DGK-targeting compounds and uses thereof

Abstract

Disclosed herein are compounds of formula (A), or pharma- ceutically acceptable salts thereof, that inhibit one or both activities of diacylglycerol kinase alpha (DGKα).These compounds are useful in the treatment of proliferative diseases (e.g., cancer) and viral infections. TIFF2025503312000936.tif5543

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 305,668, filed February 1, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens that can be recognized by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, comprised of T and B lymphocytes, possesses potent anticancer potential, a broad capacity for responding to diverse tumor antigens, and exquisite specificity. Furthermore, the immune system exhibits considerable plasticity and memory components. Successfully harnessing all these attributes of the adaptive immune system would make immunotherapy unique among all cancer treatment modalities. However, while an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, and established cancers are considered "self" and tolerated by the immune system. To contribute to this state of resistance, tumors may utilize several distinct mechanisms to actively reduce antitumor 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 tumors' use of endogenous "immune checkpoints" that reduce the strength of adaptive immune responses to evade immune destruction and protect normal tissues from collateral damage (Topalian et al. (2012) Curr. Opin. Immunol. 24:1-6; Mellman et al. (2011) Nature 480:480-89). Thus, there is a need in the art for new and novel anti-cancer agents that are safe and effective in restoring T cell activation, lowering antigen thresholds, enhancing anti-tumor function, and / or overcoming the suppressive effects of one or more endogenous immune checkpoints for the treatment of cancer. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Sjoblom et al. (2006) Science 314:268-74 [Non-patent document 2] Mizoguchi et al. (1992) Science 258:1795-98 [Non-patent document 3] Facciabene et al. (2012) Cancer Res. 72:2162-71 [Non-patent document 4] Topalian et al. (2012) Curr. Opin. Immunol. 24:1-6 [Non-patent document 5] Mellman et al. (2011) Nature 480:480-89 Summary of the Invention

[0004] Disclosed herein are compounds that have activity as inhibitors of diacylglycerol kinase alpha (DGKα). Further, in embodiments, the disclosed compounds cause the degradation of DGKα. In embodiments, the compounds described herein possess desirable efficacy, stability, bioavailability, therapeutic index, and toxicity values ​​important for pharmaceutical use.

[0005] In an embodiment, provided herein is a compound of formula (A): [ka] 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 R 3 and R 4 and a heterocyclic ring optionally further substituted in addition to R 1 is C1-C4 alkyl, R 2 is H or an electron-withdrawing functional group, Each R 3 is independently, NR 5 R 6 and Each R4 are independently C1-C4 alkyl or C1-C4 alkoxy, or One R 3 and R 4 together with the ring C atoms to which they are attached form a substituted or unsubstituted heteroaryl; R 5 and R 6 are each independently H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 and R 6 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, a compound having the structure of Formula (A): [ka] or a pharmaceutically acceptable salt thereof, wherein ring A is a substituted or unsubstituted heteroaromatic ring fused to ring B.

[0006] In an embodiment of the compound of formula (I), the compound has the structure of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 9 is H or C1-C4 alkyl.

[0007] In an embodiment of Formula II, R 9 is a straight or branched chain C1-C4 alkyl. In an embodiment of Formula II, R 9 is methyl.

[0008] In embodiments of the compound of Formula (I), the compound has the structure of Formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein R 10 is a C1-C4 alkyl or electron-withdrawing functional group.

[0009] In embodiments of formula (III), R 10 is a straight or branched chain C1-C4 alkyl.

[0010] In an embodiment of the compound of Formula (III), the compound has the structure of Formula (IIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0011] In an embodiment of the compound of Formula (III) or Formula (IIIa), R 10 are halogens, -CH3, -SO2CF3, -N(R 11 )2, -NO2, -SO2R 12 , -C≡N, -C(R 13 )3, -COR 14 , -CO2R 16 , -CON(R 17 )2, and -N=O; R 11 , R 12 , R 14 , R 15 , R 16 , and R 17 are each independently H or C1-C4 alkyl (e.g., straight-chain or branched-chain C1-C4 alkyl); Each R 13 is a halogen.

[0012] In embodiments of compounds of formula (III) and (IIIa), R 10 In embodiments of compounds of formula (III) and (IIIa), R 10 is -C≡N.

[0013] In any one embodiment of the compounds of Formula (I), (II), (III), and (IIIa), R 1is a straight or branched chain C1-C4 alkyl. In embodiments of any one of the compounds of formula (I), (II), (III), and (IIIa), R 1 is methyl.

[0014] In any one embodiment of the compounds of Formula (I), (II), (III), and (IIIa), R 2 is H, halogen, -SO2CF3, -N(R 32 )2, -NO2, -SO2R 26 , -C≡N, -C(R 27 )3, -COR 28 , -CO2R 30 , -CON(R 31 )2, and -N=O: R 32 , R 26 , R 28 , R 30 , and R 31 are each independently H or C1-C4 alkyl (e.g., straight-chain or branched-chain C1-C4 alkyl); Each R 33 is a halogen.

[0015] In any one embodiment of the compounds of Formula (I), (II), (III), and (IIIa), R 2 is H. In embodiments of compounds of Formula (I), (II), (III), and (IIIa), R 2 is -C≡N.

[0016] In any one embodiment of the compounds of Formula (I), (II), (III), and (IIIa), R 4 is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl).

[0017] In any one embodiment of the compounds of Formula (I), (II), (III), and (IIIa), R 4 is C1-C4 alkoxy.

[0018] In embodiments of any one of the compounds of Formula (I), (II), (III), and (IIIa), ring C is R 15 , R 18 , R 19 , R 20 , R 21 , and R 22 is further substituted by one or more substituents selected from:

[0019] In embodiments, in any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] is selected from During the ceremony, R 18 and R 19 are each independently H, OH, C1-C4 alkoxy, C1-C4 alkyl (e.g., straight-chain or branched-chain C1-C4 alkyl), or -NR 23 R 24 or R 18 and R 19 together with the carbon atoms to which they are attached form a substituted or unsubstituted ring, R 20 is H or C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl), or R 18 and R 20 , or R 19 and R 20 together with the carbon atoms to which they are attached form a substituted or unsubstituted ring, R 21 is H, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 22 is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 23and R 24 are each independently H, C1-C4 alkyl (e.g., straight-chain or branched-chain C1-C4 alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 15 is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; [ka] indicates the point of attachment of ring C to ring B.

[0020] In Ring C embodiments, R 21 is a straight or branched chain C1-C4 alkyl. In embodiments, R 22 is a straight or branched chain C-C alkyl. In Ring C embodiments, R 23 and R 24 are each independently H, straight or branched chain C-C alkyl, aryl, or heteroaryl. In Ring C embodiments, R 15 is a straight or branched chain C1-C4 alkyl.

[0021] In embodiments of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] where R 18 and R 19 together with the carbon atoms 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.

[0022] In embodiments of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] where R 18and R 20 , or R 19 and R 20 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.

[0023] In Ring C embodiments, R 20 is a straight or branched chain C1-C4 alkyl.

[0024] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] is selected from.

[0025] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] and R 21 teeth [ka] and: R 25 is selected from OH, halogen, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl), C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, aryl, and heteroaryl; t is 0, 1, or 2; [ka] is R 21 indicates the point of attachment to N.

[0026] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] and R 21 teeth [ka] and R 25 is selected from OH, halogen, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl), C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, aryl, and heteroaryl; t is 0, 1, or 2; [ka] is R 21 indicates the point of attachment to N.

[0027] In embodiments of Ring C, each R 25 are independently selected from OH, halogen, C1-C4 alkyl (e.g., straight chain or branched chain C1-C4 alkyl), C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0028] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] and R 21 teeth, [ka] is selected from.

[0029] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] and R21 teeth, [ka] is selected from.

[0030] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] is selected from.

[0031] In Ring C embodiments, R 22 is C1-C4 alkyl (e.g., straight or branched C1-C4 alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In Ring C embodiments, R 22 is a straight or branched chain C1-C4 alkyl.

[0032] In embodiments of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] and R 18 and R 19 are each independently -H, -OH, C1-C4 alkoxy, C1-C4 alkyl (linear or branched C1-C4 alkyl), and [ka] is selected from R 26 is H, C1-C4 alkyl (linear or branched C1-C4 alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 27 is —OH, C1-C4 alkyl (linear or branched C1-C4 alkyl), halogen, C1-C4 alkoxy, or C1-C4 haloalkoxy; or Two adjacent R 27groups and the two carbon atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered ring; q is 0, 1, or 2; [ka] is R 18 and R 19 indicates the point of attachment of one or both of the rings to ring C.

[0033] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] Selected from R 18 and R 19 are each independently -H, -OH, C1-C4 alkyl, and [ka] Selected from: R 26 is H, C1-C4 alkyl (linear or branched C1-C4 alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 27 is —OH, C1-C4 alkyl (linear or branched C1-C4 alkyl), halogen, C1-C4 alkoxy, or C1-C4 haloalkoxy; or Two adjacent R 27 groups and the two carbon atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered ring; q is 0, 1, or 2; [ka] is R 18 and R 19 indicates the point of attachment of one or both of the rings to ring C.

[0034] In Ring C embodiments, R 26is a straight or branched chain C1-C4 alkyl.

[0035] In embodiments of Ring C, each R 27 is —OH, straight or branched chain C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy.

[0036] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] [ka] [ka] [ka] [ka] is selected from.

[0037] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] is selected from. .

[0038] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] and R 18 and R 19 together with the carbon atoms to which they are attached, [ka] Form: X and Y each independently represent CH2, NR 29 , O, or C=O; R 28 is —OH, halogen, C1-C4 alkyl (linear or branched C1-C4 alkyl), C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; R 29 is H or C1-C4 alkyl (linear or branched C1-C4 alkyl), w is 0, 1, or 2.

[0039] In embodiments of Ring C, each R 28 are independently selected from -OH, halogen, straight or branched chain C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0040] In Ring C embodiments, R 29 is a straight or branched chain C1-C4 alkyl.

[0041] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] is selected from.

[0042] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] is selected from R 34 is C1-C4 alkyl.

[0043] In Ring C embodiments, R 34 is a straight or branched chain C1-C4 alkyl.

[0044] In an embodiment of any one of the compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] and R 32 teeth, [ka] is. In embodiments of compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] and R 22 is C1-C4 alkyl (eg, straight or branched chain C1-C4 alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0045] In embodiments of compounds of Formula (I), (II), (III), and (IIIa), Ring C is [ka] [ka] is selected from.

[0046] In an embodiment, ring C is [ka] is. In an embodiment, [ka] [ka] [ka] [ka]

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[0047] In an embodiment, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] a compound selected from or a pharmaceutically acceptable salt thereof, wherein: X is CH2, O, or NR 29 and R 29 is H or C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl).

[0048] In an embodiment, [ka] [ka]

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[0049] Also disclosed herein are pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient. In embodiments, the pharmaceutical composition further comprises one or more additional anti-cancer agents. In embodiments, at least one additional anti-cancer agent is an immune checkpoint inhibitor.

[0050] In an aspect, disclosed herein is a method for treating cancer, comprising administering a therapeutically effective amount of one or more compounds disclosed herein or pharmaceutical compositions thereof to a subject in need of treatment. In an embodiment, the cancer is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and neck cancer, lymphoma, lymphoma, leukemia, and melanoma.

[0051] In aspects, disclosed herein are methods of inhibiting the activity of diacylglycerol kinase alpha (DGKα), comprising administering to a subject in need of inhibition of activity a therapeutically effective amount of one or more compounds disclosed herein or a pharmaceutical composition thereof. DETAILED DESCRIPTION OF THE INVENTION

[0052] Diacylglycerol kinase (DGK) is a lipid kinase that mediates the conversion of diacylglycerol to phosphatidic acid, thereby terminating T cell function propagated via the TCR signaling pathway. Therefore, DGK functions as an intracellular checkpoint, and its inhibition is expected to enhance T cell signaling pathways and T cell activation. DGKα knockout mouse models showed hyperresponsive T cell phenotypes and improved antitumor immune activity (Zha Y et al. Nature Immunology, (2006) 12:1343, Olenchock BA et al., Nature (2006) 11:1174-81). Furthermore, tumor-infiltrating lymphocytes isolated from human renal cell carcinoma patients overexpressed DGKα, which inhibited T cell function (Prinz, PU et al. J Immunology (2012) 12:5990-6000). Therefore, DGKα may be considered a target for cancer immunotherapy (Riese MJ et al. Front Cell Dev Biol. (2016) 4:108, Chen, SS 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.

[0053] Thus, 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 of DGKα over other diacylglycerol kinases (e.g., DGKζ).

[0054] In embodiments, the disclosed compounds cause degradation of DGKα. In embodiments, the disclosed compounds cause selective degradation of DGKα. In embodiments, the disclosed compounds cause selective degradation of DGKα over other diacylglycerol kinases (e.g., DGKζ).

[0055] The disclosed compounds can be used to treat certain diseases or disorders. In embodiments, the disclosed compounds can be used to treat certain cancers (e.g., colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and neck cancer, lymphoma, leukemia, and melanoma).

[0056] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used in connection with 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 is that which is well known and commonly used in the art.

[0057] The methods and techniques of the present disclosure are generally carried out according to conventional methods well known in the art, as described in various general and more specific references cited and discussed throughout this specification, unless otherwise indicated.See, for example, "Principles of Neural Science," McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al. "Molecular Cell Biology, 4th ed.," WH Freeman & Co., New York (2000); Griffiths et al. "Introduction to Genetic Analysis, 7th ed.," WH Freeman & Co., NY (1999); and Gilbert et al. "Developmental Biology, 6th ed.," Sinauer Associates, Inc., Sunderland, MA (2000).

[0058] Chemical terms used herein are used in accordance with conventional usage in the art, as exemplified in "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, Calif. (1985).

[0059] The above, and all other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0060] 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 may be part of a tissue sample excised from an organism, such as a mammal. In embodiments, an in vitro cell may be a cell in cell culture. In embodiments, an in vivo cell is a cell that resides in an organism, such as a mammal.

[0061] As used herein, the term "contacting" refers to the binding of the indicated moieties in an in vitro system or an in vivo system. For example, contacting a DGKα enzyme with a compound of the present invention includes administering a compound of the present invention to a subject, such as a human, having DGKα, as well as introducing a compound of the present invention into a sample containing, for example, a cell preparation or purified preparation containing the DGKα enzyme.

[0062] The term "DGKα degrading agent" refers to an agent that targets the DGKα enzyme, resulting in its degradation.

[0063] The term "DGKα inhibitor" refers to an agent that can inhibit 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 enzymatic activity at either the catalytic or non-catalytic site.

[0064] 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 cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats). In embodiments, the subject is a human.

[0065] As used herein, the term "selective inhibitor of DGKα" refers to a compound that selectively inhibits the activity of DGKα compared to other diacylglycerol kinases (e.g., DGKζ).

[0066] As used herein, the term "selective degrader of DGKα" refers to a compound that selectively degrades DGKα compared to other diacylglycerol kinases (e.g., DGKζ).

[0067] "Treating" a condition or patient, and "treatment" refers to taking steps to obtain beneficial or desired results, including clinical results, through administration of a compound or composition of the invention. Beneficial or desired results include, but are not limited to, amelioration or alleviation of one or more symptoms or conditions, reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0068] "Administering" or "administration" of the compounds or compositions of the present 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 instructions of a caring healthcare provider. For example, the compounds or pharmaceutical compositions of the present invention can be administered to a subject in need of such treatment by any of the following routes: intravenous, intraarterial, intradermal, intramuscular, intraperitoneal, subcutaneous, intraocular, sublingual, buccal, oral (by ingestion), intranasal (by inhalation), intravaginal, intraspinal, intrathecal, intracerebral, and transdermal (by absorption through the skin). The compounds or compositions of the present invention can also be suitably introduced by rechargeable or biodegradable polymeric or other devices, such as patches and pumps, or formulations that provide extended, sustained, delayed, or controlled release of the compounds or compositions. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended periods.

[0069] The appropriate method of administering a compound or pharmaceutical composition of the present invention to a subject will also depend on various factors, such as the age, weight, sex, and physical condition of the subject, as well as the chemical and biological properties (e.g., solubility, absorption, bioavailability, metabolism, stability, and toxicity) of the compound or pharmaceutical composition.

[0070] In embodiments, a compound or pharmaceutical composition of the invention is administered to a subject orally, e.g., by ingestion. In embodiments, an orally administered compound or pharmaceutical composition is a controlled release (e.g., delayed release, sustained release, or extended release) formulation.

[0071] As used herein, the term "conjugate 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 (for example, the two agents are effective on the patient simultaneously, which may include the synergistic effect of the two agents).For example, different therapeutic compounds can be administered simultaneously or sequentially, either in the same formulation or in separate formulations.Therefore, individuals receiving such treatment can benefit from the combined effects of different therapeutic agents.

[0072] A "therapeutically effective amount" or "therapeutically effective dose" of a compound or pharmaceutical composition of the present invention is an amount of the agent or composition that has the intended therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a therapeutically effective amount can be administered in one or more administrations. The effective amount required for a subject depends, for example, on the subject's age, weight, health, sex, and the nature and extent of the condition (e.g., cancer) being treated. A caring healthcare provider will generally determine the effective amount for a given situation according to these and other factors.

[0073] 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 6 or fewer carbon atoms in its backbone (e.g., C1-C6 for straight-chain, C3-C6 for branched-chain), and more preferably 4 or fewer carbon atoms in its backbone.

[0074] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto, represented by -O-alkyl. For example, "C1-C4 alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0075] When used in conjunction with a chemical moiety (e.g., alkyl, alkenyl, alkoxy), "C x -C y The term "alkyl" is meant to include groups containing x to y carbons in the chain. A C1-C6 alkyl group, for example, contains 1 to 6 carbon atoms in the chain, and a C1-C4 alkyl contains 1 to 4 carbon atoms in the chain.

[0076] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. The ring is preferably 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 adjacent rings and at least two of the rings are aromatic, i.e., the other cyclic rings may be selected from cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, and combinations thereof. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0077] As used herein, the term "carbocyclic ring" refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is substituted or unsubstituted carbon. The carbocyclic ring preferably contains 3 to 10 atoms, more preferably 3 to 8 atoms, and includes 5 to 7 atoms, for example, 5 or 6 atoms.

[0078] As used herein, the term "electron-withdrawing group" means an atom or functional group that draws electron density from neighboring atoms toward itself, typically by resonance or inductive effects. Exemplary electron-withdrawing groups include the trifluoromethylsulfonyl group (-SOCF), substituted or unsubstituted ammonium groups (-NR + , where each R is H or alkyl), nitro group (—NO2), sulfonic acid group (—SOH), sulfonyl group (SOR, where R is alkyl), cyano group (—C≡N), haloformyl group (—COX, where X is Cl, Br, or I), formyl group (—CHO), acyl group (—COR, where R is alkyl), carboxyl group (—CO2H), alkoxycarboxyl group (—COR, where R is alkyl), substituted or unsubstituted aminocarbonyl group (—CONH2, —CONHR, —CONR2, where R is alkyl), halogen group, and nitroso group (—N═O).

[0079] As used herein, the terms "halo," "halogen," and "halogen group" refer to substituents from Group 17 of the Periodic Table of the Elements and include fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I) substituents.

[0080] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms.

[0081] The term "heteroaryl" or "heteroaromatic" refers to a substituted or unsubstituted aromatic monocyclic ring structure, preferably a 5- to 7-membered ring, more preferably a 5- or 6-membered ring, containing at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 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 adjacent rings, and at least one of the rings is heteroaromatic, e.g., the other cyclic ring may be selected from cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0082] As used herein, the term heteroatom means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0083] The term "heterocyclic ring" refers to a substituted or unsubstituted non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, in which the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 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 adjacent rings, and at least one of the rings is heterocyclic, e.g., the other cyclic ring may be selected from cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heterocyclyl. Heterocyclyl groups include, for example, diazinane, imidazolidine, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, octahydropyrrolo[3,4-c]pyrrole, and the like.

[0084] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. It should be understood that "substituted" or "substituted" implicitly includes the provision that such substitution is in accordance with the permissible valences of the replacing atom and substituent, and that the substitution results in a stable compound that does not undergo spontaneous transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended 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 nonaromatic 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, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Substituents can include any of the substituents described herein, including, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0085] The term "aromatic ring" includes aryl and heteroaryl rings.

[0086] The term "ring" includes aryl, cycloalkyl, heterocyclic, carbocyclic, and heteroaryl ring systems.

[0087] Certain compounds described herein can exist in various stereoisomeric forms.Stereoisomers are compounds that differ only in their spatial arrangement.When disclosed compounds are named or shown by structure that shows or does not show stereochemistry, it is understood that this name or structure encompasses all possible stereoisomers, including essentially pure stereoisomers or geometric isomers, and their combinations.

[0088] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is indicated by its chemical name (e.g., the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., the configuration is indicated by a "wedge" bond), the enrichment of the indicated configuration over the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%. The enrichment of the indicated configuration over the opposite configuration is a mole percent and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center by the total number of all compounds having the same or opposite stereochemical configuration in the mixture.

[0089] When the stereochemical configuration at a chiral center in a compound having two or more chiral centers is shown by the structure (e.g., the configuration is shown by a "wedge" bond), and the configuration around two or more chiral centers is labeled "or 1," this means that the compound contains a mixture of stereoisomers and the stereochemistry is in the depicted configuration between the two or more stereocenters. For example, [ka] is the compound [ka] and [ka] It is meant to include mixtures of

[0090] When the stereochemical configuration at a chiral center in a compound having two or more chiral centers is indicated by its structure (e.g., the configuration is indicated by a "wedge" bond), and the configuration around two or more chiral centers is labeled as "abs," this means that the compound is stereochemically enriched with or opposite the depicted stereochemistry, i.e., is absolutely of one or more other stereoisomers. For example, [ka] means that the compound is enriched in the indicated constituent compared to the opposite constituent by more than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%. [ka] or [ka] means.

[0091] Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain asymmetrically substituted carbon atoms that act as chiral centers. "Enantiomer" refers to 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 relative to a carbon-carbon double bond, a carbocyclyl ring, or a bridged bicyclic ring system.

[0092] 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 compounds as chiral salt complexes, or crystallizing the compounds in chiral solvents. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0093] 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).

[0094] In embodiments, the disclosed compounds cause degradation of DGKα. In embodiments, the disclosed compounds cause selective degradation of DGKα. In embodiments, the disclosed compounds cause selective degradation of DGKα over other diacylglycerol kinases (e.g., DGKζ).

[0095] In embodiments, the disclosed compounds have desirable efficacy, stability, bioavailability, therapeutic index, and toxicity values ​​important for use as pharmaceuticals.

[0096] In embodiments, a compound having a structure according to Formula (A): [ka] 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; R 1 is alkyl (e.g., straight or branched chain C1-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, pentyl, hexyl)); R 2 is H or an electron-withdrawing functional group, Each R 3 is independently, NR 5 R 6 and Each R 4are independently alkyl (e.g., straight or branched chain C1-C6 alkyl (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 R 3 and R 4 together with the ring C atoms to which they are attached form a substituted or unsubstituted heteroaryl; R 5 and R 6 are each independently H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 and R 6 together with the nitrogen to which they are attached form a substituted or unsubstituted ring, 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).

[0097] In an embodiment of Formula (A), a compound having a structure according to Formula (I): [ka] 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; R 1 is C1-C4 alkyl (e.g., straight-chain or branched-chain C1-C4 alkyl), R 2 is H or an electron-withdrawing functional group, Each R 3 is independently, NR 5 R 6 and Each R 4is independently C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl) or C1-C4 alkoxy; or One R 3 and R 4 together with the ring C atoms to which they are attached form a substituted or unsubstituted heteroaryl; R 5 and R 6 are each independently H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 and R 6 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.

[0098] In embodiments, a compound having a structure according to Formula (I): [ka] 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; R 1 is C1-C4 alkyl (e.g., straight-chain or branched-chain C1-C4 alkyl), R 2 is H or an electron-withdrawing functional group, Each R 3 is independently, NR 5 R 6 and Each R 4 are independently C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.) or C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), or One R 3 and R4 together with the ring C atoms to which they are attached form a substituted or unsubstituted heteroaryl; R 5 and R 6 are each independently H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 and R 6 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.

[0099] In embodiments, disclosed herein are compounds of Formula (A) or Formula (I), wherein Ring A is selected from pyridine, imidazole, thiazole, oxazole, pyrazole, and isoxazole.

[0100] In embodiments, disclosed herein are compounds of Formula (A) or Formula (I), wherein Ring A is selected from piperidine, diazinane, octahydropyrrolo[3,4-c]pyrrole, imidazolidine, and pyrrolidine.

[0101] In embodiments, a compound of Formula (A) or Formula (I) having a structure according to Formula (IIa): [ka] or a pharmaceutically acceptable salt thereof, wherein Y is S or CH or CR 33 and R 9is H, halogen, cyano (—CN), C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl), C1-C4 haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloropropyl, dichloropropyl, trichloropropyl), C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), or NR 9a and R 9a is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl), and R 33 is C1-C4 alkyl (e.g., straight or branched C1-C4 alkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl), C1-C4 haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloropropyl, dichloropropyl, trichloropropyl), or C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy). In certain embodiments, R 9 is a straight or branched chain C1-C4 alkyl. For example, in certain embodiments, R 9 is methyl, ethyl, propyl, or butyl. In certain embodiments, R 9 is methyl.

[0102] In embodiments, a compound of Formula (A) or Formula (I) having a structure according to Formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 9 is H, halogen, cyano (—CN), C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), C1-C4 haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloropropyl, dichloropropyl, trichloropropyl), C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), or NR 9a and R 9a is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl). In embodiments, R 9 is a straight or branched chain C1-C4 alkyl. For example, in certain embodiments, R 9 is methyl, ethyl, propyl, or butyl. In an embodiment of Formula (II), R 9 is methyl.

[0103] In embodiments, a compound of Formula (A) or Formula (I) having a structure according to Formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein R 10 is H, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), carbocycle (e.g., C3-C7-cycloalkyl), or an electron-withdrawing functional group, and q is 1 or 2. In an embodiment of Formula (III), R 10 is a C1-C4 alkyl (e.g., a straight or branched C1-C4 alkyl) or an electron-withdrawing functional group. 10is methyl, ethyl, propyl, isopropyl, butyl. In an embodiment of formula (III), R 10 is methyl.

[0104] In embodiments, a compound of Formula (III) having a structure according to Formula (IIIa): [ka] or a pharmaceutically acceptable salt thereof is disclosed herein.

[0105] In embodiments of Formula (IIIa), R 10 is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, or butyl). In an embodiment of Formula (IIIa), R 10 is a straight or branched chain C1-C4 alkyl. In an embodiment of Formula (IIIa), R 10 is methyl (-CH3). In embodiments, R 10 is a halogen (e.g., -F, -Cl), -CH3, -SO2CF3, -N(R 11 )2, -NO2, -SO2R 12 , -C≡N, -C(R 13 )3, -COR 14 , -CSR 15 , -CO2R 16 , -CON(R 17 )2, and -N=O: R 11 , R 12 , R 14 , R 15 , R 16 , and R 17 are each independently H or C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.); Each R 13 is a halogen (e.g., —F, —Cl).

[0106] In embodiments, R 10 is -Cl. Alternatively, R10 is -F.

[0107] In embodiments, R 10 is -C≡N.

[0108] In embodiments, R 10 is -N(R 11 )2, -SO2R 12 , or -C(R 13 )3, -CSR 15 and R 11 , R 12 , and R 15 Each of is independently H or methyl.

[0109] In embodiments, R 10 HA-COR 14 and R 14 is H or methyl. In embodiments, R 10 is -CHO. In embodiments, R 10 is -CO(CH3).

[0110] In embodiments, R 10 is -CO2(R 16 ) and R 16 is H or methyl. In embodiments, R 10 is CO2(CH3).

[0111] In embodiments, R 10 is -CON(R 17 )2, and each R 17 is independently H or methyl. In an embodiment, R 10 is -CONH(CH). In an embodiment, R 10 is -CON(CH3)2.

[0112] In embodiments, R 10 is -N=O.

[0113] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein R1 is a straight or branched chain C1-C4 alkyl. In an embodiment of any one of Formulas (A), (I), (II), (III), or (IIIa), R 1 is methyl, ethyl, propyl, or butyl. In embodiments of Formula (A), (I), (II), (III), or (IIIa), R 1 is methyl.

[0114] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein R 2 is H, halogen, -SO2CF3, -N(R 32 )2, -NO2, -SO2R 26 , -C≡N, -C(R 27 )3, -COR 28 , -CSR 29 , -CO2R 30 , -CON(R 31 )2, and -N=O: R 32 , R 26 , R 28 , R 29 , R 30 , and R 31 are each independently H or C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.); Each R 33 is a halogen (e.g., —F, —Cl).

[0115] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein R 2 is H.

[0116] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein R 2 is -C≡N.

[0117] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein R 2 is -N(R 32 )2, -SO2R 26 , -C(R 33 )3, -COR 28 , -CSR 29 , -CO2R 30 , or -CON(R 31 )2 and R 32 , R 26 , R 28 , R 29 , R 30 , and R 31 is independently H or methyl, and each R 33 is a halogen.

[0118] In embodiments of any one of the compounds of Formula (I), (II), (III), and (IIIa), ring C is R 15 , R 18 , R 19 , R 20 , R 21 , and R 22 is further substituted by one or more substituents selected from:

[0119] In embodiments of any one of the compounds of Formula (I), (II), (III), and (IIIa), ring C is R 15 , R 18 , R 19 , R 20 , R 21 , and R 22 and further substituted by one or more substituents selected from: R 15 is a straight or branched chain C1-C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 18 and R 19 are each independently C1-C4 alkoxy, C1-C4 alkyl, or -NR 23 R 24 or R18 and R 19 together with the carbon atoms to which they are attached form a substituted or unsubstituted ring, R 20 is a straight or branched chain C1-C4 alkyl or an electron withdrawing group, or R 18 and R 20 , or R 19 and R 20 together with the carbon atoms to which they are attached form a substituted or unsubstituted ring, R 21 is a straight or branched chain C1-C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 22 is a straight or branched chain C1-C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 23 and R 24 are each independently a straight or branched chain C1-C4 alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0120] In any one embodiment of the compounds of Formula (I), (II), (III), and (IIIa), R 4 is a straight or branched chain C1-C4 alkyl.

[0121] In any one embodiment of the compounds of Formula (I), (II), (III), and (IIIa), R 4 is C1-C4 alkoxy.

[0122] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] is selected from During the ceremony, R 15is a straight or branched chain C1-C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 18 and R 19 are each independently H, OH, C1-C4 alkoxy, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), or -NR 23 R 24 or R 18 and R 19 together with the carbon atoms 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); R 20 is H, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), or C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), or R 18 and R 20 , or R 19 and R 20 together with the carbon atoms to which they are attached form a ring (e.g., a 5-, 6-, or 7-membered substituted or unsubstituted carbocyclic ring, or a 5-, 6-, or 7-membered substituted or unsubstituted heterocyclic ring); R 21 is H or C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 22 is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 23 and R 24are each independently H, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; [ka] indicates the point of attachment of ring C to ring B.

[0123] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] is selected from During the ceremony, R 15 is a straight or branched chain C1-C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 18 and R 19 are each independently OH, C1-C4 alkoxy, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), or -NR 23 R 24 or R 18 and R 19 together with the carbon atoms 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); R 20 is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), or C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), or R 18 and R 20 , or R 19 and R 20together with the carbon atoms to which they are attached form a ring (e.g., a 5-, 6-, or 7-membered substituted or unsubstituted carbocyclic ring, or a 5-, 6-, or 7-membered substituted or unsubstituted heterocyclic ring); R 21 is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 22 is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 23 and R 24 are each independently H, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; [ka] indicates the point of attachment of ring C to ring B.

[0124] In Ring C embodiments, R 32 , R 26 , R 28 , R 29 , R 30 , or R 31 Any one of is a straight or branched chain C1-C4 alkyl.

[0125] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] is selected from During the ceremony, R 18 and R 19are each independently H, OH, C1-C4 alkoxy, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), or -NR 23 R 24 or R 18 and R 19 together with the carbon atoms 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); R 20 is H or C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), or R 18 and R 20 , or R 19 and R 20 together with the carbon atoms to which they are attached form a ring (e.g., a 5-, 6-, or 7-membered substituted or unsubstituted carbocyclic ring, or a 5-, 6-, or 7-membered substituted or unsubstituted heterocyclic ring); R 21 is H or C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), aryl, or heteroaryl; R 22 is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 23 and R 24 are each independently H, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 15is C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; [ka] indicates the point of attachment of ring C to ring B.

[0126] In Ring C embodiments, R 21 is a straight or branched chain C1-C4 alkyl.

[0127] In Ring C embodiments, R 22 is a straight or branched chain C1-C4 alkyl.

[0128] In Ring C embodiments, R 15 is unsubstituted C1-C4 alkyl.

[0129] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein ring C is [ka] where R 18 and R 19 together with the carbon atoms 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.

[0130] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein ring C is [ka] where R 18 and R 20 , or R 19 and R 20together 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.

[0131] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] is selected from.

[0132] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein ring C is [ka] where R 21 teeth [ka] and R 25is OH, halogen (-Cl, -F), C1-C4 alkyl (e.g., straight or branched C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), C1-C4 haloalkyl (e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -(CH2)2CH2F, -(CH2)2CHF2, -(CH2)2CF3, -(CH2 )3CH2F, -(CH2)3CHF2, -(CH2)3CF3), C1-C4 haloalkoxy (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; [ka] is R 21 indicates the point of attachment to N.

[0133] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein ring C is [ka] where R 21 teeth [ka] and Each R 25are independently OH, halogen (-Cl, -F), C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), C1-C4 haloalkyl (e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF 3, -(CH2)2CH2F, -(CH2)2CHF2, -(CH2)2CF3, -(CH2)3CH2F, -(CH2)3CHF2, -(CH2)3CF3), C1-C4 haloalkoxy (e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -O(CH2)2CH2F, -O(CH2)2CHF2, -O(CH2)2CF 3、 -O(CH2)3CH2F, -O(CH2)3CHF2, -O(CH2)3CF3), substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; t is 0, 1, or 2; [ka] is R 21 indicates the point of attachment to N.

[0134] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein ring C is [ka] where R 21 teeth, [ka] is selected from.

[0135] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein ring C is [ka] where R 21 teeth, [ka] is selected from.

[0136] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] is selected from.

[0137] In Ring C embodiments, R 22 is a straight or branched chain C1-C4 alkyl.

[0138] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein ring C is [ka] where R 18 and R 19 are each independently -H, -OH, alkyl (e.g., straight or branched chain C1-C4 alkyl), and [ka] is selected from: R 26 is H, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 27is -OH, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), halogen (-Cl, -F), C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), or C1-C4 haloalkyl (e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -(CH2)2CH2F, -(CH2)2CHF 2, -(CH2)2CF3, -(CH2)3CH2F, -(CH2)3CHF2, -(CH2)3CF3), C1-C4 haloalkoxy (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 R 27 groups and the two carbon atoms to which they are attached form a 5- or 6-membered substituted or unsubstituted ring; q is 0, 1, or 2; [ka] is R 18 and R 19 indicates the point of attachment of one or both of the rings to ring C.

[0139] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] where R 18 and R 19 are each independently -H, -OH, alkyl (e.g., straight or branched chain C1-C4 alkyl), and [ka] is selected from R 26is H, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 27 is -OH, C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), halogen (-Cl, -F), C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), or C1-C4 haloalkyl (e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -(CH2)2CH2F, -(CH2)2CHF 2, -(CH2)2CF3, -(CH2)3CH2F, -(CH2)3CHF2, -(CH2)3CF3), C1-C4 haloalkoxy (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 R 27 groups and the two carbon atoms to which they are attached form a 5- or 6-membered substituted or unsubstituted ring; q is 0, 1, or 2.

[0140] In Ring C embodiments, R 26 is a straight or branched chain C1-C4 alkyl.

[0141] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0142] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] is selected from.

[0143] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] and R 18 and R 19 together with the carbon atoms to which they are attached, [ka] to form X and Y each independently represent CH2, NR 29 , O, or C=O; R 28is -OH, halogen (-Cl, -F), C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), C1-C4 haloalkyl (e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -(CH2)2CH2F, -(CH2)2CHF2, -(CH2)2CF3, -(CH2)3CH2F, -(CH2)3CHF2, -(CH 2) 3CF3), C1-C4 alkyloxy (e.g., methoxy, ethoxy, propoxy, butoxy), or C1-C4 haloalkoxy (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 R 29 is H or C1-C4 alkyl (e.g., straight or branched chain C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.); w is 0, 1, or 2.

[0144] In Ring C embodiments, R 29 is a straight or branched chain C1-C4 alkyl.

[0145] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] is selected from.

[0146] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] is selected from R34 is C1-C4 alkyl (eg, straight or branched C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.).

[0147] In Ring C embodiments, R 34 is a straight or branched chain C1-C4 alkyl.

[0148] In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] and R 32 teeth, [ka] is.

[0149] In embodiments, disclosed herein are compounds having the structure of Formula (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] and R 22 is C1-C4 alkyl (eg, straight or branched C1-C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, etc.), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0150] In Ring C embodiments, R 22 is a straight or branched chain C1-C4 alkyl.

[0151] In embodiments, disclosed herein are compounds having the structure of Formula (A), (I), (II), (III), or (IIIa), wherein Ring C is: [ka] [ka] is selected from. In embodiments, disclosed herein are compounds having a structure according to any one of Formulas (A), (I), (II), (III), or (IIIa), wherein ring C is [ka] is.

[0152] In embodiments, disclosed herein are compounds having a chemical formula according to any one of compounds 1-234, as shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

[0153] In embodiments, disclosed herein are compounds having a chemical formula according to any one of compounds 235-311, as shown in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18] [Table 2-19] [Table 2-20] [Table 2-21] [Table 2-22] or a pharmaceutical salt thereof.

[0154] 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 [ka] To a solution of 2-bromo-5-(trifluoromethoxy)pyridine (2.67 g, 11.05 mmol, 1 equiv.) 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 equiv.) in dioxane (25 mL), 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 equiv.), and cesium carbonate (10.80 g, 33.14 mmol, 3 equiv.) were added. The mixture was stirred at 100° C. for 3 hours. The reaction mixture was added to water (30 mL) and extracted with 60 mL of ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated sodium chloride (30 mL × 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] + .

[0155] 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 [ka] 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 equiv.) was purified by SFC (Column: REGIS(S,S)WHELK-O1 (250 mm × 25 mm, 10 um), Mobile phase: [neutral ethyl alcohol], 15%-15%, 200 min) to give 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) was obtained 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) was obtained as a green oil (SFC: Rt = 1.209 min). The absolute stereochemical configurations were tentatively assigned.

[0156] 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 [ka] 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 equiv.) in dichloromethane (5 mL) was added trifluoroacetic acid (7.70 g, 67.53 mmol, 5.00 mL, 52.32 equiv.). 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] + .

[0157] 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 [ka] 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 equiv., trifluoroacetic acid) and 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (327 mg, 1.29 mmol, 1 equiv.) in acetonitrile (5 mL) was added diisopropylethylamine (833 mg, 6.44 mmol, 1.12 mL, 5 equiv.). 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 preparative HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 μm, mobile phase: [water (formic acid) - acetonitrile], 58%-88%, 58 min) 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: 505.2 507.3, 505.3 [M+1] + . 1 H NMR:(400MHz,DMSO-d6) δ:8.13(d,J=2.4Hz,1H),8.02(d,J=9.2Hz,1H),7.80(d,J=9.2Hz,1H),7.58(dd,J=2.4,9. 2Hz,1H),6.88(d,J=9.6Hz,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=4.4,13.6Hz,1H),3.50(s,3H),3.21-3.13(m,1H),2.57(d, J=6.4Hz,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)

[0158] In embodiments, disclosed herein are compounds having a chemical formula according to any one of compounds 312-390, as shown in Table 3. These compounds are made using a synthesis similar to that described for compound 312, which is discussed in more detail below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20]

[0159] In embodiments, disclosed herein are compounds having a chemical formula according to any one of compounds 391-449, as shown in Table 4. These compounds are made using syntheses similar to those described for compounds 397, 416, and 429, which are discussed in more detail below. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15]

[0160] Pharmaceutical Composition Disclosed herein is a pharmaceutical composition comprising a compound of the present invention, as defined above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.

[0161] Compositions of the invention may be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions, suspensions, or transdermal patches), for administration by inhalation (e.g., as finely divided powders), insufflation (e.g., as finely divided powders), or for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous use, or as suppositories for subcutaneous, intramuscular, intraperitoneal, or rectal or vaginal administration).

[0162] The pharmaceutical compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art and in light of the present disclosure. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents, and / or preservatives.

[0163] Pharmaceutically acceptable excipients that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-alpha-tocopherol, polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., tween®), polyethoxylated castor oil (e.g., CREMOPHOR surfactants (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, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat. Cyclodextrins (e.g., alpha-, beta-, and gamma-cyclodextrin), their chemically modified derivatives (e.g., hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrin), or other solubilizing derivatives may also be advantageously used to enhance delivery of the compounds described herein.

[0164] The amount of compound to be administered and the dosage regimen for treating a disease state using the compounds and / or compositions of the present invention depend on various factors, including the subject's age, weight, sex, medical condition, type of disease, severity of disease, route and frequency of administration, and the specific compound used.Thus, the dosage regimen can vary widely, but can be routinely determined using standard methods.The daily dose can be administered in one to four divided doses per day.Other dosage schedules include once per week and once per two-day cycle.

[0165] Treatment The compounds of the present invention as defined above, or a pharmaceutically acceptable salt thereof, are useful in the treatment of cancer.

[0166] In embodiments, the compounds of the invention disclosed herein, or pharmaceutically acceptable salts thereof, can be used to treat diseases or disorders associated with DGK target inhibition in T cells. In some such embodiments, the compounds of the invention are prepared in combination with one or more additional therapeutic agents for combined administration to treat diseases or disorders associated with DGK target inhibition in T cells.

[0167] Also provided herein is a method for treating the subject suffering from or susceptible to medical conditions associated with DGK target inhibition in T cells.For example, the compounds described herein can be used to treat or prevent proliferative diseases such as viral infection and cancer.More specifically, the diseases or conditions associated with DGK target inhibition in T cells include viral and other infectious diseases (for example, skin infection, GI infection, urinary tract infection, genitourinary infection, systemic infection) and proliferative diseases (for example, cancer).

[0168] In embodiments, the subject is being treated for cancer.Cancer types that can be treated with the compound of the present invention include but are not limited to brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer, lung cancer and bone cancer.Examples of such cancer types include neuroblastoma, intestinal cancer such as rectal cancer, colon cancer, familiar adenomatous polyp cancer and hereditary non-polypoid colorectal cancer, esophageal cancer, lip cancer, pharyngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine somatic cell carcinoma, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma. These include medulloblastoma and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia-lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In preferred embodiments, the compounds of the present invention treat colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and neck cancer, lymphoma, leukemia, and melanoma.

[0169] In embodiments, the compounds of the present invention can inhibit the activity of diacylglycerol kinase alpha (DGKα). For example, the compounds of the present invention can be used to inhibit the activity of DGKα in a cell or a subject in need of modulation of DGKα by administering a therapeutically effective amount of the compound of the present invention or a salt thereof.

[0170] In embodiments, the compounds of the present invention can cause the degradation of DGKα. For example, the compounds of the present invention can be used to degrade DGKα in cells or in a subject in need of treatment by administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Also disclosed herein are methods for treating a disease or condition associated with the activity or expression, including abnormal activity and / or overexpression, of DGKα in a subject in need of such treatment by administering a therapeutically effective amount of one or more compounds of the present invention or pharmaceutical compositions thereof to the subject. Exemplary diseases include any disease, disorder, or condition directly or indirectly associated with the expression or activity, such as overexpression or abnormal activity, of the DGKα enzyme. DGKα-associated diseases can also include any disease, disorder, or condition that can be prevented, ameliorated, or cured by modulating DGKα enzyme activity. Examples of DGKα-associated diseases include cancer and viral infections such as HIV infection, hepatitis B, and hepatitis C.

[0171] Combination therapy In embodiments, the compounds of the present invention may be co-administered with an additional anti-cancer agent, such as an immuno-oncology agent. In certain embodiments, the compounds of the present invention are administered simultaneously with the additional anti-cancer agent. Alternatively, the compounds of the present invention may be co-formulated with the anti-cancer agent.

[0172] Exemplary anti-cancer agents include, but are not limited to, 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 a humanized or human antibody.

[0173] In embodiments, the anti-cancer agent is an immuno-oncology agent. In some such embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including costimulatory) receptor, or (ii) an antagonist of an inhibitory (including co-inhibitory) signal to T cells, both of which amplify antigen-specific T cell responses (often referred to as immune checkpoint regulators).

[0174] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory 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 costimulatory or coinhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, including 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, and lymphotoxin a. 1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0175] In embodiments, T cell responses may be stimulated by a combination of a compound of the invention and one or more of: (i) antagonists (e.g., immune checkpoint inhibitors) of proteins that inhibit T cell activation, 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; or (ii) agonists of proteins that stimulate 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.

[0176] Other drugs that can be combined with the compound of the present invention for the treatment of cancer include the antagonist of inhibitory receptor on NK cell or the agonist of activating receptor on NK cell.For example, the compound of the present invention can be combined with the antagonist of KIR, such as lirilumab.

[0177] Still other agents for combination therapy 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), and FPA-008 (e.g., International Patent Publication Nos. WO11 / 140249, WO13169264, WO14 / 036357).

[0178] In certain embodiments, the compounds of the invention can be used with one or more of agonist agents that bind to positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and with one or more of agents that systemically increase the frequency of anti-tumor T cells, agents that overcome distinct immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interactions), depleting or inhibiting Tregs (e.g., with anti-CD25 monoclonal antibodies (e.g., daclizumab) or ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or exhaustion), and agents that induce innate immune activation and / or inflammation at the tumor site.

[0179] In embodiments, the additional anti-cancer agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0180] In embodiments, the additional anti-cancer agent is a PD-1 antagonist, e.g., 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. WO 2012 / 145493). The immuno-oncology agent may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach to targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224.

[0181] In embodiments, the additional anti-cancer agent is a PD-L1 antagonist, e.g., 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).

[0182] In embodiments, the additional anti-cancer agent is a LAG-3 antagonist, e.g., an antagonistic LAG-3 antibody. Suitable LAG-3 antibodies include, for example, BMS-986016 (e.g., International Patent Publication Nos. WO10 / 19570 and WO14 / 08218), or IMP-731 or IMP-321 (e.g., International Patent Publication Nos. WO08 / 132601 and WO09 / 44273).

[0183] In embodiments, the additional anti-cancer agent is a CD137 (4-1BB) agonist, e.g., an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (e.g., International Patent Publication No. WO12 / 32433).

[0184] In embodiments, the additional anti-cancer agent is a GITR agonist, e.g., an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (e.g., International Patent Publication Nos. WO06 / 105021 and WO09 / 009116), and MK-4166 (e.g., International Patent Publication No. WO11 / 028683).

[0185] 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, and WO08 / 36642), indoximod, BMS-986205, or NLG-919 (e.g., International Patent Publication Nos. WO09 / 73620, WO09 / 1156652, WO11 / 56652, and WO12 / 142237).

[0186] In embodiments, the additional anti-cancer agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0187] In embodiments, the additional anti-cancer agent is an OX4OL antagonist, such as an antagonistic OX40 antibody. Suitable OX4OL antagonists include, for example, RG-7888 (see, for example, International Patent Publication No. WO06 / 029879).

[0188] In embodiments, the additional anti-cancer agent is a CD40 agonist, e.g., an agonistic CD40 antibody. In yet another embodiment, the anti-cancer agent is a CD40 antagonist, e.g., an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0189] In embodiments, the additional anti-cancer agent is a CD27 agonist, e.g., an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, walilumab.

[0190] In embodiments, the additional anti-cancer agent is MGA271 (directed against B7H3) (eg, International Patent Publication No. WO11 / 109400).

[0191] The combination therapies disclosed herein contemplate simultaneous administration of these therapeutic agents, for example, administration of each therapeutic agent at different times, or administration of at least two therapeutic agents substantially simultaneously. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent, or multiple single dosage forms for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any suitable route, including, but not limited to, oral, parenteral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination can be administered by intravenous injection, while the other therapeutic agent of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or both therapeutic agents can be administered parenterally, for example, by intravenous injection. Combination therapy can also include the administration of the above-mentioned therapeutic agent further combined with other biologically active ingredients and non-drug therapy (for example, surgery or radiation therapy).When combination therapy further includes non-drug treatment, the non-drug treatment can be carried out at any appropriate time, as long as the beneficial effect from the synergistic action of the combination of the therapeutic agent and the non-drug treatment is achieved.For example, in appropriate cases, when the non-drug treatment is removed in time from the administration of the therapeutic agent, perhaps even several days or even weeks, the beneficial effect can still be achieved.

[0192] For example, one or more additional agents or treatment methods, such as antiviral agents, chemotherapeutic agents, or other anti-cancer agents, immunostimulants, immunosuppressants, radiation, antitumor and antiviral 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 present invention for the treatment of DGKα-associated diseases, disorders, or conditions. The agents can be combined with the compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0193] Suitable additional anti-cancer agents include alkylating agents (including, but not limited to, nitrogen mustards, ethyleneimine derivatives, alkylsulfonates, nitrosoureas, and triazenes), such as, for example, uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0194] In embodiments, suitable additional agents for use in combination with compounds of the invention in the treatment of cancer (e.g., melanoma) include dacarbazine (DTIC), the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen, optionally with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin, a combination of cisplatin, vinblastine, and DTIC, temozolomide, or YERVOY™. Compounds of the invention can also be combined with immunotherapeutic agents, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF).

[0195] In embodiments, the compounds of the present invention can also be used in combination with vaccine therapy in the treatment of cancer (for example, melanoma).Anti-melanoma vaccines are similar in some respects to the antiviral vaccines used to prevent diseases caused by viruses such as polio, measles, and mumps.Attenuated melanoma cells or parts of melanoma cells called antigens can be injected into patients to stimulate the body's immune system to destroy melanoma cells.

[0196] Suitable additional anti-cancer agents also include antimetabolites (including but not limited to folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as, for example, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0197] Suitable additional anti-cancer agents further include certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as, for example, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (taxol), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide, and teniposide.

[0198] Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, and doloxafine.

[0199] Also suitable are cytotoxic agents such as epidophyllotoxins, antitumor enzymes, topoisomerase inhibitors, platinum coordination complexes such as procarbazine, mitoxantrone, cisplatin and carboplatin, biological response modifiers, growth inhibitory agents, antihormonal therapeutic agents, leucovorin, tegafur, and hematopoietic growth factors.

[0200] Other additional anti-cancer agents include antibody therapeutics such as trastuzumab (HERCEPTIN®), antibodies against costimulatory molecules such as CTLA-4, 4-1BB, and PD-1, or antibodies against cytokines (IL-10 or TGF-β).

[0201] Other additional anti-cancer agents also include those that block immune cell migration, such as antagonists to chemokine receptors, including CCR2 and CCR4.

[0202] Other additional anti-cancer agents include those that enhance the immune system, such as adjuvants or adoptive T cell transfer.

[0203] Additional anti-cancer agents also include anti-cancer vaccines, such as, for example, dendritic cells, synthetic peptides, vaccines, and recombinant viruses.

[0204] The treatment methods of the present invention may optionally include the co-administration of at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more critical steps in a signal transduction pathway in the normal function of cancer cells, thereby resulting in apoptosis. Suitable STIs include (i) bcr / abl kinase inhibitors, such as STI 571 (GLEEVEC®), (ii) epidermal growth factor (EGF) receptor inhibitors, such as the kinase inhibitor 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 farnesyltransferase inhibitors, such as L-744,832 (Kohl et al. Nat. Med., 1(8):792-97(1995)), and (iv) inhibitors of Akt family kinases or the Akt pathway, such as rapamycin (e.g., Sekulic et al. Cancer Res., 60:3504-13(2000)), (v) cell cycle kinase inhibitors, such as flavopiridol and UCN-01 (see, e.g., Sausville Curr. Med. Chem. Anti-Canc. Agents, 3:47-56(2003)), and (vi) phosphatidylinositol kinase inhibitors, such as LY294002 (see, e.g., 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 certain embodiments of the present invention, at least one compound of the present invention and at least one STI may be administered to a patient together. In other words, at least one compound of the present invention may be administered first, or at least one STI may be administered first and the other may be administered second, or at least one compound of the present invention and at least one STI may be administered simultaneously.Furthermore, when more than one compound of the invention and / or an STI is used, the compounds may be administered in any order.

[0205] Also disclosed herein is a pharmaceutical composition for treating chronic viral infections in a subject, comprising administering a therapeutically effective amount of at least one compound of the present invention, optionally at least one chemotherapeutic agent, and optionally at least one antiviral agent in a pharmaceutically acceptable carrier.In an embodiment, one or more compounds of the present invention, one or more chemotherapeutic agents, and / or one or more antiviral agents are administered together.For example, in an embodiment, at least one compound of the present invention may be administered first, or at least one chemotherapeutic agent may be administered first.Alternatively, at least one compound of the present invention and at least one STI may be administered simultaneously.Furthermore, when two or more compounds of the present invention and / or chemotherapeutic agents are used, the compounds may be administered in any order.Similarly, any antiviral agent or STI may be administered at any time relative to the administration of the compound of the present invention.

[0206] Chronic viral infections that can be treated using this combination treatment include, but are not limited to, diseases caused by hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), vesicular zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).In particular, parasitic infections (e.g., malaria) can also be treated by the above method, where a compound known to treat parasitic conditions is optionally added instead of an antiviral agent.

[0207] Suitable antiviral agents contemplated for use in combination with the compounds of formula (I) may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral agents.

[0208] Examples of suitable NRTIs include zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (1592U89), adefovir dipivoxil [bis(POM)-PMEA], lobucavir, BCH-I0652, emitricitabine [(-)-FTC], beta-L-FD4 (also known as beta-L-D4C, also beta-L-2",3"-dicreoxy-5-fluoro-citidene), DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane), and rhodenosine (FddA). Exemplary suitable NNRTIs include nevirapine (BI-RG-587), delaviradine (BHAP, U-90152), efavirenz (DMP-266), PNU-142721, AG-1549, MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione), and (+)-calanolide A (NSC-675451) and B. Exemplary suitable protease inhibitors include saquinavir (Ro 31-8959), ritonavir (ABT-538), indinavir (MK-639), nerfunavir (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.

[0209] Also disclosed herein is a pharmaceutical kit useful for treating or preventing the DGKα-related diseases or disorders mentioned herein, for example, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention.If desired, such kits can further comprise one or more of various conventional pharmaceutical kit components, such as, for example, a container with one or more pharmaceutically acceptable carriers, additional containers that will be readily apparent to those skilled in the art.Instructions such as packaging or labels indicating the amount of components to be administered, administration guidelines, and / or guidelines for mixing components can also be included in the kit.

[0210] Preparation method The compounds of the present invention can be synthesized by many methods available to those skilled in the art in light of the present disclosure. General synthetic schemes for preparing the compounds of the present invention are described below. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art may use to prepare the compounds disclosed herein. Different methods for preparing the compounds of the present invention will be apparent to those skilled in the art. Examples of compounds of the present invention prepared by the methods described in the general schemes are presented in the Examples section below. Preparation of homochiral examples may be carried out by techniques known to those skilled in the art. For example, homochiral compounds may be prepared by separation of racemic products or diastereomers by chiral-phase preparative HPLC. Alternatively, exemplary compounds may be prepared by methods known to provide enantiomerically or diastereomerically enriched products.

[0211] The reactions and techniques described in this section are carried out in solvents appropriate to the reagents and materials employed and are suitable for the transformations being achieved. It should also be understood that in the description of synthetic methods set forth below, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and workup procedures, are selected to be standard conditions for the reaction, which should be readily recognized by one of ordinary skill in the art. Those skilled in the art of organic synthesis will understand that the functionality present on the various portions of the molecule must be compatible with the proposed reagents and reactions. Such limitations on the substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and substitutions will be necessary where incompatible substituents exist. This may necessitate the judgment of modifying the order of synthetic steps or selecting one particular process scheme over another to obtain the compounds of the invention. It will also be recognized that another major consideration in planning any synthetic route in this field is the careful selection of protecting groups used to protect reactive functional groups present in the compounds described herein. A formal explanation of the many alternatives for trained professionals is Wuts and Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, Wiley and Sons (2007). [Example]

[0212] 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) [ka]

[0213] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 7.16(d,J=8.4Hz,2H),6.56(d,J=8.8Hz,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=9.2Hz,2H),2.69(s,3H).

[0214] 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) [ka]

[0215] The title compound was prepared in a similar 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(400MHz,DMSO-d6) δ 7.03(t,J=8.8Hz,2H),6.87-6.81(m,2H),4.50(d,J=12.4Hz,1H),4.32(d, J=13.6Hz,1H),3.96(td,J=4.0,12.4Hz,1H),3.73(dd,J=2.4,13.2Hz,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 ,12.4Hz,1H),2.35-2.27(m,1H),1.76-1.68(m,1H),0.82(d,J=6.8Hz,3H).

[0216] Synthesis of compound 3 [ka]

[0217] Step 1: Preparation of tert-butyl 4-[(2,5-difluorophenyl)methyl]-4-hydroxy-piperidine-1-carboxylate [ka]

[0218] To isopropylmagnesium chloride (2 M, 6.72 mL, 1.43 equiv.) in tetrahydrofuran was added a solution of 2-bromo-1,4-difluorobenzene (1.81 g, 9.38 mmol, 1 equiv.) in tetrahydrofuran, and the resulting mixture was stirred at 25° C. for 6 hours. Bromocopper, methylsulfanylmethane (193 mg, 0.9 mmol, 0.1 equiv.) was then added, and the resulting mixture was stirred at 25° C. for 10 minutes. A solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2 g, 9.38 mmol, 1 equiv.) in tetrahydrofuran was then added over 5 minutes, maintaining the temperature at 25° C., and the reaction mixture was stirred at 25° C. for 12 hours. 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 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 afford 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] + .

[0219] Step 2: Preparation of 5-fluorospiro[3H-benzofuran-2,4″-piperidine] [ka]

[0220] A mixture of tert-butyl 4-[(2,5-difluorophenyl)methyl]-4-hydroxy-piperidine-1-carboxylate (1 g, 3.05 mmol, 1 equiv.) and potassium tert-butoxide (1 g, 9.16 mmol, 3 equiv.) 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 preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, mobile phase: [1–35% CH3CN / 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] + . 1 H NMR(400MHz,CDCl3) δ 9.84-9.44(m,2H),6.92-6.80(m,2H),6.68(dd,J=4.0,8.8Hz,1H),3.48-3.36(m,4H),3.08(s,2H),2.32-2.2(m,2H),2.16-2.12(m,2H).

[0221] 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) [ka]

[0222] The title compound was prepared in a similar 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(400MHz,DMSO-d6) δ 7.08(dd,J=2.8,8.4Hz,1H),6.92(dt,J=2.8,9.2Hz,1H),6.76(dd,J=4.4,8.8Hz,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).

[0223] 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) [ka]

[0224] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 7.01(t,J=8.8Hz,2H),6.49(dd,J=4.4,9.2Hz,2H),4.18(dd,J=5.6,9.2Hz,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).

[0225] Synthesis of compound 6 [ka]

[0226] Step 1: Preparation of tert-butyl (3S,4R)-4-(4-chloro-N-methyl-anilino)-3-methyl-piperidine-1-carboxylate [ka]

[0227] To a mixture of tert-butyl (3S,4R)-4-(4-chloroanilino)-3-methyl-piperidine-1-carboxylate (120 mg, 0.37 mmol, 1 equiv), formaldehyde (149.89 mg, 1.85 mmol, 0.14 mL, 37% purity, 5 equiv), and sodium cyanoborohydride (70 mg, 1.11 mmol, 3 equiv) in methanol (1 mL) and tetrahydrofuran (1 mL) was added acetic acid (53 mg, 0.88 mmol, 0.05 mL, 2.37 equiv) 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 a colorless oil. LC / MS (ESI) m / z: 339.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6) δ 7.22-7.13(m,2H),6.80-6.69(m,2H),4.10(d,J=2.4Hz,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=2.4,12.4Hz,1H),1.40(s,9H),0.80(d,J=7.2Hz,3H).

[0228] Step 2: Preparation of (3S,4R)-N-(4-chlorophenyl)-N,3-dimethyl-piperidin-4-amine [ka]

[0229] A mixture of tert-butyl (3S,4R)-4-(4-chloro-N-methyl-anilino)-3-methyl-piperidine-1-carboxylate (100 mg, 0.30 mmol, 1 equiv.) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 45.77 equiv.) 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] + .

[0230] 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) [ka]

[0231] The title compound was prepared in a similar 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=8.8Hz,1H),7.82(d,J=8.8Hz,1H),7.20(d,J=8.8Hz,2H),6.85(d,J= 9.2Hz,2H),4.34(d,J=12.4Hz,1H),4.14(td,J=3.2,12.4Hz,1H),4.04-3.95(m ,1H),3.91-3.83(m,1H),3.53(s,3H),3.45(t,J=11.6Hz,1H),2.85(s,3H),2.7 8-2.69(m,1H),2.33(d,J=3.6Hz,1H),1.82-1.72(m,1H),0.87(d,J=6.8Hz,3H).

[0232] Synthesis of compound 7 [ka]

[0233] 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 [ka]

[0234] 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 equiv.), 1-bromo-4-(trifluoromethoxy)benzene (274 mg, 1.14 mmol, 0.2 mL, 1 equiv.), and CsCO (1.11 g, 3.41 To a mixture of 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide (55 mg, 0.06 mmol, 0.05 equiv.) 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, and dichloropalladium (55 mg, 0.06 mmol, 0.05 equiv.) under a nitrogen atmosphere. The suspension was degassed and purged with nitrogen (3×). The reaction mixture was stirred at 80° C. under N2 for 3 h. 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] + .

[0235] 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 [ka]

[0236] 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 equiv.) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 57.99 equiv.) in dichloromethane (1 mL) was stirred for 15 minutes at 25° C. The mixture was concentrated under reduced pressure 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] + .

[0237] 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 [ka]

[0238] The title compound was prepared in a similar 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=9.2Hz,1H),7.68(d,J=8.8Hz,1H),7.13(d,J=8.4Hz,2H),6.61-6.5 3(m,2H),5.63(s,1H),5.06-4.90(m,1H),4.00(dd,J=8.4,11.2Hz,1H),3.56( dd,J=8.8,9.6Hz,1H),3.50-3.40(m,5H),3.27-3.23(m,1H),3.21(d,J=4.0Hz ,1H),3.13(dd,J=6.0,10.0Hz,1H),2.90-2.80(m,1H),1.21(d,J=6.4Hz,3H).

[0239] Synthesis of compound 8 [ka]

[0240] 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 [ka]

[0241] 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 equiv.) and 1-bromo-4-(trifluoromethoxy)benzene (255 mg, 1.06 mmol, 0.16 mL, 1.5 equiv.) in dioxane (3 mL), CsCO (690 mg, 2.12 mmol, 3 equiv.) 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 equiv.) were added, 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 give 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] + . 1 H NMR(400MHz,CDCl3) δ 7.09(d,J=8.8Hz,2H),6.51-6.46(m,2H),3.65(dd,J=7.2,11.2Hz,2H),3.51(d,J=2.8Hz,2H),3 .37(d,J=10.4Hz,1H),3.31-3.23(m,1H),3.20(dd,J=3.2,9.2Hz,2H),3.00(s,2H),1.46(s,9H).

[0242] Step 2: Preparation of (3aR,6aS)-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole [ka]

[0243] 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 equiv.) in dichloromethane (1 mL), trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 21 equiv.) was added, 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] + .

[0244] 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) [ka]

[0245] The title compound was prepared in a similar 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(400MHz,DMSO-d6) δ 8.00(d,J=9.2Hz,1H),7.78(d,J=8.8Hz,1H),7.16(d,J=8.8Hz,2H),6.61-6.54(m,2H),4.51(dd,J=6 .8,12.4Hz,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).

[0246] Synthesis of compound 9 [ka]

[0247] 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 [ka]

[0248] 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 equiv.) and 1-bromo-4-(trifluoromethoxy)benzene (225 mg, 0.93 mmol, 0.14 mL, 1.5 equiv.) in dioxane (3 mL), CsCO (610 mg, 1.87 mmol, 3 equiv.) 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 equiv.) were added, 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 give 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] + . 1 H NMR (400 MHz, CDCl3) δ 7.07(d,J=8.8Hz,2H),6.45-6.39(m,2H),3.43-3.34(m,4H),3.31-3.26(m,2H),3.22(d,J=9.6Hz,2H),1.44(s,9H),1.13(s,6H).

[0249] Step 2: Preparation of (3aR,6aS)-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole [ka]

[0250] 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 equiv.) in dichloromethane (1 mL), trifluoroacetic acid (77 mg, 6.8 mmol, 0.5 mL, 31.8 equiv.) was added, 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] + .

[0251] 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) [ka]

[0252] The title compound was prepared in a similar 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(400MHz,DMSO-d6) δ 8.00(d,J=9.2Hz,1H),7.77(d,J=9.2Hz,1H),7.15(d,J=8.4Hz,2H),6.55-6.49(m,2H),4.35-4.3 0(m,2H),4.24-4.17(m,2H),3.50(s,1H),3.49-3.46(m,4H),3.26(d,J=10.4Hz,2H),1.17(s,6H).

[0253] Synthesis of compound 10 [ka] [ka]

[0254] Step 1: Preparation of ethyl 2-methyl-5-(methylamino)thiazole-4-carboxylate [ka]

[0255] To a mixture of ethyl 5-amino-2-methyl-thiazole-4-carboxylate (15 g, 80.55 mmol, 1 equiv.) in tetrahydrofuran (150 mL), sodium hydride (4.19 g, 104.71 mmol, 60% purity, 1.3 equiv.) was added portionwise, and the mixture was stirred at 0 °C for 0.5 h. Iodomethane (19.44 g, 136.93 mmol, 8.52 mL, 1.7 equiv.) was then added, and the reaction mixture was stirred at 20 °C under nitrogen for 12 h. The mixture was diluted with aqueous NH Cl (300 mL) and then extracted with ethyl acetate (3 × 300 mL). The combined organic extracts were 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] + . 1 H NMR(400MHz,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).

[0256] Step 2: Preparation of ethyl 5-[(2-cyanoacetyl)-methyl-amino]-2-methyl-thiazole-4-carboxylate [ka]

[0257] A mixture of 2-cyanoacetic acid (3.06 g, 35.95 mmol, 1.2 equiv) in acetic anhydride (32.70 g, 320.31 mmol, 30.00 mL, 10.69 equiv) was stirred at 80 °C for 0.5 h. Ethyl 2-methyl-5-(methylamino)thiazole-4-carboxylate (6 g, 29.96 mmol, 1 equiv) was then added, and the reaction mixture was stirred under nitrogen at 80 °C for 0.5 h. 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 afford 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] + . 1 H NMR (400 MHz, CDCl3) δ 4.47-4.40(m,2H),3.43(d,J=15.2Hz,2H),3.28(s,3H),2.81-2.74(m,3H),1.42-1.37(m,3H).

[0258] Step 3: Preparation of 7-hydroxy-2,4-dimethyl-5-oxo-thiazolo[5,4-b]pyridine-6-carbonitrile [ka]

[0259] A mixture of ethyl 5-[(2-cyanoacetyl)-methyl-amino]-2-methyl-thiazole-4-carboxylate (2.5 g, 9.35 mmol, 1 equiv) 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 equiv) in ethanol (20 mL) was stirred under nitrogen at 20° C. for 0.5 h. The mixture was concentrated, and the resulting residue was purified by preparative HPLC (column: Welch Xtimate C18 250 x 70 mm #10 μm, 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] + . 1 H NMR (400 MHz, DMSO-d6) δ 3.50(s,3H),2.74(s,3H).

[0260] Step 4: Preparation of (6-cyano-2,4-dimethyl-5-oxo-thiazolo[5,4-b]pyridin-7-yl)trifluoromethanesulfonate [ka]

[0261] 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 equiv.), triethylamine (1.51 g, 14.92 mmol, 2.08 mL, 3 equiv.), and 4-dimethylaminopyridine (61 mg, 0.50 mmol, 0.1 equiv.) in dichloromethane (10 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (2.81 g, 9.94 mmol, 1.64 mL, 2 equiv.) at 0 °C, and the reaction mixture was stirred under nitrogen at 0 °C for 1 h. 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 petroleum 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] + . 1 H NMR(400MHz,DMSO-d6) δ 3.50(s,3H),2.74(s,3H).

[0262] 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) [ka]

[0263] A mixture of (6-cyano-2,4-dimethyl-5-oxo-thiazolo[5,4-b]pyridin-7-yl)trifluoromethanesulfonate (80 mg, 0.23 mmol, 1 equiv.), spiro[3H-benzofuran-2,4″-piperidine] (51 mg, 0.23 mmol, 1 equiv., hydrogen chloride), and diisopropylethylamine (88 mg, 0.68 mmol, 0.12 mL, 3 equiv.) in acetonitrile (2 mL) was degassed and purged with nitrogen (3×), then The mixture was stirred at rt under a nitrogen atmosphere at 40° C. for 4 hours. 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 give 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] + . 1 H NMR(400MHz,DMSO-d6) δ 7.21(d,J=7.2Hz,1H),7.10(t,J=7.2Hz,1H),6.86-6.77(m,2H),4.13-4.04(m,2 H),3.97-3.88(m,2H),3.49(s,3H),3.11(s,2H),2.70(s,3H),2.03-1.95(m,4H).

[0264] Synthesis of compound 11 [ka] [ka]

[0265] 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 [ka]

[0266] To a mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (3 g, 14.07 mmol, 1 equiv) and 4-chloro-2-methyl-aniline (2.39 g, 16.88 mmol, 1.2 equiv) in methanol (15 mL) and acetic acid (15 mL) was added borane 2-methylpyridine (3.01 g, 28.13 mmol, 2 equiv) and the reaction mixture was stirred under nitrogen at 25° C. for 12 hours. The mixture was concentrated in vacuo and the resulting residue was purified by preparative HPLC (column: Welch Xtimate C18 250 × 70 mm #10 um, mobile phase: [53–88% CH3CN in water (NH4HCO3)]) followed by preparative SFC (column: DAICEL CHIRALPAK AD-H (250 mm × 30 mm, 5 um), mobile phase: 20% isopropanol in CO2 (0.1% NH4OH)) to give two diastereomers.

[0267] The 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. 1 H NMR(400MHz,DMSO-d6) δ 7.02-6.97(m,2H),6.61(d,J=8.4Hz,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=3.6Hz,1H),1.74-1.62(m,1H),1.54(d,J=3.6Hz,1H),1.39(s,9H),0.76(d,J=7.2Hz,3H).

[0268] 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(400MHz,DMSO-d6) δ 7.01-6.91(m,2H),6.58(d,J=9.2Hz,1H),4.54(d,J=9.2Hz,1H),3.91(d,J=11.6Hz,2H),3.12 - 3.08(m,1H),2.85(d,J=1.6Hz,1H),2.06(s,3H),1.88(dd,J=3.2,13.2Hz,1H ),1.75-1.59(m,1H),1.40(s,9H),1.26-1.15(m,1H),0.88(d,J=6.4Hz,3H).

[0269] 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 [ka]

[0270] The enantiomers were separated by preparative SFC (column: DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 um), mobile phase: 20% isopropanol (0.1% NH4OH) in CO2).

[0271] Absolute configurations were arbitrarily assigned.

[0272] 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(400MHz,DMSO-d6) δ 7.03-6.97(m,2H),6.61(d,J=8.4Hz,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=5.2Hz) ,1H),3.10(d,J=12.0Hz,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=7.2Hz,3H).

[0273] 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] + . 1 H NMR(400MHz,DMSO-d6) δ 7.03-6.97(m,2H),6.61(d,J=8.4Hz,1H),4.34(d,J=7.6Hz,1H),3.93-3.73(m,1H),3.70-3.57(m,2H),3.34(s,3H),3.17(d, J=4.8Hz,1H),3.10(d,J=12.0Hz,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=7.2Hz,3H).

[0274] Step 3: Preparation of (3S,4R)-N-(4-chloro-2-methyl-phenyl)-3-methyl-piperidin-4-amine [ka]

[0275] 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 equiv.) in dichloromethane (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 23 equiv.) and the reaction mixture was stirred at 25° C. for 0.25 h. The mixture was concentrated in vacuo to give (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] + .

[0276] 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) [ka]

[0277] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.07(d,J=9.2Hz,1H),7.81(d,J=8.8Hz,1H),7.04-6.99(m,2H),6.72(d, J=9.2Hz,1H),4.55(d,J=8.0Hz,1H),4.18(d,J=13.8Hz,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=6.8Hz,3H).

[0278] Synthesis of compound 12

[0279] 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) [ka]

[0280] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.06(d,J=9.2Hz,1H),7.81(d,J=9.2Hz,1H),7.05-6.93(m,2H),6.75-6.65(m,1H),4.75(d,J=9.2Hz,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=6.4Hz,3H).

[0281] 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) [ka]

[0282] The title compound was prepared in a similar 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-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (yellow solid). LC / MS(ESI) m / z: 472.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.08(d,J=9.2Hz,1H),7.8(d,J=9.2Hz,1H),6.84(d,J=2.4Hz,1H),6.80-6. 76(m,1H),6.68(d,J=8.4Hz,1H),4.76(d,J=9.6Hz,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. 2,12.8Hz,1H),2.16-2.04(m,2H),1.64-1.52(m,1H),0.96(d,J=6.4Hz,3H).

[0283] 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) [ka]

[0284] The title compound was prepared in a similar 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-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (yellow solid). LC / MS(ESI) m / z: 472.1 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 8.08(d,J=8.8Hz,1H),7.80(d,J=9.2Hz,1H),6.84(d,J=2.0Hz,1H),6.80-6 .76(m,1H),6.68(d,J=8.4Hz,1H),4.76(d,J=9.6Hz,1H),4.24(t,J=13.6Hz, 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=12.0Hz,1H),2.16-2.04(m,2H),1.64-1.52(m,1H),0.96(d,J=6.4Hz,3H).

[0285] Synthesis of compound 15 Preparation of 2,4-dimethyl-5-oxo-7-spiro[indan-2,4"-piperidine]-1"-yl-thiazolo[5,4-b]pyridine-6-carbonitrile (compound 15) [ka]

[0286] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,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).

[0287] 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) [ka]

[0288] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.07(d,J=9.2Hz,1H),7.81(d,J=9.2Hz,1H),7.06-6.92(m,2H),6.73-6.67(m,1H),4.75(d,J=9.2Hz,1H),4.35-4.21(m,2H),3.64-3.56(m,1 H),3.53(s,3H),3.15(dd,J=11.2,12.8Hz,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=6.8Hz,3H).

[0289] 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) [ka]

[0290] The title compound was prepared in a similar 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-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (off-white solid). LC / MS (ESI) m / z: 472.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6) δ 8.08(d,J=9.2Hz,1H),7.80(d,J=8.8Hz,1H),6.88(d,J=2.4Hz,1H),6.84 -6.76(m,1H),6.76-6.68(m,1H),4.6(d,J=8.8Hz,1H),4.16-4.04(m,1H) ,3.92-3.8(m,6H),3.6(t,J=10Hz,1H),3.52(s,3H),2.32(dd,J=1.6,3.6 Hz,1H),2.08(d,J=2.8Hz,1H),1.88(td,J=4.4,8.8Hz,1H),0.76(s,3H).

[0291] 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) [ka]

[0292] The title compound was prepared in a similar 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(400MHz,DMSO-d6) δ 8.07(d,J=9.2Hz,1H),7.81(d,J=8.8Hz,1H),7.04-6.99(m,2H),6.72(d, J=9.2Hz,1H),4.55(d,J=8.0Hz,1H),4.18(d,J=13.8Hz,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=6.8Hz,3H).

[0293] Synthesis of compound 19 [ka] [ka] [ka]

[0294] 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 [ka]

[0295] A mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (3 g, 14.07 mmol, 1 equiv.), 4-chloro-2-methoxy-aniline (2.22 g, 14.07 mmol, 1 equiv.), and borane 2-methylpyridine (3 g, 28.13 mmol, 2 equiv.) in methanol (15 mL) and acetic acid (15 mL) was stirred at 25° C. for 12 hours. The mixture was concentrated in vacuo, 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 preparative 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 μm), mobile phase: 20% isopropanol in CO2 (0.1% NH4OH)) to give the diastereomers.

[0296] 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. 1 H NMR(400MHz,DMSO-d6) δ 6.88(d,J=2.4Hz,1H),6.80(dd,J=2.4,8.4Hz,1H),6.64(d,J=8.8Hz,1H),4.48(d,J=8.8Hz,1H),3.8(s,3H),3.68-3.52(m,2 H),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=7.2Hz,3H).

[0297] 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(400MHz,DMSO-d6) δ 6.84(d,J=2.4Hz,1H),6.76(dd,J=2.4,8.4Hz,1H),6.60(d,J=8.8Hz,1H),4.68(d,J=9.6Hz,1H),3.88(d,J=11.6Hz,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=6.4Hz,3H).

[0298] Step 2: Preparation of tert-butyl (3S,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl-piperidine-1-carboxylate and tert-butyl (3R,4S)-4-(4-chloro-2-methoxy-anilino)-3-methyl-piperidine-1-carboxylate [ka]

[0299] The enantiomers were separated by SFC (column: DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 um), mobile phase: 20% isopropanol in CO2).

[0300] Absolute configurations were arbitrarily assigned.

[0301] 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] + .

[0302] 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] + .

[0303] Step 3: Preparation of (3S,4R)-N-(4-chloro-2-methoxy-phenyl)-3-methyl-piperidin-4-amine [ka]

[0304] A mixture of tert-butyl (3S,4R)-4-(4-chloro-2-methoxy-anilino)-3-methyl-piperidine-1-carboxylate (100 mg, 0.28 mmol, 1 equiv.) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 47.93 equiv.) in dichloromethane (1 mL) was stirred at 25° C. for 15 minutes. The mixture was concentrated in vacuo 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] +

[0305] 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) [ka]

[0306] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.08(d,J=9.2Hz,1H),7.8(d,J=9.2Hz,1H),6.88(d,J=2.4Hz,1H),6.84-6.76(m,1H),6.76-6.72(m,1H),4.6(d,J=8.8Hz,1H),4.08(d,J =12.4Hz,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=7.2Hz,3H).

[0307] Synthesis of compounds 21 and 20 [ka] [ka]

[0308] 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 [ka]

[0309] A mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (3 g, 14.1 mmol, 1 equiv.), 2-amino-5-fluoro-phenol (2.68 g, 21 mmol, 1.5 equiv.), and acetic acid (84.47 mg, 1.41 mmol, 0.08 mL, 0.1 equiv.) in CHOH (30 mL) was stirred at 50° C. for 0.5 h. Sodium cyanoborohydride (2.65 g, 42 mmol, 3 equiv.) 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 preparative HPLC (column: YMC Triart C18 250 x 50 mm x 7 um, mobile phase: [37-67% CH3CN in water (NH4HCO3)]) to give the desired product.

[0310] 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. 1 H NMR(400MHz,DMSO-d6) δ 9.84(d,J=2.0Hz,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=12.0Hz,1H),2.08-2.00(m,1H),1.60-1.49(m,2H),1.39(s,9H),0.75(d,J=6.8Hz,3H).

[0311] 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(400MHz,DMSO-d6) δ 9.74(s,1H),6.52-6.46(m,2H),6.45-6.39(m,1H),4.11(d,J=9.2Hz,1H),3.88(d,J=12.4Hz,2H),3.04-2.92(m,1H),2. 90-2.73(m,1H),1.88(dd,J=3.2,13.2Hz,1H),1.59-1.52(m,1H),1.40(s,9H),1.14-1.06(m,1H),0.89(d,J=6.4Hz,3H).

[0312] Step 2: Preparation of 5-fluoro-2-[[(3S,4R)-3-methyl-4-piperidyl]amino]phenol [ka]

[0313] 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 equiv.) in dichloromethane (4 mL), trifluoroacetic acid (3.08 g, 27 mmol, 2 mL, 22 equiv.) was added, 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] + .

[0314] 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 [ka]

[0315] The title compound was prepared in a similar 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: 442.0 [M+H] + .

[0316] 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) [ka]

[0317] The enantiomers were separated by preparative HPLC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH4OH in ethanol], B%: 50%-50%, 3.2, 30 min). The enantiomers were further purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [31-61% CH3CN in water (0.225% formic acid)]).

[0318] Absolute configurations were arbitrarily assigned.

[0319] 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] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.04-9.64(m,1H),8.07(d,J=8.8Hz,1H),7.81(d,J=9.2Hz,1H),6.64(d,J= 6.0,8.8Hz,1H),6.57-6.51(m,1H),6.47(t,J=2.8,8.8Hz,1H),4.18(d,J=9. 2Hz,1H),4.11-4.00(m,1H),3.92-3.74(m,3H),3.63-3.55(m,1H),3.52(s,3 H),2.30(s,1H),2.12-2.02(m,1H),1.90-1.82(m,1H),0.84(d,J=7.2Hz,3H).

[0320] 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 μmol, 39% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 442.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6) δ 7.2(dd,J=2.4,12.0Hz,1H),7.0(dd,J=1.2,8.8Hz,1H),6.8(t,J=9.2Hz,1H),5.2(d,J=7.2Hz,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=6.8Hz,3H).

[0321] 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) [ka]

[0322] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.08(d,J=9.2Hz,1H),7.80(d,J=8.8Hz,1H),7.20(dd,J=2.4,11.6Hz,1H),7.00(d d,J=1.6,8.8Hz,1H),6.96-6.88(m,1H),5.52-5.44(m,1H),4.20-4.08(m,1H),3.9 6(dd,J=5.2,13.2Hz,1H),3.92-3.76(m,2H),3.60(t,J=10.4Hz,1H),3.52(s,3H), 2.32(d,J=2.0Hz,1H),2.28-2.16(m,1H),1.92-1.76(m,1H),0.84(d,J=6.8Hz,3H).

[0323] Synthesis of compound 23 [ka] [ka]

[0324] 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 [ka]

[0325] A mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (3 g, 14.07 mmol, 1 equiv.), 4-chloro-2-fluoro-aniline (2 g, 14.07 mmol, 1 equiv.), and borane 2-methylpyridine (3 g, 28.13 mmol, 2 equiv.) in acetic acid (15 mL) and methanol (15 mL) was stirred at 25° C. for 12 hours. The mixture was concentrated in vacuo, 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 preparative HPLC (column: YMC Triart C18 70 × 250 mm × 7 μm, mobile phase: [51–81% CHCN in water (NHHCO)]) followed by SFC (column: DAICEL CHIRALPAK AD-H (250 mm × 30 mm, 5 μm), mobile phase: 20% methanol (0.1% NHOH in CO)) to give the four desired 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 (250 mm × 30 mm, 5 μm), mobile phase: 20% methanol (0.1% NHOH in CO)). 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% NHOH in CO)).

[0326] Absolute configurations were arbitrarily assigned.

[0327] 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. 1 H NMR (400 MHz, DMSO-d6) δ 7.2(dd,J=2.4,11.6Hz,1H),7.20(td,J=1.2,8.8Hz,1H),6.80(t,J=9.2Hz,1H) ,5.20(d,J=7.2Hz,1H),3.92-3.76(m,1H),3.68(dd,J=2.8,13.2Hz,1H),3.64- 3.56(m,1H),3.08(d,J=12.0Hz,1H),2.96-2.76(m,1H),2.04(dd,J=3.6,6.8Hz ,1H),1.76-1.6(m,1H),1.52-1.48(m,1H),1.40(s,9H),0.76(d,J=7.2Hz,3H).

[0328] 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. 1 H NMR (400 MHz, DMSO-d6) δ 7.2(dd,J=2.4,11.8Hz,1H),7.0(dd,J=1.2,8.8Hz,1H),6.8(t,J=9.2Hz,1H),5.2(d,J=7.2Hz,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=6.8Hz,3H).

[0329] 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. 1 H NMR (400 MHz, DMSO-d6) δ 7.2(dd,J=2.4,12.0Hz,1H),6.96(d,J=8.4Hz,1H),6.8(t,J=9.2Hz,1H),5.4(dd,J=2.2,9.2Hz,1H),4.0-3.84(m,2H),3.12(dq,J=3.6 ,9.9Hz,1H),2.92-2.72(m,1H),1.84(dd,J=3.2,13.2Hz,1H),1.68-1.56(m,1H),1.40(s,9H),1.32-1.2(m,1H),0.88(d,J=6.8Hz,3H).

[0330] 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. 1 H NMR (400 MHz, DMSO-d6) δ 7.2(dd,J=2.4,12.0Hz,1H),6.96(td,J=1.2,8.8Hz,1H),6.80-6.72(m,1H),5.36(dd,J=2.0,9.2Hz,1H),3.96-3.80(m,2H),3.12(dq,J=4 .0,9.92Hz,1H),2.92-2.72(m,1H),1.84(dd,J=3.2,12.8Hz,1H),1.72-1.6(m,1H),1.40(s,9H),1.28-1.20(m,1H),0.84(d,J=6.4Hz,3H)

[0331] Step 2: Preparation of (3S,4R)-N-(4-chloro-2-fluoro-phenyl)-3-methyl-piperidin-4-amine [ka]

[0332] A mixture of tert-butyl (3S,4R)-4-(4-chloro-2-fluoro-anilino)-3-methyl-piperidine-1-carboxylate (100 mg, 0.29 mmol, 1 equiv.) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 46.30 equiv.) in dichloromethane (1 mL) was stirred at 25° C. for 15 minutes. The mixture was concentrated in vacuo 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] + .

[0333] 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) [ka]

[0334] A mixture of (3S,4R)-N-(4-chloro-2-fluoro-phenyl)-3-methyl-piperidin-4-amine (120 mg, 0.34 mmol, 1 equiv, trifluoroacetic acid), 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (70 mg, 0.28 mmol, 8.19 e-1 equiv), and diisopropylethylamine (371.00 mg, 2.87 mmol, 0.5 mL, 8.53 equiv) in acetonitrile (1.5 mL) was stirred at 40° C. for 3 hours. The mixture was concentrated, and the crude product was triturated in DMF (1 mL), washed with acetonitrile (1 mL x 2), and collected by filtration to give 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=9.2Hz,1H),7.60(d,J=9.2Hz,1H),7.20(dd,J=2.4,11.6Hz,1H),7.2( dd,J=2.0,8.8Hz,1H),6.96-6.88(m,1H),5.48(dd,J=2.0,8.4Hz,1H),4.20-4.0 8(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=6.8Hz,3H).

[0335] 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) [ka]

[0336] The title compound was made in a similar manner to 1,6-dimethyl-2-oxo-4-spiro[indan-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] + . 1 H NMR(400MHz,DMSO-d6) δ 7.92(d,J=8.8Hz,1H),7.60(d,J=8.8Hz,1H),7.20(d,J=7.6Hz,1H),7.12(t,J=7.6Hz,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=5.6Hz,4H).

[0337] 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) [ka]

[0338] Step 1: Preparation of (3S,4R)-N-(4-fluorophenyl)-3-methoxy-piperidin-4-amine [ka]

[0339] A mixture of tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1-carboxylate (100 mg, 0.31 mmol, 1 equiv.) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 43.81 equiv.) in dichloromethane (1 mL) was stirred at 25° C. for 15 minutes. The mixture was concentrated in vacuo 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] + .

[0340] 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) [ka]

[0341] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.08(d,J=9.2Hz,1H),7.80(d,J=9.2Hz,1H),6.92(t,J=8.8Hz,2H),6.80-6.64(m,2H),5.44(d,J=8.8Hz,1H),4.32-4.12(m, 2H),3.84(d,J=12.4Hz,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).

[0342] Synthesis of compound 26 Preparation of 1,6-dimethyl-2-oxo-4-spiro[indan-2,4"-piperidine]-1"-yl-1,5-naphthyridine-3-carbonitrile (compound 26) [ka]

[0343] To a mixture of 6-chloro-1-methyl-2-oxo-4-spiro[indan-2,4″-piperidine]-1″-yl-1,5-naphthyridine-3-carbonitrile (200 mg, 0.49 mmol, 1 equiv.), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (372 mg, 1.48 mmol, 0.41 mL, 50% pure, 3 equiv.), and potassium carbonate (137 mg, 0.99 mmol, 2 equiv.) in dioxane (2 mL) and water (0.4 mL) under nitrogen was added cyclopentyl(diphenyl)phosphane, dichloropalladium, iron (36 mg, 0.05 mmol, 0.1 equiv.). The suspension was degassed under vacuum and purged with nitrogen three times. The mixture was stirred under nitrogen at 90° C. for 12 h. The mixture was collected by filtration and the residue was purified by preparative HPLC (column: Phenomenex C18 150 x 25 mm x 10 um, mobile phase: [49-79% CH3CN in water (NH4HCO3)]) to give 1,6-dimethyl-2-oxo-4-spiro[indan-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] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.92(d,J=8.8Hz,1H),7.56(d,J=8.8Hz,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=5.2Hz,4H).

[0344] Synthesis of compound 27 [ka] 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 [ka]

[0345] The title compound was prepared in a similar 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-1-piperidinyl]-1-carboxylate (yellow solid). LC / MS (ESI) m / z: 441.9 [M+H] + .

[0346] 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 [ka]

[0347] The enantiomers were separated by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); mobile phase: 50% ethanol (0.1% NHOH) in CO₂) followed by preparative HPLC (column: Welch Ultimate C18 150 x 25 mm x 5 μm; 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. The absolute configuration was arbitrarily assigned. LC / MS (ESI) m / z: 442.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.77(s,1H),8.06(d,J=8.8Hz,1H),7.80(d,J=8.8Hz,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=6.8Hz,3H).

[0348] 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) [ka]

[0349] The title compound was made in a similar manner starting from tert-butyl (3R,4R)-4-(4-chloroanilino)-3-methyl-piperidine-1-carboxylate 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.

[0350] 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(400MHz,DMSO-d6) δ 8.06(d,J=9.2Hz,1H),7.81(d,J=9.2Hz,1H),7.17-6.97(m,2H),6.78-6.55(m,2H),5.80(d,J=8.8Hz,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=6.4Hz,3H).

[0351] 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.06(d,J=8.8Hz,1H),7.81(d,J=8.8Hz,1H),7.06(d,J=8.8Hz,2H),6.65 (d,J=8.8Hz,2H),5.80(d,J=9.2Hz,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=10.8,12.8Hz,1H),2.18- 2.08(m,1H),2.07-1.92(m,1H),1.55-1.44(m,1H),0.97(d,J=6.4Hz,3H).

[0352] 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) [ka]

[0353] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.04(d,J=9.2Hz,1H),7.80(d,J=9.2Hz,1H),7.16(dd,J=2.4,11.6Hz,1H),7.00(d d,J=2.0,8.8Hz,1H),6.92-6.84(m,1H),5.56(dd,J=2.0,9.2Hz,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=4.0,12.0Hz,1H),0.96(d,J=6.8Hz,3H).

[0354] Synthesis of compound 31 [ka]

[0355] Step 1: Preparation of tert-butyl 3,4,4-trimethoxypiperidine-1-carboxylate [ka]

[0356] To a solution of tert-butyl 3-hydroxy-4,4-dimethoxy-piperidine-1-carboxylate (500 mg, 1.91 mmol, 1 equiv.) in tetrahydrofuran (6 mL) at 0° C., sodium hydride (115 mg, 2.87 mmol, 60% purity, 1.5 equiv.) was added, and the resulting mixture was stirred at 0° C. for 0.5 h. Iodomethane (543 mg, 3.83 mmol, 0.24 mL, 2 equiv.) was then added, and the reaction mixture was stirred at 0° C. under nitrogen for 1 h. The mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The 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-carboxylate (480 mg, 1.74 mmol, 91% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6) δ 4.11(d,J=14.0Hz,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=14.0Hz,1H),1.57-1.45(m,1H),1.39(s,9H).

[0357] Step 2: Preparation of tert-butyl 3-methoxy-4-oxo-piperidine-1-carboxylate [ka]

[0358] A mixture of tert-butyl 3,4,4-trimethoxypiperidine-1-carboxylate (330 mg, 1.20 mmol, 1 equiv) and 4-methylbenzenesulfonic acid (41 mg, 0.24 mmol, 0.2 equiv) in acetone (10 mL) and water (1 mL) was stirred for 1 hour at 80° C. The mixture was concentrated in vacuo to give tert-butyl 3-methoxy-4-oxo-piperidine-1-carboxylate (280 mg, crude) as an off-white oil.

[0359] Step 3: Preparation of tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1-carboxylate [ka]

[0360] A mixture of tert-butyl 3-methoxy-4-oxo-piperidine-1-carboxylate (280 mg, 1.22 mmol, 1 equiv.), 4-fluoroaniline (135.70 mg, 1.22 mmol, 0.12 mL, 1 equiv.), and borane 2-methylpyridine (261 mg, 2.44 mmol, 2 equiv.) 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 preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [39-69% CH3CN in water (0.225% formic acid)]) to give 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(400MHz,DMSO-d6) δ 6.96-6.84(m,2H),6.72-6.64(m,2H),5.12(d,J=9.2Hz,1H),4.16(d,J=13.2Hz,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).

[0361] Step 4: Preparation of tert-butyl (3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy-piperidine-1-carboxylate [ka]

[0362] A mixture of tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1-carboxylate (90 mg, 0.28 mmol, 1 equiv.), formaldehyde (68 mg, 0.83 mmol, 0.06 mL, 37% purity, 3 equiv.), and sodium cyanoborohydride (52 mg, 0.83 mmol, 3 equiv.) in methanol (1 mL) was stirred at 25° C. for 12 hours. 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 over sodium sulfate, and concentrated under reduced pressure. The 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(400MHz,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=12.0Hz,1H),3.52-3.36(m ,1H),3.20(s,3H),2.92(q,J=13.6Hz,1H),2.80(s,3H),2.04(d,J=12.0Hz,1H),1.40(s,11H).

[0363] Step 5: Preparation of (3S,4R)-N-(4-fluorophenyl)-3-methoxy-N-methyl-piperidin-4-amine [ka]

[0364] A mixture of tert-butyl (3S,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy-piperidine-1-carboxylate (89 mg, 0.26 mmol, 1 equiv.) and trifluoroacetic acid (2 g, 13.51 mmol, 1 mL, 51.36 equiv.) in dichloromethane (1 mL) was stirred at 25° C. for 15 minutes. The mixture was concentrated in vacuo 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] + .

[0365] 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) [ka]

[0366] A mixture of (3S,4R)-N-(4-fluorophenyl)-3-methoxy-N-methyl-piperidin-4-amine (100 mg, 0.28 mmol, 1 equiv, TFA salt), 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (50 mg, 196.79 μmol, 6.93 e-1 equiv), and diisopropylethylamine (371.00 mg, 2.87 mmol, 0.5 mL, 10.11 equiv) in acetonitrile (1 mL) was stirred at 25° C. for 12 hours. The mixture was concentrated in vacuo and the crude product was triturated in DMF (0.5 mL), washed with acetonitrile (1.5 mL) and collected by filtration to give 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] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.08(d,J=9.2Hz,1H),7.84(d,J=8.8Hz,1H),7.08-7.00(m,2H),6.88(dd,J=4 .4,9.2Hz,2H),4.48(dd,J=2.4,13.2Hz,1H),4.36(d,J=13.6Hz,1H),4.12(d,J =11.6Hz,1H),3.80(d,J=13.6Hz,1H),3.64(s,1H),3.52(s,3H),3.48(t,J=11 .6Hz,1H),3.04(s,3H),2.88(s,3H),2.84-2.80(m,1H),1.68(d,J=9.6Hz,1H).

[0367] Synthesis of compound 32 [ka]

[0368] Step 1: Preparation of tert-butyl (3S,4R)-3-methyl-4-[4-(trifluoromethoxy)anilino]piperidine-1-carboxylate [ka]

[0369] A mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (2 g, 9.38 mmol, 1 equiv.), 4-(trifluoromethoxy)aniline (1.66 g, 9.38 mmol, 1 mL, 1 equiv.), sodium cyanoborohydride (884 mg, 14.07 mmol, 1.5 equiv.), and acetic acid (56 mg, 0.938 mmol, 0.05 mL, 0.1 equiv.) in methanol (20 mL) was stirred at 25 °C for 12 h. The mixture was concentrated in vacuo, 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 preparative HPLC (column: Welch Xtimate C18 250 × 50 mm × 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). + . 1 H NMR(400MHz,DMSO-d6) δ 7.04(d,J=8.4Hz,2H),6.68(d,J=9.2Hz,2H),5.72(d,J=8.4Hz,1H),3.52(dt,J=4.4,8.4Hz,2H),3.32(s,1H),3.2( dd,J=3.2,13.2Hz,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=6.8Hz,3H).

[0370] Step 2: Preparation of tert-butyl (3S,4R)-3-methyl-4-[N-methyl-4-(trifluoromethoxy)anilino]piperidine-1-carboxylate [ka]

[0371] A mixture of tert-butyl (3S,4R)-3-methyl-4-[4-(trifluoromethoxy)anilino]piperidine-1-carboxylate (140 mg, 0.37 mmol, 1 equiv.), formaldehyde (91 mg, 1.12 mmol, 0.084 mL, 37% purity, 3 equiv.), and sodium cyanoborohydride (71 mg, 1.12 mmol, 3 equiv.) in methanol (1.5 mL) was stirred for 12 h at 25° C. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel chromatography (gradient: 100 / 1 to 1:1 petroleum ether / ethyl acetate) to afford 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) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.12(d,J=8.4Hz,2H),6.8(d,J=7.6Hz,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=6.0Hz,3H).

[0372] Step 3: Preparation of (3S,4R)-N,3-dimethyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine [ka]

[0373] A mixture of tert-butyl (3S,4R)-3-methyl-4-[N-methyl-4-(trifluoromethoxy)anilino]piperidine-1-carboxylate (99 mg, 0.26 mmol, 1 equiv.) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 52.99 equiv.) in dichloromethane (1 mL) was stirred at 25° C. for 15 minutes. The mixture was concentrated in vacuo 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] + .

[0374] 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) [ka]

[0375] The title compound was prepared in a similar 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=9.2Hz,1H),7.8(d,J=8.8Hz,1H),7.2(d,J=8.8Hz,2H),6.88(d, J=9.2Hz,2H),4.4-4.28(m,1H),4.16(td,J=3.6,12.0Hz,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),2.7 6-2.64(m,1H),2.4-2.28(m,1H),1.80-1.72(m,1H),0.88(d,J=7.2Hz,3H).

[0376] Synthesis of compounds 33 and 34 [ka]

[0377] 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 [ka]

[0378] To a mixture of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (2 g, 9.38 mmol, 1 equiv.) and 4-chloroaniline (1.20 g, 9.38 mmol, 1 equiv.) in methanol (20 mL), sodium cyanoborohydride (1.47 g, 23.44 mmol, 2.5 equiv.) was added, 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 preparative HPLC (column: Welch Xtimate C18 250 × 50 mm × 10 μm, mobile phase: [40–75% CH3CN in water (0.225% formic acid)]) to give the desired product.

[0379] 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. 1 H NMR(400MHz,DMSO-d6) δ 7.08-7.03(m,2H),6.66-6.61(m,2H),5.63(d,J=8.4Hz,1H),3.79-3.60(m,1H),3.57-3.47(m,2H),3.30-3.27( m,1H),3.16(dd,J=3.6,13.6Hz,1H),2.05-1.97(m,1H),1.57-1.47(m,2H),1.39(s,9H),0.77(d,J=6.8Hz,3H).

[0380] 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. 1 H NMR(400MHz,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=13.2Hz,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=6.4Hz,3H).

[0381] Step 2: Preparation of (3S,4R)-N-(4-chlorophenyl)-3-methyl-piperidin-4-amine [ka]

[0382] To a solution of tert-butyl (3S,4R)-4-(4-chloroanilino)-3-methyl-piperidine-1-carboxylate (100 mg, 0.31 mmol, 1 equiv) in dichloromethane (1 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 43.87 equiv) dropwise, and the resulting mixture was stirred for 30 minutes at 25° C. 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.

[0383] 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 [ka]

[0384] The title compound was prepared in a similar manner to 6-chloro-4-[4-(4-chloroanilino)-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (yellow solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.06(d,J=8.8Hz,1H),7.81(d,J=8.8Hz,1H),7.10-7.05(m,2H),6.75-6.70(m,2H),5.90(d,J=8.4Hz,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=7.2Hz,3H).

[0385] 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) [ka]

[0386] The enantiomers were separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: 40% methanol (0.1% NH OH) in CO ), followed by preparative HPLC (column: Phenomenex luna C 18 150 × 25 mm × 10 μm, mobile phase: [50–80% CH CN in water (0.225% formic acid)]).

[0387] Absolute configurations were arbitrarily assigned.

[0388] 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.07(d,J=8.8Hz,1H),7.84-7.78(m,1H),7.07(d,J=8.8Hz,2H),6.80-6.63(m,2H),5.94-5.86(m,1H),4.06-3.96(m,1H),3.85(d,J=4.8H) z,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=7.2Hz,3H).

[0389] 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 μmol, 35% yield) (Compound 34). (Yellow solid) LC / MS(ESI) m / z: 442.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6) δ 8.07(d,J=8.8Hz,1H),7.81(d,J=8.8Hz,1H),7.11-7.03(m,2H),6.72(d,J=8.8Hz,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=7.2Hz,3H).

[0390] 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) [ka]

[0391] The title compound was prepared in a similar 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(400MHz,DMSO-d6) δ 8.04(d,J=9.2Hz,1H),7.80(d,J=9.2Hz,1H),7.2(dd,J=2.4,12.0Hz,1H),7.00(dd ,J=2.0,8.8Hz,1H),6.92-6.84(m,1H),5.56(dd,J=2.0,9.2Hz,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=3.2,13.2Hz,1H),1.72-1.60(m,1H),0.96(d,J=6.8Hz,3H).

[0392] Synthesis of compound 36 [ka]

[0393] Step 1: Preparation of tert-butyl 4-(4-chloro-N-methyl-anilino)piperidine-1-carboxylate [ka]

[0394] A mixture of tert-butyl 4-(4-chloroanilino)piperidine-1-carboxylate (200 mg, 0.64 mmol, 1 equiv.), sodium cyanoborohydride (61 mg, 0.97 mmol, 1.5 equiv.), and formaldehyde (57 mg, 0.71 mmol, 0.05 mL, 37% purity, 1.1 equiv.) in methanol (2 mL) was stirred for 12 h at 25 °C. The mixture was concentrated in vacuo, and the resulting residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm 10 μm, mobile phase: [56–86% CHCN in water (NHHCO)]) to afford 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 [ka] A mixture of tert-butyl 4-(4-chloro-N-methyl-anilino)piperidine-1-carboxylate (114 mg, 0.35 mmol, 1 equiv.) and trifluoroacetic acid (80 mg, 0.7 mmol, 0.05 mL, 2 equiv.) in dichloromethane (1 mL) was stirred at 25° C. for 15 minutes. The mixture was concentrated in vacuo 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] + .

[0395] Step 3: Preparation of 6-chloro-4-[4-(4-chloro-N-methyl-anilino)-1-piperidyl]-2-oxo-1H-1,5-naphthyridine-3-carbonitrile [ka] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.08(d,J=9.2Hz,1H),7.84(d,J=9.2Hz,1H),7.20(d,J=9.2Hz,2H),6.8(d,J=9.2Hz,2H),4 .28(d,J=12.4Hz,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=12.4Hz,2H).

[0396] Synthesis of compound 37 [ka]

[0397] Step 1: Preparation of tert-butyl (3S,4R)-4-(4-fluoro-2-methyl-anilino)-3-methyl-piperidine-1-carboxylate [ka] To a solution of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (2 g, 9.38 mmol, 1 equiv.) and 4-fluoro-2-methyl-aniline (1.17 g, 9.38 mmol, 1.0 equiv.) in methanol (20 mL) was added sodium cyanoborohydride (1.47 g, 23.44 mmol, 2.5 equiv.) 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 preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 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] + . 1 H NMR(400MHz,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=4.4,8.4Hz,1H),3.29(s,1 H),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=6.8Hz,3H).

[0398] Step 2: Preparation of tert-butyl (3S,4R)-4-(4-fluoro-N,2-dimethyl-anilino)-3-methyl-piperidine-1-carboxylate [ka] 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 equiv), sodium cyanoborohydride (88 mg, 1.40 mmol, 3 equiv), and formaldehyde (189 mg, 2.33 mmol, 0.17 mL, 37% purity, 5 equiv) in methanol (1 mL) and tetrahydrofuran (1 mL) was added acetic acid (105 mg, 1.75 mmol, 0.1 mL, 3.76 equiv) and the reaction mixture was stirred at 40° C. for 12 hours. 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 afford 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] + . 1 H NMR(400MHz,DMSO-d6) δ 7.23(dd,J=5.6,8.4Hz,1H),7.08-6.92(m,2H),4.17-3.67(m,2H),3.56-3.39(m,1H),2.98(td,J=4.0,11.6Hz,1H),2.93-2.7 4(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).

[0399] Step 3: Preparation of (3S,4R)-N-(4-fluoro-2-methyl-phenyl)-N,3-dimethyl-piperidin-4-amine [ka] 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 equiv.) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1.00 mL, 50.49 equiv.) in dichloromethane (1 mL) was stirred under N2 atmosphere at 25 °C for 30 minutes. 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] + .

[0400] 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) [ka] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.06(d,J=8.8Hz,1H),7.79(d,J=8.8Hz,1H),7.32(dd,J=5.6,8.8Hz,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=6.8Hz,3H).

[0401] Synthesis of compound 38 [ka]

[0402] 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 [ka] 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 equiv.) and triethylamine (715 mg, 7.07 mmol, 0.98 mL, 3 equiv.) in dichloromethane (10 mL), benzyl chloroformate (482 mg, 2.83 mmol, 0.4 mL, 1.2 equiv.) was added, and the reaction mixture was stirred at 25 °C under N 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, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex C18 250 × 50 mm × 10 μm, mobile phase: [40–70% CH3CN in water (NH4HCO3)]) to give 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] + .

[0403] Step 2: Preparation of benzyl (3aS,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate [ka] 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 equiv.) in dichloromethane (1 mL), trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 24.6 equiv.) was added, 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] + .

[0404] 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 [ka] 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 equiv., trifluoroacetic acid), 4-fluoro-1-iodo-2-methyl-benzene (245 mg, 1.04 mmol, 1.5 equiv.), CsCO (1.13 g, 3.47 mmol, 5 equiv.), 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 equiv.) in dioxane (3 mL) was degassed and purged with nitrogen (3×), and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere 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 (25 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 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] + . 1 H NMR(400MHz,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,2 H),3.39-3.31(m,2H),3.21-3.13(m,4H),2.42-2.31(m,2H),2.28(s,3H).

[0405] 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 [ka] 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 μmol, 1 equiv.) in CHOH (5 mL) was added palladium-activated carbon catalyst (50 mg, 10% purity) under nitrogen. The resulting suspension was degassed under vacuum and purged with hydrogen several times. The mixture was then stirred at 30 °C for 12 h under hydrogen (15 psi). 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] + .

[0406] 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) [ka] The title compound was prepared in a similar manner to 6-chloro-4-[4-(4-chloroanilino)-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (yellow solid) starting from (3aS,6aS)-5-(4-fluoro-2-methyl-phenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole. LC / MS(ESI) m / z: 438.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6) δ 8.01(d,J=9.2Hz,1H),7.80(d,J=9.2Hz,1H),6.94(d,J=9.6Hz,1H),6.88-6.82(m,2H),4.26-4.1 4(m,4H),3.50(s,3H),3.46(d,J=10.0Hz,2H),3.23-3.17(m,2H),2.46-2.39(m,2H),2.27(s,3H).

[0407] Synthesis of compound 39 [ka] [ka]

[0408] Step 1: Preparation of tert-butyl 4-[(4-chloro-2-hydroxy-phenyl)methyl]piperazine-1-carboxylate [ka] A mixture of tert-butyl piperazine-1-carboxylate (357 mg, 1.92 mmol, 1 equiv.), 4-chloro-2-hydroxy-benzaldehyde (300 mg, 1.92 mmol, 1 equiv.), and sodium cyanoborohydride (241 mg, 3.83 mmol, 2 equiv.) in methanol (3 mL) was stirred at 25° C. for 12 hours. The mixture was concentrated in vacuo, 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 preparative HPLC (column: Phenomenex C18 250 × 50 mm × 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] + . 1 H NMR(400MHz,CDCl3) δ 6.88(d,J=8.0Hz,1H),6.84(d,J=2.0Hz,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).

[0409] Step 2: Preparation of 5-chloro-2-(piperazin-1-ylmethyl)phenol [ka] A mixture of tert-butyl 4-[(4-chloro-2-hydroxy-phenyl)methyl]piperazine-1-carboxylate (20 mg, 0.06 mmol, 1 equiv) and trifluoroacetic acid (154 mg, 1.35 mmol, 0.1 mL, 22.07 equiv) 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] + .

[0410] 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) [ka] The title compound was prepared in a similar 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] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.21(d,J=8.8Hz,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).

[0411] Synthesis of compound 40 [ka]

[0412] 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 [ka] 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 equiv.), 1-bromo-4-fluoro-2-methyl-benzene (392 mg, 2.07 mmol, 1.1 equiv.), and potassium carbonate (781 mg, 5.65 mmol, 3 equiv.) in dioxane (4 mL), 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 equiv.) was added under a nitrogen atmosphere, and the reaction mixture was degassed and purged with nitrogen (3×), 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] + . 1 H NMR(400MHz,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).

[0413] 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 [ka] 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 equiv.) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 1 equiv.) in dichloromethane (1 mL) was stirred at 25 °C for 15 minutes. The mixture was concentrated in vacuo 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). + .

[0414] Step 3 Preparation of 6-chloro-4-((3aR,6aS)-5-(4-fluoro-2-methylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (compound 40) [ka] The title compound was prepared in a similar 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(400MHz,DMSO-d6) δ 8.0(d,J=8.4Hz,1H),7.8(d,J=8.8Hz,1H),7.2-6.8(m,3H),4.48-4.36(m,2H),4.28(d, J=12.0Hz,2H),3.52(s,3H),3.16(d,J=6.0Hz,2H),3.08(d,J=9.2Hz,4H),2.16(s,3H).

[0415] Synthesis of compound 41 [ka]

[0416] 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 [ka] 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 equiv) and triethylamine (223 mg, 2.21 mmol, 0.31 mL, 2 equiv) in dichloromethane (5 mL) was added benzyl chloroformate (226 mg, 1.33 mmol, 0.19 mL, 1.2 equiv) dropwise and the reaction mixture was stirred at 20 °C under N for 12 h. The mixture was concentrated, and the resulting residue was purified by preparative HPLC (Column: Waters xbridge 150 × 25 mm 10 μm, Mobile phase: [42-72% CHCN in water (NaHCO)]) 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(400MHz,CDCl3) δ 7.38-7.29(m,5H),5.14(d,J=3.2Hz,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).

[0417] Step 2: Preparation of benzyl 1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridine-5-carboxylate [ka] 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 equiv.) and trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 57.27 equiv.) in dichloromethane (2 mL) was stirred at 25 °C for 15 min. The mixture was concentrated in vacuo 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] + .

[0418] Step 3: Preparation of benzyl 1-(4-fluorophenyl)-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-5-carboxylate [ka] 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 equiv., trifluoroacetic acid), 1-fluoro-4-iodo-benzene (296 mg, 1.34 mmol, 0.15 mL, 2.5 equiv.), and CsCO (522 mg, 1.60 mmol, 3 equiv.) in DMF (2 mL), 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 equiv.) was added under a 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 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 afford 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] + .

[0419] Step 4: Preparation of 1-(4-fluorophenyl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridine [ka] 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 equiv.) in CHOH (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 h. 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] + .

[0420] 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) [ka] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO) δ 8.08(d,J=9.2Hz,1H),7.8(d,J=9.2Hz,1H),7.00(t,J=8.8Hz,2H),6.56(dd,J=4.4,8.8Hz,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=6.8Hz,2H),2.24-2.12(m,1H),2.12-2.04(m,2H),1.84-1.72(m,1H).

[0421] Synthesis of compound 43 [ka]

[0422] Step 1: Preparation of tert-butyl 4-(4-chloroanilino)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (600 mg, 3.01 mmol, 1 equiv.), 4-chloroaniline (384 mg, 3.01 mmol, 1 equiv.), sodium cyanoborohydride (473.10 mg, 7.53 mmol, 2.5 equiv.), and acetic acid (18 mg, 0.30 mmol, 0.017 mL, 0.1 equiv.) in methanol (6 mL) was stirred at 25° C. for 12 hours. The mixture was concentrated in vacuo, 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 anhydrous 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] + . 1 H NMR (400 MHz, CDCl3) δ 7.18-7.05(m,2H),6.58-6.50(m,2H),4.05(d,J=8.0Hz,2H),2.92(t,J=12.0Hz,2H),2.05-1.98(m,2H),1.47(s,11H),1.32(d,J=10.8Hz,2H).

[0423] Step 2: Preparation of N-(4-chlorophenyl)piperidin-4-amine [ka] A mixture of tert-butyl 4-(4-chloroanilino)piperidine-1-carboxylate (62 mg, 0.20 mmol, 1 equiv) and trifluoroacetic acid (924 mg, 8.10 mmol, 0.6 mL, 83.96 equiv) in dichloromethane (0.6 mL) was stirred at 25° C. for 15 minutes. The mixture was concentrated in vacuo 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] + .

[0424] Step 3: Preparation of 6-chloro-4-[4-(4-chloroanilino)-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile [ka] A mixture of N-(4-chlorophenyl)piperidin-4-amine (41 mg, 0.13 mmol, 6.49 e-1 equiv, trifluoroacetic acid), 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (50 mg, 0.2 mmol, 1 equiv) and diisopropylethylamine (76 mg, 0.59 mmol, 0.10 mL, 3 equiv) in acetonitrile (0.6 mL) was stirred at 40° C. for 12 hours. The mixture was concentrated in vacuo, and the resulting precipitate was triturated with dimethylformamide (1.5 mL), washed with acetonitrile (1.5 mL), and collected by filtration to give 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(400MHz,DMSO-d6) δ 8.07(d,J=9.2Hz,1H),7.81(d,J=9.2Hz,1H),7.09(d,J=8.8Hz,2H),6.66(d,J=8.8Hz,2H),5.88(d,J=8.0Hz,1H),4.20(br d,J=12.8Hz,2H),3.64-3.56(m,2H),3.53(s,3H),3.30(s,1H),2.10(d,J=10.8Hz,2H),1.77-1.55(m,2H).

[0425] Synthesis of compound 44 [ka] [ka]

[0426] Step 1: Preparation of ethyl 3-acetamido-6-chloro-pyridine-2-carboxylate [ka] A mixture of ethyl 3-amino-6-chloro-pyridine-2-carboxylate (4 g, 19.94 mmol, 1 equiv.) and acetic anhydride (2.04 g, 19.94 mmol, 1.87 mL, 1 equiv.) in dioxane (40 mL) was stirred at 110 °C for 12 h. The mixture was concentrated in vacuo, 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] + . 1 H NMR (400 MHz, CDCl3) δ 11.00(s,1H),9.12(d,J=9.2Hz,1H),7.48(d,J=8.8Hz,1H),4.51(q,J=7.2Hz,2H),2.28(s,3H),1.47(t,J=7.2Hz,3H).

[0427] Step 2: Preparation of ethyl 3-[acetyl(methyl)amino]-6-chloro-pyridine-2-carboxylate [ka] A mixture of ethyl 3-acetamido-6-chloro-pyridine-2-carboxylate (200 mg, 0.82 mmol, 1 equiv.), methyl iodide (234 mg, 1.65 mmol, 0.1 mL, 2 equiv.), and CsCO (671 mg, 2.06 mmol, 2.5 equiv.) 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 over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (gradient: 0-1:1 petroleum ether / ethyl acetate) followed by preparative HPLC (column: Waters xbridge 150 x 25 mm 10 μm, mobile phase: [10-40% CHCN / in water (NHHCO)]) 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] + . 1 H NMR(400MHz,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=7.2Hz,3H).

[0428] Step 3: Preparation of 6-chloro-4-hydroxy-1-methyl-1,5-naphthyridin-2-one [ka] To a solution of ethyl 3-[acetyl(methyl)amino]-6-chloro-pyridine-2-carboxylate (110 mg, 0.43 mmol, 1 equiv.) in tetrahydrofuran (1 mL) was added potassium bis(trimethylsilyl)amide (1 M, 0.64 mL, 1.5 equiv.) dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The pH of the mixture was adjusted to 5 by adding 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.01(d,J=8.8Hz,1H),7.72(d,J=8.8Hz,1H),6.10(s,1H),3.52(s,3H)

[0429] Step 4: Preparation of (6-chloro-1-methyl-2-oxo-1,5-naphthyridin-4-yl)trifluoromethanesulfonate [ka] A mixture of 6-chloro-4-hydroxy-1-methyl-1,5-naphthyridin-2-one (32 mg, 0.15 mmol, 1 equiv.), trifluoromethanesulfonic anhydride (107 mg, 0.38 mmol, 0.062 mL, 2.5 equiv.), triethylamine (77 mg, 0.76 mmol, 0.11 mL, 5 equiv.), and 4-dimethylaminopyridine (2 mg, 0.015 mmol, 0.1 equiv.) in dichloromethane (1 mL) was stirred under a nitrogen atmosphere at 0° C. for 2 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 afford (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(400MHz,DMSO-d6) δ 8.23(d,J=8.8Hz,1H),7.91(d,J=8.8Hz,1H),7.31(s,1H),3.63(s,3H).

[0430] Step 5: Preparation of tert-butyl 2-(4-fluorophenyl)-4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate [ka] 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 equiv.), 1-bromo-4-fluoro-benzene (185 mg, 1.06 mmol, 0.12 mL, 1.2 equiv.), CsCO (864 mg, 2.65 mmol, 3 equiv.), 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 equiv.) in dioxane (5 mL) was stirred at 100 °C under N for 3 h. 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(400MHz,CDCl3) δ 6.99-6.90(m,2H),6.50-6.42(m,2H),3.82(s,1H),3.66(dd,J=8.0,11.6Hz,1H),3.56-3.42(m,2H),3.37 (d,J=14.8Hz,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=6.4Hz,3H).

[0431] 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 [ka] 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 equiv.) and trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 27.05 equiv.) 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] + .

[0432] 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 [ka] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 7.94(d,J=8.8Hz,1H),7.67(d,J=8.8Hz,1H),6.99(t,J=8.8Hz,2H),6.56-6.47(m,2H),5.63(s,1H),5.00(s,1H),3.97(dd,J=8.4,11.6Hz,1H), 3.54-3.49(m,1H),3.48(s,3H),3.46-3.39(m,2H),3.20(d,J=7.6Hz,2H ),3.10(dd,J=6.0,9.6Hz,1H),2.88-2.79(m,1H),1.20(d,J=6.4Hz,3H).

[0433] Synthesis of compound 45 [ka]

[0434] Step 1: Preparation of (3aR,6aS)-5-(4-fluorophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole [ka] 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 equiv.) and 1-bromo-4-fluoro-benzene (247 mg, 1.41 mmol, 0.15 mL, 1.5 equiv.) in dioxane (4 mL), CsCO (921 mg, 2.83 mmol, 3 equiv.) 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 equiv.) were added, and the reaction mixture was stirred at 100 °C for 4 h. 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 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). Trifluoroacetic acid (2 mL) was added to the product, 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] + .

[0435] Step 2: Preparation of 6-chloro-4-((3aR,6aS)-5-(4-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (compound 45) [ka] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.00(d,J=9.2Hz,1H),7.82-7.74(m,1H),7.01(t,J=8.4Hz,2H),6.53(dd,J=2.4,4.8Hz,2H),4.50(dd ,J=6.4,12.4Hz,2H),4.14(d,J=12.4Hz,2H),3.50-3.43(m,5H),3.25(d,J=10.4Hz,2H),3.15(s,2H).

[0436] Synthesis of compound 46 [ka]

[0437] Step 1: Preparation of tert-butyl 4-(4-fluoro-N-(4-fluorophenyl)anilino)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-fluoroanilino)piperidine-1-carboxylate (200 mg, 0.68 mmol, 1 equiv.), 1-fluoro-4-iodo-benzene (151 mg, 0.68 mmol, 0.078 mL, 1 equiv.), tert-butylphosphorus (6 mg, 0.03 mmol, 0.007 mL, 4.42 e-2 equiv.), diacetoxypalladium (7 mg, 0.03 mmol, 4.42 e-2 equiv.), and potassium 2-methylpropan-2-olate (229 mg, 2.04 mmol, 3 equiv.) in toluene (10 mL) was stirred at 100° C. for 6 hours. The reaction mixture was filtered and 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 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] + . 1 H NMR(400MHz,DMSO-d6) δ 7.11(t,J=8.8Hz,4H),6.82(dd,J=4.8,8.8Hz,4H),3.99-3.89(m,2H),2.99-2.77( m,2H),1.88(d,J=12.0Hz,2H),1.33(s,9H),1.10-0.99(m,2H),0.89-0.77(m,1H).

[0438] Step 2: Preparation of N,N-bis(4-fluorophenyl)piperidin-4-amine [ka] To a solution of tert-butyl 4-(4-fluoro-N-(4-fluorophenyl)anilino)piperidine-1-carboxylate (70 mg, 0.18 mmol, 1 equivalent) in dichloromethane (1 mL), trifluoroacetic acid (1.20 g, 10.50 mmol, 0.78 mL, 58.29 equivalents) was added dropwise, 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] + .

[0439] 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 [ka] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.02(d,J=9.2Hz,1H),7.75(d,J=8.8Hz,1H),7.13(t,J=8.8Hz,4H),6.88(dd,J=4.8,8.8Hz,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).

[0440] Synthesis of compound 48 [ka]

[0441] 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 [ka] To a mixture of 1-bromo-4-(trifluoromethoxy)benzene (50 mg, 0.21 mmol, 0.030 mL, 1 equiv.), 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 equiv.), and CsCO (203 mg, 0.62 mmol, 3 equiv.) 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, 10 mg, 0.01 mmol, 0.05 equiv.), and the reaction mixture was stirred at 100 °C for 3 h. 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] + . 1 H NMR(400MHz,CDCl3) δ 7.09(d,J=8.4Hz,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).

[0442] Step 2: Preparation of (3aS,6aS)-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole [ka] 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 equiv.) in dichloromethane (1 mL), trifluoroacetic acid (1.69 g, 14.86 mmol, 1.1 mL, 50.29 equiv.) was added dropwise, and the resulting mixture was stirred at 25 °C for 30 min. 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] + .

[0443] 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 [ka] The title compound was prepared in a similar 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(400MHz,DMSO-d6) δ 8.05-7.99(m,1H),7.81(d,J=9.2Hz,1H),7.16(d,J=8.8Hz,2H),6.57(d,J=8.8Hz,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).

[0444] Synthesis of compound 49 [ka]

[0445] 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 [ka] To a solution of 1-bromo-4-fluoro-2-methyl-benzene (300 mg, 1.59 mmol, 1 equiv.) 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 equiv.) in dioxane (6 mL), KCO (658 mg, 4.76 mmol, 3 equiv.) 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 equiv.) were added, and the reaction mixture was stirred at 100 °C for 4 h. 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 over 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] + .

[0446] 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 [ka] 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 equiv.) in dichloromethane (0.6 mL), trifluoroacetic acid (19 mg, 0.17 mmol, 0.013 mL, 1 equiv.) was added, 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, trifluoroacetate salt) as a green solid. LC / MS (ESI) m / z: 249.0 [M+H] + .

[0447] 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) [ka] The title compound was prepared in a similar 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] + . 1 H NMR(400MHz,CDCl3) δ 7.64-7.57(m,1H),7.49(d,J=8.8Hz,1H),6.87-6.75(m,3H),4.62(d,J=12.8Hz,2H),4.24(d,J=1 2.8Hz,2H),3.61(s,3H),3.39(d,J=9.2Hz,2H),3.10(d,J=9.2Hz,2H),2.23(s,3H),1.24(s,6H).

[0448] Synthesis of compound 50 [ka]

[0449] Step 1: Preparation of tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-hydroxy-piperidine-1-carboxylate [ka] To a mixture of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (3 g, 15.06 mmol, 1 equiv.) and 4-fluoroaniline (1.67 g, 15.06 mmol, 1.44 mL, 1 equiv.) in dichloroethane (30 mL) was added scandium (3 + ), trifluoromethanesulfonate (1.48 g, 3.01 mmol, 0.2 equiv.) was added, and the reaction mixture was stirred at 80 °C under N for 8 h. 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 × 2). The combined organic extracts were dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250 × 50 mm × 10 μm, mobile phase: [20–50% CH3CN / in water (0.225% formic acid)]) to afford 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) + . 1 H NMR(400MHz,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=4.0Hz, 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).

[0450] Step 2: Preparation of tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1-carboxylate [ka] To a solution of tert-butyl (3R,4R)-4-(4-fluoroanilino)-piperidine-1-carboxylate (400 mg, 1.29 mmol, 1 equiv.) in tetrahydrofuran (5 mL) was added sodium hydride (129 mg, 3.22 mmol, 60% purity, 2.5 equiv.) at 0° C., and the resulting mixture was stirred at 0° C. for 0.5 h. Iodomethane (549 mg, 3.87 mmol, 0.024 mL, 3 equiv.) was then added, and the reaction mixture was stirred at 20° C. for 1 h under N. The mixture was diluted with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 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). + . 1 H 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=4.4Hz,1H),3.17-2.75(m,3H),2.20-2.08(m,1H),1.48(s,9H),1.43-1.32(m,1H).

[0451] Step 3: Preparation of (3R,4R)-N-(4-fluorophenyl)-3-methoxy-piperidin-4-amine [ka] A mixture of tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1-carboxylate (150 mg, 0.46 mmol, 1 equiv.) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 29.21 equiv.) in dichloromethane (1 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated in vacuo to give (3R,4R)—N-(4-fluorophenyl)-3-methoxy-piperidin-4-amine (1.1 g, crude, trifluoroacetic acid) as a white solid. LC / MS (ESI) m / z: 225.2 [M+H] + .

[0452] 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) [ka] The title compound was prepared in a similar 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] + . 1 HNMR(400MHz,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).

[0453] Synthesis of compound 51 [ka]

[0454] Step 1: Preparation of tert-butyl (3R,4R)-4-(4-fluoro-N-methyl-anilino)-3-methoxy-piperidine-1-carboxylate [ka] To a solution of tert-butyl (3R,4R)-4-(4-fluoroanilino)-3-methoxy-piperidine-1-carboxylate (140 mg, 0.43 mmol, 1 equiv.) and formaldehyde (162 mg, 2.16 mmol, 0.15 mL, 40% purity, 5 equiv.) in methanol (1 mL) and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (81 mg, 1.29 mmol, 3 equiv.), and the reaction mixture was stirred at 40° C. for 12 hours. 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 afford 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] + . 1 H NMR(400MHz,CDCl3) δ 7.00-6.87(m,2H),6.81(dd,J=4.4,8.8Hz,2H),4.71-4.29(m,1H),4.23-3.91(m,1H),3.56-3.46(m,1H),3.41(s,3 H),3.29(dt,J=4.8,9.6Hz,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).

[0455] Step 2: Preparation of (3R,4R)-N-(4-fluorophenyl)-3-methoxy-N-methylpiperidin-4-amine [ka] 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 equiv.) in dichloromethane (1 mL), trifluoroacetic acid (1.85 g, 16.21 mmol, 1.20 mL, 45.71 equiv.) was added, and the resulting mixture was stirred at 25° C. for 30 minutes. 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] + .

[0456] 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) [ka] The title compound was prepared in a similar 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] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.10(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.04-6.95(m,2H),6.89-6.82(m,2H),4.66(d,J=12.0Hz,1H),4.06(d,J=12.0Hz,1H),3. 95-3.79(m,2H),3.62(dt,J=2.8,12.4Hz,1H),3.54(s,3H),3.38(s,3H),3.07(dd,J=9.6,12.4Hz,1H),2.76(s,3H),1.95-1.76(m,2H).

[0457] Synthesis of compounds 52 and 53 [ka]

[0458] Step 1: Preparation of tert-butyl 2,5-dimethyl-4-oxo-piperidine-1-carboxylate [ka] To a solution of tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate (2.0 g, 9.38 mmol, 1.00 equiv.) in tetrahydrofuran (70 mL) was added dropwise lithium diisopropylamide (2 M, 5.16 mL, 1.10 equiv.) in tetrahydrofuran at −78° C., and the reaction mixture was stirred at −78° C. for 2 hours. Iodomethane (1.73 g, 12.19 mmol, 1.30 equiv.) was then added, and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched by adding saturated ammonium chloride solution (100 mL), and the resulting aqueous mixture was extracted with ethyl acetate (100 mL × 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] + .

[0459] Step 2: Preparation of benzyl (2S,5R)-2,5-dimethyl-4-oxo-piperidine-1-carboxylate [ka] To a solution of tert-butyl 2,5-dimethyl-4-oxo-piperidine-1-carboxylate (2.1 g, 9.24 mmol, 1.00 equiv.) in dichloromethane (10 mL), hydrochloric acid in dioxane (4 M, 10 mL, 4.33 equiv.) was added, and the mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (20 mL) and water (10 mL) and then treated with NaHCO (3.85 g, 45.83 mmol, 5.00 equiv.) and benzyl chloroformate (3.13 g, 18.33 mmol, 2.00 equiv.). 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 × 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 to 62% acetonitrile in water with 0.1% formic acid, 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(400MHz,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=5.6,6.8Hz,3H),1.18(dd,J=7.2,9.6Hz,3H). This material was purified by SFC [Method: (Column: DAICEL CHIRALPAK AY-H (250 mm x 30 mm, 10 um), Mobile phase: 15% in CO2 Further purification with HCl gave benzyl (2S,5R)-2,5-dimethyl-4-oxo-piperidine-1-carboxylate (350 mg, 1.34 mmol, 58% yield) as a yellow oil. 1 H NMR δ 7.45-7.31(m,5H),5.28-5.12(m,2H),4.65(dt,J=3.1,6.6Hz,1H),3.90-3.78(m,1H),3.75-3.65(m,1H),2.84(dd, J=6.8,15.4Hz,1H),2.60-2.47(m,1H),2.28(dd,J=3.3,15.4Hz,1H),1.26(d,J=6.8Hz,3H),1.18(d,J=7.1Hz,3H).

[0460] Step 3: Preparation of benzyl (2S,5R)-4-(4-fluoroanilino)-2,5-dimethyl-piperidine-1-carboxylate [ka] To a solution of benzyl (2S,5R)-2,5-dimethyl-4-oxo-piperidine-1-carboxylate (100 mg, 0.38 mmol, 1.00 equiv.) and 4-fluoroaniline (63 mg, 0.57 mmol, 1.50 equiv.) in methanol (2 mL), sodium cyanoborohydride (48 mg, 0.76 mmol, 2.00 equiv.) and acetic acid (2 mg, 38.27 mmol, 0.10 equiv.) were added, and the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (10 mL × 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 in water + 0.225% formic acid, 7 min) to afford (2S,5R)-4-(4-fluoroanilino)-2,5-dimethyl-piperidine-1-carboxylate (60 mg, 0.16 mmol, 43% yield) as a colorless oil. 1 H 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=6.8Hz,1H),3.78-3.61(m,1H),3.40(dd,J=4 .8,14.0Hz,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).

[0461] Step 4: Preparation of (2S,5R)-4-(4-fluoro-N-methyl-anilino)-2,5-dimethyl-piperidine-1-carboxylate [ka] To a solution of benzyl (2S,5R)-4-(4-fluoroanilino)-2,5-dimethyl-piperidine-1-carboxylate (60 mg, 0.16 mmol, 1.00 equiv.) in methanol (2 mL), sodium cyanoborohydride (15 mg, 0.25 mmol, 1.50 equiv.) and formaldehyde (136 mg, 1.68 mmol, 37% purity in water, 10.00 equiv.) were added, and the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×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] + .

[0462] Step 5: Preparation of (2S,5R)-N-(4-fluorophenyl)-N,2,5-trimethyl-piperidin-4-amine [ka] 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 equiv) in methanol (4 mL) was added palladium on activated carbon catalyst (20 mg, 10% purity) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen (3×), and the reaction mixture was stirred under hydrogen (15 Psi) at 25° C. for 2 hours. 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.

[0463] 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) [ka] To a solution of (2S,5R)-N-(4-fluorophenyl)-N,2,5-trimethyl-piperidin-4-amine (40 mg, 0.16 mmol, 1.00 equiv.) and (6-cyano-1-methyl-2-oxo-1,5-naphthyridin-4-yl)trifluoromethanesulfonate (62 mg, 0.18 mmol, 1.10 equiv.) in propan-2-ol (2 mL), N,N-diisopropylethylamine (43 mg, 0.33 mmol, 2.00 equiv.) was added, 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% CHCN in water (0.225% formic acid)) to give the desired product.

[0464] 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(400MHz,CDCl3) δ 7.86-7.79(m,1H),7.77-7.70(m,1H),6.98(t,J=8.4Hz,2H),6.83(s,2H),6.38(s,1H),3.97(dd,J=3.6,12.0Hz,1H),3.68(s,3H),3.5 2-3.26(m,2H),2.84(s,3H),2.63-2.46(m,1H),2.43-2.29(m,1H),1.89(d,J=6.8Hz,2H),1.20(d,J=5.6Hz,3H),0.89(d,J=6.4Hz,3H).

[0465] 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] + . 1 H NMR (400 MHz, CDCl3) δ 7.80(d,J=8.8Hz,1H),7.73-7.66(m,1H),7.00(t,J=8.8Hz,2H),6.81(dd,J=4. 4,9.2Hz,2H),6.16(s,1H),5.02(d,J=6.0Hz,1H),4.04-3.92(m,1H),3.76-3.6 1(m,4H),3.50(dd,J=2.4,12.8Hz,1H),2.87(s,3H),2.57(m,1H),2.42(d,J=2. 4Hz,1H),1.57(d,J=12.4Hz,1H),1.24(d,J=6.8Hz,3H),1.12(d,J=7.2Hz,3H).

[0466] Synthesis of compound 54 [ka]

[0467] Step 1: Preparation of (3aR,6aR)-5-benzyl-3-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole [ka] 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 equiv.) and HCl / dioxane (4 M, 1 mL, 6.33 equiv.) 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] + .

[0468] Step 2: Preparation of (3aR,6aS)-2-benzyl-5-(4-fluorophenyl)-4-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole [ka] 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 equiv, HCl), 1-bromo-4-fluoro-benzene (122 mg, 0.69 mmol, 0.076 mL, 1.1 equiv), and CsCO (619 mg, 1.90 mmol, 3 equiv) 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 equiv), and the reaction mixture was stirred at 100 °C under N for 3 h. 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] + .

[0469] Step 3: Preparation of (3aR,6aS)-5-(4-fluorophenyl)-4-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole [ka] 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 equiv) in ethanol (3 mL) was added palladium-activated carbon catalyst (30 mg, 10% purity) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (50 psi) at 50 °C for 12 h. The mixture was filtered, and the 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] + .

[0470] 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 [ka] The title compound was prepared in a similar 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(400MHz,DMSO-d6) δ 7.99(d,J=9.2Hz,1H),7.77(d,J=9.2Hz,1H),7.24(s,1H),7.11(s,1H), 7.03-6.98(m,2H),6.53(dd,J=4.0,8.8Hz,2H),4.53-4.44(m,2H),4.20 (d,J=12.8Hz,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=6.4Hz,3H).

[0471] Synthesis of compounds 55 and 56 [ka]

[0472] 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 [ka] 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 equiv.) and 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (112 mg, 0.44 mmol, 1 equiv.) in acetonitrile (3 mL), diisopropylethylamine (171 mg, 1.33 mmol, 3 equiv.) was added 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] + . 1 H NMR(400MHz,CDCl3) δ 7.54(d,J=8.8Hz,1H),7.43(d,J=8.8Hz,1H),4.57-4.45(m,2H),4.16-4.07(m,2H),3.87-3.78(m,1H),3.68-3.5 8(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).

[0473] Step 2: Preparation of 6-chloro-1-methyl-4-((3aR,4R,6aR)-4-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] 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 equiv) 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]pyrrole-2(1H)-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (50 mg, 0.11 mmol, 96% yield, trifluoroacetate salt) as a yellow oil. LC / MS(ESI) m / z: 344.2 [M+H] + .

[0474] 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 [ka] To a mixture of 6-chloro-1-methyl-4-((3aR,4R,6aR)-4-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (50 mg, 0.11 mmol, 1 equiv., trifluoroacetate salt) and 4-chloro-2-hydroxy-benzaldehyde (34 mg, 0.22 mmol, 2 equiv.) in 1,2-dichloroethane (3 mL), sodium triacetoxyborohydride (69 mg, 0.32 mmol, 3 equiv.) and triethylamine (33 mg, 0.32 mmol, 3 equiv.) were added and the reaction mixture was stirred at 60° C. for 12 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by semi-preparative reverse phase chromatography (Phenomenex Synergi Polar-RP 100 x 25 mm x 4 um column, mobile phase: 32-52% CH3CN in water (TFA)) to give 4-[(3aR,4R,6aR)-5-[(4-chloro-2-hydroxyphenyl)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] + .

[0475] 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) [ka] The mixture of enantiomers (40 mg, 0.08 mmol, 1 equiv.) was separated by supercritical fluid chromatography (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NHOH in CHOH], B%: 60%-60%, 3.4 min, 40 min).

[0476] 4-[(3aR,4R,6aR)-5-[(4-chloro-2-hydroxyphenyl)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) was obtained as an off-white solid. LC / MS (ESI) m / z: 484.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.60-7.52(m,1H),7.48-7.41(m,1H),6.79(d,J=8.0Hz,1H),6.75-6.70(m,1 H),6.69-6.63(m,1H),4.60(d,J=12.4Hz,1H),4.40(dd,J=2.0,12.4Hz,1H),4 .10(d,J=13.6Hz,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=5.6Hz,3H).

[0477] The second peak was purified by semi-preparative reverse-phase chromatography (column: Unisil 3-100 C18 Ultra 150 x 50 mm x 3 um, mobile phase: [5-35% CH3CN in water (0.225% formic acid)]) to give 4-[(3aS,4S,6aS)-5-[(4-chloro-2-hydroxyphenyl)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] + . 1 H NMR (400 MHz, CDCl3) δ 7.69-7.62(m,1H),7.57-7.51(m,1H),6.89(d,J=8.0Hz,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=1 3.6Hz,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=5.6Hz,3H).

[0478] Synthesis of compounds 57 and 58 [ka]

[0479] Step 1: Preparation of tert-butyl (1S,3aR,6aS)-5-(4-chloro-2-hydroxybenzyl)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ka] 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 equiv.) and 4-chloro-2-hydroxybenzaldehyde (371 mg, 2.37 mmol, 1.07 equiv.) in 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (1.40 g, 6.63 mmol, 3 equiv.) and triethylamine (447 mg, 4.42 mmol, 2 equiv.) were added, and the reaction mixture was stirred at 60 °C for 12 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL × 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] + .

[0480] Step 2: Preparation of 5-chloro-2-(((3aS,4S,6aS)-4-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)phenol [ka] 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 equiv.) 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.

[0481] 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 [ka] To a mixture of 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (0.10 g, 0.39 mmol, 1 equiv.) 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 equiv., trifluoroacetate salt) in tetrahydrofuran (5 mL) was added diisopropylethylamine (152 mg, 1.18 mmol, 3 equiv.) 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 chromatography (column: Phenomenex Synergi Polar-RP 100 x 25 mm x 4 μm, mobile phase: 32-52% CHCN in water (TFA)) to give 4-[(3aS,4S,6aR)-2-[(4-chloro-2-hydroxyphenyl)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] + .

[0482] 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) [ka] The mixture of enantiomers (0.15 g, 0.30 mmol, 1 equiv.) was separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NHOH in isopropanol], B%: 40%-40%, 3.2 min, 60 min).

[0483] Absolute configurations were arbitrarily assigned.

[0484] The first peak was further purified by semi-preparative reverse-phase chromatography (Column: Waters Xbridge 150 x 25 mm x 5 um, Mobile phase: [45-75% CHCN in water (NHOH)]) 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(400MHz,DMSO-d6) δ 8.06(d,J=9.2Hz,1H),7.85-7.78(m,1H),7.02(d,J=8.0Hz,1H),6.64(dd,J=2. 0,8.0Hz,1H),6.60-6.55(m,1H),6.00-5.86(m,1H),4.44-4.34(m,1H),3.79(br d,J=12.4Hz,1H),3.65-3.47(m,7H),3.11-3.00(m,1H),2.78-2.59(m,4H),1.21(d,J=6.4Hz,3H).

[0485] The second peak was further purified by semi-preparative reverse-phase chromatography (column: Phenomenex C18 75 x 30 mm x 3 μm, mobile phase: [12-42% CHCN 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.06(d,J=8.8Hz,1H),7.81(d,J=8.8Hz,1H),7.07(br d,J=8.0Hz,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=6.8Hz,3H).

[0486] Synthesis example 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) [ka]

[0487] 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 equiv., hydrochloride salt), triethylamine (113 mg, 1.12 mmol, 0.15 mL, 5.0 equiv.), and (6-cyano-1-methyl-2-oxo-1,5-naphthyridin-4-yl)trifluoromethanesulfonate (74 mg, 0.22 mmol, 1 equiv.) in dichloromethane (5 mL) and DMF (1 mL) was stirred at 20° C. for 15 hours. The reaction mixture was concentrated under reduced pressure. The product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [35–65% CHCN in water (NHHCO)]) followed by lyophilization to give 8-[(3aR,6aR)-2-[(4-chloro-2-hydroxyphenyl)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] + . 1 H NMR(400MHz,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).

[0488] Synthesis of compound 62 [ka]

[0489] Step 1: Preparation of 1-benzyl 4-(2-bromoanilino)piperidine-4-carbonitrile [ka] To a stirred solution of 1-benzylpiperidin-4-one (10.0 g, 52.8 mmol, 9.8 mL, 1 equiv.) and 2-bromoaniline (9.10 g, 52.8 mmol, 1 equiv.) in AcOH (40 mL) was added TMSCN (5.5 g, 56.0 mmol, 7.0 mL, 1.06 equiv.), and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then quenched by adding 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (gradient: 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] + .

[0490] Step 2: Preparation of 1"-benzylspiro[indoline-2,4"-piperidine]-3-imine [ka] To a stirred solution of 1-benzyl-4-(2-bromoanilino)piperidine-4-carbonitrile (7.4 g, 19.98 mmol, 1 equiv) in toluene (200 mL) was added AIBN (328 mg, 2.00 mmol, 0.1 equiv) and BuSnH (6.4 g, 21.98 mmol, 5.8 mL, 1.1 equiv), and the reaction mixture was stirred at 110 °C under N for 16 h. After cooling to 25 °C, the reaction mixture was quenched by adding saturated KF (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic extracts were dried over anhydrous NaSO, 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] + .

[0491] Step 3: Preparation of 1″-benzylspiro[indoline-2,4″-piperidin]-3-one [ka] A mixture of 1"-benzylspiro[indoline-2,4"-piperidine]-3-imine (7.70 g, 26.4 mmol, 1 equiv) in aqueous HCl (1 M, 232 mL, 8.8 equiv) was stirred at 100 °C for 1 h. After cooling to 25 °C, the mixture was basified with saturated aqueous NaHCO to pH = 8 and then extracted with CHCl (200 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (gradient: 0 to 1% CHOH in CHCl) to give 1"-benzylspiro[indoline-2,4"-piperidin]-3-one (3.00 g, 10.3 mmol, 38.83% yield) as a yellow solid. LC / MS(ESI) m / z:293.3 [M+H] + .

[0492] Step 4: Preparation of 1″-benzylspiro[indoline-2,4″-piperidin]-3-ol [ka] To a solution of 1"-benzylspiro[indoline-2,4"-piperidin]-3-one (500 mg, 1.71 mmol, 1 equiv) in THF (5 mL) was added LiAlH4 (1 M, 1.8 mL, 1.1 equiv) at 0 °C, and the reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched by adding water (0.3 mL), 15% aqueous NaOH (0.3 mL), and water (0.6 mL). The resulting suspension was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated in vacuo to give 1"-benzylspiro[indoline-2,4"-piperidin]-3-ol (500 mg, crude) as a white solid. LC / MS (ESI) m / z: 295.3 [M+H] + .

[0493] Step 5: Preparation of 1"-benzylspiro[indoline-2,4"-piperidine] [ka] A solution of 1"-benzylspiro[indoline-2,4"-piperidin]-3-ol (500 mg, 1.70 mmol, 1 equiv) and EtSiH (987 mg, 8.49 mmol, 1.3 mL, 5 equiv) in CHCl (10 mL) was treated with TFA (1.9 g, 16.9 mmol, 1.3 mL, 10 equiv) at 25 °C for 1 h. The mixture was adjusted to pH = 8 with saturated aqueous NaHCO, and the suspension was extracted with CHCl (20 mL × 3). The combined organic extracts were washed with brine (15 mL × 3), dried over NaSO, 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"-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] + .

[0494] Step 6: Preparation of 1"-benzyl-1-methyl-spiro[indoline-2,4"-piperidine] [ka] To a mixture of 1"-benzylspiro[indoline-2,4"-piperidine] (450 mg, 1.62 mmol, 1 equiv) and formaldehyde (655 mg, 8.08 mmol, 601 μL, 37% purity, 5 equiv) in CHOH (10 mL) was added AcOH (970 mg, 16.1 mmol, 924 μL, 10 equiv) and borane 2-methylpyridine (864 mg, 8.08 mmol, 5 equiv), and the reaction mixture was stirred at 25 °C for 10 h. The mixture was basified with triethylamine to pH = 8 and then concentrated. The crude product was purified by flash silica gel chromatography (gradient: 0 to 50% ethyl acetate in petroleum ether) to afford 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] + .

[0495] Step 7: Preparation of spiro[indoline-2,4″-piperidine] [ka] To a solution of 1"-benzyl-1-methyl-spiro[indoline-2,4"-piperidine] (150 mg, 0.513 mmol, 1 equiv) in CHOH (5 mL) was added Pd(OH) (62 mg, 0.442 mmol, 20% purity, 0.8 equiv) and AcOH (61 mg, 1.03 mmol, 58 μL, 2 equiv) under N. The resulting mixture was degassed and purged with H (3×), then stirred under H (50 Psi) at 50 °C for 2 h. The reaction mixture was filtered, the filter cake washed with CHOH (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] + .

[0496] 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) [ka] To a solution of 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (87 mg, 0.346 mol, 1 equiv.) in CH3CN (3 mL) was added 1-methylspiro[indoline-2,4"-piperidine] (70 mg, 0.346 mmol, 1 equiv.) and diisopropylethylamine (223 mg, 1.73 mmol, 305 μL, 5 equiv.), and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% in EtOH]). NH4OH], B%: 45%-45%, 5 min). The pure fractions were 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.08(d,J=9.2Hz,1H),7.82(d,J=8.8Hz,1H),7.10-6.94(m,2H),6.55(t,J=7.2Hz,1H),6.37(d,J=7.6Hz,1H),4.26 (d,J=12.8Hz,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=12.8Hz,2H).

[0497] 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) [ka]

[0498] A mixture of spiro[3H-benzofuran-2,4"-piperidine] (250 mg, 1.32 mmol, 1 equiv.), 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (336 mg, 1.32 mmol, 1 equiv.), and diisopropylethylamine (371.00 mg, 2.87 mmol, 0.5 mL, 2.17 equiv.) in acetonitrile (3 mL) was heated at 25°C for 12 h. The mixture was concentrated in vacuo and the crude product was triturated in dimethylformamide (1 mL), washed with acetonitrile, and collected by filtration to give 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.08(d,J=9.2Hz,1H),7.82(d,J=9.2Hz,1H),7.2(d,J=7.2Hz,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=5.6Hz,4H).

[0499] Synthesis of compound 64 [ka]

[0500] Step 1: Preparation of tert-butyl 2-(4-fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate [ka] To a solution of tert-butyl 3,4-bis(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate (2.0 g, 5.16 mmol, 1.0 equiv.) and potassium carbonate (7.13 g, 51.62 mmol, 10.0 equiv.) in acetonitrile (50 mL) was added 4-fluoroaniline (1.72 g, 15.49 mmol, 1.48 mL, 3.0 equiv.), and the reaction mixture was stirred at 90° C. for 15 hours. 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: petroleum ether / ethyl acetate 10 / 1 to 2 / 1) followed by preparative TLC (SiO, petroleum ether / ethyl acetate 2 / 1) to give tert-butyl 2-(4-fluorophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (0.3 g, 979.19 μmol, 19% yield) as a yellow oil. 1 H NMR(400MHz,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).

[0501] Step 2: Preparation of 5-(4-fluorophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole [ka] 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 equiv.) 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 give 5-(4-fluorophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (0.23 g, 947.60 μmol, 97% yield, HCl salt) as a yellow solid. LC / MS (ESI) m / z: 207.5 [M+H] + .

[0502] 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) [ka] 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 equiv, hydrochloride salt) and N,N-diisopropylethylamine (152 mg, 1.18 mmol, 0.2 mL, 6.00 equiv) 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 equiv), and the reaction mixture was stirred at 20° C. for 15 hours. 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 give 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 μmol, 59% yield) as a yellow solid. LC / MS (ESI) m / z: 424.1 [M+H] + . 1 H NMR(400MHz,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).

[0503] Synthesis of compounds 65, 66, 67, and 60 [ka]

[0504] Step 1: Preparation of 5-chloro-2-[(3-methyl-4-piperidyl)amino]phenol [ka] To a solution of tert-butyl 4-(4-chloro-2-hydroxy-anilino)-3-methyl-piperidine-1-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) in dichloromethane (5 mL) was added trifluoroacetic acid (33 mg, 0.29 mmol, 1.00 equiv), and the reaction mixture was stirred for 1 hour at 25° C. 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, trifluoroacetate salt) as a brown oil.

[0505] 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 [ka] To a solution of 5-chloro-2-[(3-methyl-4-piperidyl)amino]phenol (100 mg, 0.28 mmol, 1.00 equiv., trifluoroacetate salt) 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 equiv.) and N,N-diisopropylethylamine (36 mg, 0.28 mmol, 1.00 equiv.), and the reaction mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm x 3 μm, mobile phase: [45-75% CH3CN in water (0.225% formic acid)]) to give 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] + .

[0506] Step 3: 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), Preparation of 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) [ka]

[0507] The isomers (100 mg, 0.21 mmol) were separated by SFC. Purification by the first SFC method (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: 60% ethanol (0.1% NH OH in CO )) 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 and 6-chloro-4-[(3R,4R)-4-(4-chloro-2-hydroxy-anilino)-3-methyl-1-piperidyl]-1-methyl-2-oxo A 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 a mixture of 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 gave the individual isomers.

[0508] SFC (column: Daicel ChiralPak IG (250 × 30 mm, 10 μm), mobile phase: 45% ethanol in CO (0.1% NHOH)) afforded 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.

[0509] SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm), mobile phase: 50% methanol in CO (0.1% NHOH)) afforded 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.

[0510] Absolute configurations were arbitrarily assigned.

[0511] 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] + . 1 HNMR(400MHz,CD3OD) δ 8.01(d,J=8.8Hz,1H),7.68(d,J=8.8Hz,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=6.8Hz,3H).

[0512] 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(400MHz,CD3OD) δ 8.02(d,J=8.8Hz,1H),7.69(d,J=8.8Hz,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=7.2Hz,3H)

[0513] 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] + . 1 HNMR(400MHz,DMSO-d6) δ 8.01(d,J=8.8Hz,1H),7.68(d,J=8.8Hz,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=6.4Hz,3H).

[0514] 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(400MHz,DMSO-d6) δ 8.01(d,J=8.8Hz,1H),7.69(d,J=8.8Hz,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=6.4Hz,3H).

[0515] Synthesis of compound 68 [ka]

[0516] Step 1: Preparation of spiro[indoline-2,4″-piperidin]-3-one [ka] To a solution of 1"-benzylspiro[indoline-2,4"-piperidin]-3-one (150 mg, 0.513 mmol, 1 equiv) in CHCl (3 mL) was added 1-chloroethyl carbonochloridate (733 mg, 5.13 mmol, 10 equiv) and the reaction mixture was stirred at 45 °C for 10 h. The reaction mixture was concentrated to give a residue. A mixture of the residue in CHOH (5 mL) was stirred at 60 °C for 1 h. The mixture was concentrated to give spiro[indoline-2,4"-piperidin]-3-one (100 mg, crude) as a yellow solid. LC / MS (ESI) m / z: 203.3 [M+H] + .

[0517] Step 2: Preparation of 6-chloro-1-methyl-2-oxo-4-(3-oxospiro[indoline-2,4″-piperidine]-1″-yl)-1,5-naphthyridine-3-carbonitrile [ka] The title compound was prepared in a similar manner starting from spiro[indoline-2,4"-piperidin]-3-one as 6-chloro-4-[4-(4-fluoro-N-methyl-anilino)-1-piperidyl]-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile. LC / MS (ESI) m / z: 419.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6) δ 8.09(d,J=8.8Hz,2H),7.83(d,J=9.2Hz,1H),7.57-7.38(m,2H),6.92(d,J=8.4Hz,1H),6.74(t,J=7.2Hz ,1H),4.27(d,J=13.6Hz,2H),3.79(t,J=11.6Hz,2H),3.55(s,3H),2.10-2.09(m,2H),1.51-1.50(m,2H).

[0518] Synthesis of compounds 69 and 43 [ka]

[0519] 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 [ka] The enantiomers were separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm x 30 mm, 10 um), mobile phase: 10% CHOH (0.1% NHOH) in CO). The absolute configuration was arbitrarily assigned.

[0520] 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).

[0521] 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).

[0522] 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) [ka]

[0523] The title compound was prepared in a manner similar 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.

[0524] 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=9.2Hz,1H),7.80(d,J=9.2Hz,1H),7.01(t,J=8.8Hz,2H),6.60-6.43(m,2H),4 .28-4.17(m,4H),3.52-3.46(m,5H),3.39(dd,J=2.4,3.6Hz,2H),3.18(t,J=9.2Hz,2H).

[0525] 4-[(3aS,6aS)-2-(4-フルオロフェニル)-1,3,3a,4,6,6a-ヘキサヒドロピロロ[3,4-c]ピロール-5-イル]-6-クロロ-1-メチル-2-オキソ-1,5-ナフチリジン-3-カルボニトリル (yellow solid) (Compound 43). LC / MS(ESI) m / z:424.0 [M+H] + . 1 H 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=8.8Hz,2H).

[0526] MS (ESI) m / z:424.0 [M+1] + 1 H NMR: (400MHz, DMSO-d6) δ=8.02(d,J=9.2Hz,1H),7.80(d,J=9.2Hz,1H),7.01(t,J=8.8Hz,2H),6.60-6.43(m,2H) ,4.28-4.17(m,4H),3.52-3.46(m,5H),3.39(dd,J=2.4,3.6Hz,2H),3.18(t,J=9.2Hz,2H)

[0527] Synthesis of Compound 71

change

change

[0528] Step 1: Preparation of ethyl 3-amino-6-chloro-pyridine-2-carboxylate [ka] To a solution of 3-amino-6-chloro-pyridine-2-carboxylic acid (10.0 g, 58.0 mmol, 1 equiv) in EtOH (100 mL) was added SOCl (8.96 g, 75.3 mmol, 1.3 equiv) and the reaction mixture was stirred at 85 °C for 16 h. 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] + .

[0529] Step 2: Preparation of ethyl 6-chloro-3-[(2-cyanoacetyl)amino]pyridine-2-carboxylate [ka] To a solution of ethyl 3-amino-6-chloro-pyridine-2-carboxylate (8.00 g, 33.7 mmol, 1 equiv., HCl) in DMF (50 mL), triethylamine (17.1 g, 169 mmol, 5 equiv.), 2-cyanoacetic acid (8.61 g, 101 mmol, 3 equiv.), and 1-propanephosphonic anhydride (34.4 g, 54.0 mmol, 50% purity, 1.6 equiv.) were added, and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL × 3). The combined organic extracts were washed with brine (80 mL × 3), dried over anhydrous NaSO, 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] + .

[0530] Step 3: Preparation of 6-chloro-4-hydroxy-2-oxo-1H-1,5-naphthyridine-3-carbonitrile [ka] To a solution of ethyl 6-chloro-3-[(2-cyanoacetyl)amino]pyridine-2-carboxylate (8.71 g, 32.5 mmol, 1 equiv.) in THF (90 mL) was added potassium bis(trimethylsilyl)amide (1 M, 39.05 mL, 1.2 equiv.) at −78° C., and the reaction mixture was stirred under N at −78° C. for 1 h. The reaction mixture was quenched by the addition of 1 M aqueous HCl, adjusted to pH=3, and then concentrated under reduced pressure. The resulting residue was suspended in water (150 mL), and the suspension was cooled in an ice bath and 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] + .

[0531] Step 4: Preparation of 6-chloro-4-hydroxy-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile [ka] 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 equiv.) in DMF (80 mL) was added NaH (4.81 g, 120 mmol, 60% purity, 5.74 equiv.) at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h under N. Iodomethane (10.2 g, 72.2 mmol, 3.45 equiv.) was then added, and the reaction mixture was stirred at 25 °C for 16 h under N. The mixture was slowly poured into water (100 mL), and the pH of the resulting mixture was adjusted to pH = 3 with 1 N 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.12(d,J=8.8Hz,1H),7.87(d,J=9.2Hz,1H),3.54(s,3H).

[0532] Step 5: Preparation of 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile [ka] To a solution of 6-chloro-4-hydroxy-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (5.14 g, 21.8 mmol, 1 equiv.) and N,N-diisopropylethylamine (16.9 g, 131 mmol, 6 equiv.) in CH3CN (100 mL) was added benzyl(triethyl)ammonium chloride (9.94 g, 43.6 mmol, 2 equiv.) and POCl3 (16.7 g, 109 mmol, 5 equiv.) at 0 °C. The reaction mixture was stirred at 25 °C under N2 for 16 h. The mixture was concentrated under reduced pressure. The resulting residue was poured into ice and saturated NaHCO3 solution (30 mL), and the mixture was extracted with C2Cl2 (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 / CHCl) 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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.29(d,J=9.2Hz,1H),8.00(d,J=8.8Hz,1H),3.65(s,3H).

[0533] Step 6: Preparation of 6-chloro-1-methyl-2-oxo-4-spiro[indan-2,4″-piperidine]-1″-yl-1,5-naphthyridine-3-carbonitrile [ka] A mixture of spiro[indane-2,4"-piperidine] (300 mg, 1.34 mmol, 1 equiv., HCl), 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (341 mg, 1.34 mmol, 1 equiv.), and diisopropylethylamine (693 mg, 5.36 mmol, 0.934 mL, 4 equiv.) in acetonitrile (3 mL) was stirred at 40 °C for 3 h. The mixture was concentrated in vacuo and the resulting precipitate was triturated in dimethylformamide (1 mL), washed with acetonitrile (5 mL) and collected by filtration to give 6-chloro-1-methyl-2-oxo-4-spiro[indan-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] + . 1 H NMR(400MHz,DMSO-d6) δ 8.04(d,J=9.2Hz,1H),7.60(d,J=9.2Hz,1H),7.24-7.2(m,2H),7.12(dd,J=3.2, 5.6Hz,2H),3.84(d,J=4.8Hz,4H),3.52(s,3H),2.92(s,4H),1.88-1.76(m,4H).

[0534] Synthesis of compound 72 [ka]

[0535] Step 1: Preparation of tert-butyl 2-[(4-chlorophenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate [ka] To a solution of tert-butyl 3,4-bis(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate (2.0 g, 5.16 mmol, 1 equiv.) and (4-chlorophenyl)methanamine (2.19 g, 15.49 mmol, 1.89 mL, 3.0 equiv.) in acetonitrile (50 mL), potassium carbonate (7.13 g, 51.62 mmol, 10.0 equiv.) was added, and the reaction mixture was stirred at 90° C. for 15 hours. 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 in vacuo. 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 preparative TLC (dichloromethane / ethyl acetate / methanol=2 / 10 / 1) to give 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. 1 H NMR(400MHz,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).

[0536] Step 2: Preparation of 5-[(4-chlorophenyl)methyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole [ka] 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 equiv.) in methanol (5 mL) was added hydrochloric acid / dioxane (4 M, 10 mL), and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give 5-[(4-chlorophenyl)methyl]-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (81 mg, 296.49 μmol, hydrochloride salt) as a yellow solid. LC / MS (ESI) m / z: 237.1 [M+H] + .

[0537] 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) [ka] 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 equiv., hydrochloride salt) and N,N-diisopropylethylamine (152 mg, 1.18 mmol, 0.2 mL, 6.00 equiv.) 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 equiv.), and the reaction mixture was stirred at 20° C. for 15 hours. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). 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 give 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] + . 1 H NMR(400MHz,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),3.91-3.7 8(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).

[0538] 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) [ka]

[0539] 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 equiv., hydrochloride salt) and N,N-diisopropylethylamine (186 mg, 1.44 mmol, 0.25 mL, 6.00 equiv.) 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 equiv.), and the reaction mixture was stirred at 20° C. for 15 hours. 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 × 2), then concentrated at 40 °C to give 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 μmol, 42% yield) as a yellow solid. LC / MS (ESI) m / z: 390.1 [M+H] + . 1 H 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).

[0540] Synthesis of compounds 74 and 75 [ka]

[0541] Step 1: Preparation of tert-butyl 5-oxo-2H-pyrrole-1-carboxylate [ka] To a solution of (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid (40.00 g, 189.55 mmol, 1 equiv.) in tetrahydrofuran (500 mL) at 0 °C under argon was added a solution of NaBO 4H O (72.91 g, 473.88 mmol, 2.5 equiv.) in water (300 mL), 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 × 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. 1 H NMR(400MHz,CDCl3) δ 7.21-7.14(m,1H),6.19-6.09(m,1H),4.37-4.31(m,2H),1.55(s,9H).

[0542] Step 2: Preparation of tert-butyl 2-[tert-butyl(dimethyl)silyl]oxypyrrole-1-carboxylate [ka] To a solution of tert-butyl 5-oxo-2H-pyrrole-1-carboxylate (25.00 g, 136.46 mmol, 1 equiv.) in dichloromethane (500 mL) at 0 °C under argon, triethylamine (41.42 g, 409.38 mmol, 56.98 mL, 3.0 equiv.) was added, followed by [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (43.29 g, 163.75 mmol, 1.2 equiv.), 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: petroleum ether / ethyl acetate 100 / 0 to 10 / 1) to give tert-butyl 2-[tert-butyl(dimethyl)silyl]oxypyrrole-1-carboxylate (32.00 g, 107.58 mmol, 79% yield) as a yellow oil.

[0543] Step 3: Preparation of tert-butyl 2-methyl-5-oxo-2H-pyrrole-1-carboxylate [ka] To a solution of tert-butyl 2-[tert-butyl(dimethyl)silyl]oxypyrrole-1-carboxylate (32.00 g, 107.58 mmol, 1 equiv.) in dichloromethane (400 mL) under nitrogen, iodomethane (45.81 g, 322.73 mmol, 20.09 mL, 3.0 equiv.) was added and the mixture was cooled to 0° C. Silver trifluoroacetate (71.29 g, 322.73 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at 20° C. for 15 hours. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (30 mL × 2). The filtrate was concentrated at 30 °C, and the resulting residue was purified by silica gel column chromatography (gradient: petroleum ether / ethyl acetate from 1 / 0 to 10 / 1) to give tert-butyl 2-methyl-5-oxo-2H-pyrrole-1-carboxylate (5.30 g, 26.87 mmol, 25% yield) as a yellow oil. 1 H NMR(400MHz,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=6.8Hz,3H).

[0544] Step 4: Preparation of tert-butyl (1R,3aS,6aR)-5-benzyl-1-methyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ka] To a solution of tert-butyl 2-methyl-5-oxo-2H-pyrrole-1-carboxylate (5.30 g, 26.87 mmol, 1 equiv.) and trifluoroacetic acid (1.53 g, 13.44 mmol, 0.5 equiv.) in dichloromethane (100 mL) was added dropwise a solution of N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanamine (10.13 g, 36.28 mmol, 85% purity, 1.35 equiv.) in dichloromethane (20 mL) under nitrogen, 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: petroleum ether / ethyl acetate 50 / 1 to 1 / 1) to give 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] + .

[0545] Step 5: Preparation of tert-butyl (1R,3aS,6aR)-5-benzyl-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ka] To a mixture of (1R,3aS,6aR)-5-benzyl-1-methyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (8.00 g, 24.21 mmol, 1 equiv.) in tetrahydrofuran (50 mL) under nitrogen at 0° C., borane dimethyl sulfide complex solution (10 M, 6.0 mL, 2.48 equiv.) was added dropwise, and the reaction mixture was stirred at 90° C. for 0.5 h. The reaction was quenched by the addition of CHOH (50 mL) and refluxed. The mixture was concentrated in vacuo, and the resulting residue was purified by semi-preparative reverse-phase separation (column: Phenomenex Luna C18 250 x 80 mm x 10 um, mobile phase: [20-45% CHCN in water (TFA)]) to give 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] + . 1 H NMR(400MHz,CDCl3) δ 7.28(s,5H),4.05(s,2H),3.69(s,3H),3.32(s,2H),3.03(d,J=8.0Hz,1H ),2.67(s,1H),2.47(d,J=4.0Hz,2H),1.33(s,9H),1.01(d,J=6.4Hz,3H).

[0546] Step 6: Preparation of tert-butyl (1R,3aS,6aR)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ka] 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 equiv.) in methanol (30 mL) was added palladium on activated carbon (0.20 g, 10% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 60 °C for 12 h under hydrogen (20 Psi). The reaction mixture was filtered, and the filtrate was concentrated to give 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.

[0547] Step 7: Preparation of tert-butyl (1S,3aR,6aS)-5-(4-fluorobenzyl)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ka] To a mixture of 4-fluorobenzaldehyde (219 mg, 1.77 mmol, 2 equiv.), tert-butyl (1R,3aS,6aR)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (200 mg, 0.88 mmol, 1 equiv.), and triethylamine (268 mg, 2.65 mmol, 0.37 mL, 3 equiv.) in 1,2-dichloroethane (20 mL), sodium cyanoborohydride (111 mg, 1.77 mmol, 2 equiv.) was added 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 × 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 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] + .

[0548] Step 8: Preparation of (1S,3aS,6aS)-5-(4-fluorobenzyl)-1-methyloctahydropyrrolo[3,4-c]pyrrole [ka] 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 equiv.) in dichloromethane (10 mL) under nitrogen, trifluoroacetic acid (456 mg, 4.00 mmol, 2 mL, 11.15 equiv.) was added in one portion, and the reaction mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated under 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.

[0549] 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 [ka] To a mixture of (6-cyano-1-methyl-2-oxo-1,5-naphthyridin-4-yl)trifluoromethanesulfonate (115 mg, 0.34 mmol, 1 equiv.) and (1S,3aS,6aS)-5-(4-fluorobenzyl)-1-methyloctahydropyrrolo[3,4-c]pyrrole (120 mg, 0.34 mmol, 1 equiv., trifluoroacetate salt) in isopropyl alcohol (10 mL), diisopropylethylamine (134 mg, 1.03 mmol, 3 equiv.) was added 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 semi-preparative reverse-phase separation (column: Phenomenex Synergi Polar-RP 100 x 25 mm x 4 um, mobile phase: 26-46% CHCN in water (TFA)) 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 (120 mg, 0.29 mmol, 83% yield) as a yellow gum. LC / MS (ESI) m / z: 418.2 [M+H] + .

[0550] 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) [ka] The mixture of enantiomers (100 mg, 0.24 mmol, 1 equiv.) was separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NHOH in CHOH], B%: 65%-65%, 4.2 min, 50 min).

[0551] Absolute configurations were arbitrarily assigned.

[0552] The first peak was further purified by semi-preparative reverse-phase chromatography (Column: Waters Xbridge 150 x 25 mm x 5 um, Mobile phase: [36-66% CHCN in water (NHOH)]) 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] + . 1 H NMR(400MHz,CDCl3) δ 7.82(d,J=8.8Hz,1H),7.69(d,J=8.8Hz,1H),7.35-7.29(m,2H),7.02(t,J=8.8Hz, 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=6.4Hz,3H).

[0553] The second peak was 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]+ . 1 H NMR(400MHz,CDCl3) δ 7.72(d,J=8.8Hz,1H),7.60(d,J=8.8Hz,1H),7.26-7.20(m,2H),6.92(t,J=8.8Hz, 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=6.4Hz,3H).

[0554] Synthesis of compounds 76 and 70 [ka]

[0555] 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 [ka] To a mixture of (6-cyano-1-methyl-2-oxo-1,5-naphthyridin-4-yl)trifluoromethanesulfonate (295 mg, 0.88 mmol, 1 equiv.) and tert-butyl (1R,3aS,6aR)-1-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (200 mg, 0.88 mmol, 1 equiv.) in n-butyl alcohol (20 mL) was added diisopropylethylamine (343 mg, 2.65 mmol, 3 equiv.) 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: petroleum ether / ethyl acetate 5 / 1 to 0 / 1) 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] + .

[0556] Step 2: Preparation of 5-methyl-8-((3aR,4R,6aR)-4-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] 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 equiv) in dichloromethane (20 mL) was added trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 55.30 equiv) under nitrogen and the reaction mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated in vacuo to give 5-methyl-8-((3aR,4R,6aR)-4-methylhexahydropyrrolo[3,4-c]pyrrole-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] + .

[0557] 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 [ka] To a mixture of 4-fluorobenzaldehyde (106 mg, 0.85 mmol, 2 equiv.), triethylamine (215 mg, 2.13 mmol, 5 equiv.), and 5-methyl-8-((3aR,4R,6aR)-4-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (180 mg, 0.43 mmol, 1 equiv., trifluoroacetate salt) in 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (270 mg, 1.28 mmol, 3 equiv.) was added 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×2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by semi-preparative reverse-phase separation (column: Phenomenex Synergi Polar-RP 100 x 25 mm x 4 μm, mobile phase: 26-46% CHCN in water (TFA)) to give 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] + .

[0558] 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) [ka] The mixture of enantiomers (150 mg, 0.35 mmol, 1 equiv.) was separated by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NHOH in CHOH], B%: 40%-40%, 2.9 min, 25 min).

[0559] Absolute configurations were arbitrarily assigned.

[0560] 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) was obtained as an off-white solid. LC / MS (ESI) m / z: 418.2 [M+H] + . 1 H NMR(400MHz,CDCl3) δ 7.71(d,J=8.8Hz,1H),7.58(d,J=8.8Hz,1H),7.23(br t,J=6.4Hz,2H),6.93(t,J=8.8Hz,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).

[0561] 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) was obtained as a yellow solid. LC / MS (ESI) m / z: 418.2 [M+H] + . 1H NMR(400MHz,CDCl3) δ:7.76(d,J=8.8Hz,1H),7.65(d,J=8.8Hz,1H),7.46-7.38(m,2H),7.10-7.02(m,2H),5.95(s,1H),4.49(br d,J=12.8Hz,1H),4.11(br d,J=11.2Hz,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).

[0562] Synthesis of compound 78 [ka]

[0563] Step 1: Preparation of tert-butyl 2-benzyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate [ka] To a solution of tert-butyl 3,4-bis(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate (0.4 g, 1.03 mmol, 1.0 equiv) and potassium carbonate (1.43 g, 10.32 mmol, 0.64 mL, 10.0 equiv) in acetonitrile (20 mL) was added benzylamine (331 mg, 3.10 mmol, 0.33 mL, 3.0 equiv), and the reaction mixture was stirred at 90° C. for 15 hours. 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 in vacuo. The resulting residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 2 / 3) to give 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).

[0564] Step 2: Preparation of tert-butyl 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate [ka] 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 equiv.) in ethanol (10 mL) under nitrogen, palladium on activated carbon catalyst (0.05 g, 10% purity) was added, and the reaction mixture was degassed with hydrogen (3×) and stirred under hydrogen (15 psi) at 20° C. for 15 h. The reaction mixture was degassed with hydrogen (3×) and stirred under hydrogen (15 psi) at 20° C. for 15 h. The reaction mixture was filtered, and the cake was washed with ethanol (10 mL×2). The filtrate was concentrated under reduced pressure to give 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] + . 1 H NMR(400MHz,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).

[0565] 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 [ka] 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 equiv) and 4-chloro-2-hydroxy-benzaldehyde (79 mg, 0.51 mmol, 1.2 equiv) in ethanol (10 mL) and dichloromethane (5 mL) was stirred for 2 hours at 20° C. Sodium cyanoborohydride (79 mg, 1.27 mmol, 3.0 equiv) was added and the reaction mixture was stirred under nitrogen at 20° C. for 13 hours. The product was purified by preparative TLC (petroleum ether / ethyl acetate = 1 / 2) followed by preparative TLC (dichloromethane / methanol = 10 / 1) to give 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] + . 1 H NMR(400MHz,CDCl3) δ 6.99-6.95(m,1H),6.94-6.90(m,1H),6.78(dd,J=1.8,7.8Hz,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).

[0566] Step 4: Preparation of 2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-ylmethyl)-5-chloro-phenol [ka] To a solution of tert-butyl 2-[(4-chloro-2-hydroxyphenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (40 mg, 0.11 mmol, 1 equiv.) in dichloromethane (5 mL), hydrochloric acid / methanol (4 M, 10 mL) was added, and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give 2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-ylmethyl)-5-chlorophenol (33 mg, crude, hydrochloride salt) as a yellow solid. LC / MS (ESI) m / z: 253.0 [M+H] + .

[0567] 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) [ka] A solution of 2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-ylmethyl)-5-chlorophenol (33 mg, 0.11 mmol, 1 equiv., hydrochloride salt), triethylamine (57 mg, 0.57 mmol, 0.08 mL, 5.0 equiv.), and 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (29 mg, 0.11 mmol, 1 equiv.) 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 preparative HPLC (Column: Waters Xbridge 150 × 25 mm × 5 μm, Mobile phase: [45–75% CHCN in water (NHHCO)]). The pure fractions were lyophilized to give 4-[(3aR,6aR)-2-[(4-chloro-2-hydroxyphenyl)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] + . 1 H NMR(400MHz,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,4 H),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).

[0568] Synthesis of compounds 79 and 80 [ka]

[0569] Step 1: Preparation of tert-butyl 4-[4-fluoro-N-methyl-anilino)-3-methyl-piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-fluoroanilino)-3-methyl-piperidine-1-carboxylate (300 mg, 0.97 mmol, 1 equiv.) in methanol (5 mL), paraformaldehyde (292 mg, 9.73 mmol, 0.26 mL, 10 equiv.) and sodium cyanoborohydride (61 mg, 0.97 mmol, 1 equiv.) were added, 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] + .

[0570] Step 2: Preparation of N-(4-fluorophenyl)-N,3-dimethyl-piperidin-4-amine [ka] To a solution of tert-butyl 4-(4-fluoro-N-methyl-anilino)-3-methyl-piperidine-1-carboxylate (50 mg, 0.15 mmol, 1 equiv.) in dichloromethane (5 mL) was added trifluoroacetic acid (17 mg, 0.15 mmol, 0.01 mL, 1 equiv.), and the reaction mixture was stirred for 1 hour at 25° C. 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.

[0571] 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 [ka] To a solution of N-(4-fluorophenyl)-N,3-dimethyl-piperidin-4-amine (50 mg, 148.67 μmol, 1 equiv., trifluoroacetic acid) in acetonitrile (5 mL), diisopropylethylamine (19.21 mg, 148.67 μmol, 25.89 μL, 1 equiv.) and 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (30.22 mg, 118.93 μmol, 0.8 equiv.) were added, 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 preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [33-63% CHCN in water (formic acid)]) to give the desired product.

[0572] 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] + . 1 HNMR (400MHz, DMSO-d6) δ 8.08(d,J=9.2Hz,1H),7.82(d,J=9.2Hz,1H),7.09-6.99(m,2H),6.86(dd,J= 4.4,9.2Hz,2H),4.33(d,J=12.0Hz,1H),4.06-3.96(m,1H),4.06-3.95(m,1H) ,3.84(dd,J=2.4,12.8Hz,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=11.2Hz,1H),0.87(d,J=6.4Hz,3H).

[0573] 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] + . 1 HNMR(400MHz,DMSO-d6) δ 8.07(d,J=9.2Hz,1H),7.81(d,J=8.8Hz,1H),7.07-6.96(m,2H),6.90-6. 83(m,2H),4.28(d,J=12.4Hz,2H),3.73(dt,J=3.6,11.1Hz,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, 6.4Hz,1H),1.97-1.84(m,1H),1.77-1.65(m,1H),0.83(d,J=6.4Hz,3H).

[0574] Synthesis of compound 81 [ka]

[0575] Step 1: Preparation of (3S,4R)-N-(4-fluorophenyl)-3-methyl-piperidin-4-amine [ka] To a solution of tert-butyl (3S,4R)-4-(4-fluoroanilino)-3-methyl-piperidine-1-carboxylate (100.00 mg, 324.26 μmol, 1 equiv.) in dichloromethane (5 mL) was added trifluoroacetic acid (36.97 mg, 324.26 μmol, 24.01 μL, 1 equiv.), and the reaction mixture was stirred for 1 hour at 25° C. 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 a brown oil.

[0576] 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) [ka] The title compound was prepared in a similar 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] + . 1 HNMR(400MHz,DMSO-d6) δ 8.06(d,J=9.2Hz,1H),7.80(d,J=8.8Hz,1H),6.90(t,J=8.8Hz,2H),6.76-6.65(m,2H),5.60(d,J=8.8Hz,1H),4.01(d,J=2.4Hz,1H),3.85( d,J=4.8Hz,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=3.2,9.6Hz,1H),0.86(d,J=6.8Hz,3H).

[0577] 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) [ka]

[0578] The title compound was prepared in a similar 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] + . 1 HNMR(400MHz,DMSO-d6) δ 8.06(d,J=9.2Hz,1H),7.81(d,J=9.2Hz,1H),6.95-6.85(m,2H),6.68-6.56(m,2H),5.48(d,J=9.2Hz,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=6.4Hz,3H).

[0579] Synthesis of compound 83 [ka]

[0580] Step 1: Preparation of tert-butyl 4-[(4-chloro-2-hydroxy-phenyl)methyl-methyl-amino]piperidine-1-carboxylate [ka] To a mixture of tert-butyl 4-(methylamino)piperidine-1-carboxylate (500 mg, 2.33 mmol, 1.0 equiv) and 4-chloro-2-hydroxybenzaldehyde (365 mg, 2.33 mmol, 1.0 equiv) in dichloroethane (5 mL) and CHOH (5 mL) was added acetic acid (560 mg, 9.33 mmol, 4.0 equiv), and the resulting mixture was stirred at 25 °C for 5 h. NaBH(OAc) (2.47 g, 11.67 mmol, 5.0 equiv) was then added, and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Xtimate C18 150 x 40 mm x 10 um, mobile phase: [0-30% CH3CN in water (0.225% formic acid)]. Pure fractions were combined and then lyophilized to give 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] + . 1 H NMR(400MHz,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,1 H),2.78-2.68(m,2H),2.46(s,3H),2.01(d,J=11.6Hz,2H),1.66-1.61(m,2H),1.47(s,9H).

[0581] Step 2: Preparation of 5-chloro-2-[[methyl(4-piperidyl)amino]methyl]phenol [ka] 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 equiv.) in dichloromethane (1 mL) was added HCl / dioxane (4 M, 1 mL, 11.8 equiv.) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give 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]+.

[0582] 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) [ka] To a mixture of 5-chloro-2-[[methyl(4-piperidyl)amino]methyl]phenol (95 mg, 0.374 mmol, 1.0 equiv.) and 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (95 mg, 0.374 mmol, 1.0 equiv.) in CH3CN (4 mL), diisopropylethylamine (1.87 mmol, 326 μL, 5.0 equiv.) was added at 20 °C, and the reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by preparative HPLC (column: Xtimate C18 100 × 30 mm × 10 μm, mobile phase: [15–45% CH3CN in water (0.225% formic acid)]). The pure fractions were combined and then lyophilized to give 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(400MHz,DMSO-d6) δ 8.06(d,J=9.2Hz,1H),7.80(d,J=9.2Hz,1H),7.14(d,J=8.0Hz,1H),6.79(dd,J=2.0,8.0Hz,1H),6.76(d,J=2.0Hz,1H),4.29(d,J =13.2Hz,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=10.4Hz,2H),1.90-1.77(m,2H).

[0583] Synthesis of compound 84 [ka]

[0584] Step 1: Preparation of tert-butyl 4-(4-fluoro-N-methyl-anilino)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-fluoroanilino)piperidine-1-carboxylate (300 mg, 1.02 mmol, 1.0 equiv) in DMF (2 mL), KCO (155 mg, 1.12 mmol, 1.1 equiv) and iodomethane (2.55 mmol, 159 μL, 2.5 equiv) were added dropwise at 25 °C, and the reaction mixture was stirred at 60 °C for 12 h under N. The reaction mixture was filtered, and the residue was purified by preparative HPLC (column: Xtimate C18 150 × 40 mm × 10 μm, mobile phase: [30-60% CHCN in water (0.225% formic acid)]). The pure fractions were combined and then lyophilized to give 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] + .

[0585] Step 2: Preparation of N-(4-fluorophenyl)-N-methyl-piperidin-4-amine [ka] To tert-butyl 4-(4-fluoro-N-methyl-anilino)piperidine-1-carboxylate (100 mg, 0.324 mmol, 1.0 equiv.) in dichloromethane (1 mL) was added HCl / dioxane (4 M, 1 mL, 12.3 equiv.) in one portion at 25° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo to give 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] + .

[0586] 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) [ka] To a mixture of N-(4-fluorophenyl)-N-methyl-piperidin-4-amine (67 mg, 0.322 mmol, 1.0 equiv.) and 4,6-dichloro-1-methyl-2-oxo-1,5-naphthyridine-3-carbonitrile (82 mg, 0.322 mmol, 1.0 equiv.) in CH3CN (2 mL) was added diisopropylamine (1.61 mmol, 280 μL, 5.0 equiv.) at 25 °C, and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by preparative HPLC (Column: Xtimate C18 100 × 30 mm × 10 μm, Mobile phase: [0-60% CH3CN in water (0.225% formic acid)]). The pure fractions were combined and then lyophilized to give 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...

Claims

1. A compound having the structure of formula (A): 【Chemistry 682】 or a pharma- ceutically acceptable salt thereof, Ring A is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic ring fused to Ring B; Ring C is R ３ and R ４ and optionally further substituted heterocyclic ring, R １ But, C １ -C ４ is alkyl, R ２ is H or an electron-withdrawing functional group; Each R ３ But independently, NR ５ R ６ and Each R ４ became independent and C １ -C ４ Alkyl or C １ -C ４ is alkoxy, or One R ３ and R ４ together with the ring C atom to which they are attached form a substituted or unsubstituted heteroaryl; R ５ and R ６ are each independently H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R ５ and R ６ together with the nitrogen to which they are attached form a substituted or unsubstituted ring, A compound, or a pharma- ceutically acceptable salt thereof, wherein m and n are each independently 0, 1, 2, 3, or 4.

2. 10. The compound of claim 0, wherein ring A is a substituted or unsubstituted heteroaromatic ring fused to ring B, or a pharma- ceutically acceptable salt thereof.

3. Structure of formula (II): 【Chemistry 683】 wherein R ９ is H or a straight or branched chain C １ -C ４ 13. The compound of claim 0 or 0, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

4. R ９ The compound of claim 3 , wherein is methyl.

5. Structure of formula (III): 【Chemistry 684】 wherein R １０ But linear C １ -C ４ Alkyl or branched chain C １ -C ４ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl or electron-withdrawing functional group.

6. Structure of Formula (IIIa): 【Chemistry 685】 6. The compound of claim 1, 2, or 5, having the formula:

7. R １０ is halogen, -CH ３ , -SO ２ CF ３ , -N(R １１ ) ２ , -NO ２ , -SO ２ R １２ , -C≡N, -C(R １３ ) ３ , -COR １４ , -CO ２ R １６ , -CON(R １７ ) ２ and -N=O; R １１ , R １２ , R １４ , R １６ , or R １７ each independently represents H, or a straight or branched chain C １ -C ４ is alkyl, Each R １３ The compound according to claim 5 or 6, wherein is a halogen.

8. R １０ The compound according to any one of claims 5 to 7, wherein is -Cl.

9. R １０ The compound according to any one of claims 5 to 7, wherein is -C≡N.

10. R １ is a straight or branched chain C １ -C ４ The compound according to any one of claims 1 to 9, which is alkyl.

11. R １ The compound according to any one of claims 1 to 10, wherein is methyl.

12. Each R ４ are independently linear or branched chain C １ -C ４ Alkyl or C １ -C ４ Alkoxy or one R ３ and one R ４ taken together with the atom of Ring C to which they are attached form a substituted or unsubstituted ring.

13. R ２ H, halogen, -SO ２ CF ３ , -N(R ３２ ) ２ , -NO ２ , -SO ２ R ２６ , -C≡N, -C(R ３３ ) ３ , -COR ２８ , -CHO, -COR ２９ , -CO ２ R ３０ , -CON(R ３１ ) ２ and -N=O; R ３２ , R ２６ , R ２８ , R ２９ , R ３０ , or R ３１ each independently is H or C １ -C ４ is alkyl, Each R ３３ The compound according to any one of claims 0 to 12, wherein is halogen.

14. R ２ H, halogen, -SO ２ CF ３ , -N(R ３２ ) ２ , -NO ２ , -SO ２ R ２６ , -C≡N, -C(R ３３ ) ３ , -COR ２８ , -CHO, -COR ２９ , -CO ２ R ３０ , -CON(R ３１ ) ２ and -N=O; R ３２ , R ２６ , R ２８ , R ２９ , R ３０ , or R ３１ each independently represents H, or a straight or branched chain C １ -C ４ is alkyl, Each R ３３ The compound according to any one of claims 0 to 12, wherein is halogen.

15. R ２ The compound according to any one of claims 0 to 14, wherein is H.

16. R ２ The compound according to any one of claims 0 to 14, wherein is -C≡N.

17. Ring C is R １５ , R １８ , R １９ , R ２０ , R ２１ , and R ２２ is further substituted by one or more substituents selected from R １５ But, C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R １８ and R １９ are each independently H, OH, C １ -C ４ Alkoxy, C １ -C ４ Alkyl or -NR ２３ R ２４ or R １８ and R １９ together with the carbon atom to which they are attached form a substituted or unsubstituted ring, R ２０ But, H, C １ -C ４ alkyl, or an electron withdrawing group, or R １８ and R ２０ , or R １９ and R ２０ together with the carbon atom to which they are attached form a substituted or unsubstituted ring, R ２１ But, H, C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ２２ But, C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ２３ and R ２４ However, independently, H, C １ -C ４ The compound of any one of claims 0 to 16, which is alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

18. Ring C is R １５ , R １８ , R １９ , R ２０ , R ２１ , and R ２２ is further substituted by one or more substituents selected from R １５ is a linear or branched chain C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R １８ and R １９ are each independently H, OH, C １ -C ４ Alkoxy, straight or branched chain C １ -C ４ Alkyl or -NR ２３ R ２４ or R １８ and R １９ together with the carbon atom to which they are attached form a substituted or unsubstituted ring, R ２０ is H, linear or branched chain C １ -C ４ alkyl, or an electron withdrawing group, or R １８ and R ２０ , or R １９ and R ２０ together with the carbon atom to which they are attached form a substituted or unsubstituted ring, R ２１ is H, linear or branched chain C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ２２ is a linear or branched chain C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ２３ and R ２４ each independently represents H, a straight or branched chain C １ -C ４ The compound of any one of claims 0 to 16, which is alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

19. Ring C is R １５ , R １８ , R １９ , R ２０ , R ２１ , and R ２２ is further substituted by one or more substituents selected from R １５ is a linear or branched chain C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R １８ and R １９ are each independently １ -C ４ Alkoxy, C １ -C ４ Alkyl or -NR ２３ R ２４ or R １８ and R １９ together with the carbon atoms to which they are attached form a substituted or unsubstituted ring, R ２０ is a linear or branched chain C １ -C ４ alkyl, or an electron withdrawing group, or R １８ and R ２０ , or R １９ and R ２０ together with the carbon atoms to which they are attached form a substituted or unsubstituted ring, R ２１ is a linear or branched chain C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ２２ is a linear or branched chain C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ２３ and R ２４ each independently represents a linear or branched chain C １ -C ４ The compound of any one of claims 0 to 16, which is alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

20. The ring C is 【Chemistry 686】 is selected from During the ceremony, 【Chemistry 687】 The compound according to any one of claims 1 to 19, wherein indicates the point of attachment of ring C to ring B.

21. R ２１ is a linear or branched chain C １ -C ４ The compound according to any one of claims 17 to 20, which is alkyl.

22. R ２２ is a linear or branched chain C １ -C ４ The compound according to any one of claims 17 to 21, which is alkyl.

23. R １５ is a linear or branched chain C １ -C ４ The compound according to any one of claims 17 to 22, which is alkyl.

24. Ring C 【Chemistry 688】 and R １８ and R １９ together with the carbon atoms 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. Ring C 【Chemistry 689】 and R １８ and R ２０ , or R １９ and R ２０ together with the carbon atom 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. R ２０ is a linear or branched chain C １ -C ４ The compound according to any one of claims 17 to 25, which is alkyl.

27. Ring C is 【Chemistry 690】 The compound according to any one of claims 0 to 16, selected from:

28. Ring C 【Chemistry 691】 and R ２１ but 【Chemical Formula 692】 and Each R ２５ are independently OH, halogen, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ selected from haloalkoxy, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; t is 0, 1, or 2; 【Chemistry 693】 is R ２１ 17. The compound of any one of claims 1 to 16, showing the point of attachment to the N of:

29. Ring C 【Chemical Formula 694】 and R ２１ but 【Chemistry 695】 and Each R ２５ are independently OH, halogen, linear or branched chain C １ -C ４ Alkyl, C １－ C ４ Alkoxy, straight or branched chain C １ -C ４ Haloalkyl, C １ -C ４ selected from haloalkoxy, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; t is 0, 1, or 2; 【Chemistry 696】 is R ２１ 17. The compound of any one of claims 1 to 16, showing the point of attachment to the N of:

30. Each R ２５ are independently OH, halogen, C １ -C ４ Alkyl, C １－ C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ 30. The compound of claim 28 or 29, wherein the compound is selected from haloalkoxy, unsubstituted aryl, and unsubstituted heteroaryl.

31. Each R ２５ are independently OH, halogen, linear or branched chain C １ -C ４ Alkyl, C １ -C ４ Alkoxy, straight or branched chain C １ -C ４ Haloalkyl, C １ -C ４ 30. The compound of claim 28 or 29, wherein the compound is selected from haloalkoxy, unsubstituted aryl, and unsubstituted heteroaryl.

32. Ring C 【Chemical Formula 697】 30. The compound of claim 29,

33. R ２１ but, 【Chemistry 698】 The compound according to any one of claims 17 to 20 and 27 to 32, selected from:

34. Ring C is 【Chemistry 699】 23. The compound according to any one of claims 17 to 19, and 22, selected from:

35. R ２２ But, C １ -C ４ The compound of any one of claims 17 to 19, 27, and 34, which is alkyl, unsubstituted aryl, or unsubstituted heteroaryl.

36. R ２２ is a linear or branched chain C １ -C ４ 36. The compound of claim 35, which is alkyl.

37. Ring C 【Chemical 700】 and R １８ and R １９ are each independently -H, -OH, alkyl, and 【Chemistry 701】 Selected from: R ２６ But, H, C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R ２７ But -OH, C １ -C ４ Alkyl, halogen, C １ -C ４ Alkoxy, or C １ -C ４ haloalkoxy, or Two adjacent R ２７ the groups and the two carbon atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered ring; q is 0, 1, or 2; 【Chemistry 702】 But, R １８ and R １９ 17. The compound of any one of claims 1 to 16, wherein the C-ring is one or both of the points of attachment to ring C.

38. Ring C 【Chemistry 703】 and R １８ and R １９ are each independently -H, -OH, C １ -C ４ Alkyl, and 【Chemistry 704】 Selected from: R ２６ But, H, C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R ２７ But -OH, C １ -C ４ Alkyl, halogen, C １ -C ４ Alkoxy, or C １ -C ４ haloalkoxy, or Two adjacent R ２７ the groups and the two carbon atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered ring; q is 0, 1, or 2; 【Chemistry 705】 But, R １８ and R １９ 17. The compound of any one of claims 1 to 16, wherein the C-ring is one or both of the points of attachment to ring C.

39. Ring C 【Chemistry 706】 and R １８ and R １９ are each independently -H, -OH, straight or branched chain C １ -C ４ Alkyl, and 【Chemistry 707】 is selected from R ２６ is H, linear or branched chain C １ -C ４ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R ２７ is -OH, linear or branched C １ -C ４ Alkyl, halogen, C １ -C ４ Alkoxy, or C １ -C ４ haloalkoxy, or Two adjacent R ２７ the groups and the two carbon atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered ring; q is 0, 1, or 2; 【Chemistry 708】 But, R １８ and R １９ 17. The compound of any one of claims 1 to 16, wherein the C-ring is one or both of the points of attachment to ring C.

40. R ２６ is a linear or branched chain C １ -C ４ The compound of any one of claims 37 to 39, which is alkyl.

41. Ring C 【Chemistry 709】 The compound according to any one of claims 1 to 19, selected from:

42. R １８ and R １９ together with the carbon atoms to which they are attached 【Chemistry 710】 Forming X and Y are each independently CH ２ , N.R. ２９ , O, or C═O; Each R ２８ are independently -OH, halogen, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C １ -C ４ Alkoxy, and C １ -C ４ haloalkoxy; R ２９ is H or C １ -C ４ is alkyl, 42. The compound of any one of claims 27 and 34-41, wherein w is 0, 1, or 2.

43. R １８ and R １９ together with the carbon atoms to which they are attached, 【Chemistry 711】 Forming X and Y each independently represent CH ２ , N.R. ２９ , O, or C═O; Each R ２８ are independently -OH, halogen, linear or branched chain C １ -C ４ Alkyl, linear or branched chain C １ -C ４ Haloalkyl, C １ -C ４ Alkoxy, and C １ -C ４ haloalkoxy; R ２９ is H or C １ -C ４ is alkyl, 42. The compound of any one of claims 27 and 34-41, wherein w is 0, 1, or 2.

44. Ring C is 【Chemistry 712】 【Chemistry 713】 【Chemical 714】 【Chemistry 715】 【Chemical Formula 716】 The compound according to any one of claims 0 to 16, selected from:

45. Ring C is 【Chemistry 717】 The compound according to any one of claims 0 to 16, selected from:

46. Ring C is 【Chemical 718】 The compound according to any one of claims 1 to 16, selected from:

47. Ring C 【Chemical 719】 is selected from R ３４ C １ -C ４ The compound according to any one of claims 1 to 16, which is alkyl.

48. Ring C is 【Chemistry 720】 is selected from R ３４ is a linear or branched chain C １ -C ４ The compound according to any one of claims 1 to 16, which is alkyl.

49. Ring C 【Chemistry 721】 and R １５ but, 【Chemical 722】 17. The compound according to any one of claims 0 to 16, which is: or a pharma- ceutically acceptable salt thereof.

50. Ring C is 【Chemical 723】 【Chemical 724】 The compound according to any one of claims 0 to 16, selected from:

51. Ring C is 【Chemistry 725】 The compound according to any one of claims 0 to 16, 【Request 52】 【Chemical 726】 【Chemical 727】 【Chemical 728】 【Chemical 729】 【Chemistry 730】 【Chemistry 731】 【Chemical 732】 【Chemical 733】 【Chemical 734】 【Chemical 735】 【Chemical 736】 【Chemical 737】 【Chemical 738】 【Chemical 739】 【Chemistry 740】 【Chemical 741】 【Chemical 742】 【Chemical 743】 【Chemical 744】 【Chemical 745】 【Chemical 746】 【Chemical 747】 【Chemical 748】 【Chemical 749】 【Chemistry 750】 【Chemistry 751】 【Chemical Formula 752】 【Chemical 753】 【Chemical 754】 【Chemistry 755】 【Chemical 756】 【Chemical 757】 【Chemical 758】 【Chemical 759】 or a pharma- ceutically acceptable salt thereof. 【Request 53】 【Chemical 760】 【Chemical 761】 【Chemical 762】 【Chemical 763】 【Chemical 764】 【Chemical 765】 【Chemical 766】 【Chemical 767】 【Chemical 768】 【Chemical 769】 A compound selected from or a pharma- ceutically acceptable salt thereof, X is CH ２ , O, or NR ２９ and R ２９ is H or C １ -C ４ The compound, or a pharma- ceutically acceptable salt thereof, wherein:

54. R ２９ is a linear or branched chain C １ -C ４ 54. The compound of claim 53, which is alkyl.

55. 1. A compound comprising: 【Chemistry 770】 【Chemical 771】 【Chemical 772】 【Chemical 773】 【Chemical 774】 【Chemical 775】 【Chemical 776】 【Chemical 777】 【Chemical 778】 【Chemical 779】 【Chemistry 780】 【Chemical 781】 【Chemical 782】 【Chemical 783】 【Chemical 784】 【Chemistry 785】 【Chemical 786】 【Chemical 787】 【Chemistry 788】 【Chemical 789】 【Chemical 790】 【Chemical 791】 【Chemical Formula 792】 【Chemical Formula 793】 【Chemical 794】 【Chemical 795】 【Chemical 796】 【Chemical 797】 or a pharma- ceutically acceptable salt thereof.

56. A pharmaceutical composition comprising a compound according to any one of claims 0 to 55 and a pharma- ceutically acceptable excipient.

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

58. 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 prostate cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 55 or a pharmaceutical composition according to any one of claims 56 to 58.

60. 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 neck cancer, lymphoma, lymphoma, leukemia, and melanoma.

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

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