - 6.95 (m, 2H), 6.57 - 6.43 (m, 2H), 5.70 - 5.63 (m, 1H), 3.91 (br s, 2H), 3.78 - 3.57 (m, 2H), 3.54 - 3.50 (m, 3H), 3.49 - 3.44 (m, 2H), 3.24 - 3.11 (m, 4H). Synthesis of Compounds 74 and 75 Step 1: Preparation of tert-butyl 5-oxo-2H-pyrrole-1-carboxylate To a solution of (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid (40.00 g, 189.55 mmol, 1 eq) in tetrahydrofuran (500 mL) at 0 °C was added a solution of NaBO3·4H2O (72.91 g, 473.88 mmol, 2.5 eq) in water (300 mL) under argon, and the reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (300 mL x 2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 5-oxo-2H-pyrrole-1- carboxylate (25.00 g, 136.46 mmol, 72% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.21 - 7.14 (m, 1H), 6.19 - 6.09 (m, 1H), 4.37 - 4.31 (m, 2H), 1.55 (s, 9H). Step 2: Preparation of tert-butyl 2-[tert-butyl(dimethyl)silyl]oxypyrrole-1-carboxylate To a solution of tert-butyl 5-oxo-2H-pyrrole-1-carboxylate (25.00 g, 136.46 mmol, 1 eq) in dichloromethane (500 mL) under argon at 0 °C was added triethylamine (41.42 g, 409.38 mmol, 56.98 mL, 3.0 eq) followed by [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate (43.29 g, 163.75 mmol, 1.2 eq), and the reaction mixture was stirred at 20 °C for 2 h. The mixture was concentrated at 30 °C, and the resulting residue was purified by silica gel column chromatography (gradient: 100 / 0 to 10 / 1 petroleum ether / ethyl acetate) to afford tert- butyl 2-[tert-butyl(dimethyl)silyl]oxypyrrole-1-carboxylate (32.00 g, 107.58 mmol, 79% yield) as a yellow oil. Step 3: Preparation of tert-butyl 2-methyl-5-oxo-2H-pyrrole-1-carboxylate To a solution of tert-butyl 2-[tert-butyl(dimethyl)silyl]oxypyrrole-1-carboxylate (32.00 g, 107.58 mmol, 1 eq) in dichloromethane (400 mL) under nitrogen was added iodomethane (45.81 g, 322.73 mmol, 20.09 mL, 3.0 eq), and the mixture was cooled to 0 °C. Silver trifluoroacetate (71.29 g, 322.73 mmol, 3.0 eq) was added, and the reaction mixture was stirred at 20 °C for 15 h. The mixture was filtered, and the cake was washed with dichloromethane (30 mL x 2). The filtrate was concentrated at 30 °C, and the resulting residue was purified by silica gel column chromatography (gradient: 1 / 0 to 10 / 1 petroleum ether / ethyl acetate) to afford tert-butyl 2-methyl-5-oxo-2H-pyrrole-1-carboxylate (5.30 g, 26.87 mmol, 25% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.14 - 7.07 (m, 1H), 6.12 - 6.01 (m, 1H), 4.68 - 4.57 (m, 1H), 1.58 - 1.54 (m, 9H), 1.44 (d, J = 6.8 Hz, 3H). Step 4: Preparation of tert-butyl (1R,3aS,6aR)-5-benzyl-1-methyl-3- oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate To a solution of tert-butyl 2-methyl-5-oxo-2H-pyrrole-1-carboxylate (5.30 g, 26.87 mmol, 1 eq) and trifluoroacetic acid (1.53 g, 13.44 mmol, 0.5 eq) in dichloromethane (100 mL) under nitrogen 0 °C was added a solution of N-(methoxymethyl)-1-phenyl-N- (trimethylsilylmethyl)methanamine (10.13 g, 36.28 mmol, 85% purity, 1.35 eq) in dichloromethane (20 mL) dropwise, and the reaction mixture was stirred at 20 °C for 15 h. The mixture was concentrated at 30 °C, and the resulting residue was purified by silica gel column chromatography (gradient: 50 / 1 to 1 / 1 petroleum ether / ethyl acetate) to afford tert- butyl (1R,3aS,6aR)-5-benzyl-1-methyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (8.00 g, 24.21 mmol, 90% yield) as a yellow oil. LC / MS (ESI) m / z: 331.1 [M+H]+. Step 5: Preparation of tert-butyl (1R,3aS,6aR)-5-benzyl-1- methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate To a mixture of tert-butyl (1R,3aS,6aR)-5-benzyl-1-methyl-3-oxohexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (8.00 g, 24.21 mmol, 1 eq) in tetrahydrofuran (50 mL) under nitrogen at 0°C was added borane dimethyl sulfide complex solution (10 M, 6.0 mL, 2.48 eq) dropwise, and the reaction mixture was stirred at 90 °C for 0.5 h. The reaction was quenched by addition of CH3OH (50 mL) and refluxed. The mixture was concentrated in vacuum, and the resulting residue was purified by semi-preparative reverse phase separation (column: Phenomenex luna C18250*80mm*10 um; mobile phase: [20-45% CH3CN in water (TFA)]) to afford tert-butyl (1R,3aS,6aR)-5-benzyl-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (3.60 g, 11.38 mmol, 47% yield) as a colorless oil. LC / MS (ESI) m / z: 317.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.28 (s, 5H), 4.05 (s, 2H), 3.69 (s, 3H), 3.32 (s, 2H), 3.03 (d, J = 8.0 Hz, 1H), 2.67 (s, 1H), 2.47 (d, J = 4.0 Hz, 2H), 1.33 (s, 9H), 1.01 (d, J = 6.4 Hz, 3H). Step 6: Preparation of tert-butyl (1R,3aS,6aR)-1-methylhexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate To a solution of tert-butyl (1R,3aS,6aR)-5-benzyl-1-methylhexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate (2.00 g, 6.32 mmol, 1 eq) in methanol (30 mL) was added palladium on activated carbon (0.20 g, 10% purity) under nitrogen, and the suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (20 psi) at 60 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated to afford tert-butyl (1R,3aS,6aR)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.20 g, 5.30 mmol, 84% yield) as a colorless oil. Step 7: Preparation of tert-butyl (1S,3aR,6aS)-5-(4-fluorobenzyl)-1- methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate To a mixture of 4-fluorobenzaldehyde (219 mg, 1.77 mmol, 2 eq), tert-butyl (1R,3aS,6aR)-1- methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (200 mg, 0.88 mmol, 1 eq), and triethylamine (268 mg, 2.65 mmol, 0.37 mL, 3 eq) in 1,2-dichloroethane (20 mL) was added sodium cyanoborohydride (111 mg, 1.77 mmol, 2 eq) in one portion under nitrogen, and the reaction mixture was stirred at 60 °C for 10 h. The residue was poured into ice-water (w / w = 1 / 1) (10 mL), and the aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic extract was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum to afford tert-butyl (1S,3aR,6aS)-5-(4- fluorobenzyl)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (130 mg, 0.39 mmol, 44% yield) as a yellow gum. LC / MS (ESI) m / z: 334.9 [M+H]+. Step 8: Preparation of (1S,3aS,6aS)-5-(4-fluorobenzyl)-1- methyloctahydropyrrolo[3,4-c]pyrrole To a mixture of tert-butyl (1S,3aR,6aS)-5-(4-fluorobenzyl)-1-methylhexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (120 mg, 0.36 mmol, 1 eq) in dichloromethane (10 mL) was added trifluoroacetic acid (456 mg, 4.00 mmol, 2 mL, 11.15 eq) in one portion under nitrogen, and the reaction mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated in reduced pressure to afford (1S,3aS,6aS)-5-(4-fluorobenzyl)-1- methyloctahydropyrrolo[3,4-c]pyrrole (120 mg, 0.34 mmol, 96% yield, TFA salt) as a yellow gum. Step 9: Preparation of 8-[(3aS,4S,6aR)-2-[(4-fluorophenyl)methyl] -4-methyl- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-5-methyl-6-oxo-1,5- naphthyridine-2-carbonitrile To a mixture of (6-cyano-1-methyl-2-oxo-1,5-naphthyridin-4-yl) trifluoromethanesulfonate (115 mg, 0.34 mmol, 1 eq) and (1S,3aS,6aS)-5-(4-fluorobenzyl)-1- methyloctahydropyrrolo[3,4-c]pyrrole (120 mg, 0.34 mmol, 1 eq, trifluoroacetate) in isopropyl alcohol (10 mL) was added diisopropylethylamine (134 mg, 1.03 mmol, 3 eq) in one portion under nitrogen, and the reaction mixture was stirred at 100 °C for 10 h. The mixture was concentrated in reduced pressure, and the resulting residue was purified by semi- preparative reverse phase separation (column: Phenomenex Synergi Polar-RP 100*25mm*4um; mobile phase: [26-46% CH3CN in water (TFA)]) to afford 8- [(3aS,4S,6aR)-2-[(4-fluorophenyl)methyl] -4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (120 mg, 0.29 mmol, 83% yield) as a yellow gum. LC / MS (ESI) m / z: 418.2 [M+H]+. Step 10: Preparation of 8-[(3aS,4S,6aR)-2-[(4-fluorophenyl)methyl] -4-methyl- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-5-methyl-6-oxo-1,5- naphthyridine-2-carbonitrile (Compound 74) and 8-[(3aR,4R,6aS)-2-[(4- fluorophenyl)methyl] -4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-5- methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (Compound 75) The mixture of enantiomers (100 mg, 0.24 mmol, 1 eq) was separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK AS(250mm*30mm,10um); mobile phase: [0.1%NH4OH in CH3OH]; B%: 65%-65%, 4.2 min; 50 min). Absolute configuration was arbitrarily assigned. The first peak was purified further by semi-preparative reverse phase (column: Waters Xbridge 150*25mm*5um; mobile phase: [36-66% CH3CN in water (NH4OH)]) to give 8- [(3aS,4S,6aR)-2-[(4-fluorophenyl)methyl] -4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (14.6 mg, 0.03 mmol, 14% yield) (Compound 74) as an off-white solid. LC / MS (ESI) m / z: 418.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.02 (t, J = 8.8 Hz, 2H), 5.91 (s, 1H), 5.33 - 5.18 (m, 1H), 3.81 - 3.74 (m, 1H), 3.68 - 3.54 (m, 6H), 3.05 (br s, 3H), 2.76 - 2.66 (m, 1H), 2.53 - 2.43 (m, 1H), 2.39 - 2.29 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H). The second peak to give 8-[(3aR,4R,6aS)-2-[(4-fluorophenyl)methyl]-4-methyl-1,3,3a,4,6,6a -hexahydropyrrolo[3,4-c]pyrrol-5-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (17.7 mg, 0.04 mmol, 17% yield) (Compound 75) as an off-white solid. LC / MS (ESI) m / z: 418.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.26 - 7.20 (m, 2H), 6.92 (t, J = 8.8 Hz, 2H), 5.82 (s, 1H), 5.22 - 5.08 (m, 1H), 3.71 - 3.65 (m, 1H), 3.58 - 3.45 (m, 6H), 2.96 (br s, 3H), 2.63 (br s, 1H), 2.46 - 2.35 (m, 1H), 2.31 - 2.17 (m, 1H), 1.00 (d, J = 6.4 Hz, 3H). Synthesis of Compounds 76 and 70

[0071] Step 1: Preparation of tert-butyl (1R,3aS,6aR)-5-(6-cyano-1-methyl-2-oxo-1,2-dihydro- 1,5-naphthyridin-4-yl)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate To a mixture of (6-cyano-1-methyl-2-oxo-1,5-naphthyridin-4-yl) trifluoromethanesulfonate (295 mg, 0.88 mmol, 1 eq) and tert-butyl (1R,3aS,6aR)-1-methylhexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (200 mg, 0.88 mmol, 1 eq) in n-butyl alcohol (20 mL) was added diisopropylethylamine (343 mg, 2.65 mmol, 3 eq) in one portion under nitrogen, and the reaction mixture was stirred at 100 °C for 10 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (gradient: 5 / 1 to 0 / 1 petroleum ether / ethyl acetate) to afford tert-butyl (1R,3aS,6aR)-5-(6- cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-1-methylhexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (210 mg, 0.51 mmol, 58% yield) as a yellow gum. LC / MS (ESI) m / z: 354.1 [M-56+H]+. Step 2: Preparation of 5-methyl-8-((3aR,4R,6aR)-4-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile racemic To a mixture of tert-butyl (1R,3aS,6aR)-5-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5- naphthyridin-4-yl)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (200 mg, 0.49 mmol, 1 eq) in dichloromethane (20 mL) was added trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 55.30 eq) under nitrogen, and the reaction mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under vacuum to give 5-methyl-8-((3aR,4R,6aR)-4- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2- carbonitrile (180 mg, 0.43 mmol, 87% yield, TFA salt) as a yellow gum. LC / MS (ESI) m / z: 309.8 [M+H]+. Step 3: Preparation of 8-[(3aR,4R,6aR)-5-[(4-fluorophenyl)methyl] -4-methyl- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]-5-methyl-6-oxo-1,5- naphthyridine-2-carbonitrile To a mixture of 4-fluorobenzaldehyde (106 mg, 0.85 mmol, 2 eq), triethylamine (215 mg, 2.13 mmol, 5 eq), and 5-methyl-8-((3aR,4R,6aR)-4-methylhexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (180 mg, 0.43 mmol, 1 eq, trifluoroacetate) in 1,2-dichloroethane (10 mL) was added sodium triacetoxyborohydride (270 mg, 1.28 mmol, 3 eq) in one portion under nitrogen, and the reaction mixture was stirred at 60 °C for 10 h. The residue was poured into ice-water (w / w = 1 / 1) (10 mL), and the aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic extract was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The resulting residue was purified by semi-preparative reverse phase separation (column: Phenomenex Synergi Polar-RP 100*25mm*4µm; mobile phase: [26-46% CH3CN in water (TFA)]) to afford 8-[(3aR,4R,6aR)-5-[(4-fluorophenyl)methyl] -4- methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]-5-methyl-6-oxo-1,5-naphthyridine- 2-carbonitrile (150 mg, 0.36 mmol, 85% yield) as a yellow gum. LC / MS (ESI) m / z: 418.2 [M+H]+. Step 4: Preparation of WC-ARV-JM-004-E, 8-[(3aR,4R,6aR)-5-[(4- fluorophenyl)methyl] -4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]-5- methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (Compound 76) and 8-[(3aS,4S,6aS)- 5-[(4-fluorophenyl)methyl] -4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2- yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (Compound 70) The mixture of enantiomers (150 mg, 0.35 mmol, 1 eq) was separated by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um); mobile phase: [0.1%NH4OH in CH3OH]; B%: 40%-40%, 2.9 min; 25 min). Absolute configuration was arbitrarily assigned. 8-[(3aR,4R,6aR)-5-[(4-fluorophenyl) methyl]-4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (44.1 mg, 0.10 mmol, 28% yield, 98% purity) (Compound 76) as an off-white solid. LC / MS (ESI) m / z: 418.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.23 (br t, J = 6.4 Hz, 2H), 6.93 (t, J = 8.8 Hz, 2H), 5.80 (s, 1H), 4.02 - 3.78 (m, 3H), 3.63 - 3.51 (m, 5H), 3.26 - 3.07 (m, 2H), 2.92 - 2.76 (m, 1H), 2.59 - 2.45 (m, 1H), 2.43 - 2.28 (m, 1H), 2.17 - 2.00 (m, 1H), 1.31 - 1.14 (m, 3H). 8-[(3aS,4S,6aS)-5-[(4-fluorophenyl)methyl]-4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo [3,4- c]pyrrol-2-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile (95.2 mg, 0.22 mmol, 62% yield, 98% purity) (Compound 70) as a yellow solid. LC / MS (ESI) m / z: 418.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ: 7.76 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.10 - 7.02 (m, 2H), 5.95 (s, 1H), 4.49 (br d, J = 12.8 Hz, 1H), 4.11 (br d, J = 11.2 Hz, 1H), 3.90 - 3.71 (m, 3H), 3.57 (s, 3H), 3.38 - 3.19 (m, 3H), 3.10 - 2.93 (m, 2H), 2.70 - 2.56 (m, 1H), 1.70 - 1.56 (m, 3H). Synthesis of Compound 78 Step 1: Preparation of tert-butyl 2-benzyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrole-5-carboxylate To a solution of tert-butyl 3,4-bis(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate (0.4 g, 1.03 mmol, 1.0 eq) and potassium carbonate (1.43 g, 10.32 mmol, 0.64 mL, 10.0 eq) in acetonitrile (20 mL) was added benzylamine (331 mg, 3.10 mmol, 0.33 mL, 3.0 eq), and the reaction mixture was stirred at 90 °C for 15 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate=2 / 3) to afford tert-butyl 2-benzyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (0.15 g, 496.02 µmol, 48% yield) as a yellow oil. LC / MS (ESI) m / z: 303.5 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.36 - 7.28 (m, 5H), 3.99 - 3.81 (m, 2H), 3.63 - 3.46 (m, 2H), 3.02 - 2.83 (m, 4H), 2.73 - 2.50 (m, 2H), 2.33 - 2.15 (m, 2H), 1.46 (s, 9H). Step 2: Preparation of tert-butyl 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole- 5-carboxylate To a stirred solution of tert-butyl 2-benzyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5- carboxylate (150.00 mg, 0.5 mmol, 1 eq) in ethanol (10 mL) was added palladium on activated carbon catalyst (0.05 g, 10% purity) under nitrogen, and the reaction mixture was degassed with hydrogen (3X) and stirred at 20 °C for 15 h under hydrogen (15 psi). The reaction mixture was degassed with hydrogen (3X) and stirred at 20 °C for 15 h under hydrogen (15 psi). The reaction mixture was filtered, and the cake was washed with ethanol (10 mL x 2). The filtrate was concentrated under reduced pressure to afford tert-butyl 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (90 mg, 423.95 µmol, 85% yield) as a white solid. LC / MS (ESI) m / z: 156.9 [M-55]+.1H NMR (400 MHz, CDCl3) δ 4.43 - 4.16 (m, 1H), 3.76 - 3.53 (m, 2H), 2.91 (br s, 6H), 2.45 - 2.19 (m, 2H), 1.53 - 1.39 (m, 9H). Step 3: Preparation of tert-butyl 2-[(4-chloro-2-hydroxy-phenyl)methyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate A solution of tert-butyl 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (90 mg, 0.42 mmol, 1 eq) and 4-chloro-2-hydroxy-benzaldehyde (79 mg, 0.51 mmol, 1.2 eq) in ethanol (10 mL) and dichloromethane (5 mL) was stirred at 20 °C for 2 h. Sodium cyanoborohydride (79 mg, 1.27 mmol, 3.0 eq) was then added, and the reaction mixture was stirred at 20 °C for 13 h under nitrogen. The product was purified by prep-TLC (petroleum ether / ethyl acetate=1 / 2) followed by prep-TLC (dichloromethane / methanol=10 / 1) to afford tert-butyl 2-[(4-chloro-2-hydroxy-phenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrole-5-carboxylate (40 mg, 113.36 µmol, 27% yield) as a yellow solid. LC / MS (ESI) m / z: 353.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 6.99 - 6.95 (m, 1H), 6.94 - 6.90 (m, 1H), 6.78 (dd, J = 1.8, 7.8 Hz, 1H), 4.12 - 3.96 (m, 2H), 3.67 - 3.57 (m, 2H), 3.19 - 3.07 (m, 2H), 3.02 - 2.93 (m, 2H), 2.76 - 2.65 (m, 2H), 2.34 - 2.25 (m, 2H), 1.47 - 1.46 (m, 9H). Step 4: Preparation of 2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5- ylmethyl)-5-chloro-phenol To a solution of tert-butyl 2-[(4-chloro-2-hydroxy-phenyl)methyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (40 mg, 0.11 mmol, 1 eq) in dichloromethane (5 mL) was added hydrochloric acid / methanol (4 M, 10 mL) and the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 2- (2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-ylmethyl)-5-chloro-phenol (33 mg, crude, hydrochloride) as a yellow solid. LC / MS (ESI) m / z: 253.0 [M+H]+.

[0072] Step 5: Preparation of 4-[(3aR,6aR)-2-[(4-chloro-2-hydroxy-phenyl)methyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile (Compound 78) A solution of 2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-ylmethyl)-5-chloro- phenol (33 mg, 0.11 mmol, 1 eq, hydrochloride), triethylamine (57 mg, 0.57 mmol, 0.08 mL, 5.0 eq), and 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (29 mg, 0.11 mmol, 1 eq) in dichloromethane (5 mL) and DMF (1 mL) was stirred at 20 °C for 15 h. The reaction mixture was concentrated under reduced pressure, and the product was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5µm; mobile phase: [45-75% CH3CN in water (NH4HCO3)]). Pure fractions were lyophilized to afford 4-[(3aR,6aR)-2-[(4-chloro-2- hydroxy-phenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-6-chloro-1- methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (13.3 mg, 28.28 µmol, 25% yield) as a white solid. LC / MS (ESI) m / z: 470.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.02 - 7.96 (m, 1H), 7.81 - 7.73 (m, 1H), 7.15 - 7.10 (m, 1H), 6.83 - 6.73 (m, 2H), 4.15 - 4.05 (m, 4H), 4.01 - 3.89 (m, 2H), 3.49 (s, 3H), 3.00 - 2.91 (m, 2H), 2.71 - 2.67 (m, 2H), 2.44 - 2.35 (m, 2H).

[0073] Synthesis of Compounds 79 and 80 Step 1: Preparation of tert-butyl 4-(4-fluoro-N-methyl-anilino)-3-methyl-piperidine-1- carboxylate To a solution of tert-butyl 4-(4-fluoroanilino)-3-methyl-piperidine-1-carboxylate (300 mg, 0.97 mmol, 1 eq) in methanol (5 mL) were added paraformaldehyde (292 mg, 9.73 mmol, 0.26 mL, 10 eq) and sodium cyanoborohydride (61 mg, 0.97 mmol, 1 eq), and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (gradient: 1 / 0 to 20 / 1 petroleum ether / ethyl acetate) to afford tert-butyl 4-(4-fluoro-N-methyl- anilino)-3-methyl-piperidine-1 -carboxylate (200 mg, 0.62 mmol, 64% yield) as a yellow oil. LC / MS (ESI) m / z: 323.2 [M+H]+. Step 2: Preparation of N-(4-fluorophenyl)-N,3-dimethyl-piperidin-4-amine To a solution of tert-butyl 4-(4-fluoro-N-methyl-anilino)-3-methyl-piperidine-1-carboxylate (50 mg, 0.15 mmol, 1 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (17 mg, 0.15 mmol, 0.01 mL, 1 eq), and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give N-(4-fluorophenyl)-N,3- dimethyl-piperidin-4-amine (50 mg, 148.67 µmol, 96% yield, TFA salt) as a brown oil. Step 3: Preparation of 6-chloro-4-[(3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile and 6-chloro-4-[(3R,4R)- 4-(4-fluoro-N-methyl-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5- naphthyridine-3-carbonitrile To a solution of N-(4-fluorophenyl)-N,3-dimethyl-piperidin-4-amine (50 mg, 148.67 µmol, 1 eq, trifluoroacetic acid) in acetonitrile (5 mL) were added diisopropylethylamine (19.21 mg, 148.67 µmol, 25.89 µL, 1 eq) and 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3 - carbonitrile (30.22 mg, 118.93 µmol, 0.8 eq), and the reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10µm; mobile phase: [33-63% CH3CN in water (formic acid)]) to afford the desired products. 6-Chloro-4-[(3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (19.8 mg, 42.85 µmol, 29% yield) (Compound 79) was obtained as a yellow solid. LC / MS (ESI) m / z: 440.0 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.09 - 6.99 (m, 2H), 6.86 (dd, J = 4.4, 9.2 Hz, 2H), 4.33 (d, J = 12.0 Hz, 1H), 4.06 - 3.96 (m, 1H), 4.06 - 3.95 (m, 1H), 3.84 (dd, J = 2.4, 12.8 Hz, 1H), 3.53 (s, 3H), 3.46 - 3.40 (m, 1H), 2.82 (s, 3H), 2.68 - 2.62 (m, 1H), 2.33 (s, 1H), 1.74 ( d, J = 11.2 Hz, 1H), 0.87 (d, J = 6.4 Hz, 3H). 6-Chloro-4-[(3R,4R)-4-(4-fluoro-N-methyl-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (5.8 mg, 12.37 µmol, 8% yield) (Compound 80) was obtained as a yellow solid. LC / MS (ESI) m / z: 440.0 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.07 - 6.96 (m, 2H), 6.90 - 6.83 (m, 2H), 4.28 (d, J = 12.4 Hz, 2H), 3.73 (dt, J = 3.6, 11.1 Hz, 1H), 3.66 - 3.55 (m, 1H), 3.53 (s, 3H), 3.17 (s, 1H), 2.70 - 2.66 (m, 3H), 2.28 (dd, J = 4.0, 6.4 Hz, 1H), 1.97 - 1.84 (m, 1H), 1.77 - 1.65 (m, 1H), 0.83 (d, J = 6.4 Hz, 3H). Synthesis of Compound 81

[0074] Step 1: Preparation of (3S,4R)-N-(4-fluorophenyl)-3-methyl-piperidin-4-amine To a solution of tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methyl-piperidine-1-carboxylate (100.00 mg, 324.26 µmol, 1 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (36.97 mg, 324.26 µmol, 24.01 µL, 1 eq), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give (3S,4R)-N-(4- fluorophenyl)-3-methyl-piperidin-4-amine (100 mg, 310.27 µmol, 96% yield, TFA salt) as brown oil. Step 2: Preparation of 6-chloro-4-[(3S,4R)-4-(4-fluoroanilino)-3-methyl-1-piperidyl]- 1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 81) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-chloroanilino)- 1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from (3S,4R)-N-(4- fluorophenyl)-3-methyl-piperidin-4-amine. (yellow solid). LC / MS (ESI) m / z: 426.1 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 6.90 (t, J = 8.8 Hz, 2H), 6.76 - 6.65 (m, 2H), 5.60 (d, J = 8.8 Hz, 1H), 4.01 (d, J = 2.4 Hz, 1H), 3.85 ( d, J = 4.8 Hz, 2H), 3.77 - 3.59 (m, 2H), 3.52 (s, 3H), 2.41 - 2.21 (m, 1H), 2.13 - 2.04 (m, 1H), 1.84 (ddd, J = 3.2, 9.6 Hz, 1H), 0.86 (d, J = 6.8 Hz, 3H). Synthesis of Compound 82 Preparation of 6-chloro-4-[(3R,4R)-4-(4-fluoroanilino)-3-methyl-1-piperidyl]-1- methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 82) The title compound was made in an analogous manner to 6-chloro-4-[(3S,4R)-4-(4- fluoroanilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile starting from tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-methyl-piperidine-1-carboxylate. (yellow solid). LC / MS (ESI) m / z: 426.1 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 6.95 - 6.85 (m, 2H), 6.68 - 6.56 (m, 2H), 5.48 (d, J = 9.2 Hz, 1H), 4.32 - 4.15 (m, 2H), 3.65 - 3.54 (m, 1H), 3.52 (s, 3H), 3.26 - 3.09 (m, 2H), 2.20 - 2.09 (m, 1H), 2.08 - 1.92 (m, 1H), 1.57 - 1.40 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H).

[0075] Synthesis of Compound 83 Step 1: Preparation of tert-butyl 4-[(4-chloro-2-hydroxy-phenyl)methyl-methyl- amino]piperidine-1-carboxylate To a mixture of tert-butyl 4-(methylamino)piperidine-1-carboxylate (500 mg, 2.33 mmol, 1.0 eq) and 4-chloro-2-hydroxy-benzaldehyde (365 mg, 2.33 mmol, 1.0 eq) in dichloroethane (5 mL) and CH3OH (5 mL) was added acetic (560 mg, 9.33 mmol, 4.0 eq), and the resulting mixture was stirred at 25 °C for 5 hours. NaBH(OAc)3(2.47 g, 11.67 mmol, 5.0 eq) was then added, and the reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was purified by prep-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [0-30% CH3CN in water (0.225% formic acid)]). Pure fractions were combined, then lyophilized to afford tert-butyl 4-[(4- chloro-2-hydroxy-phenyl)methyl-methyl-amino]piperidine-1-carboxylate (335 mg, 0.906 mmol, 39% yield) as a white solid. LC / MS (ESI) m / z: 355.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.04 - 6.92 (m, 2H), 6.88 - 6.80 (m, 1H), 4.34 - 4.17 (m, 2H), 4.02 - 3.82 (m, 2H), 3.08 - 2.93 (m, 1H), 2.78 - 2.68 (m, 2H), 2.46 (s, 3H), 2.01 (d, J = 11.6 Hz, 2H), 1.66 - 1.61 (m, 2H), 1.47 (s, 9H). Step 2: Preparation of 5-chloro-2-[[methyl(4-piperidyl)amino]methyl]phenol To a mixture of tert-butyl 4-[(4-chloro-2-hydroxy-phenyl)methyl-methyl-amino]piperidine-1- carboxylate (120 mg, 0.338 mmol, 1.0 eq) in dichloromethane (1 mL) was added HCl / dioxane (4 M, 1 mL, 11.8 eq) in one portion at 25°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuum to afford 5-chloro-2- [[methyl(4-piperidyl)amino]methyl]phenol (86 mg, 0.311 mmol, 92% yield) as a white solid. LC / MS (ESI) m / z: 255.2 [M+H]+. Step 3: Preparation of 6-chloro-4-[4-[(4-chloro-2-hydroxy-phenyl)methyl-methyl- amino]-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 83) To a mixture of 5-chloro-2-[[methyl(4-piperidyl)amino]methyl]phenol (95 mg, 0.374 mmol, 1.0 eq) and 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (95 mg, 0.374 mmol, 1.0 eq) in CH3CN (4 mL) at 20°C was added diisopropylethylamine (1.87 mmol, 326 µL, 5.0 eq), and the reaction mixture was stirred at 40 °C for 1 hour. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by prep-HPLC (column: Xtimate C18100*30mm*10 µm; mobile phase: [15-45% CH3CN in water (0.225% formic acid)]). Pure fractions were combined, then lyophilized to afford 6-chloro-4-[4-[(4-chloro-2- hydroxy-phenyl)methyl-methyl-amino]-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (80.3 mg, 0.168 mmol, 45% yield) as a yellow solid. LC / MS (ESI) m / z: 472.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.79 (dd, J = 2.0, 8.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 4.29 (d, J = 13.2 Hz, 2H), 3.77 (s, 2H), 3.55 (s, 2H), 3.52 (s, 3H), 2.96 - 2.90 (m, 1H), 2.22 (s, 3H), 1.96 (d, J = 10.4 Hz, 2H), 1.90 - 1.77 (m, 2H). Synthesis of Compound 84 Step 1: 3.2 Preparation of tert-butyl 4-(4-fluoro-N-methyl-anilino)piperidine-1- carboxylate To a solution of tert-butyl 4-(4-fluoroanilino)piperidine-1-carboxylate (300 mg, 1.02 mmol, 1.0 eq) in DMF (2 mL) at 25°C was added K2CO3(155 mg, 1.12 mmol, 1.1 eq) and iodomethane (2.55 mmol, 159 µL, 2.5 eq) dropwise, and the reaction mixture was stirred at 60 °C for 12 hours under N2. The reaction mixture was filtered, and the residue was purified by prep-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [30-60% CH3CN in water (0.225% formic acid)]). Pure fractions were combined, then lyophilized to afford tert- butyl 4-(4-fluoro-N-methyl-anilino)piperidine-1-carboxylate (100 mg, 292 mmol, 29% yield) as a white solid. LC / MS (ESI) m / z: 309.3 [M+H]+. Step 2: Preparation of N-(4-fluorophenyl)-N-methyl-piperidin-4-amine To tert-butyl 4-(4-fluoro-N-methyl-anilino)piperidine-1-carboxylate (100 mg, 0.324 mmol, 1.0 eq) in dichloromethane (1 mL) was added HCl / dioxane (4 M, 1 mL, 12.3 eq) in one portion at 25 °C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuum to afford N-(4-fluorophenyl)-N-methyl-piperidin-4-amine (67 mg, 0.322 mmol, 99% yield) as a white solid. LC / MS (ESI) m / z: 209.0 [M+H]+. Step 3: Preparation of 6-chloro-4-[4-(4-fluoro-N-methyl-anilino)-1-piperidyl]-1- methyl-2-oxo-1, 5-naphthyridine-3-carbonitrile (Compound 84) To a mixture of N-(4-fluorophenyl)-N-methyl-piperidin-4-amine (67 mg, 0.322 mmol, 1.0 eq) and 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (82 mg, 0.322 mmol, 1.0 eq) in CH3CN (2 mL) at 25°C was added diisopropylamine (1.61 mmol, 280 µL, 5.0 eq), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuum, and the resulting residue was purified by prep-HPLC (column: Xtimate C18100*30mm*10um; mobile phase: [0-60% CH3CN in water (0.225% formic acid)]). Pure fractions were combined, then lyophilized to afford 6-chloro-4-[4-(4-fluoro-N- methyl-anilino)-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (64.3 mg, 0.146 mmol, 45% yield) as a yellow solid. LC / MS (ESI) m / z: 426.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.09 - 6.97 (m, 2H), 6.93 - 6.86 (m, 2H), 4.29 (d, J = 12.8 Hz, 2H), 4.02 (tt, J = 3.6, 11.6 Hz, 1H), 3.57 - 3.48 (m, 5H), 2.70 (s, 3H), 1.98 (dq, J = 3.2, 12.0 Hz, 2H), 1.79 (d, J = 10.4 Hz, 2H). Synthesis of Compound 85 Step 1: Preparation of spiro[indoline-2,4'-piperidine] To a solution of 1'-benzylspiro[indoline-2,4'-piperidine] (230 mg, 0.826 mmol) in CH3OH (5 mL) was added Pd(OH)2(100 mg, 0.712 mmol) and AcOH (99.23 mg, 1.65 mmol, 94.50 µL) under N2. The mixture was degassed and purged with H2(3X) and stirred at 50 °C for 3 hours under H2(50 Psi). The reaction mixture was filtered, and the filter cake was washed with CH3OH (200 mL). The filtrate was concentrated under reduced pressure to give spiro[indoline-2,4'-piperidine] (150 mg, crude) as a white solid. LC / MS (ESI) m / z: 189.3 [M+H]+. Step 2: Preparation of 6-chloro-1-methyl-2-oxo-4-spiro[indoline-2,4'-piperidine]-1'- yl-1,5-naphthyridine-3-carbonitrile (Compound 85) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-fluoro-N- methyl-anilino)-1-piperidyl]-1-methyl-2-oxo-1, 5-naphthyridine-3-carbonitrile starting from spiro[indoline-2,4'-piperidine]. (yellow solid). LC / MS (ESI) m / z: 406.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.53-6.43 (m, 2H), 6.09 (s, 1H), 4.04-3.91 (m, 2H), 3.89- 3.77 (m, 2H), 3.53 (s, 3H), 2.90 (s, 2H), 1.93-1.83 (m, 4H). Synthesis of Compound 86 Step 1: Preparation of 1'-benzyl-1-methyl-spiro[indoline-2,4'-piperidine]-3-one To a solution of 1'-benzylspiro[indoline-2,4'-piperidine]-3-one (500 mg, 1.71 mmol) in DMF (5 mL) at 0°C was added NaH (68 mg, 1.71 mmol, 60% purity), and the reaction mixture was stirred at 25 °C for 1 hour. Iodomethane (242 mg, 1.71 mmol, 106 µL) was then added at 0°C, and mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into saturated aqueous NH4Cl (10 mL), and the resulting mixture was extracted with ethyl acetate (10 mL×3). The combined organic extracts were washed with brine (10 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (gradient: 0~50% ethyl acetate in petroleum ether) to afford 1'-benzyl-1-methyl-spiro[indoline-2,4'-piperidine]-3-one (480 mg, 1.25 mmol, 73% yield) as a yellow oil. LC / MS (ESI) m / z: 307.2 [M+H]+. Step 2: Preparation of 1-methylspiro[indoline-2,4'-piperidine]-3-one To a solution of 1'-benzyl-1-methyl-spiro[indoline-2,4'-piperidine]-3-one (50 mg, 0.163 mmol, 1 eq) in dichloroethane (2 mL) was added 1-chloroethyl carbonochloridate (122 mg, 0.855 mmol, 5.24 eq), and the reaction mixture was stirred at 50°C for 3 hours. The mixture was concentrated to give a residue. A mixture of the residue in MeOH (5 mL) was stirred at 25°C for 0.5 hour. The mixture was concentrated to give 1-methylspiro[indoline-2,4'- piperidine]-3-one (30 mg, crude) as a yellow solid. LC / MS (ESI) m / z: 217.0 [M+H]+. Step 3: Preparation of 6-chloro-1-methyl-4-(1-methyl-3-oxo-spiro[indoline-2,4'- piperidine]-1'-yl)-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 86) The title compound was prepared in an analogous manner to 6-chloro-4-[4-(4-fluoro-N- methyl-anilino)-1-piperidyl]-1-methyl-2-oxo-1, 5-naphthyridine-3-carbonitrile starting from 1-methylspiro[indoline-2,4'-piperidine]-3-one. (yellow solid). LC / MS (ESI) m / z: 434.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 4.20-4.12 (m, 4H), 3.55 (s, 3H), 2.93 (s, 3H), 2.36-2.29 (m, 2H), 1.62 (d, J = 13.6 Hz, 2H). Synthesis of Compounds 87 and 42 Step 1: Preparation of tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methyl-piperidine-1- carboxylate and tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-methyl-piperidine-1- carboxylate To a solution of 4-fluoroaniline (1 g, 9.00 mmol, 0.86 mL, 1 eq) in methanol (10 mL) were added tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (1.92 g, 9.00 mmol, 1 eq), sodium cyanoborohydride (565 mg, 9.00 mmol, 1 eq), and acetic acid (54 mg, 0.9 mmol, 51.47 uL, 0.1 eq), and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (gradient: 1 / 1 to 13 / 1 petroleum ether / ethyl acetate) to afford the desired products. tert-Butyl (3S,4R)-4-(4-fluoroanilino)-3-methyl-piperidine-1-carboxylate (500 mg, 1.62 mmol, 18.00% yield) was obtained as a yellow solid.1HNMR (400 MHz, DMSO-d6) δ 6.93 - 6.83 (m, 1H), 6.88 (t, J = 8.8 Hz, 1H), 6.65 - 6.58 (m, 2H), 5.34 (d, J = 8.8 Hz, 1H), 3.78 - 3.44 (m, 3H), 3.19 - 2.94 (m, 2H), 2.05 - 1.96 (m, 1H), 1.57 - 1.46 (m, 2H), 1.39 (s, 9H), 0.77 (d, J = 7.2 Hz, 3H). tert-Butyl (3R,4R)-4-(4-fluoroanilino)-3-methyl-piperidine-1-carboxylate (500 mg, 1.62 mmol, 18.02% yield) was obtained as a yellow solid.1HNMR (400 MHz, DMSO-d6) δ 6.90 - 6.85 (m, 2H), 6.57 - 6.53 (m, 2H), 5.30 - 5.27 (m, 1H), 3.88 - 3.84 (m, 2H), 2.99 - 2.94 (m, 2H), 2.85 - 2.81 (m, 1H), 2.64 - 2.60 (m, 1H), 1.92 - 1.88 (m, 1H), 1.47 - 1.45 (m, 1H), 1.42 (s, 9H), 1.09 - 1.05 (m, 1H), 0.90 (d, J = 7.2 Hz, 3H) Step 2: Preparation of tert-butyl (3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methyl- piperidine-1-carboxylate A mixture of tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methyl-piperidine-1-carboxylate (200 mg, 0.65 mmol, 1 eq), sodium cyanoborohydride (61 mg, 0.97 mmol, 1.5 eq), and formaldehyde (58 mg, 0.71 mmol, 0.053 mL, 37% purity, 1.1 eq) in CH3OH (2 mL) was stirred at 25 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: 100:1 to 1:1 petroleum ether / ethyl acetate) to give tert-butyl (3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methyl-piperidine-1- carboxylate (180 mg, 0.56 mmol, 86% yield) as a white solid. LC / MS (ESI) m / z: 267.2 (M- 55)+. Step 3: Preparation of 6-chloro-4-[(3R,4R)-4-(4-fluoroanilino)-3-methoxy-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile A mixture of tert-butyl (3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methyl-piperidine-1- carboxylate (100 mg, 0.31 mmol, 1 eq) and trifluoroacetic acid (35 mg, 0.31 mmol, 0.023 mL, 1 eq) in dichloromethane (1 mL) was stirred at 25°C for 15 minutes. The mixture was concentrated under vacuum to give (3S,4R)-N-(4-fluorophenyl)-N,3-dimethyl-piperidin-4- amine (105 mg, crude, TFA salt) as a red oil. LC / MS (ESI) m / z: 223.1 [M+H]+. Step 4: Preparation of 6-chloro-4-[(3R,4R)-4-(4-fluoroanilino)-3-methoxy-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile A mixture of (3S,4R)-N-(4-fluorophenyl)-N,3-dimethyl-piperidin-4-amine (105 mg, 0.31 mmol, 1 eq, trifluoroacetic acid), 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3- carbonitrile (79 mg, 0.31 mmol, 1 eq), and diisopropylethylamine (121 mg, 0.94 mmol, 0.16 mL, 3 eq) in acetonitrile (1 mL) was stirred at 40 °C for 12 h. The mixture was concentrated under vacuum, and the precipitate was triturated in DMF (2 mL) and collected by filtration to afford 6-chloro-4-[(3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methyl-1-piperidyl]-1-methyl-2- oxo-1,5-naphthyridine-3-carbonitrile (59 mg, 0.13 mmol, 43% yield) as a yellow solid. LC / MS (ESI) m / z: 440.0 [M+H]+. Step 5: Preparation of 6-chloro-4-[(3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methyl-1- piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (Compound 87) and 6- chloro-4-[(3R,4S)-4-(4-fluoro-N-methyl-anilino)-3-methyl-1-piperidyl]-1-methyl-2- oxo-1,5-naphthyridine-3-carbonitrile (Compound 42) The enantiomers were separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm, 10 µm); mobile phase: ethanol (0.1% NH4OH) in CO2). The absolute configuration was arbitrarily assigned. 6-Chloro-4-[(3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (30.3 mg, 0.07 mmol, 51% yield) (Compound 87) was obtained as a yellow solid. LC / MS (ESI) m / z: 440.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.08 - 7.01 (m, 2H), 6.87 (dd, J = 4.4, 9.2 Hz, 2H), 4.38 - 4.29 (m, 1H), 4.06 - 3.94 (m, 2H), 3.89 - 3.79 (m, 1H), 3.53 (s, 3H), 3.47 - 3.39 (m, 2H), 2.82 (s, 3H), 2.61 (s, 1H), 1.80 - 1.69 (m, 1H), 0.87 (d, J = 6.8 Hz, 3H). 6-Chloro-4-[(3R,4S)-4-(4-fluoro-N-methyl-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo- 1,5-naphthyridine-3-carbonitrile (11.9 mg, 0.03 mmol, 20% yield) (Compound 42) was obtained as a yellow solid. LC / MS (ESI) m / z: 440.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.04 (t, J = 8.8 Hz, 2H), 6.86 (dd, J = 4.4, 8.8 Hz, 2H), 4.39 - 4.27 (m, 1H), 4.09 - 3.91 (m, 2H), 3.84 (d, J = 12.8 Hz, 1H), 3.53 (s, 3H), 3.48 - 3.38 (m, 2H), 2.82 (s, 3H), 2.62 (d, J = 3.2 Hz, 1H), 1.74 (d, J = 11.2 Hz, 1H), 0.87 (d, J = 6.8 Hz, 3H). Synthesis of Compounds 89 Step 1: Preparation of (3aS,6aR)-5-benzyl-3a,6a-dimethyl-4,6-dihydrofuro[3,4- c]pyrrole-1,3-dione

[0076] To a solution of tert-butyl (3aS,6aR)-3a,6a-dimethyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c] pyrrole-5-carboxylate (0.5 g, 2.08 mmol, 1 eq) and (4-fluorophenyl)boronic acid (582.17 mg, 4.16 mmol, 2 eq) in dichloromethane (20 mL) were added copper acetate (755.73 mg, 4.16 mmol, 2 eq) and triethylamine (421.02 mg, 4.16 mmol, 579.12 µL, 2 eq), and the reaction mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (gradient: 5 / 1 to 1 / 1 petroleum ether / ethyl acetate) to afford tert-butyl (3aS,6aR)-2-(4-fluorophenyl)- 3a,6a- dimethyl-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate (0.4 g, 1.20 mmol, 57% yield) as a yellow oil. LC / MS (ESI) m / z: 335.1 [M+H]+. St...

Claims

CLAIMS 1. A compound having the structure of Formula (A): (A) or a pharmaceutically acceptable salt thereof, wherein: Ring A is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic ring fused to ring B; Ring C is a heterocyclic ring, which may be further substituted in addition to R3and R4; R1is C1–C4alkyl; R2is H or an electron withdrawing functional group; each R3is independently NR5R6; each R4is independently C1–C4alkyl or C1–C4alkoxy, or one R3and one R4, together with the atoms of ring C to which they are attached, form a substituted or unsubstituted ring; R5and R6are each independently H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R5and R6, together with the nitrogen to which they are attached, form a substituted or unsubstituted ring; m and n are each independently 0, 1, 2, 3, or 4.

2. The compound of claim 0, or a pharmaceutically acceptable salt thereof, wherein Ring A is a substituted or unsubstituted heteroaromatic ring fused to ring B.

3. The compound of claim 0 or 0, having the structure of Formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein R9is H or straight or branched C1–C4alkyl.

4. The compound of claim 3 wherein R9is methyl.

5. The compound of claim 1 or 2, having the structure of Formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein R10is straight or branched C1–C4alkyl C1–C4alkyl or an electron withdrawing functional group.

6. The compound of any one of claims 1, 2, and 5, having the structure of Formula (IIIa): (IIIa) or a pharmaceutically acceptable salt thereof.

7. The compound of claims 5 or 6 wherein R10is selected from halogen, -CH3, -SO2CF3, -N(R11)2, -NO2, -SO2R12, -C≡N, - C(R13)3, -COR14, -CO2R16, -CON(R17)2, and -N=O, wherein: each of R11, R12, R14, R16, or R17is independently H or straight or branched C1–C4alkyl; and each R13is halogen.

8. The compound of any one of claims 5-7 wherein R10is -Cl.

9. The compound of any one of claims 5-7 wherein R10is -C≡N.

10. The compound of any one of claims 1-9 wherein R1is straight or branched chain C1– C4alkyl.

11. The compound of any one of claims 1-10 wherein R1is methyl.

12. The compound of any one of claims 1-11wherein each R4is independently straight or brached C1–C4alkyl or C1–C4alkoxy, or one R3and one R4, together with the atoms of ring C to which they are attached, form a substituted or unsubstituted ring.

13. The compound of any one of claims 0-12 wherein R2is selected from H, halogen, - SO2CF3, -N(R32)2, -NO2, -SO2R26, -C≡N, -C(R33)3, -COR28, -CHO, -COR29, -CO2R30, - CON(R31)2, and -N=O, wherein: each of R32, R26, R28, R29, R30, or R31is independently H or C1–C4alkyl; and each R33is halogen.

14. The compound of any one of claims 0-12 or wherein R2is selected from H, halogen, - SO2CF3, -N(R32)2, -NO2, -SO2R26, -C≡N, -C(R33)3, -COR28, -CHO, -COR29, -CO2R30, - CON(R31)2, and -N=O, wherein: each of R32, R26, R28, R29, R30, or R31is independently H or straight or branched C1– C4 alkyl; and each R33is halogen.

15. The compound of any one of claims 0-14 wherein R2is H.

16. The compound of any one of claims 0-14 wherein R2is -C≡N.

17. The compound of any one of claims 0-16 wherein ring C is further substituted by one or more substituents selected from R15, R18, R19, R20, R21, and R22, wherein: R15is C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R18and R19are each, independently H, OH, C1–C4alkoxy, C1–C4alkyl, or -NR23R24, or R18and R19, together with the carbon atom to which they are attached, form a substituted or unsubstituted ring; R20is H, C1–C4alkyl, or an electron withdrawing group, or R18and R20, or R19and R20, together with the carbon atoms to which they are attached, form a substituted or unsubstituted ring; R21is H, C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R22is C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R23an R24are each, independently H, C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

18. The compound of any one of claims 0-16 wherein ring C is further substituted by one or more substituents selected from R15, R18, R19, R20, R21, and R22, wherein: R15is straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R18and R19are each, independently H, OH, C1–C4alkoxy, straight or branched C1–C4alkyl, or -NR23R24, or R18and R19, together with the carbon atom to which they are attached, form a substituted or unsubstituted ring; R20is H, straight or branched C1–C4alkyl, or an electron withdrawing group, or R18and R20, or R19and R20, together with the carbon atoms to which they are attached, form a substituted or unsubstituted ring; R21is H, straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R22is straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R23an R24are each, independently H, straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

19. The compound of any one of claims 0-16 wherein ring C is further substituted by one or more substituents selected from R15, R18, R19, R20, R21, and R22, wherein: R15is straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R18and R19are each, independently C1–C4alkoxy, C1–C4alkyl, or -NR23R24, or R18and R19, together with the carbon atom to which they are attached, form a substituted or unsubstituted ring; R20is straight or branched C1–C4alkyl, or an electron withdrawing group, or R18and R20, or R19and R20, together with the carbon atoms to which they are attached, form a substituted or unsubstituted ring; R21is straight or branched C1–C4alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R22is straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R23and R24are each, independently straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

20. The compound of any one of claims 1 to 19 wherein ring C is selected from ; ; ; and , wherein: indicates the point of attachment of ring C to ring B.

21. The compound of any one of claims 17-20, wherein R21is straight or branched C1–C4alkyl.

22. The compound of any one of claims 17-21, wherein R22is straight or branched C1–C4alkyl.

23. The compound of any one of claims 17-22, wherein R15is straight or branched C1–C4alkyl.

24. The compound of any one of claims 1 to 16 wherein ring C is , wherein R18and R19, together with the carbon atom to which they are attached, form a substituted or unsubstituted 5- or 6-membered carbocyclic ring or a substituted or unsubstituted 5- or 6-membered heterocyclic ring.

25. The compound of any one of claims 1 to 16 wherein ring C is , wherein R18and R20, or R19and R20, together with the carbon atoms to which they are attached form a substituted or unsubstituted 5-, 6-, or 7-membered carbocyclic ring or a substituted or unsubstituted 5-, 6-, or 7-membered heterocyclic ring.

26. The compound of any one of claims 17-25 wherein R20is straight or brached C1–C4alkyl.

27. The compound of any one of claims 0-16 wherein ring C is selected from, , , , , , ,, and.

28. The compound of any one of claims 1-16 wherein ring C is , wherein R21is , wherein each R25is independently selected from OH, halogen, C1–C4alkyl, C1–C4alkoxy, C1– C4haloalkyl, C1–C4haloalkoxy, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; t is 0, 1, or 2; and indicates the point of attachment of R21to N.

29. The compound of any one of claims 1-16 wherein ring C is , wherein R21is , whereineach R25is independently selected from OH, halogen, straight or branched C1–C4alkyl, C1–C4alkoxy, straight or branched C1–C4haloalkyl, C1–C4haloalkoxy, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; t is 0, 1, or 2; and indicates the point of attachment of R21to N.

30. The compound of claim 28 or 29 wherein each R25is independently selected from OH, halogen, C1–C4alkyl, C1–C4alkoxy, C1–C4haloalkyl, C1–C4haloalkoxy, unsubstituted aryl, and unsubstituted heteroaryl.

31. The compound of claim 28 or 29 wherein each R25is independently selected from OH, halogen, straight or branched C1–C4alkyl, C1–C4alkoxy, straight or branched C1–C4haloalkyl, C1–C4haloalkoxy, unsubstituted aryl, and unsubstituted heteroaryl. N N 32. The compound of claim 29 wherein ring C is R21.

33. The compound of any one of claims 017-20, and 27-32 wherein R21is selected from ; ; ; ; ; ; and .

34. The compound of any one of claims 17-19 and 22 wherein ring C is selected from ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and .

35. The compound of any one of claims 17-19, 27, and 34 wherein R22is C1–C4alkyl, unsubstituted aryl, or unsubstituted heteroaryl.

36. The compound of claim 35 wherein R22is straight or branched C1–C4alkyl.

37. The compound of any one of claims 1 to 16 wherein ring C is , wherein R18and R19are each independently selected from -H, -OH, alkyl, and , wherein: R26is H, C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R27is -OH, C1–C4alkyl, halogen, C1–C4alkoxy, or C1–C4haloalkoxy, or two adjacent R27groups, and the carbon atoms two which they are attached, form a substituted or unsubstituted 5- or 6-membered ring; q is 0, 1, or 2; and indicates the point of attachment of one or both of R18and R19to ring C.

38. The compound of any one of claims 1 to 16 wherein ring C is , wherein R18and R19are each independently selected from -H, -OH, C1–C4alkyl, and , wherein: R26is H, C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R27is -OH, C1–C4alkyl, halogen, C1–C4alkoxy, or C1–C4haloalkoxy, or two adjacent R27groups, and the carbon atoms two which they are attached, form a substituted or unsubstituted 5- or 6-membered ring; q is 0, 1, or 2; and indicates the point of attachment of one or both of R18and R19to ring C.

39. The compound of any one of claims 1 to 16 wherein ring C is , or a pharmaceutically acceptable salt thereof, wherein R18and R19are each independently selected from -H, -OH, straight or branched C1–C4alkyl, and , wherein: R26is H, straight or branched C1–C4alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R27is -OH, straight or branched C1–C4alkyl, halogen, C1–C4alkoxy, or C1–C4haloalkoxy, or two adjacent R27groups, and the carbon atoms two which they are attached, form a substituted or unsubstituted 5- or 6-membered ring; q is 0, 1, or 2; and indicates the point of attachment of one or both of R18and R19to ring C.

40. The compound of any one of claims 37-39 wherein R26is straight or branched C1–C4alkyl.

41. The compound of any one of claims 1 to 19 wherein ring C is selected from;42. The compound of any one of claims 27 and 34-41 wherein R18and R19, together with the carbon atom to which they are attached, form , wherein: X and Y are each, independently CH2, NR29, O, or C=O; each R28is independently selected from -OH, halogen, C1–C4alkyl, C1–C4haloalkyl, C1–C4alkoxy, and C1–C4haloalkoxy; R29is H or C1–C4alkyl; and w is 0, 1, or 2.

43. The compound of any one of claims 27 and 34-41 wherein R18and R19, together with the carbon atom to which they are attached, form , wherein: X and Y are each, independently CH2, NR29, O, or C=O; each R28is independently selected from -OH, halogen, straight or branched C1–C4alkyl, straight or branched C1–C4haloalkyl, C1–C4alkoxy, and C1–C4haloalkoxy; R29is H or C1–C4alkyl; and w is 0, 1, or 2.

44. The compound of any one of claims 0–16 wherein ring C is selected from ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;; ; ; ; ; ;; and45. The compound of any one of claims 0–16 wherein ring C is selected from; ; ;; ; and.

46. The compound of any one of claims 1-16 wherein ring C is selected from ; ; ; ; ; ; ; and .

47. The compound of any one of claims 1-16 wherein ring C is selected from ; ; ; and , wherein R34is C1–C4alkyl.

48. The compound of any one of claims 1-16 wherein ring C is selected from ; ; ; and , wherein R34is straight or branched C1–C4alkyl.

49. The compound of any one of claims 0-16, or a pharmaceutically acceptable salt thereof, wherein ring C is , wherein R15is ; ; ; or .

50. The compound of any one of claims 0-16 wherein ring C is selected from ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;; ; ; ;; and.

51. The compound of any one of claims 0-16 wherein ring C is or .

52. A compound selected from: ; ; ; ; ; ; ;;;; and and; or a pharmaceutically acceptable salt thereof.

53. A compound selected from:; ; ;; ; ; ;; and , or a pharmaceutically acceptable salt thereof, wherein: X is CH2, O, or NR29; and R29is H or C1–C4alkyl.

54. The compound of claim 53, wherein R29is straight or branched C1–C4alkyl.

55. A compound, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

56. A pharmaceutical composition comprising a compound any one of claims 0–55 and a pharmaceutically acceptable excipient.

57. The pharmaceutical composition of claim 56, further comprising one or more additional anti-cancer agents.

58. The pharmaceutical composition of claim 57, wherein at least one of the additional anti-cancer agents is an immune checkpoint inhibitor.

59. A method of treating cancer, comprising administering a therapeutically effective amount of the compound of any one of claims 1-55 or the pharmaceutical composition of any one of claims 56-58 to a subject in need thereof.

60. The method of claim 59, wherein the cancer is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and / or neck cancer, lymphoma, lymphoma, leukemia, and melanoma.

61. A method of inhibiting the activity of diacylglycerol kinase alpha (DGKα), comprising administering a therapeutically effective amount of the compound of any one of claims 1-55 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 56-58 to a subject in need thereof.

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