Transcription factor EB activator and uses thereof

Abstract

Provided are pharmaceutical compositions comprising a pharma- ceutical acceptable carrier or diluent and a compound of formula (I), or a pharma- ceutical acceptable salt thereof, that are useful for treating various diseases or conditions, such as activation of TFEB and lysosomal storage diseases. JPEG2025513555000263.jpg2764

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 333,669, filed April 22, 2022. The entire contents of the aforementioned application are incorporated herein by reference.

[0002] The present disclosure relates to activators of transcription factor EB (TFEB), and pharma- ceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, their use in the treatment of disease, their use in any combination with a pharma- ceutically acceptable carrier for the manufacture of a pharmaceutical preparation, the use of the pharmaceutical preparation in the treatment of disease, and methods of treating disease comprising administering a TFEB activator to a warm-blooded animal, in particular a human. [Background technology]

[0003] Autophagy is a process by which cells recycle intracellular materials for energy, thus avoiding cell death due to stress, nutrient depletion, or cell damage (Mizushima et al, 2008, Nature, 451(7182), 1069-1075). In addition to providing nutrients, the autophagy pathway also functions as a "self-cleaning" pathway, degrading misfolded or otherwise non-functional proteins, cellular components, or any other material that is either harmful to the cell or no longer needed. During autophagy, cellular components tagged for degradation are encapsulated by phagophores that form autophagosomes, which then fuse with lysosomes to begin the degradation process. This degradative metabolic process regenerates amino acid building blocks and other cellular materials that can be used in the synthesis of other proteins and also generates ATP, which is used for energy in other cellular processes (Glick et al (2010) The Journal of Pathology, 221(1), 3-12).

[0004] Transcription factor EB (TFEB) has been shown to be a master regulator of the autophagy process, activating genes involved in the expression of lysosomes as well as other related functions (Settembre et al, (2011), Science, 332(6036), 1429-1433). Upon activation, TFEB translocates from the cycloplasm to the nucleus where it activates the synthesis of autophagy genes (Sardiello et al, (2009), Science, 325(5939), 473-477). Due to its role in stimulating autophagy, activation of TFEB is a potential therapeutic option for various diseases that have either the accumulation of non-functional or harmful proteins, such as Alzheimer's disease, or inappropriate lysosomal activity, such as lysosomal storage diseases (Napolitano et al, 2016, J. Cell. Sci., 129(13), 2475-2481).

[0005] Thus, there is a need for TFEB activators as potential therapeutic agents for treating diseases or disorders responsive to TFEB activation. Summary of the Invention

[0006] The present disclosure provides compounds that are TFEB activators, or pharmaceutical compositions thereof. It is unexpected to find that the compounds disclosed herein have better potency and / or lower in vitro clearance compared to known compounds. In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I): [ka] or a pharma- ceutically acceptable salt thereof. The definition of each variable is provided herein.

[0007] In another aspect, the disclosure provides a method of treating a disease or disorder responsive to activation of TFEB in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

[0008] Another aspect of the present disclosure relates to the use of at least one compound as described herein or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or disorder responsive to activation of TFEB.Also provided is a compound as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound as described herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier or diluent, for use in the treatment of a disease or disorder responsive to activation of TFEB. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful for treating diseases or disorders through activation of TFEB function / activity. In some embodiments, the compounds of the present disclosure are activators of TFEB.

[0010] Compounds and Compositions In a first embodiment, the present disclosure provides a compound represented by formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R 1 H, halo, C 1-6 Alkyl, non-aromatic C 3-8 carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; 1-6 The alkyl group may optionally be one to three R1a Substituted with non-aromatic C 3-8 Carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered bicyclic heteroaryl each optionally contain 1 to 3 R 1c is replaced by R 1a For each occurrence, independently, halo, -OR 1b , non-aromatic C 3-8 carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl, and non-aromatic C 3-8 Carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered bicyclic heteroaryl each optionally contain 1 to 3 R 1c is replaced by R 1b , H, C 1-6 Alkyl, or -[CH2-CH2-O] z -CH3, z is 1 to 3; R 1c For each occurrence, independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 1b , -NR 1d R 1d , -CN, -NO2, -C(O)R 1b , -C(O)OR 1b , -C(O)NR 1d R 1d , or -NR 1d C(O)R 1b and R 1d is H or C 1-6 is alkyl, R 2 is H or C 1-6 Is it an alkyl group? Or R 1 and R 2together with the carbon to which they are attached form non-aromatic C 3-8 carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl, each of which is optionally joined by 1-3 R 1c is replaced by R 3 H, halo, C 1-6 Alkyl, non-aromatic C 3-8 carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; 1-6 The alkyl group may optionally be one to three R 3a Substituted with non-aromatic C 3-8 Carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered bicyclic heteroaryl each optionally contain 1 to 3 R 3c is replaced by R 3a For each occurrence, independently, halo, -OR 3b , non-aromatic C 3-8 carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl, and non-aromatic C 3-8 Carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered bicyclic heteroaryl each optionally contain 1 to 3 R 3c is replaced by R 3b , H, C 1-6 Alkyl, or -[CH2-CH2-O] y -CH3, y is 1 to 3; R 3c For each occurrence, independently, halo, C1-6 Alkyl, C 1-6 Haloalkyl, -OR 3b , -NR 3d R 3d , -CN, -NO2, -C(O)R 3b , -C(O)OR 3b , -C(O)NR 3d R 3d , or -NR 3d C(O)R 3b and R 3d is H or C 1-6 is alkyl, R 4 is H or C 1-6 is alkyl, R 5 H, halo, -NR 5a R 5b , C 1-6 Alkyl or C 1-6 is haloalkyl, R 5a and R 5b are each independently H or C 1-6 and provided that the pharmaceutical composition comprises a compound of the formula: [ka] or a pharma- ceutical acceptable salt thereof.

[0011] In a second embodiment, the present disclosure provides a pharmaceutical composition according to the first embodiment, comprising R 5 is -CH3, and the remainder of the variables are as described in the first embodiment.

[0012] In a third embodiment, the present disclosure provides a pharmaceutical composition according to the first or second embodiment, comprising R 1 , H, C 1-6 Alkyl, non-aromatic C 3-8 carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- or 6-membered monocyclic heteroaryl; 1-6The alkyl group may optionally be one to three R 1a Substituted with non-aromatic C 3-8 Carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- or 6-membered monocyclic heteroaryl each optionally has one or two R 1c or R 1 and R 2 together with the carbons to which they are attached, optionally one or two R 1c and the remaining variables of the first or second embodiment are as described in the first or second embodiment, respectively.

[0013] In a fourth embodiment, the present disclosure provides a pharmaceutical composition according to the first or second embodiment, comprising R 1 is a non-aromatic C 3-8 carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- or 6-membered monocyclic heteroaryl; 3-8 Carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- or 6-membered monocyclic heteroaryl each optionally have one or two R 1c and the remaining variables are as described in the first or second embodiment.

[0014] In a fifth embodiment, the present disclosure provides a pharmaceutical composition according to the first or second embodiment, comprising R 1 is selected from the group consisting of bicyclo[1.1.1]pentanyl, phenyl, pyridyl, thiophenyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which optionally contains one or two R 1c and the remaining variables are as described in the first or second embodiment.

[0015] In a sixth embodiment, the present disclosure provides a pharmaceutical composition according to the first or second embodiment, comprising R 1is selected from the group consisting of bicyclo[1.1.1]pentanyl, phenyl, thiophenyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which optionally contains one or two R 1c and the remaining variables are as described in the first or second embodiment.

[0016] In a seventh embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, or sixth embodiment, comprising R 1c For each occurrence, C 1-6 Alkyl, -OR 1b , or halo, R 1b is -[CH2-CH2-O] z and the remainder of the variables are as described in the first, second, third, fourth, fifth, or sixth embodiment.

[0017] In an eighth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, or seventh embodiment, comprising R 3 , H, C 1-6 alkyl, 6-10 membered bicyclic heterocyclyl, phenyl, or 5- or 6-membered monocyclic heteroaryl; 1-6 The alkyl group may optionally be one to three R 3a and the 6- to 10-membered bicyclic heterocyclyl, phenyl, or 5- or 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R 3c and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0018] In a ninth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, or seventh embodiment, comprising R 3 is a 6- to 10-membered bicyclic heterocyclyl, phenyl, or a 5- or 6-membered monocyclic heteroaryl, each of which may optionally be one or two R3c and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0019] In a tenth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, or seventh embodiment, comprising R 3 is a 6- to 10-membered bicyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, each of which may optionally be one or two R 3c and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0020] In an eleventh embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, comprising R 3 is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, benzodioxoyl, furanyl, oxazoyl, oxadiazoyl, pyrazoyl, or triazoyl, each of which may optionally be selected from one to two R 3c and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0021] In a twelfth embodiment, the disclosure relates to a pharmaceutical composition according to the first embodiment, wherein the compound is represented by formula (II) or [ka] or a pharma- ceutically acceptable salt thereof, m is 0 to 2; R 1c Independently, Halo, C 1-6Alkyl or -OR 1b and R 1b is -[CH2-CH2-O] z -CH3, R 3 optionally one or two R 3c is a 5- or 6-membered monocyclic heteroaryl substituted with R 3c is halo or C 1-6 alkyl, and the remainder of the variables are as described in the first embodiment.

[0022] In a thirteenth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, comprising R 3 is pyridyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[0023] In a fourteenth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment, comprising R 3c For each occurrence, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 3b or -C(O)NR 3b R 3d and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0024] In a fifteenth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, comprising R 3cis, at each occurrence, -CH3, -CF3, -Cl, -F, -OCH3, -OCH(CH3)2, or -C(O)NH2, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, thirteenth, or fourteenth embodiment.

[0025] In a sixteenth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, comprising R 2 and R 4 are both H, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.

[0026] In a seventeenth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second or third embodiment, comprising R 1a -OR 1b and R 3a For each occurrence, independently, halo, -OR 3b or 5- or 6-membered monocyclic heteroaryl, and the remainder of the variables are as described in the first, second, or third embodiment.

[0027] In an eighteenth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, comprising R 1c is -F, -Cl, or -CH3, R 3c is -F, Cl, or -CH3, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0028] In a nineteenth embodiment, the present disclosure provides a pharmaceutical composition comprising a compound described herein (e.g., any one of Examples 1-81), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

[0029] In another embodiment, the present disclosure provides: 6-benzyl-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-(3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((6-methylpyridin-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N,6-dibenzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-methoxyethyl)-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(4-(trifluoromethyl)benzyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(1-(pyridin-2-yl)ethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyrimidin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-methoxyethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyrazin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridazin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyrimidin-5-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((3-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-6-(1-phenylethyl)-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((5-chloropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(cyclohexylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-N,6-bis(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N,2-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(4-carbamoylbenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-isopropyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-6-phenyl-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2,6-dimethyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((5-chloro-4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-((5-chloropyridin-2-yl)methyl)-6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-((5-chloropyridin-2-yl)methyl)-6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((4-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(4-isopropoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(benzo[d][1,3]dioxol-5-ylmethyl)-6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-6-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-methoxyethyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(2-(furan-2-yl)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-amino-6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-N-((5-(2-(2-methoxyethoxy)ethoxy)pyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, and 6-(3,5-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0030] In a twentieth embodiment, the present disclosure provides a compound represented by formula (II): [ka] or a pharma- ceutically acceptable salt thereof, R 2 is H or C 1-6 is alkyl, R 4 is H or C 1-6 is alkyl, R 1c are independently halo or C 1-6 is alkyl, m is 0 to 2; If m is 0, R 3is a 5-membered monocyclic heteroaryl or 6-membered monocyclic heteroaryl selected from the group consisting of oxazoyl, oxadiazoyl, pyrazoyl, and triazoyl, each of which optionally contains one or two R 3c or When m is 1 or 2, R 3 is optionally followed by one or two R 3c is a 5- or 6-membered monocyclic heteroaryl substituted with R 3c is halo or C 1-6 wherein the aryl group is an alkyl group.

[0031] In a twenty-first embodiment, the present disclosure provides a compound according to the twentieth embodiment, or a pharma- ceutically acceptable salt thereof, comprising R 2 and R 4 are both H, and the remaining variables are as described in the twentieth embodiment, or a pharma- ceutically acceptable salt thereof.

[0032] In a twenty-second embodiment, the present disclosure relates to a compound according to the twentieth or twenty-first embodiment, or a pharma- ceutically acceptable salt thereof, wherein R 3 is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazoyl, oxadiazoyl, pyrazoyl, or triazoyl, each of which is optionally selected from one to two R 3c and the remaining variables are as described in the twentieth or twenty-first embodiment, or a pharma- ceutically acceptable salt thereof.

[0033] In a twenty-third embodiment, the present disclosure relates to a compound according to the twentieth, twenty-first, or twenty-second embodiment, or a pharma- ceutically acceptable salt thereof, wherein R 3 is pyridyl, and the remaining variables are as described in the twentieth, twenty-first, or twenty-second embodiment, or a pharma- ceutically acceptable salt thereof.

[0034] In a twenty-fourth embodiment, the present disclosure relates to a compound according to the twentieth, twenty-first, twenty-second, or twenty-third embodiment, or a pharma- ceutically acceptable salt thereof, wherein each R 1c is independently H, -Cl, -F, or -CH3, and each R 3c is independently -F, -Cl, or -CH3, and the remaining variables are as described in the twentieth, twenty-first, twenty-second, or twenty-third embodiment, or a pharma- ceutically acceptable salt thereof.

[0035] In a twenty-fifth embodiment, the present disclosure relates to a compound according to the twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment, or a pharma- ceutically acceptable salt thereof, wherein R 1c is H, -Cl, or -CH3, R 3c is -F and the remaining variables are as described in the twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment, or a pharma- ceutically acceptable salt thereof.

[0036] In a twenty-sixth embodiment, the present disclosure provides a method for producing a composition comprising: 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-(3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((6-methylpyridin-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-methoxyethyl)-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(4-(trifluoromethyl)benzyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(1-(pyridin-2-yl)ethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyrimidin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-methoxyethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyrazin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridazin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyrimidin-5-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((3-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-6-(1-phenylethyl)-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((5-chloropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(cyclohexylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-N,6-bis(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N,2-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(4-carbamoylbenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-isopropyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-6-phenyl-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2,6-dimethyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((5-chloro-4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-((5-chloropyridin-2-yl)methyl)-6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-((5-chloropyridin-2-yl)methyl)-6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((4-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-amino-6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-N-((5-(2-(2-methoxyethoxy)ethoxy)pyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, and 6-(3,5-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0037] In a twenty-seventh embodiment, the present disclosure provides a pharmaceutical composition comprising a compound according to the twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

[0038] In a twenty-eighth embodiment, the present disclosure provides a method of treating a lysosomal storage disorder, an infectious disease, a metabolic disease, a muscle disease, a neurodegenerative disease, a kidney disease, a blood disease, or an ocular disease, comprising administering to a subject an effective amount of a compound according to the twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twenty-seventh embodiment.

[0039] In a 29th embodiment, the present disclosure relates to a method according to the 28th embodiment, comprising: Lysosomal storage disorders include Gaucher disease, Pompe disease, NPC, cystinosis, Krabbe disease, Sanfilippo syndrome, multiple sulfatase deficiency, alpha-mannosidosis, Fabry disease, Hunter syndrome, Scheie syndrome, Maroteaux-Lamy syndrome, hyaluronidase deficiency, sialidosis, mucolipidin 1 deficiency, neuronal ceroid lipofuscinosis (Batten disease), mucopolysaccharidoses I, II, III, IV, VI, VII, and IX, Hurler-Scheie syndrome, Morquio syndrome, and glycoprotein disease, glycogen storage disease, metachromatic leukodystrophy, Sly syndrome, I-cell disease, Danon disease, Niemann-Pick disease types A, B, C1, and C2, Sandhoff disease, lysosomal acid lipase deficiency, GM2 gangliosidosis, Tay-Sachs disease, Gaucher disease, Salla disease, cholesteryl ester storage disease, aspartylglucosaminuria, cystinosis, mucolipidosis types I-IV, Schindler disease types I and II, Wolman disease, fucosidosis, pyknodysostosis, and free sialic acid storage disease; the infection is selected from a bacterial infection, a viral infection, and a eukaryotic parasite; The metabolic and muscular disorder is selected from a1-antitrypsin deficiency, polymyositis, and DMD; the neurodegenerative disease is selected from Parkinson's disease, Huntington's disease, Alzheimer's disease, and dementia with Lewy bodies; The kidney disease is selected from PKD, AKI, renal interstitial fibrosis, and diabetic kidney disease; The blood disorder is β-thalassemia. Methods are provided wherein the ophthalmic disease is selected from macular degeneration and retinitis pigmentosa.

[0040] In a thirtieth embodiment, the present disclosure provides a method for treating a disease or disorder mediated by TFEB, comprising administering to a subject an effective amount of a pharmaceutical composition disclosed herein or a compound disclosed herein.

[0041] The compounds and intermediates described herein may be isolated and used as the compounds themselves, i.e., in neutral form. Alternatively, if moieties capable of forming salts are present, the compounds or intermediates may be isolated and used as their corresponding salts. As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds described herein. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds described herein and are typically not biologically or otherwise unsuitable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0042] Pharmaceutically acceptable acid addition salts include those salts of inorganic or organic acids, such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, hydrogensulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lact ... It can be formed in the form of tobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0043] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0044] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0045] Salts can be synthesized by conventional chemical methods from compounds containing a basic or acidic moiety. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable where feasible. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985) and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0046] How to use The compounds disclosed herein have TFEB activating or stimulating activity. As used herein, "TFEB activating activity" or "TFEB stimulating activity" refers to the ability of a compound or composition to induce a detectable increase in TFEB activity in vivo or in vitro (e.g., at least a 10% increase in TFEB activity as measured by a given assay, such as the bioassays described in the Examples and known in the art).

[0047] In certain embodiments, the disclosure provides a method of treating a disease or disorder responsive to activation of TFEB activity (referred to herein as a TFEB-mediated disease or disorder) in a subject in need thereof. The method includes administering to the subject a compound described herein (e.g., a pharmaceutical composition of any one of the first to nineteenth or twenty-seventh embodiments, or a compound of any one of the twentieth to twenty-sixth embodiments), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0048] In certain embodiments, the disclosure provides for the use of a compound described herein (e.g., a pharmaceutical composition of any one of the first to nineteenth, or twenty-seventh embodiments, or a compound of any one of the twentieth to twenty-sixth embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating a TFEB-mediated disease or disorder in a subject in need thereof.

[0049] In certain embodiments, the disclosure provides a compound described herein (e.g., a pharmaceutical composition of any one of the first to nineteenth, or twenty-seventh embodiments, or a compound of any one of the twentieth to twenty-sixth embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for use in treating a TFEB-mediated disease or disorder in a subject in need thereof.

[0050] In certain embodiments, the disclosure provides a method of treating a lysosomal storage disorder, an infectious disease, a metabolic disease, a muscular disease, a neurodegenerative disease, a renal disease, a hematological disease, or an ocular disease in a subject in need thereof, the method comprising administering to the subject a compound described herein (e.g., a pharmaceutical composition of any one of the first through nineteenth or twenty-seventh embodiments, or a compound of any one of the twentieth through twenty-sixth embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0051] In certain embodiments, the disclosure provides for the use of a compound described herein (e.g., a pharmaceutical composition of any one of the first through nineteenth, or twenty-seventh embodiments, or a compound of any one of the twentieth through twenty-sixth embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating a lysosomal storage disorder, an infectious disease, a metabolic disease, a muscular disease, a neurodegenerative disease, a renal disease, a hematological disease, or an ocular disease in a subject in need thereof.

[0052] In certain embodiments, the disclosure provides a compound described herein (e.g., a pharmaceutical composition of any one of the first through nineteenth, or twenty-seventh embodiments, or a compound of any one of the twentieth through twenty-sixth embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for use in treating a lysosomal storage disorder, an infectious disease, a metabolic disease, a muscular disease, a neurodegenerative disease, a renal disease, a hematological disease, or an ocular disease in a subject in need thereof.

[0053] In some embodiments, the lysosomal storage disorder is Gaucher disease, Pompe disease, NPC, cystinosis, Krabbe disease, Sanfilippo syndrome, multiple sulfatase deficiency, alpha-mannosidosis, Fabry disease, Hunter syndrome, Scheie syndrome, Maroteaux-Lamy syndrome, hyaluronidase deficiency, sialidosis, mucolipidin 1 deficiency, neuronal ceroid lipofuscinosis (Batten disease), mucopolysaccharidosis types I, II, III, IV, VI, VII, and IX, Hurler-Scheie syndrome, Morquio syndrome. group, glycoproteinosis, glycogen storage disease, metachromatic leukodystrophy, Sly syndrome, I-cell disease, Danon disease, Niemann-Pick disease types A, B, C1, and C2, Sandhoff disease, lysosomal acid lipase deficiency, GM2 gangliosidosis, Tay-Sachs disease, Gaucher disease, Salla disease, cholesteryl ester storage disease, aspartylglucosaminuria, cystinosis, mucolipidosis types I-IV, Schindler disease types I and II, Wolman disease, fucosidosis, pyknodysostosis, and free sialic acid storage disease.

[0054] In some embodiments, the infection is selected from a bacterial infection, a viral infection, and a eukaryotic parasite.

[0055] In some embodiments, the metabolic and muscle disorder is selected from a1 antitrypsin deficiency, polymyositis, and Duchenne muscular dystrophy (DMD).

[0056] In some embodiments, the neurodegenerative disease is selected from Parkinson's disease, Huntington's disease, Alzheimer's disease, and Lewy body dementia.

[0057] In some embodiments, the renal disease is selected from polycystic kidney disease (PKD), acute kidney injury (AKI), renal interstitial fibrosis, and diabetic kidney disease.

[0058] In some embodiments, the blood disorder is β-thalassemia.

[0059] In some embodiments, the ocular disease is selected from macular degeneration and retinitis pigmentosa.

[0060] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a mammal, hi certain embodiments, the subject is a primate, hi certain embodiments, the subject is a human.

[0061] As used herein, "effective amount" and "therapeutically effective amount" may be used interchangeably. This refers to an amount effective to treat or reduce the severity of one or more of the diseases, disorders, or conditions listed herein. In some embodiments, an effective dose may be between 10 μg and 500 mg.

[0062] The compounds and compositions according to the disclosed methods may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases, disorders, or conditions listed above.

[0063] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered parenterally, in certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically, or intranasally, in certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered systemically.

[0064] The compounds of the present invention can be used as pharmaceutical compositions (e.g., a compound of the present invention and at least one pharma- ceutically acceptable carrier or diluent). As used herein, the term "pharma- ceutically acceptable carrier or diluent" includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and the like, and combinations thereof, as would be known to one skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). In therapeutic or pharmaceutical compositions, the use of any conventional carrier is contemplated, except where incompatible with the active ingredient. For purposes of this disclosure, solvates and hydrates are considered to be pharmaceutical compositions that include a compound of the present invention and a solvent (i.e., a solvate) or water (i.e., a hydrate).

[0065] The formulation can be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., the compound of the present invention, or a stable form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compound of the present invention is typically formulated into a pharmaceutical dosage form to provide an easily controllable drug dosage and provide a convenient and easy-to-handle product to the patient.

[0066] The pharmaceutical composition (or formulation) for application can be packaged in various ways depending on the method used to administer the drug. In general, the article for distribution can include a container having the pharmaceutical formulation disposed therein in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container can also include a tamper-evident assembly to prevent inadvertent access to the contents of the package. In addition, the container has a label disposed thereon that describes the contents of the container. The label can also include appropriate warnings.

[0067] Pharmaceutical compositions containing the compounds of the present disclosure will generally be formulated for parenteral or oral administration, or alternatively, for use as a suppository.

[0068] For example, the pharmaceutical oral compositions of the present disclosure may be configured in a solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in a liquid form (including but not limited to solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical processes such as sterilization and / or may contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0069] Typically, a pharmaceutical composition contains, together with an active ingredient, a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol, for tablets, and c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, if necessary; d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) Tablets or gelatin capsules containing absorbents, colorants, flavoring agents, and sweetening agents.

[0070] Tablets may be film coated or enteric coated according to methods known in the art.

[0071] Compositions suitable for oral administration include the compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharma- ceutically convenient and palatable preparation. Tablets may contain the active ingredient in admixture with non-toxic pharma-ceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used.Formulations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0072] Parenteral compositions (e.g., intravenous (IV) formulations) are isotonic aqueous solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically useful substances. The compositions are generally prepared according to conventional mixing, granulating, or coating methods, respectively, and contain about 0.1-75% active ingredient, or about 1-50% active ingredient.

[0073] The compounds of the present disclosure or pharmaceutical compositions thereof for use in subjects (e.g., humans) are typically administered orally or parenterally in therapeutic doses. When administered intravenously via infusion, the dosage may depend on the infusion rate at which the IV formulation is administered. In general, the therapeutically effective dosage of the compounds, pharmaceutical compositions, or combinations thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. An ordinary physician, pharmacist, clinician, or veterinarian can easily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of the disorder or disease.

[0074] The above dosage characteristics are demonstrable in vitro and in vivo, advantageously using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and preparations thereof. The compounds of the invention can be applied in vitro in the form of solutions, e.g. aqueous solutions, and in vivo either enterally or parenterally, advantageously intravenously, e.g. as a suspension or in aqueous solution. The in vitro dosage is about 10 -3 Molar ~ 10 -9 It may be in the molar range.

[0075] definition As used herein, a "patient," "subject," or "individual" is used interchangeably and refers to either a human or a non-human animal. The term includes mammals, such as humans. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., a human; male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

[0076] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0077] As used herein, the terms "stimulate," "stimulation," "activate," or "activation" refer to a significant increase in the baseline activity of a biological activity or process.

[0078] As used herein, the terms "treat", "treating" or "treatment" of any disease, condition or disorder refer to the management and care of a patient for the purpose of combating the disease, condition or disorder, and include administration of the compounds of the present invention to obtain the desired pharmacological and / or physiological effect. Treatment includes therapeutic and prophylactic treatment. Therapeutic treatment includes partially or substantially achieving one or more of the following results: partially or completely reducing the extent of the disease, condition or disorder, improving or enhancing clinical symptoms, complications, or indicators associated with the disease, condition or disorder, or delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or disorder. Prophylactic treatment is the reduction of the likelihood of developing a disease in a subject with known risk factors.

[0079] As used herein, a subject (preferably a human) is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0080] As used herein, the phrase "optionally substituted" is used synonymously with the phrase "substituted or unsubstituted". In general, the term "optionally substituted" refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and descriptions of the compounds and their examples. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions.

[0081] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-4 The term "alkyl" refers to an alkyl having 1 to 4 carbon atoms. 1-3 Alkyl" and "C 1-2 The term "alkyl" should be construed accordingly. 1-4 Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy has the same definition as above. When indicated as "optionally substituted," the alkane radical or alkyl moiety can be unsubstituted or substituted with one or more substituents (generally 1 to 3 substituents, except in the case of perhalogenation, such as perchloro or perfluoroalkyl).

[0082] As used herein, the term “alkoxy” refers to an oxygen bridge (i.e., C 1-4 alkyl is as defined herein; 1-4Alkoxy refers to a fully saturated branched or unbranched alkyl moiety bonded via an alkyl group (alkyl group). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. Preferably, an alkoxy group has about 1-4 carbons, more preferably about 1-2 carbons. The term "C 1-2 "Alkoxy" should be construed accordingly.

[0083] As used herein, "C 1-4 Alkoxy C 1-4 The term "alkyl" means that at least one of the hydrogen atoms is C 1-4 C, as defined herein, which is replaced by alkoxy. 1-4 Refers to an alkyl group. 1-4 Alkoxy C 1-4 The alkyl group is connected through the remainder of the molecule described herein via the alkyl group.

[0084] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx ", where x and xx are integers. For example, "C 1-3 "Alkyl" is an alkyl group having 1 to 3 carbon atoms.

[0085] "Halogen" or "halo" can be fluorine, chlorine, bromine, or iodine.

[0086] As used herein, "halo-substituted -C 1-4 Alkyl" or "C 1-4 The term "haloalkyl" refers to any of the C 1-4 C refers to an alkyl group in which at least one of the hydrogen atoms is replaced by a halo atom. 1-4 The haloalkyl group is a monohalo-C 1-4 Alkyl, dihalo-C 1-4 Alkyl or perhalo-C 1-4 Polyhalo-C containing alkyl 1-4 It can be alkyl. 1-4The alkyl may have one iodo, bromo, chloro, or fluoro within the alkyl group. 1-4 Alkyl and polyhalo-C 1-4 The alkyl group may have two or more of the same halo atoms or a combination of different halo groups within the alkyl group. Typically, polyhalo-C 1-4 The alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. 1-4 Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. 1-4 An alkyl group is a C group in which all hydrogen atoms have been replaced by halo atoms. 1-4 Refers to an alkyl group.

[0087] The term "aryl" refers to an aromatic carbocyclic mono- or bicyclic system having two aromatic carbocyclic rings containing from 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0088] The term "heteroaryl" refers to a 5-12 membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some cases, the nitrogen atom in a heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". Heteroaryl groups may be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridyl, furanyl, oxadiazolyl, thiophenyl, and the like. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, imidazopyridinyl, and indolyl.

[0089] The term "non-aromatic carbocycle" or "non-aromatic carbocyclyl" refers to a 3- to 12-membered saturated or partially unsaturated hydrocarbon ring system, which may exist as a monocyclic or polycyclic ring, e.g., a bicyclic ring (including fused, spiro, or bridged carbocycles) or a tricyclic ring. Bicyclic non-aromatic carbocyclyl groups include, for example, an unsaturated carbocyclic radical fused to another unsaturated carbocyclic radical, a cycloalkyl, or an aryl, such as 2,3-dihydroindenyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless otherwise specified, non-aromatic carbocycles generally contain from 4 to 10 ring members.

[0090] The term "C3-6 cycloalkyl" refers to a fully saturated carbocycle, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0091] The term "heterocycle" or "heterocyclyl" refers to a 4-12 membered saturated or partially unsaturated heterocycle containing 1-4 heteroatoms independently selected from N, O, and S. Heterocyclyl groups can be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic rings). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and piperdinyl. Bicyclic heterocyclyl groups include, for example, an unsaturated heterocyclic radical fused to another unsaturated heterocyclic radical, a cycloalkyl, aryl, or heteroaryl ring, such as benzo[d][1,3]dioxolyl, tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-oxabicyclo[2.1.1]hexanyl, and 9-azabicyclo[3.3.1]nonanyl. In some embodiments, the heterocyclyl group is a 4-6 membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 4-6 membered monocyclic saturated heterocyclyl group. In some embodiments, the heterocyclyl group is an 8-10 membered bicyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8-10 membered bicyclic saturated heterocyclyl group.

[0092] As used herein, the term "spiro" ring refers to a two-ring system in which both rings share one common ring atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptanyl, and the like.

[0093] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. Fused heterocycles have at least one ring system that contains a ring atom that is a heteroatom selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0094] As used herein, the term "bridged" refers to a two-ring system containing 5 to 10 ring atoms and having three or more ring atoms in common, where two bridgehead ring atoms are separated by a bridge containing at least one atom (e.g., bicyclo[1.1.1]pentane or 5-oxabicyclo[2.1.1]hexane).

[0095] The phrase "pharmacologically acceptable" indicates that the substance, composition, or dosage form must be chemically compatible with the other ingredients in a formulation. Alternatively, or in addition, the phrase "pharmacologically acceptable" indicates that the substance, composition, or dosage form must be toxicologically compatible with the mammal being treated therewith.

[0096] Unless otherwise specified, the term "compounds of the present disclosure" refers to compounds of formula (I) and all stereoisomers (including diastereoisomers and enantiomers), rotamers, and tautomers. Where moieties capable of forming salts are present, salts are also included, particularly pharma- ceutically acceptable salts.

[0097] As used herein, the terms "a," "an," "the," and similar terms used in the context of the present invention (particularly in the context of the claims) should be construed to cover both the singular and the plural, unless otherwise stated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended to better clarify the invention and does not limit the scope of the disclosure unless otherwise asserted.

[0098] It is also possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by rearrangement of some of the bonding electrons.

[0099] In one embodiment, the disclosure relates to a compound of formula (I) as defined herein in free form. In another embodiment, the disclosure relates to a compound of formula (I) as defined herein in salt form. In another embodiment, the disclosure relates to a compound of formula (I) as defined herein in acid addition salt form. In a further embodiment, the disclosure relates to a compound of formula (I) as defined herein in pharma- ceutically acceptable salt form. In yet a further embodiment, the disclosure relates to a compound of formula (I) as defined herein in pharma- ceutically acceptable acid addition salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in free form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in acid addition salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in pharma- ceutically acceptable salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in pharma- ceutically acceptable acid addition salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in pharma- ceutically acceptable acid addition salt form.

[0100] The compounds of the present disclosure can be synthesized by synthetic routes that include processes similar to those well known in the chemical arts, particularly in light of the description contained herein.Starting materials are generally available from commercial sources such as Sigma-Aldrich, or can be easily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967-1999 ed.) or Beilsteins Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin) (including supplementary documents) (also available via Beilstein online database).

[0101] For illustrative purposes, the reaction schemes shown below provide possible routes for synthesizing the compounds of the present disclosure as well as key intermediates. For more detailed descriptions of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are shown in the schemes and discussed below, other starting materials and reagents may be readily substituted to provide a variety of derivatives and / or reaction conditions. EXAMPLES

[0102] [Table 1]

[0103] Example 1: 6-benzyl-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] [ka] 1. Synthesis of (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate diethyl [ka] To a solution of diethyl 2,6-dimethylpyridine-3,5-dicarboxylate (520 mg, 2.069 mmol) in DMF (5 mL) was added (diethoxymethyl)dimethylamine (365.5 mg, 2.483 mmol) and the resulting solution was stirred at 100° C. for 8 h. The desired product can be detected by LCMS. Proceed to the next step without any workup. LCMS (ESI+): C 16 H 23 N2O4[M+H] + Calculated m / z: 307; measured value: 307.

[0104] Synthesis of ethyl 2.6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (300 mg, 0.979 mmol) and benzylamine (125.9 mg, 1.175 mmol) in EtOH (3 mL) was stirred at 80° C. for 8 h. The precipitated solid was collected by filtration and washed with water (2×5 mL) to give ethyl 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (300 mg, yield: 90.2%). LCMS (ESI+): C 19 H 18 N2O3[M+H] + Calculated m / z: 323; measured: 323.

[0105] 3. Synthesis of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (322 mg, 0.999 mmol) and NaOH (47.9 mg, 1.199 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40°C for 3 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (250 mg, yield: 67.4%). LCMS (ESI+): C 17 H 15 N2O3[M+H] + Calculated m / z: 295; measured: 295.

[0106] 4. Synthesis of 6-benzyl-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-1,6-naphthyridine-3-carboxylic acid (350 mg, 1.189 mmol) in DMF (5 mL) at 0° C., EDC.HCl (276.9 mg, 1.784 mmol) and HOBT (241.0 mg, 1.784 mmol) were added, followed by 1-(5-methylfuran-2-yl)methanamine (198.3 mg, 1.784 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude product was purified using the following conditions (column: XBridge Prep OBD C 18 Purification by Prep-HPLC using column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min, gradient: 33% B to 43% B in 8min, 43%) to give 6-benzyl-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (136mg, yield: 29.4%). LCMS (ESI+): C 23 H22 N3O3[M+H] + Calculated m / z: 388; measured: 388. 1 HNMR(400MHz,DMSO-d6,δ):9.06(t,J=5.6Hz,1H),8.43(s,1H),7.91(d,J=7.6Hz,1H),7.36-7.27(m,5H),6.72(d,J=7 .6Hz,1H),6.20(d,J=2.8Hz,1H),6.02(d,J=1.6Hz,1H),5.22(s,2H),4.43(d,J=5.6Hz,2H),2.65(s,3H),2.26(s,3H).

[0107] Example 2: 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (200 mg, 0.653 mmol) and 1-(5-fluoropyridin-2-yl)methanamine (98.8 mg, 0.784 mmol) in EtOH (2 mL) was stirred overnight at 80° C. under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (100 mg, yield: 44.8%). LCMS (ESI+): C 18 H 17 FN3O3[M+H] + Calculated m / z: 342.1; measured: 342.1.

[0108] 2. Synthesis of 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (90 mg, 0.264 mmol) and NaOH (15.8 mg, 0.396 mmol) in MeOH (1 mL) and H2O (0.3 mL) was stirred at 40°C for 2 h. The residue was acidified to pH 7 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a yellow solid (80 mg, yield: 92.0%). LCMS (ESI+): C 16 H 13 FN3O3[M+H] + Calculated m / z: 314.1; measured: 314.1.

[0109] 3. Synthesis of 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (42.5 mg, 0.136 mmol) and DIPEA (52.6 mg, 0.407 mmol) in DMF (1 mL) was added EDC.HCl (38.9 mg, 0.203 mmol) and HOBT (27.5 mg, 0.204 mmol) at 0° C., followed by 1-(5-methylfuran-2-yl)methanamine (22.6 mg, 0.203 mmol). The reaction mixture was stirred at room temperature for 3 h. The crude product was purified by Prep-HPLC using the following conditions (Column: XBridge Prep Phenyl OBD column, 19*250mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3), Mobile phase B: MeOH--HPLC; Flow rate: 25mL / min, Gradient: 60% B to 60% B in 10min, 60%) to give 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (10mg, Yield: 18.1%). LCMS (ESI+): C 22 H 20 FN4O3[M+H] + Calculated m / z: 407.1; measured: 407.1. 1 HNMR(400MHz,DMSO-d6,δ):9.05(t,J=5.6Hz,1H),8.48(d,J=2.8Hz,1H),8.38(s,1H),7.89(d,J=7.6Hz,1H),7.74-7.69(m,1H),7.44-7. 41(m,1H),6.72(d,J=7.6Hz,1H),6.18(d,J=2.8Hz,1H),6.02-6.01(m,1H),5.31(s,2H),4.41(d,J=5.6Hz,2H),2.66(s,3H),2.25(s,3H).

[0110] Example 3: 6-Benzyl-2-methyl-N-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-2-methyl-N-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (200 mg, 0.680 mmol) and DIPEA (263.4 mg, 2.040 mmol) in DMF (2 mL) at 0° C., EDC.HCl (158.2 mg, 1.020 mmol) and HOBT (137.7 mg, 1.020 mmol) were added, followed by (5-methyloxazol-2-yl)methanamine (114.3 mg, 1.020 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude product was purified using the following conditions (column: XBridge Prep OBD C 18 Purification by Prep-HPLC using column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min, gradient: 23% B to 33% B in 8min, 33%) to give 6-benzyl-2-methyl-N-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (22.8mg, yield: 8.58%). LCMS(ESI+):C 22 H 21 N4O3[M+H] + Calculated m / z: 389.2; measured: 389.2. 1 HNMR(400MHz,DMSO-d6,δ):9.25(t,J=5.8Hz,1H),8.49(s,1H),7.91(d,J=7.6Hz,1H),7.35-7.29(m,5H), 6.80-6.79(m,1H),6.73-6.71(m,1H),5.22(s,2H),4.53(d,J=5.6Hz,2H),2.68(s,3H),2.30-2.29(m,3H).

[0111] Example 4: 6-Benzyl-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (200 mg, 0.680 mmol) in DMF (2 mL) at 0° C., EDC.HCl (195.4 mg, 1.020 mmol) and HOBT (137.7 mg, 1.020 mmol) were added, followed by (2-methyloxazol-5-yl)methanamine (114.3 mg, 1.020 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude product was purified using the following conditions (column: XBridge Prep OBD C 18 Purification by Prep-HPLC using column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min, gradient: 22% B to 32% B in 8min, 32%) to give 6-benzyl-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (86.6mg, yield: 32.7%). LCMS(ESI+):C 22 H 21 N4O3[M+H] + Calculated m / z: 389.2; measured: 389.1. 1HNMR(400MHz,DMSO-d6,δ):9.13(t,J=5.4Hz,1H),8.44(s,1H),7.91(d,J=7.6Hz,1H),7.36-7.28(m ,5H),6.92(s,1H),6.72-6.70(m,1H),5.21(s,2H),4.49(d,J=5.2Hz,2H),2.65(s,3H),2.39(s,3H).

[0112] Example 5: 6-benzyl-2-methyl-N-(3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-N-(3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (200 mg, 0.680 mmol) in DMF (4 mL) was added EDC.HCl (195.4 mg, 1.020 mmol) and HOBT (137.7 mg, 1.020 mmol), followed by m-tolylmethanamine (56 mg, 0.518 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude product was purified by Prep-HPLC using the following conditions (Column: XBridge Shield RP18 OBD column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min, Gradient: 40% B to 55% B, 55% B in 8 min) to give 6-benzyl-2-methyl-N-((3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (125.7mg, Yield: 46.1%). LCMS (ESI+): C 25 H 24 N3O2[M+H] + Calculated m / z: 398.2; measured: 398.2. 1HNMR(300MHz,DMSO-d6,δ):9.12(t,J=5.9Hz,1H),8.46(s,1H),7.91-7.89(m,1H),7.36-7.23(m,6H),7.17-7.14 (m,2H),7.10-7.07(s,1H),6.71(d,J=7.5Hz,1H),5.21(s,2H),4.45(d,J=6.0Hz,2H),2.66(s,3H),2.31(s,3H).

[0113] Example 6: 6-Benzyl-2-methyl-N-((6-methylpyridin-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-2-methyl-N-((6-methylpyridin-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (250 mg, 0.849 mmol) in DMF (2.5 mL) at 0° C., EDC.HCl (197.8 mg, 1.273 mmol) and HOBT (172.1 mg, 1.273 mmol) were added, followed by (6-methylpyridin-2-yl)methanamine (155.6 mg, 1.273 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude product was purified using the following conditions (column: XBridge Prep OBD C 18 Purification by Prep-HPLC using column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min, gradient: 25% B to 35% B, 35% B in 8 min) to give 6-benzyl-2-methyl-N-((6-methylpyridin-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a pale yellow solid (136.4mg, yield: 40.2%). LCMS (ESI+): C24 H 23 N4O2[M+H] + Calculated m / z: 399.2; measured: 399.2. 1 HNMR(400MHz,DMSO-d6,δ):9.20(t,J=6.0Hz,1H),8.55(s,1H),7.91(d,J=7.6Hz,1H),7.69(t,J=7.7Hz,1H),7.40-7.24( m,5H),7.17(dd,J=15.4,7.7Hz,2H),6.73(d,J=7.6Hz,1H),5.23(s,2H),4.54(d,J=6.0Hz,2H),2.69(s,3H),2.48(s,3H).

[0114] Example 7: 6-Benzyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) in DMF (2 mL) was added EDC.HCl (97.7 mg, 0.510 mmol) and HOBT (68.87 mg, 0.510 mmol), followed by 2-pyridinemethanamine (55.1 mg, 0.510 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (52.1 mg, yield: 39.8%). LCMS (ESI+): C 23 H 21 N4O2[M+H] +Calculated m / z: 385.2; measured: 385.1. 1 HNMR(400MHz,DMSO-d6,δ):9.23(t,J=6.0Hz,1H),8.55-8.54(m,2H),7.92(d,J=7.6Hz,1H),7.83-7. 79(m,1H),7.42-7.28(m,7H),6.73(d,J=7.6Hz,1H),5.22(s,2H),4.59(d,J=5.6Hz,2H),2.69(s,3H).

[0115] Example 8: 6-Benzyl-2-methyl-N-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-2-methyl-N-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) and DIEA (131.7 mg, 1.020 mmol) in DMF (1 mL) was added EDC.HCl (97.7 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol), followed by (1-methyl-1H-1,2,3-triazol-4-yl)methanamine hydrochloride (76.2 mg, 0.515 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% MeOH / HO (0.5% TFA)) to give 6-benzyl-2-methyl-N-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (5.0 mg, yield: 3.8%). LCMS (ESI+): C 21 H 21N6O2[M+H] + Calculated m / z: 389; measured value: 389. 1 HNMR(400MHz,MeOH-d4,δ):8.67-8.63(m,1H),7.96(s,1H),7.80-7.56(m,1H),7.57-7.31 (m,5H),6.79(d,J=7.6Hz,1H),5.27(s,2H),4.18-4.13(m,2H),2.68(s,3H),2.76(s,3H).

[0116] Example 9: 6-Benzyl-2-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-2-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) and DIEA (142.2 mg, 1.102 mmol) in DMF (1 mL) was added EDC.HCl (98.2 mg, 0.514 mmol) and HOBT (70.1 mg, 0.519 mmol) followed by (2-methyl-2H-1,2,3-triazol-4-yl)methanamine hydrochloride (78.5 mg, 0.528 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% MeOH / HO (0.5% FA)) to give 6-benzyl-2-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (6.6 mg, yield: 3.8%). LCMS (ESI+): C 21 H 21N6O2[M+H] + Calculated m / z: 389; measured value: 389. 1 HNMR(400MHz,DMSO-d6,δ):9.17-9.11(m,1H),8.46(m,1H),7.91(d,J=7.6Hz,1H),7.67(s,1H),7. 33-7.26(m,5H),6.71(d,J=7.6Hz,1H),5.22(s,2H),4.52-4.51(m,2H),4.13(s,3H),2.66(s,3H).

[0117] Example 10: 6-Benzyl-2-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-2-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) and DIPEA (131.7 mg, 1.020 mmol) in DMF (2 mL) was added EDC.HCl (97.7 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol), followed by (3-methyl-1,2,4-oxadiazol-5-yl)methanamine hydrochloride (70.1 mg, 0.469 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% MeCN / HO (0.5% FA) to give 6-benzyl-2-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (11.8 mg, yield: 8.8%). LCMS (ESI+): C 21 H20 N5O3[M+H] + Calculated m / z: 390.2; measured: 390.2. 1 HNMR(400MHz,DMSO-d6,δ):9.47(t,J=5.6Hz,1H),8.54(s,1H),7.93(d,J=7.6Hz,1H),7.37-7. 27(m,5H),6.73(d,J=7.6Hz,1H),5.23(s,2H),4.74(d,J=5.6Hz,2H),2.68(s,3H),2.36(s,3H).

[0118] Example 11: N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (1.0 g, 3.267 mmol) and 1-(oxolan-2-yl)methanamine (396.5 mg, 3.9204 mmol) in EtOH (5 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (457.0 mg, 44.1% yield). LCMS (ESI+): C 17 H 21 N2O4[M+H] + Calculated m / z: 317; measured: 317.

[0119] 2. Synthesis of 2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate (200 mg, 0.632 mmol) and NaOH (76 mg, 1.900 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40° C. for 2 h. The residue was acidified to pH 7 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (120 mg, yield: 65.8%). LCMS (ESI+): C 15 H 16 N2O4[M+H] + Calculated m / z: 289; measured value: 289.

[0120] 3. Synthesis of N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (120 mg, 0.416 mmol) in DMF (2 mL) was added EDC.HCl (120 mg, 0.626 mmol) and HOBT (84 mg, 0.622 mmol) followed by 1-(4-chlorophenyl)methanamine (88 mg, 0.621 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (96.9 mg, yield: 56.3%). LCMS (ESI+): C 22 H 23 ClN3O3[M+H] + Calculated m / z: 412; measured: 412. 1 HNMR(400MHz,DMSO-d6,δ):9.19(t,J=5.9Hz,1H),8.47(s,1H),7.73(d,J=7.6Hz,1H),7.45-7.39(m,4H),6.66(d,J=7.6Hz,1H),4.48(d,J=6.0Hz,2H) ),4.18-4.12(m,2H),3.97-3.92(m,1H),3.80-3.76(m,1H),3.66-3.61(m, 1H),2.66(s,3H),1.98-1.88(m,1H),1.86-1.74(m,2H),1.64-1.52(m,1H).

[0121] Example 12: 6-Benzyl-2-methyl-5-oxo-N-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-5-oxo-N-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) in DMF (2 mL) at 0° C., EDC.HCl (98 mg, 0.511 mmol) and HOBT (69 mg, 0.511 mmol) were added, followed by 4-pyridinemethanamine (56 mg, 0.518 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-2-methyl-5-oxo-N-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (43.4 mg, yield: 33.1%). LCMS(ESI+):C 23 H 21 N4O2[M+H] + Calculated m / z: 385.2; measured: 385.2. 1 HNMR(400MHz,DMSO-d6,δ):9.26(t,J=5.8Hz,1H),8.55(d,J=4.0Hz,3H),7.92(d,J=7.6Hz,1H ),7.37-7.27(m,7H),6.72(d,J=7.6Hz,1H),5.23(s,2H),4.52(d,J=6.0Hz,2H),2.68(s,3H).

[0122] Example 13: 6-benzyl-2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (200 mg, 0.680 mmol) and DIPEA (131.7 mg, 1.020 mmol) in DMF (2 mL) was added EDC.HCl (195.4 mg, 1.020 mmol) and HOBT (137.7 mg, 1.020 mmol) followed by (5-methyl-1,3,4-oxadiazol-2-yl)methanamine hydrochloride (115.3 mg, 0.774 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The crude product was purified by Prep-HPLC using the following conditions (Column: XBridge Shield RP18 OBD column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min, Gradient: 20% B to 35% B in 80min, 35%) to give 6-benzyl-2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (28.3mg, Yield: 10.7%). LCMS (ESI+): C 21 H 20 N5O3[M+H] + Calculated m / z: 390; measured value: 390. 1 HNMR(300MHz,DMSO-d6,δ):9.37(t,J=6.2Hz,1H),8.51(s,1H),7.94(d,J=7.8Hz,1H),7.34-7. 28(m,5H),6.72(d,J=7.5Hz,1H),5.22(s,2H),4.67(d,J=5.7Hz,2H),2.87(s,3H),2.51(s,3H).

[0123] Example 14: 6-Benzyl-2-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (200 mg, 0.680 mmol) in DMF (2 mL) at 0° C., EDC.HCl (195.4 mg, 1.020 mmol) and HOBT (137.74 mg, 1.020 mmol) were added, followed by 1-(1-methylpyrazol-3-yl)methanamine (113.3 mg, 1.020 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude product was purified using the following conditions (column: Xselect CSH C 18 Purification by Prep-HPLC using OBD column 30*150mm 5μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL / min, gradient: 20% B to 40% B in 12 min, 40%) to give 6-benzyl-2-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (45mg, yield: 16.8%). LCMS (ESI+): C 22 H 22 N5O2[M+H] + Calculated m / z: 388.2; measured: 388.2. 1 HNMR(400MHz,DMSO-d6,δ):9.02-9.01(m,1H),8.41(s,1H),7.91-7.89(m,1H),7.62-7.61(m,1H),7.40-7.26 (m,5H),6.71-6.69(m,1H),6.21-6.17(m,1H),5.21(s,2H),4.40(d,J=5.6Hz,2H),3.80(s,3H),2.65(s,3H).

[0124] Example 15: 6-Benzyl-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) in DMF (1 mL) was added EDC.HCl (97.7 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol), followed by 1-(1-methylpyrazol-4-yl)methanamine (56.6 mg, 0.510 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / HO (0.5% FA)) to give 6-benzyl-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (31.4 mg, yield: 23.7%). LCMS (ESI+): C 22 H 22 N5O2[M+H] + Calculated m / z: 388.2; measured: 388.2. 1 HNMR(400MHz,DMSO-d6,δ):8.94(t,J=5.6Hz,1H),8.41(s,1H),7.90(d,J=7.6Hz,1H),7.65(s,1H),7. 40-7.26(m,6H),6.70(d,J=7.6Hz,1H),5.21(s,2H),4.31(d,J=5.6Hz,2H),3.81(s,3H),2.65(s,3H).

[0125] Example 16: 6-Benzyl-N-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-N-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) in DMF (1.5 mL) was added EDC.HCl (79.1 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol), followed by 1-(2-fluorophenyl)methanamine (63.7 mg, 0.510 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (73.4 mg, yield: 52.3%). LCMS (ESI+): C 24 H 21 FN3O2[M+H] + Calculated m / z: 402.2; measured: 402.2. 1 HNMR(400MHz,DMSO-d6,δ):9.15(t,J=5.8Hz,1H),8.47(s,1H),7.90(d,J=7.6Hz,1H),7.50-7.41(m,1H),7. 39-7.27(m,6H),7.29-7.18(m,2H),6.72(d,J=7.6Hz,1H),5.21(s,2H),4.53(d,J=5.7Hz,2H),2.65(s,3H).

[0126] Example 17: N,6-Dibenzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of N,6-dibenzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) in DMF (2 mL) at 0° C., EDC.HCl (97.7 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol) were added, followed by benzylamine (54.6 mg, 0.510 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give N,6-dibenzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (32.7 mg, yield: 25%). LCMS (ESI+): C 24 H 22 N3O2[M+H] + Calculated m / z: 384.2; measured: 384.2. 1 HNMR(400MHz,DMSO-d6,δ):9.16(t,J=5.8Hz,1H),8.48(s,1H),7.91(d,J=7.2Hz,1H),7 .40-7.26(m,10H),6.72-6.71(m,1H),5.22(s,2H),4.50(d,J=6.0Hz,2H),2.67(s,3H).

[0127] Example 18: 6-Benzyl-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) in DMF (2 mL) was added EDC.HCl (79.1 mg, 0.510 mmol) and HOBT (70 mg, 0.518 mmol) followed by (2-methyloxazol-4-yl)methanamine (57.1 mg, 0.510 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / HO (0.5% FA)) to give 6-benzyl-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a yellow solid (12.2 mg, yield: 9.2%). LCMS (ESI+): C 22 H 21 N4O3[M+H] + Calculated m / z: 389; measured value: 389. 1 HNMR(400MHz,DMSO-d6,δ):9.02(t,J=5.6Hz,1H),8.45(s,1H),7.90(d,J=7.6Hz,1H),7.85(s,1H), 7.35-7.28(m,5H),6.71(d,J=7.6Hz,1H),5.22(s,2H),4.33-4.31(m,2H),2.66(s,3H),2.40(s,3H).

[0128] Example 19: 6-benzyl-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) and DIPEA (131.7 mg, 1.020 mmol) in DMF (2 mL) was added EDC.HCl (97.7 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol) followed by (5-methyl-1,2,4-oxadiazol-3-yl)methanamine hydrochloride (71 mg, 0.476 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% MeOH / HO (0.5% FA) to give 6-benzyl-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (15.8 mg, yield: 11.8%). LCMS (ESI+): C 21 H 20 N5O3[M+H] + Calculated m / z: 390.2; measured: 390.1. 1 HNMR(400MHz,DMSO-d6,δ):9.29(t,J=5.8Hz,1H),8.50(s,1H),7.92(d,J=7.6Hz,1H),7.34-7. 26(m,5H),6.72(d,J=7.6Hz,1H),5.22(s,2H),4.57(d,J=5.6Hz,2H),2.68(s,3H),2.51(s,3H).

[0129] Example 20: N-(4-chlorobenzyl)-6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (900 mg, 2.938 mmol) and 2-methoxyethan-1-amine (264.7 mg, 3.526 mmol) in EtOH (9 mL) was stirred at 80° C. for 8 h. The precipitated solid was collected by filtration and washed with water (2×5 mL) to give ethyl 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (850 mg, yield: 96.7%). LCMS (ESI+): C 15 H 19 N2O4[M+H] + Calculated m / z: 291.1; measured: 291.0.

[0130] Synthesis of 2.6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (700 mg, 2.411 mmol) and NaOH (144.6 mg, 3.617 mmol) in MeOH (7 mL) and H2O (2 mL) at room temperature. The resulting mixture was stirred at 40° C. for 3 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a yellow solid (600 mg, yield: 90.1%). LCMS (ESI+): C 13 H 15 N2O4[M+H] + Calculated m / z: 263; measured: 263.

[0131] 3. Synthesis of N-(4-chlorobenzyl)-6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (200 mg, 0.763 mmol) in DMF (2 mL) was added EDC.HCl (219.2 mg, 1.145 mmol) and HOBT (154.5 mg, 1.145 mmol), followed by 1-(4-chlorophenyl)methanamine (161.9 mg, 1.145 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give N-(4-chlorobenzyl)-6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (121.2 mg, yield: 40.8%). LCMS (ESI+): C 20 H 21 ClN3O3[M+H] + Calculated m / z: 386; measured: 386. 1 HNMR(400MHz,DMSO-d6,δ):9.18(t,J=5.8Hz,1H),8.47(s,1H),7.73(d,J=7.6Hz,1H),7.45-7.39(m,4H),6. 66(d,J=7.6Hz,1H),4.48(d,J=6.0Hz,2H),4.18-4.15(m,2H),3.64-3.62(m,2H),3.25(s,3H),2.66(s,3H).

[0132] Example 21: 6-(2-Methoxyethyl)-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 6-(2-methoxyethyl)-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (150 mg, 0.573 mmol) in DMF (1 mL) was added EDC.HCl (140.5 mg, 0.736 mmol) and HOBT (119.2 mg, 0.883 mmol) followed by (2-methyloxazol-5-yl)methanamine (76.1 mg, 0.679 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% MeOH / HO (0.5% FA)) to give 6-(2-methoxyethyl)-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (80.3 mg, yield: 39.3%). LCMS (ESI+): C 18 H 21 N4O4[M+H] + Calculated m / z: 357; measured: 357. 1 HNMR(400MHz,DMSO-d6,δ):9.12(t,J=5.6Hz,1H),8.44(s,1H),7.73(d,J=7.6Hz,1H),6.93(s,1H),6.67-6.65(m ,1H),4.51(d,J=5.6Hz,2H),4.17(t,J=5.2Hz,2H),3.63(t,J=5.2Hz,2H),3.25(s,3H),2.66(s,3H),2.40(s,3H).

[0133] Example 22: 6-benzyl-N-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-N-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (150 mg, 0.510 mmol) in DMF (2 mL) was added EDC.HCl (147 mg, 0.767 mmol) and HOBT (104 mg, 0.770 mmol), followed by 1-(4-chlorophenyl)methanamine (108 mg, 0.763 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (47.2 mg, yield: 22.09%). LCMS (ESI+): C 24 H 21 ClN3O2[M+H] + Calculated m / z: 418; measured: 418. 1 HNMR(400MHz,DMSO-d6,δ):9.18-9.16(m,1H),8.49(s,1H),7.92-7.90(m,1H),7. 45-7.29(m,9H),6.73-6.68(m,1H),5.22(s,2H),4.48-4.47(m,2H),2.66(s,3H).

[0134] Example 23: 6-Benzyl-2-methyl-5-oxo-N-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-5-oxo-N-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) and in DMF (2 mL) was added EDC.HCl (98 mg, 0.511 mmol) and HOBT (69 mg, 0.511 mmol), followed by 3-pyridinemethanamine (56 mg, 0.518 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / HO (0.5% FA) to give 6-benzyl-2-methyl-5-oxo-N-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (58.9 mg, yield: 44.9%). LCMS (ESI+): C 23 H 21 N4O2[M+H] + Calculated m / z: 385.2; measured: 385.2. 1 HNMR(400MHz,DMSO-d6,δ):9.22(t,J=5.8Hz,1H),8.59(d,J=1.2Hz,1H),8.49(d,J=3.2Hz,2H),7.91(d,J=7.6Hz,1H),7.78(d ,J=8.0Hz,1H),7.42-7.39(m,1H),7.36-7.26(m,5H),6.71(d,J=7.6Hz,1H),5.22(s,2H),4.51(d,J=5.6Hz,2H),2.66(s,3H).

[0135] Example 24: 6-benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) and 1,2-dimethyl-2,4-dimethylphenyl-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) in DMF (2 mL) at 0° C., EDC.HCl (98 mg, 0.631 mmol) and HOBT (69 mg, 0.511 mmol) were added, followed by (4-methoxyphenyl)methanamine (70 mg, 0.510 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / HO (0.5% FA)) to give 6-benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (47.2 mg, yield: 33.5%). LCMS(ESI+):C 25 H 24 N3O3[M+H] + Calculated m / z: 414.2; measured: 414.2. 1 HNMR(400MHz,DMSO-d6,δ):9.10(t,J=5.8Hz,1H),8.44(s,1H),7.91(d,J=7.6Hz,1H),7.36-7.26(m,7H),6 .93(d,J=8.8Hz,2H),6.71(d,J=7.6Hz,1H),5.21(s,2H),4.42(d,J=6.0Hz,2H),3.73(s,3H),2.66(s,3H).

[0136] Example 25: 6-benzyl-2-methyl-5-oxo-N-(4-(trifluoromethyl)benzyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-5-oxo-N-(4-(trifluoromethyl)benzyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) and in DMF (2 mL) was added EDC.HCl (98 mg, 0.511 mmol) and HOBT (69 mg, 0.511 mmol), followed by 1-[4-(trifluoromethyl)phenyl]methanamine (89 mg, 0.508 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / HO (0.5% FA) to give 6-benzyl-2-methyl-5-oxo-N-(4-(trifluoromethyl)benzyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (72.5 mg, yield: 47.1%). LCMS (ESI+): C 25 H 21 F3N3O2[M+H] + Calculated m / z: 452.2; measured: 452.2. 1 HNMR(400MHz,DMSO-d6,δ):9.28(t,J=5.8Hz,1H),8.53(s,1H),7.93(d,J=7.6Hz,1H),7.75(d,J=8.0Hz,2H),7. 59(d,J=8.0Hz,2H),7.34-7.26(m,5H),6.72(d,J=7.2Hz,1H),5.22(s,2H),4.58(d,J=5.6Hz,2H),2.68(s,3H).

[0137] Example 26: N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of ethyl 2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (500 mg, 1.710 mmol) and (tetrahydro-2H-pyran-2-yl)methanamine (230 mg, 1.997 mmol) in EtOH (5 mL) was stirred at 80° C. for 8 h. The precipitated solid was collected by filtration and washed with water (2×5 mL) to give ethyl 2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (392 mg, yield: 69.4%). LCMS (ESI+): C 18 H 23 N2O4[M+H] + Calculated m / z: 331; measured: 331.

[0138] 2. Synthesis of 2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate (350 mg, 1.059 mmol) and sodium hydroxide (127 mg, 3.175 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40°C for 3 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (129 mg, yield: 40.8%). LCMS (ESI+): C 16 H 19 N2O4[M+H] + Calculated m / z: 303; measured: 303.

[0139] 3. Synthesis of N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (120 mg, 0.397 mmol) and in DMF (1.2 mL) was added EDC.HCl (185 mg, 0.965 mmol) and HOBT (86 mg, 0.636 mmol) followed by 1-(4-chlorophenyl)methanamine (88 mg, 0.621 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (56.8 mg, yield: 33.60%). LCMS (ESI+): C 23 H 25 ClN3O3[M+H] + Calculated m / z: 426; measured: 426. 1 HNMR(400MHz,DMSO-d6,δ):9.21-9.18(m,1H),8.46(s,1H),7.69(d,J=7.6 Hz,1H),7.45-7.39(m,4H),6.64(d,J=7.6Hz,1H),4.49(d,J=6Hz,2H),4.13 -4.09(m,1H),3.93-3.84(m,2H),3.63-3.60(m,1H),3.29-3.20(m,1H),2. 65(s,3H),1.77(s,1H),1.61(s,1H),1.53-1.50(m,3H),1.21-1.10(m,1H).

[0140] Example 27: N-(4-chlorobenzyl)-2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (400 mg, 1.306 mmol) and 1-(oxetan-2-yl)methanamine (208 mg, 2.387 mmol) in EtOH (6 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as an orange solid (350 mg, yield: 88.6%). LCMS (ESI+): C 16 H 19 N2O4[M+H] + Calculated m / z: 303.1; measured: 303.1.

[0141] 2. Synthesis of 2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (350 mg, 1.158 mmol) and NaOH (187 mg, 4.675 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40° C. overnight. The residue was acidified to pH 7 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as an orange oil (200 mg, yield: 62.9%). LCMS (ESI+): C 14 H 15 N2O4[M+H] + Calculated m / z: 275.1; measured: 275.1.

[0142] 3. Synthesis of N-(4-chlorobenzyl)-2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (200 mg, 0.729 mmol) in DMF (2 mL) was added EDC.HCl (211 mg, 1.101 mmol) and HOBT (148 mg, 1.095 mmol) followed by 1-(4-chlorophenyl)methanamine (155 mg, 1.095 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give N-(4-chlorobenzyl)-2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (188.1 mg, yield: 63.4%). LCMS (ESI+): C 21 H 21 ClN3O3[M+H] +Calculated m / z: 398.1; measured: 398.1. 1 HNMR(400MHz,DMSO-d6,δ):9.19(d,J=5.6Hz,1H),8.48(s,1H),7.78(d,J=7.6Hz,1H),7.45-7.38(m,4H),6.68(d,J=7. 6Hz,1H),5.00(s,1H),4.52-4.47(m,3H),4.38-4.31(m,2H),4.23-4.18(m,1H),2.69-2.62(m,4H),2.40-2.35(m,1H).

[0143] Example 28: 6-Benzyl-2-methyl-5-oxo-N-(1-(pyridin-2-yl)ethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-5-oxo-N-(1-(pyridin-2-yl)ethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) and in DMF (2 mL) was added EDC.HCl (98 mg, 0.511 mmol) and HOBT (69 mg, 0.511 mmol) followed by 1-(pyridin-2-yl)ethanamine (63 mg, 0.516 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3) to give 6-benzyl-2-methyl-5-oxo-N-(1-(pyridin-2-yl)ethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (50.2 mg, yield: 37.0%). LCMS (ESI+): C 24 H 23 N4O2[M+H] + Calculated m / z: 399.2; measured: 399.2. 1HNMR(400MHz,DMSO-d6,δ):9.08(d,J=8.0Hz,1H),8.56-8.49(m,2H),7.91(d,J=7.6Hz,1H),7.82-7.78(m,1H),7.4 5(d,J=8.0Hz,1H),7.37-7.27(m,6H),6.71(d,J=7.6Hz,1H),5.22-5.15(m,3H),2.63(s,3H),1.50(d,J=6.8Hz,3H).

[0144] Example 29: 6-Benzyl-2-methyl-5-oxo-N-(pyrimidin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-5-oxo-N-(pyrimidin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) and in DMF (2 mL) was added EDC.HCl (98 mg, 0.511 mmol) and HOBT (69 mg, 0.511 mmol) followed by 1-(pyrimidin-2-yl)methanamine (56 mg, 0.513 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (52.0 mg, yield: 39.2%). LCMS (ESI+): C 22 H 20 N5O2[M+H] + Calculated m / z: 386.2; measured: 386.2. 1HNMR(400MHz,DMSO-d6,δ):9.19(t,J=6.0Hz,1H),8.82(d,J=4.8Hz,2H),8.60(d,J=14.8Hz,1H),7.91(d, J=7.6Hz,1H),7.43-7.26(m,6H),6.72(d,J=7.6Hz,1H),5.23(s,2H),4.67(d,J=6.0Hz,2H),2.70(s,3H).

[0145] Example 30: 6-(2-Methoxyethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (500 mg, 1.632 mmol) and ethanamine, 2-methoxy- (160 mg, 2.130 mmol) in EtOH (5 mL) was stirred at 80° C. for 8 h. The precipitated solid was collected by filtration and washed with water (2×5 mL) to give ethyl 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (450 mg, yield: 94.9%). LCMS (ESI+): C 15 H 19 N2O4[M+H] + Calculated m / z: 291; measured: 291.

[0146] Synthesis of 2.6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (500 mg, 1.722 mmol) and sodium hydroxide (210 mg, 5.250 mmol) in MeOH (4 mL) and H2O (1.5 mL) was stirred at 40°C for 8 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (340 mg, yield: 5.2%). LCMS (ESI+): C 13 H 15 N2O4[M+H] + Calculated m / z: 263; measured: 263.

[0147] 3. Synthesis of 6-(2-methoxyethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (115 mg, 0.483 mmol) and in DMF (2 mL) was added EDC.HCl (124 mg, 0.674 mmol) and HOBT (88.0 mg, 0.651 mmol) followed by 2-pyridinemethanamine (72 mg, 0.666 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The crude was purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(2-methoxyethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (27 mg, yield: 17.47%). LCMS (ESI+): C 19 H 21 N4O3[M+H] + Calculated m / z: 353; measured: 353. 1HNMR(400MHz,DMSO-d6,δ):9.25-9.22(m,1H),8.56-8.53(m,2H),7.84-7.80(m,1H),7.74(d,J=7.6Hz,1H),7.42(d,J=7.6Hz,1H) ,7.32-7.29(m,1H),6.68(d,J=7.6Hz,1H),4.60(d,J=5.6Hz,2H),4.19-4.16(m,2H),3.65-3.62(m,2H),3.35(s,3H),2.68(s,3H).

[0148] Example 31: 6-(4-chlorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of ethyl 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (500 mg, 1.632 mmol) and 1-(4-chlorophenyl)methanamine (268 mg, 1.893 mmol) in EtOH (5 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (270.0 mg, yield: 46.3%). LCMS (ESI+): C 19 H 18 ClN2O3[M+H] + Calculated m / z: 357; measured: 357.

[0149] 2. Synthesis of 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (330 mg, 0.925 mmol) and sodium hydroxide (114 mg, 2.850 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40°C for 8 h. The residue was acidified to pH 7 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (240 mg, yield: 78.9%). LCMS (ESI+): C 17 H 14 ClN2O3[M+H] + Calculated m / z: 329; measured value: 329.

[0150] 3. Synthesis of 6-(4-chlorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (122 mg, 0.371 mmol) in DMF (2 mL) was added EDC.HCl (107 mg, 0.558 mmol) and HOBT (76 mg, 0.562 mmol), followed by 2-pyridinemethanamine (60 mg, 0.555 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(4-chlorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (75.3 mg, yield: 48.4%). LCMS (ESI+): C 23 H 20 ClN4O2[M+H] +Calculated m / z: 419.1; measured: 419.1. 1 HNMR(400MHz,DMSO-d6,δ):9.24-9.22(m,1H),8.55-8.53(m,2H),7.94(d,J=7.6Hz,1H),7.83-7.79(m,1H),7.42-7.40 (m,3H),7.39-7.28(m,2H),7.33-7.26(m,1H),6.74(d,J=7.2Hz,1H),5.21(s,2H),4.59(d,J=6.0Hz,2H),2.69(s,3H).

[0151] Example 32: 6-Benzyl-2-methyl-5-oxo-N-(pyrazin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-5-oxo-N-(pyrazin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) and in DMF (4 mL) was added EDC.HCl (98 mg, 0.631 mmol) and HOBT (69 mg, 0.511 mmol), followed by 1-(pyrazin-2-yl)methanamine (56 mg, 0.513 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-2-methyl-5-oxo-N-(pyrazin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (67.2 mg, yield: 51.1%). LCMS (ESI+): C 22 H 20 N5O2[M+H] + Calculated m / z: 386.2; measured: 386.2. 1HNMR(400MHz,DMSO-d6,δ):9.30(t,J=5.4Hz,1H),8.71(s,1H),8.63(s,1H),8.56(d,J=13.2Hz,2H),7.92( d,J=7.2Hz,1H),7.36-7.28(m,5H),6.72(d,J=7.6Hz,1H),5.22(s,2H),4.64(d,J=5.6Hz,2H),2.63(s,3H).

[0152] Example 33: 6-Benzyl-2-methyl-5-oxo-N-(pyridazin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-5-oxo-N-(pyridazin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (52 mg, 0.177 mmol) in DMF (2 mL) was added EDC.HCl (51 mg, 0.266 mmol) and HOBT (35 mg, 0.259 mmol) followed by 1-(pyridazin-3-yl)methanamine (30 mg, 0.275 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-2-methyl-5-oxo-N-(pyridazin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (8.9 mg, yield: 13.0%). LCMS (ESI+): C 22 H 20 N5O2[M+H] + Calculated m / z: 386.2; measured: 386.2. 1HNMR(400MHz,DMSO-d6,δ):9.37-9.25(m,1H),9.17(s,1H),8.56(s,1H),7.93(d,J=7.6Hz,1H),7.72-7 .71(m,2H),7.36-7.28(m,5H),6.73(d,J=6.4Hz,1H),5.22(s,2H),4.78(d,J=6.0Hz,2H),2.67(s,3H).

[0153] Example 34: 6-Benzyl-2-methyl-5-oxo-N-(pyrimidin-5-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-5-oxo-N-(pyrimidin-5-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (51 mg, 0.173 mmol) in DMF (1.5 mL) at 0° C., EDC.HCl (48 mg, 0.250 mmol) and HOBT (34 mg, 0.252 mmol) were added, followed by 4-pyridinemethanamine (56 mg, 0.518 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-2-methyl-5-oxo-N-(pyrimidin-5-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (16.7 mg, yield: 25.0%). LCMS(ESI+):C 22 H 20 N5O2[M+H] + Calculated m / z: 386.2; measured: 386.2. 1HNMR(400MHz,DMSO-d6,δ):9.24-9.23(m,1H),9.12(s,1H),8.83(s,2H),8.52(s,1H),7.93(d,J=7. 6Hz,1H),7.36-7.30(m,5H),6.73(d,J=7.6Hz,1H),5.22(s,2H),4.53(d,J=5.6Hz,2H),2.72(s,3H).

[0154] Example 35: 6-benzyl-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (51 mg, 0.173 mmol) in DMF (2 mL) was added EDC.HCl (48 mg, 0.250 mmol) and HOBT (35 mg, 0.259 mmol) followed by 1-(5-fluoropyridin-2-yl)methanamine (32 mg, 0.254 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (13.5 mg, yield: 19.4%). LCMS (ESI+): C 23 H 20 FN4O2[M+H] + Calculated m / z: 403.2; measured: 403.2. 1HNMR(400MHz,DMSO-d6,δ):9.26-9.24(m,1H),8.55-8.53(m,2H),7.92(d,J=7.6,1H),7.72-7.70(m,1H),7. 50(d,J=2.4,1H),7.49-7.23(m,5H),6.73(d,J=7.6Hz,1H),5.22(s,2H),4.58(d,J=5.6Hz,2H),2.68(s,3H).

[0155] Example 36: 6-Benzyl-N-((3-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-N-((3-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) in DMF (2 mL) was added EDC.HCl (102 mg, 0.532 mmol) and HOBT (70 mg, 0.518 mmol) and DIEA (78 mg, 0.603 mmol) at 0° C., followed by 1-(3-fluoropyridin-2-yl)methanamine (83 mg, 0.658 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-((3-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (52.6 mg, yield: 38.47%). LCMS (ESI+): C 23 H 20 FN4O2[M+H] + Calculated m / z: 403.2; measured: 403.2. 1HNMR(400MHz,DMSO-d6,δ):9.17-9.14(m,1H),8.50(s,1H),8.43(d,J=3.6Hz,1H),7.92(s,1H),7.76-7.71(m,1H) ),7.45-7.41(m,1H),7.36-7.27(m,5H),6.73(d,J=7.2Hz,1H),5.22(s,2H),4.67(d,J=5.6Hz,2H),2.66(s,3H).

[0156] Example 37: 2-Methyl-5-oxo-6-(1-phenylethyl)-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 2-methyl-5-oxo-6-(1-phenylethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.816 mmol) and (+ / -)-α-methylbenzylamine (145 mg, 1.197 mmol) in EtOH (3 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 2-methyl-5-oxo-6-(1-phenylethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a brown solid (200 mg, yield: 72.8%). LCMS (ESI+): C 20 H 21 N2O3[M+H] + Calculated m / z: 337.2; measured: 337.1.

[0157] 2. Synthesis of 2-methyl-5-oxo-6-(1-phenylethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-5-oxo-6-(1-phenylethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate (200 mg, 0.595 mmol) and NaOH (90 mg, 2.250 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40° C. overnight. The residue was acidified to pH 7 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-5-oxo-6-(1-phenylethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a brown oil (138 mg, yield: 75.2%). LCMS (ESI+): C 18 H 17 N2O3[M+H] + Calculated m / z: 309.1; measured: 309.1.

[0158] 3. Synthesis of 2-methyl-5-oxo-6-(1-phenylethyl)-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-5-oxo-6-(1-phenylethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (140 mg, 0.454 mmol) in DMF (2 mL) was added EDC.HCl (131 mg, 0.683 mmol) and HOBT (92 mg, 0.681 mmol), followed by 2-pyridinemethanamine (74 mg, 0.684 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 2-methyl-5-oxo-6-(1-phenylethyl)-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (59.4 mg, yield: 32.8%). LCMS (ESI+): C 24 H 23 N4O2[M+H] + Calculated m / z: 399.2; measured: 399.2. 1HNMR(400MHz,DMSO-d6,δ):9.24(t,J=5.8Hz,1H),8.55(d,J=5.6Hz,2H),7.82(t,J=7.8Hz,1H),7.73(d,J=8.0Hz,1H),7.42-7.31( m,5H),7.29(d,J=6.4Hz,2H),6.70(d,J=7.6Hz,1H),6.29-6.23(m,1H),4.59(d,J=5.6Hz,2H),2.68(s,3H),1.78(d,J=7.2Hz,3H).

[0159] Example 38: 6-benzyl-N-((5-chloropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-N-((5-chloropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (50 mg, 0.170 mmol) and in DMF (4 mL) was added EDC.HCl (49 mg, 0.316 mmol) and HOBT (35 mg, 0.259 mmol) followed by 1-(5-chloropyridin-2-yl)methanamine (37 mg, 0.259 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-((5-chloropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (34.3 mg, yield: 47.7%). LCMS (ESI+): C 23 H 20 ClN4O2[M+H] + Calculated m / z: 419.1; measured: 419.1. 1HNMR(400MHz,DMSO-d6,δ):9.27(s,1H),8.59(s,1H),8.54(s,1H),7.96-7.91(m,2H),7.46(d,J=8. 4Hz,1H),7.35-7.28(m,5H),6.72(d,J=7.6Hz,1H),5.22(s,2H),4.57(d,J=6.0Hz,2H),2.67(s,3H).

[0160] Example 39: 6-benzyl-N-((4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-N-((4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (65 mg, 0.221 mmol) in DMF (1.8 mL) was added EDC.HCl (60 mg, 0.313 mmol) and HOBT (42 mg, 0.311 mmol) and DIPEA (45 mg, 0.348 mmol) at 0° C., followed by 1-(4-fluoropyridin-2-yl)methanamine (52 mg, 0.412 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-((4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (18.0 mg, yield: 20.2%). LCMS (ESI+): C 23 H 20 FN4O2[M+H] + Calculated m / z: 403.2; measured: 403.2. 1HNMR(400MHz,DMSO-d6,δ):9.25(m,1H),8.65-8.57(m,2H),7.94(s,1H),7.2 9-7.23(m,7H),6.75(s,1H),5.22(s,2H),4.61(d,J=6.0Hz,2H),2.80(s,3H).

[0161] Example 40: 6-(cyclohexylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 1,6-(cyclohexylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (200 mg, 0.653 mmol) and (aminomethyl)cyclohexane (135 mg, 1.193 mmol) in EtOH (3 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 6-(cyclohexylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a brown solid (190 mg, yield: 88.6%). LCMS (ESI+): C 19 H 25 N2O3[M+H] + Calculated m / z: 329.2; measured: 329.2.

[0162] Synthesis of 2.6-(cyclohexylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(cyclohexylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (190 mg, 0.579 mmol) and NaOH (70 mg, 1.750 mmol) in MeOH (3 mL) and HO (1 mL) was stirred at 40° C. overnight. The residue was acidified to pH 7 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO and concentrated in vacuo to give 6-(cyclohexylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (170 mg, yield: 97.8%). LCMS (ESI+): C 17 H 21 N2O3[M+H] + Calculated m / z: 301.2; measured: 301.1.

[0163] 3. Synthesis of 6-(cyclohexylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(cyclohexylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (130 mg, 0.433 mmol) in DMF (2 mL) was added EDC.HCl (125 mg, 0.652 mmol) and HOBT (88 mg, 0.651 mmol), followed by 2-pyridinemethanamine (71 mg, 0.657 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(cyclohexylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (59.8 mg, yield: 35.2%). LCMS (ESI+): C 23 H 27 N4O2[M+H] + Calculated m / z: 391.2; measured: 391.2. 1HNMR(400MHz,DMSO-d6,δ):9.22(d,J=6.0Hz,1H),8.55-8.52(t,J=7.0,2H),7.83- 7.81(m,1H),7.79-7.73(m,1H),7.41(d,J=7.6Hz,1H),7.31-7.28(m,1H),6.65(d,J =7.2Hz,1H),4.58(d,J=6.0Hz,2H),3.84(d,J=7.2Hz,2H),2.51-2.49(m,3H),1.84- 1.75(m,1H),1.67-1.60(m,2H),1.57-1.54(m,3H),1.15(s,3H),1.04-0.96(m,2H).

[0164] Example 41: 2-Methyl-5-oxo-N,6-bis(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 2-methyl-5-oxo-6-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.816 mmol) and 2-pyridinemethanamine (106 mg, 0.980 mmol) in EtOH (2 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 2-methyl-5-oxo-6-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (200 mg, yield: 75.8%). LCMS (ESI+): C 18 H 18 N3O3[M+H] + Calculated m / z: 324.1; measured: 324.1.

[0165] 2. Synthesis of 2-methyl-5-oxo-6-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-5-oxo-6-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate (400 mg, 1.237 mmol) and NaOH (150 mg, 3.750 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40° C. overnight. The residue was acidified to pH 7 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-5-oxo-6-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a yellow solid (300 mg, yield: 82.1%). LCMS (ESI+): C 16 H 13 N3O3[M+H] + Calculated m / z: 296.1; measured: 296.1.

[0166] 3. Synthesis of 2-methyl-5-oxo-N,6-bis(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-5-oxo-6-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (150 mg, 0.508 mmol) in DMF (2 mL) was added EDC.HCl (147 mg, 0.767 mmol) and HOBT (103 mg, 0.762 mmol), followed by 2-pyridinemethanamine (83 mg, 0.767 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 2-methyl-5-oxo-N,6-bis(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (17.9 mg, yield: 8.9%). LCMS (ESI+): C 22 H 20 N5O2[M+H] + Calculated m / z: 386.2; measured: 386.2. 1 HNMR(400MHz,DMSO-d6,δ):9.22(d,J=6.0Hz,1H),8.54-8.47(m,3H),7.90(d,J=7.6Hz,1H),7.82-7.75(m,2H),7 .39(d,J=7.6Hz,1H),7.30-7.27(m,3H),6.73(d,J=7.6Hz,1H),5.31(s,2H),4.58(d,J=6.0Hz,2H),2.69(s,3H).

[0167] Example 42: 6-Benzyl-N,2-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-N,2-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (57 mg, 0.194 mmol) in DMF (2.5 mL) at 0° C., EDC.HCl (57 mg, 0.297 mmol) and HOBT (45 mg, 0.333 mmol) and DIEA (58 mg, 0.449 mmol) were added, followed by CH3NH2HCl (21 mg, 0.311 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N,2-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (28.7 mg, yield: 48.2%). LCMS(ESI+):C 18 H 18 N3O2[M+H] + Calculated m / z: 308.1; measured: 308.1. 1 HNMR(400MHz,DMSO-d6,δ):8.54-8.53(m,1H),8.43(s,1H),7.90(d,J=7.6Hz,1H),7.3 7-7.27(m,5H),6.72(d,J=7.6Hz,1H),5.22(s,2H),2.81(d,J=4.4Hz,3H),2.68(s,3H).

[0168] Example 43: 6-benzyl-N-(4-carbamoylbenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-N-(4-carbamoylbenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (52 mg, 0.177 mmol) in DMF (1.5 mL) was added EDC.HCl (50 mg, 0.261 mmol) and HOBT (35 mg, 0.259 mmol) and DIEA (45 mg, 0.348 mmol) at 0° C., followed by 4-(aminomethyl)benzamide hydrochloride (48 mg, 0.257 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-(4-carbamoylbenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (35.4 mg, 46.9%). LCMS (ESI+): C 25 H 23 N4O3[M+H] + Calculated m / z: 427.2; measured: 427.2. 1 HNMR(400MHz,DMSO-d6,δ):9.22(m,1H),8.50(s,1H),7.92-7.86(m,4H),7.54-7.44(m,2H) ,7.39-7.26(m,6H),6.73(d,J=7.6Hz,1H),5.22(s,2H),4.54(d,J=6.0Hz,2H),2.67(s,3H).

[0169] Example 44: 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (90.0 mg, 0.28 mmol) and in DMF (2 mL) was added EDC.HCl (83.0 mg, 0.44 mmol) and HOBT (57.0 mg, 0.44 mmol), followed by 2-pyridinemethanamine (50.7 mg, 0.46 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The crude was purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (50.5 mg, yield: 43.58%). LCMS (ESI+): C 22 H 19 FN5O2[M+H] + Calculated m / z: 404.1; measured: 404.2. 1 HNMR(400MHz,DMSO-d6,δ):9.24-9.21(m,1H),8.54-8.48(m,3H),7.91(d,J=7.6Hz,1H),7.82-7.80(m,1H),7.72-7.70 (m,1H),7.45-7.41(m,2H),7.31-7.28(m,1H),6.74(d,J=7.6Hz,1H),5.37(s,2H),4.58(d,J=6.0Hz,2H),2.85(s,3H).

[0170] Example 45: 6-Isopropyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 1,6-isopropyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] Under nitrogen, a solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.82 mmol) and isopropylamine (102 mg, 1.726 mmol) in EtOH (2.5 mL) was stirred at 80° C. overnight. The mixture was cooled to 0° C. and the solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 6-isopropyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (200.0 mg, yield: 89.3%). LCMS (ESI+): C 15 H 19 N2O3[M+H] + Calculated m / z: 275; measured: 275.

[0171] Synthesis of 2.6-isopropyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-isopropyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (200 mg, 0.729 mmol) and NaOH (90 mg, 2.250 mmol) in MeOH (0.9 mL) and THF (0.9 mL) HO (0.3 mL) was stirred at 40° C. for 4 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO and concentrated in vacuo to give 6-isopropyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a yellow solid (60 mg, yield: 33.4%). LCMS (ESI+): C 13 H 15 N2O3[M+H] + Calculated m / z: 247; measured: 247.

[0172] 3. Synthesis of 6-isopropyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-isopropyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (60 mg, 0.258 mmol) in DMF (2 mL) at 0° C., EDC.HCl (66 mg, 0.344 mmol) and HOBT (51 mg, 0.377 mmol) were added, followed by 2-pyridinemethanamine (42 mg, 0.388 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-isopropyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (19.4 mg, yield: 22.3%). LCMS(ESI+):C 19 H 21 N4O2[M+H] + Calculated m / z: 337.2; measured: 337.3. 1 HNMR(400MHz,DMSO-d6,δ):9.24-9.21(m,1H),8.56-8.52(m,2H),7.88-7.80(m,2H),7.42(d,J=8.0Hz,1H) ,7.32-7.30(m,1H),6.71(s,1H),5.18-5.12(m,1H),4.60(d,J=6.0Hz,2H),2.68(s,3H),1.37-1.35(m,6H).

[0173] Example 46: 2-Methyl-5-oxo-6-phenyl-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 2-methyl-5-oxo-6-phenyl-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (100 mg, 0.32 mmol) and aniline (129 mg, 1.38 mmol) in EtOH (1.5 mL) was stirred at 80 °C under nitrogen atmosphere for 3 days. The reaction mixture was purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give ethyl 2-methyl-5-oxo-6-phenyl-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a white solid (50 mg, yield: 49.68%). LCMS (ESI+): C 18 H 17 N2O3[M+H] + Calculated m / z: 309; measured value: 309.

[0174] 2. Synthesis of 2-methyl-5-oxo-6-phenyl-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-5-oxo-6-phenyl-5,6-dihydro-1,6-naphthyridine-3-carboxylate (50 mg, 0.16 mmol) and NaOH (20 mg, 0.50 mmol) in MeOH (3 mL) and H2O (1 m) was stirred at 40° C. overnight. The residue was acidified to pH 7 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-5-oxo-6-phenyl-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (30 mg, yield: 66.0%). LCMS (ESI+): C 16 H 13 N2O3[M+H] + Calculated m / z: 281.1; measured: 281.0.

[0175] 3. Synthesis of 2-methyl-5-oxo-6-phenyl-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-5-oxo-6-phenyl-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (30 mg, 0.10 mmol) in DMF (1 mL) at 0° C., EDC.HCl (31 mg, 0.16 mmol) and HOBT (22 mg, 0.16 mmol) were added, followed by 2-pyridinemethanamine (18 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 2-methyl-5-oxo-6-phenyl-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (8.5 mg, yield: 21.35%). LCMS(ESI+):C 22 H 19 N4O2[M+H] + Calculated m / z: 371.1; measured: 371.1. 1 HNMR(400MHz,DMSO-d6,δ):9.25(t,J=5.9Hz,1H),8.55(d,J=4.8Hz,2H),7.85-7.77(m,2H),7.57(m,2H),7.5 3-7.47(m,3H),7.42(d,J=7.8Hz,1H),7.30(m,1H),6.76(d,J=7.6Hz,1H),4.60(d,J=5.9Hz,2H),2.72(s,3H).

[0176] Example 47: 6-(4-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 6-(4-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.816 mmol) and 4-fluorobenzylamine (154 mg, 1.231 mmol) in EtOH (3 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 6-(4-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (180.0 mg, yield: 64.8%). LCMS (ESI+): C 19 H 18 FN2O3[M+H] + Calculated m / z: 341; measured: 341.

[0177] Synthesis of 2.6-(4-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(4-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (180 mg, 0.529 mmol) and NaOH (65.57 mg, 1.640 mmol) in MeOH (1.5 mL) and THF (1.5 mL) and H2O (0.5 mL) was stirred at 40°C for 4 h. The residue was acidified to pH 7 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-(4-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a yellow solid (100 mg, yield: 60.5%). LCMS (ESI+): C 17 H 14 FN2O3[M+H] + Calculated m / z: 313; measured: 313.

[0178] 3. Synthesis of 6-(4-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(4-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.320 mmol) in DMF (2.5 mL) was added EDC.HCl (111 mg, 0.579 mmol) and HOBT (71 mg, 0.525 mmol) followed by 2-pyridinemethanamine (55 mg, 0.509 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(4-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (57.1 mg, yield: 44.3%). LCMS (ESI+): C 23 H 20 FN4O2[M+H] + Calculated m / z: 403.2; measured: 403.3. 1 HNMR(400MHz,DMSO-d6,δ):9.25-9.21(m,1H),8.56-8.54(m,2H),7.95(d,J=7.6Hz,1H),7.83-7.79(m,1H),7.43-7.40 (m,3H),7.39-7.32(m,1H),7.29-7.16(m,2H),6.74(d,J=7.6Hz,1H),5.20(s,2H),4.59(d,J=6.0Hz,2H),2.69(s,3H).

[0179] Example 48: 2-Methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of ethyl 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (50 mg, 0.16 mmol) and (5-methyloxazol-2-yl)methanamine hydrochloride (29 mg, 0.19 mmol) in EtOH (1 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (50 mg, yield: 93.59%). LCMS (ESI+): C 17 H 18 N3O4[M+H] + Calculated m / z: 328; measured: 328.

[0180] 2. Synthesis of 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (52 mg, 0.15 mmol) and NaOH (20 mg, 0.50 mmol) in MeOH (2 mL), THF (2 mL), and HO (1 mL) was stirred at 40° C. for 4 h. The residue was acidified to pH 7 with concentrated HCl, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (10 mg, yield: 21.03%). LCMS (ESI+): C15 H 14 N3O4[M+H] + Calculated m / z: 300.1; measured: 300.1.

[0181] 3. Synthesis of 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (10 mg, 0.03 mmol) in DMF (1 mL) was added EDC.HCl (10 mg, 0.05 mmol) and HOBT (7 mg, 0.05 mmol) followed by 2-pyridinemethanamine (6 mg, 0.05 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (2.5 mg, yield: 19.08%). LCMS (ESI+): C 21 H 20 N5O3[M+H] + Calculated m / z: 390.2; measured: 390.1. 1 HNMR(400MHz,DMSO-d6,δ):9.23(t,J=6.0Hz,1H),8.63-8.34(m,2H),7.93-7.74(m,2H),7.41(d,J=7.8Hz,1 H),7.34-7.25(m,1H),6.75(d,J=8.4Hz,2H),5.30(s,2H),4.59(d,J=5.9Hz,2H),2.70(s,3H),2.26(s,3H).

[0182] Example 49: 2-Methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of ethyl 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.81 mmol) and 1-(1-methylpyrazol-4-yl)methanamine (109 mg, 0.98 mmol) in EtOH (3 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (73 mg, yield: 27.41%). LCMS (ESI+): C 17 H 19 N4O3[M+H] + Calculated m / z: 327.1; measured: 327.1.

[0183] 2. Synthesis of 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (304 mg, 0.93 mmol) and NaOH (112 mg, 2.80 mmol) in MeOH (4 mL), THF (4 mL), and HO (2 mL) was stirred at 40° C. for 4 h. The residue was acidified to pH 7 with concentrated HCl, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (90 mg, yield: 32.39%). LCMS (ESI+): C 15 H 15 N4O3[M+H] + Calculated m / z: 299.1; measured: 299.1.

[0184] 3. Synthesis of 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (110 mg, 0.36 mmol) in DMF (4 mL, 51.68 mmol) was added EDC.HCl (107 mg, 0.55 mmol) and HOBT (75 mg, 0.55 mmol) followed by 2-pyridinemethanamine (60 mg, 0.55 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (33.2 mg, yield: 22.30%). LCMS (ESI+): C21 H 21 N6O2[M+H] + Calculated m / z: 389.2; measured: 389.1. 1 HNMR(400MHz,DMSO-d6,δ):9.23(t,J=6.0Hz,1H),8.58-8.47(m,2H),7.89(d,J=7.6Hz,1H),7.82(m,1H),7.72(s,1H),7. 47-7.39(m,2H),7.34-7.27(m,1H),6.68(d,J=7.6Hz,1H),5.02(s,2H),4.59(d,J=5.9Hz,2H),3.78(s,3H),2.67(s,3H).

[0185] Example 50: 6-Benzyl-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of tert-butyl ((4,5-difluoropyridin-2-yl)methyl)carbamate [ka] A solution of 2-bromo-4,5-difluoropyridine (200 mg, 1.03 mmol), potassium tert-butyl N-[(trifluoro-lambda 4-boranyl)methyl]carbamate (270 mg, 1.13 mmol), Pd(PCy3)2Cl2 (114 mg, 0.15 mmol), and K3PO4 (660 mg, 3.10 mmol) in dioxane (10 mL) and HO (2 mL) was stirred at 90 °C overnight under nitrogen atmosphere. The resulting mixture was filtered, extracted with EtOAc, and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with EtOAc (0-50%) in petroleum ether to give tert-butyl ((4,5-difluoropyridin-2-yl)methyl)carbamate as a colorless oil (28 mg, yield: 11.12%). LCMS(ESI+):C 11 H 15 F2N2O2[M+H]+ Calculated m / z: 245.1; measured: 245.1.

[0186] 2. Synthesis of (4,5-difluoropyridin-2-yl)methanamine hydrochloride [ka] A solution of tert-butyl ((4,5-difluoropyridin-2-yl)methyl)carbamate (28 mg, 0.11 mmol) in HCl (gas) in 1,4-dioxane (1 mL) and DCM (1 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give the crude product, (4,5-difluoropyridin-2-yl)methanamine hydrochloride (15 mg, yield: 90.7%), which was used directly in the next step without further purification. LCMS (ESI+): C6H7F2N2[M+H] + Calculated m / z: 145.1; measured: 145.0.

[0187] 3. Synthesis of 6-benzyl-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (25 mg, 0.08 mmol) in DMF (1 mL) was added EDC.HCl (24 mg, 0.12 mmol) and HOBT (17 mg, 0.12 mmol) at 0° C., followed by (4,5-difluoropyridin-2-yl)methanamine hydrochloride (15 mg, 0.10 mmol) and DIEA (33 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-((4,5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (16.5 mg, yield: 46%). LCMS (ESI+): C 23 H 19 F2N4O2[M+H] + Calculated m / z: 421.1; measured: 421.1. 1 HNMR(400MHz,DMSO-d6,δ):9.24(t,J=6.0Hz,1H),8.73(m,1H),8.57(s,1H),7.92(d,J=7.5Hz,1H),7. 59(m,1H),7.39-7.23(m,5H),6.72(d,J=7.6Hz,1H),5.23(s,2H),4.57(d,J=5.9Hz,2H),2.68(s,3H).

[0188] Example 51: 6-(4-chlorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of ethyl 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.816 mmol) and 1-(4-chlorophenyl)methanamine (165 mg, 1.165 mmol) in EtOH (4 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (150.0 mg, yield: 51.2%). LCMS (ESI+): C 19 H 18 ClN2O3[M+H] + Calculated m / z: 357; measured: 357.

[0189] 2. Synthesis of 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (150 mg, 0.420 mmol) and NaOH (33 mg, 0.825 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40°C for 8 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (100 mg, yield: 72.3%). LCMS (ESI+): C 17 H 14 ClN2O3[M+H] + Calculated m / z: 329; measured value: 329.

[0190] 3. Synthesis of 6-(4-chlorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (150 mg, 0.456 mmol) in DMF (2 mL) was added EDC.HCl (57 mg, 0.396 mmol) and HOBT (87 mg, 0.455 mmol), followed by 1-(5-fluoropyridin-2-yl)methanamine (57 mg, 0.452 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(4-chlorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (82.6 mg, yield: 41.4%). LCMS (ESI+): C 23 H 19 ClFN4O2[M+H] + Calculated m / z: 437.1; measured: 437.1. 1 HNMR(400MHz,DMSO-d6,δ):9.26-9.26(m,1H),8.55-8.53(m,2H),7.94(d,J=7.6Hz,1H),7.77-7.72(m,1H),7.51(d,J=4 .8Hz,1H),7.49-7.48(m,2H),7.43-7.41(m,2H),6.74(d,J=7.6Hz,1H),5.21(s,2H),4.59(d,J=5.6Hz,2H),2.68(s,3H).

[0191] Example 52: 2-Methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 2-methyl-5-oxo-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (300.5 mg, 0.979 mmol) and pyridin-4-ylmethanamine (211.5 mg, 1.958 mmol) in EtOH (3 mL) was stirred at 80° C. for 8 h. The mixture was added with water (10 mL) at 0° C. The solid was collected by filtration to give ethyl 2-methyl-5-oxo-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (300.6 mg, yield: 94.8%). LCMS (ESI+): C 18 H 18 N3O3[M+H] + Calculated m / z: 324; measured: 324.

[0192] 2. Synthesis of 2-methyl-5-oxo-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-5-oxo-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate (200.5 mg, 0.62 mmol) and NaOH (74.4 mg, 1.86 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40° C. for 3 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-5-oxo-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (123.5 mg, yield: 67.4%). LCMS (ESI+): C 16 H 14 N3O3[M+H] + Calculated m / z: 296; measured: 296.

[0193] 3. Synthesis of 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-5-oxo-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (80.5 mg, 0.27 mmol) and in DMF (5 mL) at 0° C., EDC.HCl (78.2 mg, 0.405 mmol) and HOBT (55.3 mg, 0.405 mmol), DIPEA (70.5 mg, 0.54 mmol) were added, followed by pyridin-2-ylmethanamine (43.7 mg, 0.405 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude product was purified using the following conditions (column: XBridge Prep OBD C 18 Purification by Prep-HPLC using column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min, gradient: 33% B to 43% B in 8min, 43%) to give 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (8.4mg, yield: 8%). LCMS (ESI+): C 22 H 20 N5O2[M+H] + Calculated m / z: 386.2; measured: 386.2. 1 HNMR(400MHz,DMSO-d6,δ):9.24(t,J=6.0Hz,1H),8.58-8.50(m,4H),7.93(d,J=7.6Hz,1H),7.86-7.76(m,1H),7.41(d,J= 7.8Hz,1H),7.33-7.27(m,1H),7.26-7.21(m,2H),6.77(d,J=7.6Hz,1H),5.26(s,2H),4.58(d,J=5.9Hz,2H),2.70(s,3H).

[0194] Example 53: 2,6-Dimethyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of ethyl 2,6-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.816 mmol) and methylamine (151 mg, 4.862 mmol) in EtOH (3 mL) was stirred at 80° C. for 8 h. The precipitated solid was collected by filtration and washed with water (2×5 mL). The solid was collected by filtration to give ethyl 2,6-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (240 mg, yield: 74.64%). LCMS (ESI+): C 13 H 15 N2O3[M+H] + Calculated m / z: 247; measured: 247.

[0195] 2. Synthesis of 2,6-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2,6-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (150 mg, 0.61 mmol) and NaOH (75.0 mg, 1.88 mmol) in MeOH (0.9 mL) and THF (0.9) and H2O (0.3 mL) was stirred at 40°C for 4 h. The reaction was acidified to pH 4 with concentrated HCl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2,6-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a yellow solid (80 mg, yield: 60.2%). LCMS (ESI+): C11 H 11 N2O3[M+H] + Calculated m / z: 219; measured value: 219.

[0196] 3. Synthesis of 2,6-dimethyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2,6-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (80 mg, 0.367 mmol) and 1,6-naphthyridine-3-carboxylic acid in DMF (2 mL) at 0° C., EDC.HCl (100 mg, 0.522 mmol) and HOBT (73 mg, 0.540 mmol) were added, followed by 2-pyridinemethanamine (62 mg, 0.573 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 2,6-dimethyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (18.2 mg, yield: 16.1%). LCMS (ESI+): C 17 H 17 N4O2[M+H] + Calculated m / z: 309.1; measured: 309.2. 1 HNMR(400MHz,DMSO-d6,δ):9.26-9.25(m,1H),8.56-8.52(m,2H),7.84-7.80(m,2H),7.42(d,J=7.6 Hz,1H),7.32-7.29(m,1H),6.68(d,J=7.2Hz,1H),4.60(d,J=6.0Hz,2H),3.54(s,3H),2.68(s,3H).

[0197] Example 54: 2-Methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 2-methyl-6-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.81 mmol) and p-tolylmethanamine (119 mg, 0.98 mmol) in EtOH (3 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the solid was collected by filtration and washed with HO (3×5 mL) to give the crude product, ethyl 2-methyl-6-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, as a yellow solid (290 mg, yield: 88.1%). LCMS (ESI+): C 20 H 21 N2O3[M+H] + Calculated m / z: 337; measured: 337.

[0198] 2. Synthesis of 2-methyl-6-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-6-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (290 mg, 0.86 mmol) and NaOH (104 mg, 2.60 mmol) in MeOH (6 mL) and H2O (2 mL) was stirred at 40° C. overnight. The residue was acidified to pH 7 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-6-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a yellow solid (150 mg, yield: 56.43%). LCMS (ESI+): C 18 H 17 N2O3[M+H] + Calculated m / z: 309; measured value: 309.

[0199] 3. Synthesis of 2-methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-6-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.32 mmol) in DMF (4 mL) was added EDC.HCl (94.1 mg, 0.49 mmol) and HOBT (66.5 mg, 0.48 mmol), followed by 2-pyridinemethanamine (53.8 mg, 0.49 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 2-methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (54 mg, yield: 41.74%). LCMS (ESI+): C 24 H 23 N4O2[M+H] + Calculated m / z: 399.2; measured: 399.1. 1 HNMR(400MHz,DMSO-d6,δ):9.23(t,J=6.0Hz,1H),8.59-8.47(m,2H),7.89(d,J=7.6Hz,1H),7.83-7.80(m,1H),7.41(m,1H),7.30 (m,1H),7.23(d,J=8.1Hz,2H),7.15(d,J=7.8Hz,2H),6.71(m,1H),5.17(s,2H),4.58(d,J=5.9Hz,2H),2.68(s,3H),2.27(s,3H).

[0200] Example 55: 6-(3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 6-(3-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (500 mg, 1.63 mmol) and 1-(3-fluorophenyl)methanamine (310 mg, 2.47 mmol) in EtOH (5 mL) was stirred at 80° C. for 8 h. The precipitated solid was collected by filtration and washed with water (2×5 mL) to give ethyl 6-(3-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (400 mg, yield: 72.0%). LCMS (ESI+): C 19 H 18 FN2O3[M+H] + Calculated m / z: 341; measured: 341.

[0201] Synthesis of 2.6-(3-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(3-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (400 mg, 1.226 mmol) and NaOH (141 mg, 3.52 mmol) in MeOH (3 mL) and THF (3 mL) and H2O (1 mL) was stirred at 40° C. for 4 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-(3-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a yellow solid (200 mg, yield: 52.2%). LCMS (ESI+): C 17 H 14 FN2O3[M+H]+ Calculated m / z: 313; measured: 313.

[0202] 3. Synthesis of 6-(3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(3-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (200 mg, 0.640 mmol) in DMF (3.5 mL) was added EDC.HCl (194 mg, 1.012 mmol) and HOBT (130 mg, 0.962 mmol), followed by 2-pyridinemethanamine (120 mg, 1.110 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (78.3 mg, yield: 30.3%). LCMS (ESI+): C 23 H 20 FN4O2[M+H] + Calculated m / z: 403.2; measured: 403.3. 1 HNMR(400MHz,DMSO-d6,δ):9.25(d,J=6.0Hz,1H),8.55(d,J=5.2Hz,2H),7.95(d,J=7.6Hz,1H),7.83-7.80(m,1H),7.41-7. 37(m,2H),7.31(d,J=5.2Hz,1H),7.28-7.21(m,3H),6.75(d,J=7.6Hz,1H),5.23(s,2H),4.59(d,J=5.6Hz,2H),2.69(s,3H).

[0203] Example 56: 6-(2-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 6-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.81 mmol) and 1-(2-fluorophenyl)methanamine (123 mg, 0.98 mmol) in EtOH (3 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 6-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (223 mg, yield: 80.29%). LCMS (ESI+): C 19 H 18 FN2O3[M+H] + Calculated m / z: 341; measured: 341.

[0204] Synthesis of 2.6-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (385 mg, 1.13 mmol) and NaOH (136 mg, 3.40 mmol) in MeOH (6 mL), THF (6 mL), and H2O (2 mL) was stirred at 40°C for 4 h. The residue was acidified to pH 7 with concentrated HCl, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (196 mg, yield: 55%). LCMS (ESI+): C 17 H 13 FN2O3[M+H] + Calculated m / z: 313; measured: 313.

[0205] 3. Synthesis of 6-(2-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (190 mg, 0.60 mmol) in DMF (6 mL) was added EDC.HCl (240 mg, 1.25 mmol) and HOBT (124 mg, 0.91 mmol), followed by 2-pyridinemethanamine (99 mg, 0.91 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(2-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (126.3 mg, yield: 51.38%). LCMS (ESI+): C 23 H 20 FN4O2[M+H] + Calculated m / z: 403.2; measured: 403.1. 1HNMR(400MHz,DMSO-d6,δ):9.23(t,J=6.0Hz,1H),8.60-8.45(m,2H),7.94-7.75(m,2H),7 .44-7.09(m,6H),6.75(d,J=7.6Hz,1H),5.27(s,2H),4.58(d,J=5.9Hz,2H),2.69(s,3H).

[0206] Example 57: 6-benzyl-N-((5-chloro-4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of tert-butyl ((5-chloro-4-fluoropyridin-2-yl)methyl)carbamate [ka] A solution of 2-bromo-5-chloro-4-fluoropyridine (50 mg, 0.23 mmol), potassium tert-butyl N-[(trifluoro-lambda 4-boranyl)methyl]carbamate (63 mg, 0.26 mmol), Pd(PCy3)2Cl2 (27 mg, 0.03 mmol), and K3PO4 (153 mg, 0.72 mmol) in dioxane (2 mL) and HO (0.4 mL) was stirred at 90 °C overnight under nitrogen atmosphere. The resulting mixture was filtered, extracted with EtOAc, and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with EtOAc (0-50%) in petroleum ether to give tert-butyl ((5-chloro-4-fluoropyridin-2-yl)methyl)carbamate as a colorless oil (10 mg, yield: 16.14%). LCMS(ESI+):C 11 H 15 ClFN2O2[M+H] + Calculated m / z: 261.1; measured: 261.0.

[0207] 2. Synthesis of (5-chloro-4-fluoropyridin-2-yl)methanamine hydrochloride [ka] A solution of tert-butyl ((5-chloro-4-fluoropyridin-2-yl)methyl)carbamate (10 mg, 0.03 mmol) in HCl (gas) in 1,4-dioxane (1 mL) and DCM (1 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give the crude product, (5-chloro-4-fluoropyridin-2-yl)methanamine hydrochloride (5 mg, yield: 89%), which was used directly in the next step without further purification. LCMS (ESI+): C6H7ClFN2[M+H] + Calculated m / z: 161.0; measured: 161.0.

[0208] 3. Synthesis of 6-benzyl-N-((5-chloro-4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (14 mg, 0.04 mmol) in DMF (1 mL, 12.92 mmol) was added EDC.HCl (19 mg, 0.09 mmol) and HOBT (13 mg, 0.09 mmol) at 0° C., followed by (5-chloro-4-fluoropyridin-2-yl)methanamine hydrochloride (5 mg, 0.03 mmol) and DIEA (19 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-((5-chloro-4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (9.6 mg, yield: 46%). LCMS (ESI+): C 23 H 19 ClFN2O2[M+H] + Calculated m / z: 437.1; measured: 437.1. 1HNMR(400MHz,DMSO-d6,δ):9.26(t,J=5.8Hz,1H),8.74(d,J=9.7Hz,1H),8.58(s,1H),7.92(m,1H),7.55(d ,J=10.2Hz,1H),7.40-7.25(m,5H),6.72(d,J=7.5Hz,1H),5.23(s,2H),4.59(d,J=5.8Hz,2H),2.68(s,3H).

[0209] Example 58: 2-Methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 2-methyl-5-oxo-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (300.3 mg, 0.979 mmol) and pyridin-3-ylmethanamine (211.5 mg, 1.958 mmol) in EtOH (3 mL) was stirred at 80° C. for 8 h. Water (10 mL) was added at 0° C. and the solid was collected by filtration to give ethyl 2-methyl-5-oxo-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (300.5 mg, yield: 94.8%). LCMS (ESI+): C 18 H 18 N3O3[M+H] + Calculated m / z: 324; measured: 324.

[0210] 2. Synthesis of 2-methyl-5-oxo-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 2-methyl-5-oxo-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate (200.2 mg, 0.62 mmol) and NaOH (74.4 mg, 1.86 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40°C for 3 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-methyl-5-oxo-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (123.3 mg, yield: 67.4%). LCMS (ESI+): C 16 H 14 N3O3[M+H] + Calculated m / z: 296; measured: 296.

[0211] 3. Synthesis of 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 2-methyl-5-oxo-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (80.5 mg, 0.27 mmol) and in DMF (5 mL) at 0° C., EDC.HCl (78.3 mg, 0.405 mmol) and HOBT (55.6 mg, 0.405 mmol), DIPEA (70.1 mg, 0.54 mmol) were added, followed by pyridin-2-ylmethanamine (43.7 mg, 0.405 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude product was purified using the following conditions (column: XBridge Prep OBD C 18Purification by Prep-HPLC using column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min, gradient: 33% B to 43% B in 8min, 43%) to give 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (20.3mg, yield: 19%). LCMS (ESI+): C 22 H 20 N5O2[M+H] + Calculated m / z: 386.2; measured: 386.2. 1 HNMR(400MHz,DMSO-d6,δ):9.22(t,J=6.0Hz,1H),8.63(d,J=2.3Hz,1H),8.54(d,J=8.6Hz,2H),8.51-8.49(m,1H),8.00(d,J=7.6Hz,1H),7.84 -7.78(m,1H),7.76-7.72(m,1H),7.43-7.35(m,2H),7.32-7.28(m,1H), 6.75(d,J=7.6Hz,1H),5.25(s,2H),4.58(d,J=6.0Hz,2H),2.69(s,3H).

[0212] Example 59: N-((5-chloropyridin-2-yl)methyl)-6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of ethyl 6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.816 mmol) and 1-[2-(2-aminoethoxy)ethoxyl]-2-methoxyethane (265 mg, 1.624 mmol) in EtOH (2.5 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give ethyl 6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (200.0 mg, yield: 64.7%). LCMS (ESI+): C 19 H 27 N2O6[M+H] + Calculated m / z: 379; measured value: 379.

[0213] 2. Synthesis of 6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (200 mg, 0.549 mmol) and NaOH (63 mg, 1.575 mmol) in MeOH (3 mL) and HO (1 mL) was stirred at 40° C. for 4 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO and concentrated in vacuo to give 6-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (70 mg, yield: 36.4%). LCMS (ESI+): C 17 H 23 N2O6[M+H] + Calculated m / z: 351; measured: 351.

[0214] 3. Synthesis of N-((5-chloropyridin-2-yl)methyl)-6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (70 mg, 0.20 mmol) in DMF (2 mL) was added EDC.HCl (57 mg, 0.29 mmol) and HOBT (40 mg, 0.29 mmol) followed by 1-(5-chloropyridin-2-yl)methanamine (42 mg, 0.295 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give N-((5-chloropyridin-2-yl)methyl)-6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (36.3 mg, yield: 38.2%). LCMS (ESI+): C 23 H 28 ClN4O5[M+H] + Calculated m / z: 475.2; measured: 475.2. 1 HNMR(400MHz,DMSO-d6,δ):9.28-9.25(m,1H),8.61(d,J=2.4Hz,1H),8.53(s ,1H),7.97-7.94(m,1H),7.76(d,J=7.6Hz,1H),7.48(d,J=8.4Hz,1H),6.67(d ,J=7.5Hz,1H),4.59(d,J=6.0Hz,2H),4.19-4.15(m,2H),3.72-3.70(m,2H), 3.54-3.52(m,2H),3.49-3.44(m,4H),3.37(s,2H),3.20(s,3H),2.68(s,3H).

[0215] Example 60: 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 1,6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (345 mg, 1.12 mmol) and 1-{bicyclo[1.1.1]pentan-1-yl}methanamine (150 mg, 1.54 mmol) in EtOH (4.0 mL) was stirred overnight at 80 °C under nitrogen atmosphere. The crude was purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give ethyl 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (300 mg, yield: 85.2%) as a yellow solid. LCMS (ESI+): C 18 H 21 N2O3[M+H] + Calculated m / z: 313; measured: 313.

[0216] Synthesis of 2.6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (300 mg, 0.960 mmol) and NaOH (125 mg, 3.12 mmol) in MeOH (3 mL) and HO (1 mL) was stirred at 40° C. for 4 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (150 mg, yield: 54.9%) as a white solid. LCMS (ESI+): C 16 H 17 N2O3[M+H] + Calculated m / z: 285; measured: 285.

[0217] 3. Synthesis of 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (50 mg, 0.176 mmol) in DMF (2 mL) was added EDC.HCl (50 mg, 0.261 mmol) and HOBT (35 mg, 0.259 mmol) followed by 2-pyridinemethanamine (28 mg, 0.259 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide (17.5 mg, yield: 26.2%) as a white solid. LCMS (ESI+): C 22 H 23N4O2[M+H] + Calculated m / z: 375.1; measured: 375.1. 1 HNMR(400MHz,DMSO-d6,δ):9.26-9.24(m,1H),8.56-8.53(m,2H),7.84-7.80(m,1H),7.68(d,J=7.5Hz,1H),7.42(d,J=7.9Hz, 1H),7.31(d,J=2.6Hz,1H),6.68(d,J=7.5Hz,1H),4.59(d,J=5.9Hz,2H),4.08(s,2H),2.69(s,3H),2.47(s,1H),1.69(s,6H).

[0218] Example 61: 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (500 mg, 1.63 mmol) and 1-(3,4-difluorophenyl)methanamine (282 mg, 1.97 mmol) in EtOH (5 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×10 mL) to give crude ethyl 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (510 mg) as an orange solid. LCMS (ESI+): C 19 H 17 F2N2O3[M+H] + Calculated m / z: 359; measured value: 359.

[0219] Synthesis of 2.6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (500 mg, 1.39 mmol) and NaOH (158 mg, 3.95 mmol) in MeOH (10 mL) and H2O (3 mL) was stirred at 40° C. overnight. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (410 mg, yield: 88.9%) as a yellow solid. LCMS (ESI+): C 17 H 13 F2N2O3[M+H] + Calculated m / z: 331; measured: 331.

[0220] 3. Synthesis of 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] At 0° C., a solution of 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.30 mmol) in DMF (3 mL) was added with EDC.HCl (88 mg, 0.45 mmol) and HOBT (62 mg, 0.45 mmol), followed by 2-pyridinemethanamine (49 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The crude was then purified by reverse phase column: ACN / H2O (0.5% NH4HCO3) to give 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide (67.2 mg, yield: 52.7%) as a white solid. LCMS(ESI+):C 23 H 19 F2N4O2[M+H] + Calculated m / z: 421.1; measured: 421.1. 1 HNMR(400MHz,DMSO-d6,δ):9.22(t,J=6.0Hz,1H),8.58-8.46(m,2H),7.95(d,J=7.6Hz,1H),7.81(m,1H),7.55-7. 34(m,3H),7.31-7.28(m,1H),7.20(m,1H),6.74(d,J=7.6Hz,1H),5.20(s,2H),4.59(d,J=5.9Hz,2H),2.69(s,3H).

[0221] Example 62: 6-(3,4-difluorobenzyl)-N-((4,5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 6-(3,4-difluorobenzyl)-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] A solution of 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (28 mg, 0.08 mmol) in DMF (1 mL) was added with EDC.HCl (22 mg, 0.11 mmol), HOBT (15 mg, 0.11 mmol), and DIEA (22 mg, 0.17 mmol) at 0° C., followed by addition of 1-(4,5-difluoropyridin-2-yl)methanamine hydrochloride (10 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(3,4-difluorobenzyl)-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide 14 mg, yield: 35.7%) as a white solid. LCMS (ESI+): C 23 H 17 F4N4O2[M+H] + Calculated m / z: 457.1; measured: 457.2. 1 HNMR(400MHz,DMSO-d6,δ):9.23(t,J=5.9Hz,1H),8.74-8.71(m,1H),8.56(s,1H),7.94(d,J=7.6Hz,1H),7.60-7.56( m,1H),7.49-7.36(m,2H),7.23-7.15(m,1H),6.73(d,J=7.6Hz,1H),5.19(s,2H),4.56(d,J=5.8Hz,2H),2.67(s,3H).

[0222] Example 63: 6-(3,4-difluorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 6-(3,4-difluorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] A solution of 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.30 mmol) in DMF (2 mL) was added with EDC.HCl (88 mg, 0.45 mmol) and HOBT (62 mg, 0.45 mmol) at 0° C., followed by addition of 1-(5-fluoropyridin-2-yl)methanamine (58 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The crude was then purified by reverse phase column: ACN / H2O (0.1% NH4HCO3)) to give 6-(3,4-difluorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (74.5 mg, yield: 55.0%) as a white solid. LCMS (ESI+): C 23 H 18 F3N4O2[M+H] + Calculated m / z: 439.1; measured: 439.1. 1 HNMR(400MHz,DMSO-d6,δ):9.25(t,J=6.0Hz,1H),8.61-8.46(m,2H),7.95(d,J=7.6Hz,1H),7.77-7.72(m,1H) ,7.57-7.33(m,3H),7.21-7.18(m,1H),6.74(d,J=7.5Hz,1H),5.20(s,2H),4.58(d,J=5.9Hz,2H),2.68(s,3H).

[0223] Example 64: N-((5-chloropyridin-2-yl)methyl)-6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of tert-butyl (4-(2-(2-methoxyethoxy)ethoxy)benzyl)carbamate [ka] A solution of tert-butyl (4-hydroxybenzyl)carbamate (300 mg, 1.34 mmol), 1-bromo-2-(2-methoxyethoxy)ethane (245 mg, 1.34 mmol), and Cs2CO3 (1.31 g, 4.03 mmol) in MeCN (3 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The reaction was quenched with water (3 mL). The mixture was extracted with EtOAc (3 x 5 mL) to give tert-butyl (4-(2-(2-methoxyethoxy)ethoxy)benzyl)carbamate (324 mg, yield: 74.1%) as a white solid. LCMS (ESI+): C 17 H 28 NO5[M+H] + Calculated m / z: 326; measured value: 326.

[0224] 2. Synthesis of (4-(2-(2-methoxyethoxy)ethoxy)phenyl)methanamine hydrochloride [ka] A solution of tert-butyl (4-(2-(2-methoxyethoxy)ethoxy)benzyl)carbamate (324 mg, 0.996 mmol) in HCl (gas) in 1,4-dioxane (3 mL) was stirred at room temperature for 30 min. The precipitated solid was collected by filtration to give (4-(2-(2-methoxyethoxy)ethoxy)phenyl)methanamine hydrochloride (227 mg, yield: 87.1%) as a grey solid. LCMS (ESI+): C 12 H 20 NO3[M+H] + Calculated m / z: 226; measured value: 226.

[0225] 3. Synthesis of ethyl 6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] To a stirred solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (150 mg, 0.490 mmol) in EtOH (1.6 mL) was added (4-(2-(2-methoxyethoxy)ethoxy)phenyl)methanamine hydrochloride (220 mg, 0.980 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. overnight. The reaction was quenched by adding water (2 mL) at 0° C. The mixture was extracted with EtOAc (3×5 mL). The organic layer was concentrated under reduced pressure to give ethyl 6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (180 mg, yield: 83.4%) as a yellow solid. LCMS (ESI+): C 24 H 29 N2O6[M+H] + Calculated m / z: 441; measured: 441.

[0226] 4. Synthesis of 6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (120 mg, 0.272 mmol) and NaOH (32.7 mg, 0.816 mmol) in MeOH:HO=3:1 (2 mL) was stirred at 40° C. overnight. The mixture was acidified to pH 5 with HCl (aq). The residue was purified by reverse flash chromatography, 15% to 45% in 20 min, using MeOH in water (0.1% HCl) to give 6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, yield: 89.0%) as a yellow solid. LCMS(ESI+):C 22 H 25 N2O6[M+H] +Calculated m / z: 413; measured: 413.

[0227] 5. Synthesis of N-((5-chloropyridin-2-yl)methyl)-6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.242 mmol) in DMF under nitrogen atmosphere, EDC.HCl (69.7 mg, 0.363 mmol), DIPEA (94.0 mg, 0.726 mmol), and 1-(5-chloropyridin-2-yl)methanamine (51.8 mg, 0.363 mmol) were added at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was purified by reverse flash chromatography using MeOH in water (10 mmol / L NH4HCO3), 30% to 60% in 30 min, to give N-((5-chloropyridin-2-yl)methyl)-6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (27 mg, yield: 20.5%) as a white solid. LCMS (ESI+): C 28 H 30 ClN4O5[M+H] + Calculated m / z: 537.1; measured: 537.1. 1HNMR(400MHz,DMSO-d6,δ):9.30-9.24(m,1H),8.60(d,J=2.5Hz,1H),8.54(s,1H), 7.97-7.88(m,2H),7.47(d,J=8.4Hz,1H),7.31(d,J=8.4Hz,2H),6.91(d,J=8.5Hz, 2H),6.70(d,J=7.6Hz,1H),5.14(s,2H),4.58(d,J=5.9Hz,2H),4.08-4.02(m,2H), 3.75-3.68(m,2H),3.60-3.54(m,2H),3.47-3.42(m,2H),3.23(s,3H),2.67(s,3H).

[0228] Example 65: 6-Benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of diethyl 1,2-methylpyridine-3,5-dicarboxylate [ka] Under nitrogen atmosphere, Et3N (0.77 g, 7.61 mmol) was added dropwise to a mixture of ethyl 2-formyl-3-oxopropanoate (1 g, 6.93 mmol) in Et2O (7 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h, then the solvent was evaporated under reduced pressure. The residue was diluted with DMF (5 mL) and methylbenzenesulfonyl (1.45 g, 7.606 mmol) in DMF (6 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 4 h. To the mixture was added a solution of ethyl (2Z)-3-aminobut-2-enoate (0.95 g, 7.35 mmol) and pyridine (2.2 g, 27.8 mmol) in DMF (5 mL) at 25 °C. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with saturated brine (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient, 10% to 30% EtOAc / petroleum ether) to give diethyl 2-methylpyridine-3,5-dicarboxylate (950 mg, yield: 57.7%) as a yellow solid. LCMS (ESI+): C 12 H 16 NO4[M+H] + Calculated m / z: 238; measured: 238.

[0229] 2. Synthesis of (E)-2-(2-(dimethylamino)vinyl)pyridine-3,5-dicarboxylate diethyl [ka] To a solution of diethyl 2-methylpyridine-3,5-dicarboxylate (950 mg, 4.00 mmol) in DMF (10 mL) was added (diethoxymethyl)dimethylamine (884 mg, 6.00 mmol) and the resulting solution was stirred at 100° C. for 8 h. The resulting solution was carried on directly to the next step. LCMS (ESI+): C 15 H 21 N2O4[M+H] + Calculated m / z: 293; measured: 293.

[0230] 3. Synthesis of ethyl 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)pyridine-3,5-dicarboxylate (950 mg, 3.25 mmol) and benzylamine (522 mg, 4.87 mmol) in EtOH (10 mL) was stirred at 80° C. for 8 h. The precipitated solid was collected by filtration and washed with water (2×5 mL) to give ethyl 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (400 mg, yield: 39.9%) as a yellow solid. LCMS (ESI+): C 18 H 17 N2O3[M+H] + Calculated m / z: 309; measured value: 309.

[0231] 4. Synthesis of 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (100 mg, 0.324 mmol) and NaOH (38 mg, 0.950 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40°C for 3 h. The residue was acidified to pH 4 with concentrated HCl. The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (250 mg, 60.6%) as a white solid. LCMS (ESI+): C 16 H 13 N2O3[M+H] + Calculated m / z: 281; measured: 281.

[0232] 5. Synthesis of 6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (60 mg, 0.214 mmol) in DMF (2 mL) at 0° C., EDC.HCl (61.5 mg, 0.321 mmol) and HOBT (43.4 mg, 0.321 mmol) were added, followed by 2-pyridinemethanamine (34.7 mg, 0.321 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude was then purified by reverse phase column: ACN / H2O (0.1% NH4HCO3) to give 6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide (24.6 mg, yield: 31.0%) as a white solid. LCMS (ESI+): C 22 H 19 N4O2[M+H] + Calculated m / z: 371.1; measured: 371.1. 1 HNMR(400MHz,DMSO-d6,δ):9.63-9.49(m,1H),9.37(d,J=2.3Hz,1H),9.09(d,J=2.3Hz,1H),8.58-8.48(m,1H),7.9 9(d,J=7.6Hz,1H),7.80-7.73(m,1H),7.41-7.24(m,7H),6.83(d,J=7.6Hz,1H),5.25(s,2H),4.62(d,J=5.9Hz,2H).

[0233] Example 66: 6-benzyl-2-methyl-N-((4-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of (4-methyloxazol-2-yl)methanamine hydrochloride [ka] A solution of 4-methyloxazole-2-carbaldehyde (20.0 mg, 0.181 mmol) in MeOH (0.5 mL) was added with NH3 ammonia (g) in MeOH (0.5 mL, 3.50 mmol) and stirred at 25 °C for 3 h. NaBH4 (13.2 mg, 0.349 mmol) was added and the resulting mixture was stirred at 25 °C for 1 h. The reaction was quenched with water / ice and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure, followed by addition of HCl (gas) in 1,4-dioxane (1 mL, 4.0 mmol) and stirred at 0 °C for 5 min. The resulting mixture was concentrated under reduced pressure to give (4-methyloxazol-2-yl)methanamine hydrochloride (22 mg, yield: 82.1%) as a yellow oil. LCMS (ESI+): C5H9N2O[M+H] + Calculated m / z: 113; measured: 113.

[0234] 2. Synthesis of 6-benzyl-2-methyl-N-((4-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (43.6 mg, 0.148 mmol) in DMF (2 mL) at 0° C. was added EDC.HCl (40.6 mg, 0.212 mmol) and HOBT (29.5 mg, 0.218 mmol), followed by (4-methyloxazol-2-yl)methanamine hydrochloride (20.5 mg, 0.138 mmol). The residue was purified by reverse flash chromatography eluting with MeCN in water (0.5% NH4HCO3) with a gradient of 10% to 100% in 30 min to give 6-benzyl-2-methyl-N-((4-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (3.6 mg, yield: 6.7%) as a white solid. LCMS (ESI+): C 22 H 21 N4O3[M+H] +Calculated m / z: 389.2; measured: 389.2. 1 HNMR(400MHz,DMSO-d6,δ):9.39(t,J=6.0Hz,1H),8.50(s,1H),7.95-7.90(m,1H),7.77-7.71(m,1H) ,7.43-7.33(m,5H),6.73-6.71(m,1H),5.22(s,2H),4.55(d,J=5.6Hz,2H),2.67(s,3H),2.20(s,3H).

[0235] Example 67: 6-benzyl-N-(4-isopropoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-N-(4-isopropoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.34 mmol) in DMF (3 mL) was added EDC.HCl (98 mg, 0.51 mmol), HOBT (69 mg, 0.51 mmol), and DIEA (88 mg, 0.68 mmol) followed by 1-(4-isopropoxyphenyl)methanamine hydrochloride (103 mg, 0.51 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-(4-isopropoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (81.3 mg, yield: 54.03%) as a white solid. LCMS (ESI+): C 27 H 28 N3O3[M+H] + Calculated m / z: 442.2; measured: 442.2. 1HNMR(400MHz,DMSO-d6,δ):9.07(t,J=6.0Hz,1H),8.44(s,1H),7.90(m,1H),7.41-7.15(m,7H),6.98-6.82(m,2H),6. 71(d,J=7.5Hz,1H),5.21(s,2H),4.62-4.56(m,1H),4.40(d,J=5.8Hz,2H),2.65(d,J=1.7Hz,3H),1.41-1.24(m,6H).

[0236] Example 68: 6-benzyl-2-methyl-N-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1.6-benzyl-2-methyl-N-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) in DMF (2 mL) at 0° C., EDC.HCl (65.1 mg, 0.340 mmol) and HOBT (68.8 mg, 0.510 mmol) were added, followed by benzenemethanamine, 4-methyl- (61.7 mg, 0.510 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was purified by reverse phase column 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-2-methyl-N-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (58.8 mg, yield: 42.7%) as a white solid. LCMS(ESI+):C 25 H 24 N3O2[M+H] + Calculated m / z: 398.2; measured: 398.1. 1HNMR(400MHz,DMSO-d6,δ):9.12-9.10(m,1H),8.45(s,1H),7.91(d,J=7.6Hz,1H),7.36-7.32(m,7H),7. 18(d,J=8.0Hz,2H),6.72(d,J=7.6Hz,1H),5.22(s,2H),4.45(d,J=6.0Hz,2H),2.67(s,3H),2.30(s,3H).

[0237] Example 69: N-(benzo[d][1,3]dioxol-5-ylmethyl)-6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of N-(benzo[d][1,3]dioxol-5-ylmethyl)-6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.340 mmol) in DMF (2 mL) was added EDC.HCl (97.7 mg, 0.510 mmol) and HOBT (68.9 mg, 0.510 mmol), followed by 1-(2H-1,3-benzodioxol-5-yl)methanamine (77.0 mg, 0.510 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The crude was purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give N-(benzo[d][1,3]dioxol-5-ylmethyl)-6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (60.9 mg, yield: 41.1%) as a white solid. LCMS (ESI+): C 25 H 22 N3O4[M+H] + Calculated m / z: 428.2; measured: 428.1. 1HNMR(400MHz,DMSO-d6,δ):9.10-9.07(m,1H),8.44(s,1H),7.99(d,J=7.6Hz,1H),7.36-7.32(m,5H) ,7.30-7.29(m,3H),6.88-6.85(m,1H),6.01(s,2H),5.98(s,2H),4.39(d,J=5.6Hz,2H),2.66(s,3H).

[0238] Example 70: 2-Methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-6-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-6-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide 2-Methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-6-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide was synthesized in a similar manner to Example 1 as a white solid (13.7 mg). LCMS (ESI+): C 21 H 20 N3O3S[M+H] + Calculated m / z: 394.1; measured: 394.1. 1 HNMR(400MHz,DMSO-d6,δ):9.10-9.07(m,1H),8.45-8.44(m,1H),7.94(d,J=7.6Hz,1H),7.47-7.44(m,1H),7.22-7.21(m,1H),7.01-6.9 8(m,1H),6.72(d,J=7.6Hz,1H),6.20(d,J=2.8Hz,1H),6.03-6.02(m,1H),5.37(s,2H),4.43(d,J=5.6Hz,2H),2.66(s,3H),2.26(s,3H).

[0239] Example 71: 6-benzyl-2-methyl-5-oxo-N-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-2-methyl-5-oxo-N-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide 6-Benzyl-2-methyl-5-oxo-N-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide was synthesized in a similar manner to Example 1 as a white solid (74.1 mg). LCMS (ESI+): C 22 H 20 N3O2S[M+H] + Calculated m / z: 390.1; measured: 390.1. 1 HNMR(400MHz,DMSO-d6,δ):9.28-9.26(m,1H),8.45(s,1H),7.92(d,J=7.6Hz,1H),7.44-7.43(m,1H),7.37-7.27(m ,5H),7.06-7.01(m,1H),7.00-6.99(m,1H),6.72(d,J=7.6Hz,1H),5.22(s,2H),4.66(d,J=6.0Hz,2H),2.67(s,3H).

[0240] Example 72: 6-(2-Methoxyethyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 6-(2-methoxyethyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide 6-(2-Methoxyethyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide was synthesized in a similar manner to Example 20 as a white solid (14.9 mg). LCMS (ESI+): C 19 H 22 N3O4[M+H] + Calculated m / z: 356.1; measured: 356.1. 1 HNMR(400MHz,DMSO-d6,δ):9.06-9.05(m,1H),8.42(s,1H),7.73(d,J=7.6Hz,1H),6.66(d,J=7.6Hz,1H),6.20(d,J=2.4Hz, 1H),6.03(s,1H),4.43(d,J=5.2Hz,2H),4.18-4.15(m,2H),3.64-3.61(m,2H),3.25-3.24(m,3H),2.65(s,3H),2.26(s,3H).

[0241] Example 73: 6-benzyl-N-(2-(furan-2-yl)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of 1,6-benzyl-N-(2-(furan-2-yl)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide 6-Benzyl-N-(2-(furan-2-yl)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide was synthesized as a white solid (65.0 mg) in a similar manner to Example 1. LCMS (ESI+): C 23 H 22 N3O3[M+H] + Calculated m / z: 388.1; measured: 388.1. 1HNMR(400MHz,DMSO-d6,δ):8.72-8.69(m,1H),8.41(s,1H),7.90(d,J=7.6Hz,1H),7.55(s,1H),7.37-7.29(m,5H),6.71(d ,J=7.6Hz,1H),6.39-6.38(m,1H),6.21(d,J=3.2Hz,1H),5.22(s,2H),3.56-3.51(m,2H),2.92-2.89(m,2H),2.62(s,3H).

[0242] Example 74: 2-Amino-6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of diethyl 1,2-methylpyridine-3,5-dicarboxylate [ka] A solution of ethyl 2-formyl-3-oxopropanoate (10.0 g, 69.38 mmol) in ether (100 mL) was added dropwise with Et3N (7.7 g, 76.09 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and dissolved in DMF (150 mL), after which 4-methylbenzene-1-sulfonyl chloride (14.6 g, 76.58 mmol) was added dropwise at 0° C., and the resulting mixture was stirred at room temperature for 4 h. Ethyl (2Z)-3-aminobut-2-enoate (9.4 g, 72.77 mmol) and pyridine (21.8 g, 275.60 mmol) were added to the mixture. The reaction was stirred at 80° C. overnight under nitrogen atmosphere. The reaction was quenched with H2O at 0° C. and extracted with EtOAc. The combined organic layers were washed with NaCl(aq) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with EtOAc (0-50%) in petroleum ether to give diethyl 2-methylpyridine-3,5-dicarboxylate (8.4 g, yield: 51.0%) as a yellow solid. LCMS (ESI+): C 12 H16 NO4[M+H] + Calculated m / z: 238; measured: 238.

[0243] 2. Synthesis of (E)-2-(2-(dimethylamino)vinyl)pyridine-3,5-dicarboxylate diethyl [ka] A solution of diethyl 2-methylpyridine-3,5-dicarboxylate (2.0 g, 8.43 mmol) and (diethoxymethyl)dimethylamine (1.5 g, 10.2 mmol) in DMF (20 mL) was stirred overnight at 100° C. under a nitrogen atmosphere. The reaction solution was used in the next step without further treatment. LCMS (ESI+): 15 H 21 N2O4[M+H] + Calculated m / z: 293; measured: 293.

[0244] 3. Synthesis of ethyl 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)pyridine-3,5-dicarboxylate (from previous step, 20 mL DMF solution) and benzylamine (1.1 g, 10.26 mmol) in EtOH (10 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO to give ethyl 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (2.2 g, yield: 88.3%) as a white solid. The crude was used in the next step without further purification. LCMS (ESI+): C 18 H 17 N2O3[M+H] + Calculated m / z: 309; measured value: 309.

[0245] 4. Synthesis of 6-benzyl-3-(ethoxycarbonyl)-5-oxo-5,6-dihydro-1,6-naphthyridine 1-oxide [ka] A solution of ethyl 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (1 g, 3.24 mmol) in DCM (10 mL) was added to m-CPBA (2.7 g, 15.6 mmol) in portions at 0 °C, and the solution was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was diluted with H2O and quenched by adding Na2SO3 at 0 °C. The resulting mixture was extracted with CHCl2, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with MeOH (0-10%) in CHCl2 to give 880 mg (crude) of 6-benzyl-3-(ethoxycarbonyl)-5-oxo-5,6-dihydro-1,6-naphthyridine 1-oxide as a yellow solid. LCMS (ESI+): C 18 H 17 N2O4[M+H] + Calculated m / z: 325; measured: 325.

[0246] Synthesis of ethyl 6-benzyl-2-chloro-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of 6-benzyl-3-(ethoxycarbonyl)-5-oxo-5,6-dihydro-1,6-naphthyridine 1-oxide (880 mg, 2.71 mmol) in POCl3 (6 mL) and dioxane (4 mL) was stirred at 100° C. for 4 h under nitrogen atmosphere. The reaction was quenched by addition of water at 0° C., extracted with EtOAc, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by reverse flash chromatography eluting with MeCN, 5% to 100% in water (0.1% FA) to give ethyl 6-benzyl-2-chloro-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (400 mg, yield: 47.3%) as a yellow solid. LCMS (ESI+): C 18 H 16 ClN2O3[M+H] + Calculated m / z: 343; measured: 343.

[0247] 6. Synthesis of ethyl 6-benzyl-2-((tert-butoxycarbonyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of ethyl 6-benzyl-2-chloro-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (400 mg, 1.16 mmol), tert-butyl carbamate (290 mg, 2.47 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), Xantphos (140 mg, 0.24 mmol), and Cs2CO3 (1.2 g, 3.68 mmol) in THF (10 mL) was stirred at 60° C. for 2 h under nitrogen atmosphere. The resulting mixture was filtered, extracted with EtOAc, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by reverse flash chromatography eluting with MeCN, 5% to 100% in water (0.1% FA) to give ethyl 6-benzyl-2-((tert-butoxycarbonyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (200 mg, yield: 40.4%) as a yellow solid. LCMS (ESI+): C 23 H26 N3O5[M+H] + Calculated m / z: 424; measured: 424.

[0248] 7. Synthesis of 6-benzyl-2-((tert-butoxycarbonyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-benzyl-2-((tert-butoxycarbonyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (200 mg, 0.47 mmol) and NaOH (114 mg, 2.85 mmol) in MeOH (1.5 mL), THF (1.5 mL), and HO (0.5 mL) was stirred at 40° C. for 1 h. The mixture was acidified to pH 7 with concentrated HCl (1 mol / L) and purified by reverse flash chromatography eluting with MeCN, 5% to 100% in water (0.1% FA) to give 6-benzyl-2-((tert-butoxycarbonyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (55 mg, yield: 29.4%) as a yellow solid. LCMS (ESI+): C 21 H 22 N3O5[M+H] + Calculated m / z: 396; measured: 396.

[0249] 8. Synthesis of tert-butyl (6-benzyl-5-oxo-3-((pyridin-2-ylmethyl)carbamoyl)-5,6-dihydro-1,6-naphthyridin-2-yl)carbamate [ka] To a solution of 6-benzyl-2-((tert-butoxycarbonyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (55 mg, 0.13 mmol) in DMF (1 mL) was added EDC.HCl (40 mg, 0.20 mmol) and HOBT (28 mg, 0.20 mmol), followed by 2-pyridinemethanamine (23 mg, 0.21 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. The crude was then purified by reverse flash chromatography eluting with MeOH in water (0.5% NH4HCO3), 5% to 100%, to give tert-butyl (6-benzyl-5-oxo-3-((pyridin-2-ylmethyl)carbamoyl)-5,6-dihydro-1,6-naphthyridin-2-yl)carbamate (45 mg, yield: 66.6%) as a yellow solid. LCMS (ESI+): C 27 H 28 N5O4[M+H] + Calculated m / z: 486; measured: 486.

[0250] 9. Synthesis of 2-amino-6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] A solution of tert-butyl (6-benzyl-5-oxo-3-((pyridin-2-ylmethyl)carbamoyl)-5,6-dihydro-1,6-naphthyridin-2-yl)carbamate (45 mg, 0.09 mmol) in HCl (gas) in 1,4-dioxane (1 mL) was stirred at 30° C. for 3 h. The resulting mixture was concentrated under reduced pressure and purified by reverse flash chromatography eluting with MeOH, 5% to 100%, in water (0.5% NH4HCO3) to give 2-amino-6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridin-3-carboxamide (5.9 mg, yield: 16.4%) as a white solid. LCMS (ESI+): C 22 H 20 N5O2[M+H] +Calculated m / z: 386.1; measured: 386.1. 1 HNMR(400MHz,DMSO-d6,δ):9.43(t,J=5.8Hz,1H),8.76(s,1H),8.52(d,J=4.8Hz,1H),7.79 -7.74(m,4H),7.37-7.26(m,7H),6.31(d,J=7.6Hz,1H),5.14(s,2H),4.54(d,J=5.6Hz,2H).

[0251] Example 75: 6-(4-chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 6-(4-chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide 6-(4-chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide was synthesized in a similar manner to Example 61 as a white solid (20.5 mg). LCMS (ESI+): C 23 H 19 ClFN4O2[M+H] + Calculated m / z: 437.1; measured: 437.1. 1 HNMR(400MHz,DMSO-d6,δ):9.25-9.22(m,1H),8.56-8.53(m,2H),7.95(d,J=7.6Hz,1H),7.84-7.79(m,1H),7.60-7.56(m,1H),7 .43-7.40(m,2H),7.34-7.29(m,1H),7.20-7.18(m,1H),6.75(d,J=7.6Hz,1H),5.22(s,2H),4.59(d,J=6.0Hz,2H),2.69(s,3H).

[0252] Example 76: 6-(3,4-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 6-(3,4-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (66 mg, 0.200 mmol) in DMF (2 mL) was added EDC.HCl (57.4 mg, 0.300 mmol) and HOBT (40.5 mg, 0.300 mmol) followed by (2-methyloxazol-4-yl)methanamine (33.6 mg, 0.300 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(3,4-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (49.1 mg, yield: 57%) as a white solid. LCMS (ESI+): C 22 H 19 F2N4O3[M+H] + Calculated m / z: 425.1; measured: 425.1. 1 HNMR(400MHz,DMSO-d6,δ):9.04-9.01(m,1H),8.44(s,1H),7.94(d,J=7.6Hz,1H),7.85(s,1H),7.46-7.37(m,2 H),7.19(d,J=8.3Hz,1H),6.73(d,J=7.6Hz,1H),5.18(s,2H),4.32(d,J=5.6Hz,2H),2.65(s,3H),2.40(s,3H).

[0253] Example 77: 6-(4-chlorobenzyl)-N-((5-(2-(2-methoxyethoxy)ethoxy)pyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 6-(4-Chlorobenzyl)-N-((5-(2-(2-methoxyethoxy)ethoxy)pyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide was synthesized in a similar manner to Example 51 as a white solid (42.0 mg). LCMS (ESI+): C 28 H 30 ClN4O5[M+H] + Calculated m / z: 537.2; measured: 537.2.

[0254] Example 78: 6-(4-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 6-(4-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(4-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (50 mg, 0.160 mmol) in DMF (2 mL) was added EDC.HCl (50 mg, 0.261 mmol) and HOBT (34 mg, 0.252 mmol) followed by (2-methyloxazol-4-yl)methanamine (60 mg, 0.535 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The residue was purified by reverse flash chromatography eluting with a gradient of 10% to 100% MeCN in water (0.5% NH4HCO3) in 40 min to give 6-(4-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (27.9 mg, yield: 47.6%). LCMS (ESI+): C 22 H 20 FN4O3[M+H] + Calculated m / z: 407.1; measured: 407.2. 1 HNMR(400MHz,DMSO-d6,δ):9.03-9.00(m,1H),8.45(s,1H),7.93(d,J=7.6Hz,1H),7.86(s,1H),7.42-7.38( m,2H),7.20-7.15(m,2H),6.72(d,J=7.2Hz,1H),5.19(s,2H),4.33-4.31(m,2H),2.64(s,3H),2.40(s,3H).

[0255] Example 79: 6-(3-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 6-(3-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(3-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (50 mg, 0.160 mmol) and in DMF (2 mL) was added EDC.HCl (46.0 mg, 0.240 mmol) and HOBT (12.9 mg, 0.096 mmol) at 0° C., followed by (2-methyloxazol-4-yl)methanamine (26.9 mg, 0.240 mmol). The reaction mixture was stirred at room temperature for 2 h. The residue was purified by reverse flash chromatography eluting with a gradient of 10% to 100% MeCN in water (0.5% NH4HCO3) in 40 min to give 6-(3-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (22.3 mg, yield: 34.2%). LCMS (ESI+): C 22 H 20 FN4O3[M+H] + Calculated m / z: 407.1; measured: 407.1. 1 HNMR(400MHz,DMSO-d6,δ):9.02-9.01(m,1H),8.45(s,1H),7.94(d,J=7.6Hz,1H),7.86(s,1H),7.42-7.38(m ,1H),7.24-7.11(m,3H),6.72(d,J=7.2Hz,1H),5.23(s,2H),4.32(d,J=5.6Hz,2H),2.66(s,3H),2.40(s,3H).

[0256] Example 80: 6-(4-chlorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] 1. Synthesis of 6-(4-chlorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (100 mg, 0.304 mmol) in DMF (2 mL) was added EDC.HCl (87 mg, 0.456 mmol) and HOBT (61 mg, 0.456 mmol), followed by (2-methyloxazol-4-yl)methanamine (51 mg, 0.456 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(4-chlorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (55.9 mg, yield: 45.9%). LCMS (ESI+): C 22 H 20 ClN4O3[M+H] + Calculated m / z: 423.1; measured: 423.1. 1 HNMR(400MHz,DMSO-d6,δ):9.02-8.99(m,1H),8.44(s,1H),7.92(d,J=7.6Hz,1H),7.85(s,1H),7 .42-7.34(m,4H),6.73-6.71(m,1H),5.20(s,2H)4.32(d,J=4.8Hz,2H),2.66(s,3H),2.40(s,3H).

[0257] Example 81: 6-(3,5-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 6-(3,5-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate [ka] A solution of (E)-diethyl 2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.816 mmol) and 1-(3,5-difluorophenyl)methanamine (233.6 mg, 1.63 mmol) in EtOH (2.5 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The mixture was cooled to 0° C. and the precipitated solid was collected by filtration and washed with HO (3×2 mL) to give ethyl 6-(3,5-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (170 mg, 58.1%). LCMS (ESI+): C 19 H 17 F2N2O3[M+H] + Calculated m / z: 359; measured value: 359.

[0258] Synthesis of 2.6-(3,5-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid [ka] A solution of ethyl 6-(3,5-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (180 mg, 0.502 mmol) and NaOH (60 mg, 1.50 mmol) in MeOH (3 mL) and H2O (1 mL) was stirred at 40°C for 8 h. The residue was acidified to pH 4 with concentrated HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 6-(3,5-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a white solid (120 mg, yield: 72.3%). LCMS (ESI+): C 17 H 13 F2N2O3[M+H] + Calculated m / z: 331; measured: 331.

[0259] 3. Synthesis of 6-(3,5-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide [ka] To a solution of 6-(3,5-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (50 mg, 0.151 mmol) in DMF (2 mL) was added EDC.HCl (46 mg, 0.240 mmol) and HOBT (32 mg, 0.237 mmol), followed by (2-methyloxazol-4-yl)methanamine (64 mg, 0.571 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The crude was then purified by reverse phase column (gradient: 0-50% ACN / H2O (0.5% NH4HCO3)) to give 6-(3,5-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (25.5 mg, yield: 38.5%). LCMS (ESI+): C 22 H 19 F2N4O3[M+H] + Calculated m / z: 425.1; measured: 425.1. 1 HNMR(400MHz,DMSO-d6,δ):9.02-9.01(m,1H),8.45(s,1H),7.92(d,J=7.6Hz,1H),7.86(d,J=1.1Hz,1H),7.20 -7.14(m,1H),7.10-7.00(m,2H),6.79-6.72(m,1H),5.22(s,2H),4.41-4.08(m,2H),2.67(s,3H),2.40(s,3H).

[0260] Biological Examples TFEB-translocation assay HEK-293T-oEX-TFEB-GFP cell line [Table 2]

[0261] 2. Cell Culture and Compound Dilution Cultivation of HEK-293T-oEX-TFEB-GFP cell line 1).2×10 6 The cells were added to a T75 flask containing 15 mL of DMEM medium (containing 10% FBS, 1% PS, 1X GLUTAMAX, 1X MEM NEAA, 1X HEPES buffer, and 5 ug / mL blasticidin). 2). Culture for 48-72 hours. Cells in the logarithmic growth phase were harvested for the experiment. Other cells were passaged as described in step 1. 3).1×10 4 30 μL / well of cells were seeded in a 384-well plate (BD 356663) and cultured overnight at 37° C. in a 5% CO2 incubator. 4). Note: Cells used were <10 passages 2.2. Compound Dilution and Treatment 1) Compounds were first diluted in DMSO to the required stocks (10 mM), aliquoted and stored at -20°C. 2) One aliquot was taken each time and 3-fold or 2-fold dilutions were made as indicated for a total of 10 doses + 1 DMSO control well in the source plate. 3) 150 or 90 nL / well compound solution was added to the assay plate by ECHO and incubated at 37° C. and 5% CO 2 incubator for 6 or 18 hours, respectively.

[0262] 3. Translocation Assay 3.1. Cell fixation 1) 30uL of 8% PFA was added to the wells and incubated at room temperature for 20 minutes. 2) The medium was discarded and the wells were washed twice with DPBS to remove bubbles and air bubbles in the wells. Nuclear staining 1) Hoechest-333824 was diluted in DPBS to give a 2ug / mL solution and 30uL / well was added to the assay plate and incubated at room temperature for 20 minutes. 2) The supernatant was discarded and the wells were washed twice with DPBS to remove bubbles and air bubbles in the wells. Then, 20 uL of DPBS was added per well. 3) The plates were scanned using Operetta. 3.3. Plate map for TFEB translocation assay 1) Reference compound: Torin 1 2).Test compounds: C1, C2, C3, C4, C5, C6. 3) Compounds were diluted into a 384 LDV dilution plate according to the dilution plate map. 4). Compound starting concentrations: Torin 1: 300 nM and test compound: 50 uM.

[0263] 4. Data Analysis: TFEB Translocation Positive Cell Ratio 1) All nuclei were selected by Operetta as "all cells". 2) The average EGFP intensity within the nuclear region was calculated. 3) The population with EGFP mean intensity in the nuclear region > background was selected as EGFP positive cells. 4) A region around the nucleus was selected and the average EGFP intensity of the region was calculated. 5) Within the EGFP-positive cell population, cells with EGFP average intensity in the nuclear region / EGFP average intensity in the surrounding region = 1.2 (this ratio can be slightly adjusted at any time) were selected as translocation-positive cells. 6) The ratio of translocation positive cells / EGFP positive cells was output as the translocation positive ratio. 7) Each time, the ratio of the DMSO group (control group) was set to approximately 15%, and then the compound groups were normalized to the DMSO group. EC of reference compound Torin 1 50 was 28.34 nM.

[0264] Example data [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]

[0265] In vitro hepatic microsomal metabolic stability assays for different species 1. Liver microsomes were stored at -80°C before use. The information of liver microsomes is listed in Table 2. [Table 4]

[0266] 2. A master solution was prepared according to Table 3. [Table 5]

[0267] 3. 40 μL of 10 mM NADPH solution was added to each well. The final concentration of NADPH was 1 mM. The mixture was pre-warmed at 37°C for 5 min. A negative control sample was prepared by replacing the NADPH solution with 40 μL of ultrapure H2O. The negative control was used to eliminate misleading factors due to the instability of the chemical itself. Samples containing NADPH were prepared in duplicate. One negative control was prepared.

[0268] 4. The reaction was started by adding 2 μL of 200 μM control or test compound solution. Verapamil was used as a positive control in this study. The final concentration of test or control compound was 1 μM.

[0269] 5. Aliquots of 50 μL were removed from the reaction solution at 0 and 30 min. The reaction was stopped by the addition of 4 volumes of cold acetonitrile containing internal standards (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen). The samples were centrifuged at 3,220 g for 40 min. An aliquot of 90 μL of the supernatant was mixed with 90 μL of ultrapure HO and then used for LC-MS / MS analysis.

[0270] 6. Data Analysis All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. Slope values ​​k were determined by linear regression of the natural logarithm of the percentage remaining parent drug versus incubation time curve.

[0271] In vitro half-life (in vitro t 1 / 2 ) was determined from the gradient value:

number

number

number

Table 6

Table 7

Claims

1. A pharmaceutically acceptable carrier or diluent and a compound represented by formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (in the formula, R １ H, Halo, C １－６ Alkyl, non-aromatic C ３－８ Carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryl, or 9 or 10 membered bicyclic heteroaryl, and the C １－６ Alkyl groups optionally have 1 to 3 R groups. １ａ Substituted with the non-aromatic C ３－８ Carbocyclyls, 4-6 membered monocyclic heterocyclyls, 6-10 membered bicyclic heterocyclyls, phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryls, and 9 or 10 membered bicyclic heteroaryls each optionally contain 1 to 3 R groups. １ｃ Replaced by, R １ａ is, for each occurrence, independently, halo, -OR １ｂ , non-aromatic C ３－８ carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl, wherein the non-aromatic C ３－８ carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered bicyclic heteroaryl are each, optionally, substituted with 1 to 3 R １ｃ groups, R １ｂ H, C １－６ Alkyl, or -[CH ２ -CH ２ -O] ｚ -CH ３ And, z is between 1 and 3. R １ｃ For each occurrence, independently, Halo, C １－６ Alkyl, C １－６ Haloalkyl, -OR １ｂ , -NR １ｄ R １ｄ -CN, -NO ２ , -C(O)R １ｂ , -C(O)OR １ｂ , -C(O)NR １ｄ R １ｄ , or -NR １ｄ C(O)R １ｂ And, R １ｄ is H or C １－６ It is alkyl, R ２ is H or C １－６ Is it alkyl? Or R １ and R ２ These, together with the carbon atoms to which they bond, form non-aromatic C ３－８ Carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryl, or 9 or 10 membered bicyclic heteroaryl, each of which optionally forms 1-3 R groups. １ｃ Replaced by, R ３ H, Halo, C １－６ Alkyl, non-aromatic C ３－８ Carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryl, or 9 or 10 membered bicyclic heteroaryl, and the C １－６ Alkyl groups optionally have 1 to 3 R groups. ３ａ Substituted with the non-aromatic C ３－８ Carbocyclyls, 4-6 membered monocyclic heterocyclyls, 6-10 membered bicyclic heterocyclyls, phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryls, and 9 or 10 membered bicyclic heteroaryls each optionally contain 1 to 3 R groups. ３ｃ Replaced by, R ３ａ For each occurrence, independently, halo, -OR ３ｂ , non-aromatic C ３－８ Carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryl, or 9 or 10 membered bicyclic heteroaryl, and the non-aromatic C ３－８ Carbocyclyls, 4-6 membered monocyclic heterocyclyls, 6-10 membered bicyclic heterocyclyls, phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryls, and 9 or 10 membered bicyclic heteroaryls each optionally contain 1 to 3 R groups. ３ｃ Replaced by, R ３ｂ H, C １－６ Alkyl, or -[CH ２ -CH ２ -O] ｙ -CH ３ And, y is between 1 and 3. R ３ｃ For each occurrence, independently, Halo, C １－６ Alkyl, C １－６ Haloalkyl, -OR ３ｂ , -NR ３ｄ R ３ｄ -CN, -NO ２ , -C(O)R ３ｂ , -C(O)OR ３ｂ , -C(O)NR ３ｄ R ３ｄ , or -NR ３ｄ C(O)R ３ｂ And, R ３ｄ is H or C １－６ It is alkyl, R ４ is H or C １－６ It is alkyl, R ５ H, Halo, -NR ５ａ R ５ｂ , C １－６ Alkyl, or C １－６ It is a haloalkyl, R ５ａ and R ５ｂ Each of these is independently H or C １－６ A pharmaceutical composition containing (which is alkyl), However, if the pharmaceutical composition is a compound of the following formula: 【Chemistry 2】 A pharmaceutical composition that does not contain any pharmaceutically acceptable salts thereof.

2. R ５ However, -CH ３ The pharmaceutical composition according to claim 1.

3. R １ is H, C １－６ alkyl, non-aromatic C ３－８ carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- or 6-membered monocyclic heteroaryl, wherein said C １－６ alkyl is optionally substituted with 1 to 3 R １ａ s, and said non-aromatic C ３－８ carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- or 6-membered monocyclic heteroaryl is each optionally substituted with 1 or 2 R １ｃ s, or R １ and R ２ together with the carbon to which they are attached optionally form a phenyl substituted with 1 or 2 R １ｃ s, the pharmaceutical composition according to claim 1 or 2.

4. R １ is a non-aromatic C ３－８ carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- or 6-membered monocyclic heteroaryl, and the non-aromatic C ３－８ carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- or 6-membered monocyclic heteroaryl is each optionally substituted with one or two R １ｃ The pharmaceutical composition according to claim 1 or 2.

5. R １ However, the group consisting of bicyclo[1.1.1]pentanyl, phenyl, pyridyl, thiophenyl, tetrahydropyranil, tetrahydrofuranil, and oxetanil is selected, and each of these is optionally selected from one or two R １ｃ A pharmaceutical composition according to claim 1 or 2, which is substituted with

6. R １ However, the group consisting of bicyclo[1.1.1]pentanyl, phenyl, thiophenyl, tetrahydropyranil, tetrahydrofuranil, and oxetanil is selected, and each of these is optionally selected to have one or two R １ｃ A pharmaceutical composition according to claim 1 or 2, which is substituted with

7. R １ｃ However, for each occurrence, C １－６ Alkyl, -OR １ｂ , or halo, R １ｂ However, -[CH ２ -CH ２ -O] ｚ -CH ３ The pharmaceutical composition according to claim 1 or 2.

8. R ３ However, H, C １－６ Alkyl, 6-10 membered bicyclic heterocyclyl, phenyl, or 5 or 6 membered monocyclic heteroaryl, and the C １－６ Alkyl groups optionally have 1 to 3 R groups. ３ａ The 6-10 membered bicyclic heterocyclyl, phenyl, or 5 or 6 membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R ３ｃ A pharmaceutical composition according to claim 1 or 2, which is substituted with

9. R ３ However, the compound is a 6-10 membered bicyclic heterocycline, phenyl, or a 5 or 6 membered monocyclic heteroaryl, and each of the 6-10 membered bicyclic heterocycline, phenyl, or 5 or 6 membered monocyclic heteroaryls is optionally comprised of one or two R ３ｃ A pharmaceutical composition according to claim 1 or 2, which is substituted with

10. R ３ However, the compound is a 6-10 membered bicyclic heterocycline or a 5 or 6 membered monocyclic heteroaryl, and each of the 6-10 membered bicyclic heterocycline or 5 or 6 membered monocyclic heteroaryl is optionally composed of one or two R ３ｃ A pharmaceutical composition according to claim 1 or 2, which is substituted with

11. R ３ The compounds are phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridazinyl, pyrazinyl, thiophenyl, benzodioxoyl, furanyl, oxazoyl, oxadiazoyl, pyrazoyl, or triazoyl, and each of the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, benzodioxoyl, furanyl, oxazoyl, oxadiazoyl, pyrazoyl, or triazoyl is optionally composed of 1 to 2 R compounds. ３ｃ A pharmaceutical composition according to claim 1 or 2, which is substituted with

12. The compound is represented by formula (II), 【Transformation 3】 or a pharmaceutically acceptable salt thereof (in the formula, m is between 0 and 2. R １ｃ It is independent, Haro, C １－６ Alkyl, or -OR １ｂ And, R １ｂ is, -[CH ２ -CH ２ -O] ｚ -CH ３ And, R ３ This is an optional choice of one or two R ３ｃ A 5- or 6-membered monocyclic heteroaryl that is substituted with, R ３ｃ is a halo or C １－６ The pharmaceutical composition according to claim 1, wherein it is alkyl.

13. R ３ The pharmaceutical composition according to claim 1 or 2, wherein the compound is pyridyl.

14. R ３ｃ However, for each appearance, Halo, C １－６ Alkyl, C １－６ Haloalkyl, -OR ３ｂ , or -C(O)NR ３ｄ R ３ｄ The pharmaceutical composition according to claim 1 or 2.

15. R ３ｃ However, for each occurrence, -CH ３ , -CF ３ , -Cl, -F, -OCH ３ , -OCH(CH ３ ) ２ , or -C(O)NH ２ The pharmaceutical composition according to claim 1 or 2.

16. R ２ and R ４ The pharmaceutical composition according to claim 1 or 2, wherein both are H.

17. R １ａ However, -OR １ｂ And R ３ａ However, for each occurrence, independently, halo, -OR ３ｂ The pharmaceutical composition according to claim 1 or 2, wherein the composition is a 5- or 6-membered monocyclic heteroaryl.

18. R １ｃ However, -F, -Cl, or -CH ３ And R ３ｃ However, -F, Cl, or -CH ３ The pharmaceutical composition according to claim 1 or 2.

19. The aforementioned compound, 6-benzyl-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-((5-fluoropyridine-2-yl)methyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((5-methyloxazole-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((2-methyloxazole-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-(3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((6-methylpyridine-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((1-methyl-1H-1,2,3-triazole-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((2-methyl-2H-1,2,3-triazole-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((3-methyl-1,2,4-oxadiazole-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridine-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((5-methyl-1,3,4-oxadiazole-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((1-methyl-1H-pyrazole-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((1-methyl-1H-pyrazole-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N,6-dibenzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((2-methyloxazole-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((5-methyl-1,2,4-oxadiazole-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-methoxyethyl)-2-methyl-N-((2-methyloxazole-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide 6-benzyl-2-methyl-5-oxo-N-(pyridine-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(4-(trifluoromethyl)benzyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(4-chlorobenzyl)-2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(1-(pyridine-2-yl)ethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyrimidine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-methoxyethyl)-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyrazine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyridazine-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(pyrimidine-5-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((5-fluoropyridine-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((3-fluoropyridine-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-6-(1-phenylethyl)-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((5-chloropyridine-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((4-fluoropyridine-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(cyclohexylmethyl)-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-N,6-bis(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N,2-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(4-carbamoylbenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-((5-fluoropyridine-2-yl)methyl)-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-Isopropyl-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-6-phenyl-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-fluorobenzyl)-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-6-((5-methyloxazole-2-yl)methyl)-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-6-((1-methyl-1H-pyrazole-4-yl)methyl)-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((4,5-difluoropyridine-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-N-((5-fluoropyridine-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-6-(pyridine-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2,6-dimethyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-fluorobenzyl)-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-((5-chloro-4-fluoropyridine-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-6-(pyridine-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-((5-chloropyridine-2-yl)methyl)-6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-N-((4,5-difluoropyridine-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-N-((5-fluoropyridine-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-((5-chloropyridine-2-yl)methyl)-6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-((4-methyloxazole-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(4-isopropoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-N-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, N-(benzo[d][1,3]dioxol-5-ylmethyl)-6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-6-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-2-methyl-5-oxo-N-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(2-methoxyethyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-benzyl-N-(2-(furan-2-yl)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 2-amino-6-benzyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridine-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-N-((5-(2-(2-methoxyethoxy)ethoxy)pyridine-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3,4-difluorobenzyl)-2-methyl-N-((2-methyloxazole-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-fluorobenzyl)-2-methyl-N-((2-methyloxazole-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(3-fluorobenzyl)-2-methyl-N-((2-methyloxazole-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, 6-(4-chlorobenzyl)-2-methyl-N-((2-methyloxazole-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, and Selected from 6-(3,5-difluorobenzyl)-2-methyl-N-((2-methyloxazole-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide, The pharmaceutical composition according to claim 1, or a pharmaceutically acceptable salt thereof.

20. Compounds represented by formula (II): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof (in the formula, R ２ is H or C １－６ It is alkyl, R ４ is H or C １－６ It is alkyl, R １ｃ These are independently, halo or C １－６ It is alkyl, m is between 0 and 2. If m is 0, R ３ This is a five-membered monocyclic heteroaryl or six-membered monocyclic heteroaryl selected from the group consisting of oxazoyl, oxadiazoyl, pyrazoyl, and triazoyl, each of which can optionally contain one or two R ３ｃ It is replaced by, or If m is 1 or 2, R ３ This is an optional selection of one or two R's. ３ｃ A 5- or 6-membered monocyclic heteroaryl that is substituted with, R ３ｃ is a halo or C １－６ (It is alkyl.)

21. R ２ and R ４ The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein both are H.

22. R ３ These are pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazoyl, oxadiazoyl, pyrazoyl, or triazoyl, each of which can be optionally given one or two R ３ｃ A compound according to claim 20 or 21, or a pharmaceutically acceptable salt thereof, substituted with.

23. R ３ The compound according to claim 20 or 21, or a pharmaceutically acceptable salt thereof, wherein the compound is pyridyl.

24. Each R １ｃ However, independently, H, -Cl, -F, or -CH ３ And each R ３ｃ However, independently, -F, -Cl, or -CH ３ The compound according to claim 20 or 21, or a pharmaceutically acceptable salt thereof.

25. R １ｃ However, H, -Cl, or -CH ３ And R ３ｃ The compound according to claim 20 or 21, or a pharmaceutically acceptable salt thereof, wherein the compound is -F.

26. A compound according to claim 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 1, for treating a disease mediated by the transcription factor EB.

27. A compound according to claim 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 1, for treating lysosomal storage disorders, infections, metabolic diseases, muscle diseases, neurodegenerative diseases, renal diseases, hematological diseases, or ocular diseases.

28. The aforementioned lysosomal storage disorders include Gaucher disease, Pompe disease, NPC, cystinosis, Krabbe disease, Sanfilippo syndrome, multiple sulfatase deficiencies, alpha-mannose disease, Fabry disease, Hunter syndrome, Schayet syndrome, Maloto-Lamy syndrome, hyaluronidase deficiency, sialidosis, mucolipidine 1 deficiency, neuronal ceroid lipofuscinosis (Batten disease), mucopolysaccharidosis types I, II, III, IV, VI, VII, and IX, Haller-Schaye syndrome, Morquio syndrome, and glycoprotein The following conditions are selected: leukemia, glycogen storage disease, metachromatic leukodystrophy, Sly syndrome, I-cell disease, Danon disease, Niemann-Pick disease types A, B, C1, and C2, Sandhoff disease, lysosomal acid lipase deficiency, GM2 ganglioside storage disease, Tay-Sachs disease, Gaucher disease, Salah disease, cholesteryl ester storage disease, aspartylglucosamiuria, cystinosis, mucolipidosis types I-IV, Schindler disease types I and II, Wolmann disease, fucoside disease, concentrated dysostosis, and free sialic acid storage disease. The aforementioned infections are selected from bacterial infections, viral infections, and eukaryotic parasites. The aforementioned metabolic and muscle diseases are selected from α1 antitrypsin deficiency, polymyositis, and DMD. The aforementioned neurodegenerative disease is selected from Parkinson's disease, Huntington's disease, Alzheimer's disease, and Lewy body dementia. The aforementioned kidney disease is selected from PKD, AKI, renal interstitial fibrosis, and diabetic nephropathy. The aforementioned blood disorder is β-thalassemia. The compound according to claim 27, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the ocular disease is selected from macular degeneration and retinitis pigmentosa.

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