Transcription factor EB activating factor and application thereof

Abstract

Provided herein are pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Formula (I): # imgabs0 # or a pharmaceutically acceptable salt thereof, which are useful for activating TFEB and treating a variety of diseases or conditions such as lysosomal storage disease.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 333,669, filed Apr. 22, 2022. The entire content of the above application is hereby expressly incorporated by reference. Technical Field

[0003] The present disclosure relates to transcription factor EB (TFEB) activators and pharmaceutically acceptable salts thereof, compositions of these compounds, methods for their preparation, their use for treating diseases, their use, optionally in combination with a pharmaceutically acceptable carrier, for manufacturing a pharmaceutical formulation, the use of the pharmaceutical formulation for treating diseases, and methods of treating diseases, including administering a TFEB activator to a warm-blooded animal, particularly a human. Background Art

[0004] Autophagy is a process by which cells recycle intracellular materials to obtain energy and thereby avoid cell death caused by stress, nutrient deprivation, or cell damage (Mizushima et al., 2008, Nature, 451(7182), 1069-1075). In addition to providing nutrients, the autophagy pathway also acts as a “self-cleaning” pathway, breaking down misfolded or otherwise non-functional proteins, cellular components, or any other harmful or unwanted substances that the cell no longer needs. During autophagy, cellular components marked for degradation are enclosed in a phagophore, forming an autophagosome, which then fuses with a lysosome, initiating the degradation process. This catabolic process regenerates amino acid building blocks and other cellular materials that can be used to synthesize other proteins, and also generates ATP, the energy used in other cellular processes (Glick et al. (2010) The Journal of Pathology, 221(1), 3-12).

[0005] Transcription factor EB (TFEB) has been shown to be a major regulator of the autophagy process, activating genes involved in lysosome expression and other related functions (Settembre et al., (2011), Science, 332(6036), 1429-1433). When activated, TFEB translocates from the cytoplasm 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 autophagy stimulation, activation of TFEB is a potential therapeutic option for a variety of diseases that either have an accumulation of non-functional or harmful proteins (such as Alzheimer's disease) or have inappropriate lysosomal activity (such as lysosomal storage diseases) (Napolitano et al., 2016, J. Cell. Sci., 129(13), 2475-2481).

[0006] Accordingly, there is a need for TFEB activators as potential therapeutic agents for treating diseases or disorders responsive to TFEB activation. SUMMARY OF THE INVENTION

[0007] The present disclosure provides compounds or pharmaceutical compositions thereof as TFEB activators. Unexpectedly, the compounds disclosed herein have better potency and / or lower in vitro clearance compared to known compounds. In one aspect, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof. Definitions of each variable are described herein.

[0010] In another aspect, the present disclosure provides a method of treating a disease or disorder responsive to TFEB activation in a subject, the method comprising administering to the subject an effective amount of at least one compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof described herein and a pharmaceutically acceptable carrier or diluent.

[0011] Another aspect of the present disclosure relates to the use of at least one compound or a pharmaceutically acceptable salt thereof described herein in the preparation of a medicament for treating a disease or disorder responsive to TFEB activation. Also provided are the compounds or pharmaceutically acceptable salts thereof described herein, or a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof described herein and a pharmaceutically acceptable carrier or diluent, for treating a disease or disorder responsive to TFEB activation. Detailed implementation manners

[0012] The present disclosure provides compounds and pharmaceutical compositions thereof that can be used to treat diseases or disorders by activating the function / activity of TFEB. In some embodiments, the compounds of the present disclosure are TFEB activators.

[0013] Compounds and compositions

[0014] In a first embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by formula (I):

[0015]

[0016] or a pharmaceutically acceptable salt thereof, wherein

[0017] R 1 is H, a halogen group, C 1-6 alkyl, non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein the C 1-6 alkyl is optionally substituted by one to three R 1a substituents, and wherein the non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl are each optionally substituted by one to three R 1c substituents;

[0018] R 1a is independently, each time it appears, a halogen group, -OR 1b , non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein the non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl are each optionally substituted by one to three R 1c substituents;

[0019] R 1b is H, C 1-6 alkyl or -[CH2-CH2-O] z -CH3;

[0020] z is from 1 to 3;

[0021] R 1c is independently, each time it appears, a halogen group, C1-6 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 ;

[0022] R 1d is H or C 1-6 alkyl;

[0023] R 2 is H or C 1-6 alkyl;

[0024] or R 1 and R 2 together with the carbon to which it is attached form a non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, each of which is optionally substituted by one to three R 1c substituents;

[0025] R 3 is H, halo, C 1-6 alkyl, non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein the C 1-6 alkyl is optionally substituted by one to three R 3a substituents, wherein the non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl are each optionally substituted by one to three R 3c substituents;

[0026] R 3a is independently at each occurrence halo, -OR 3b , non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein the non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl are each optionally substituted by one to three R3c Substituted;

[0027] R 3b is H, C 1-6 alkyl or -[CH2-CH2-O] y -CH3;

[0028] y is from 1 to 3;

[0029] R 3c is independently, at each occurrence, a halogen group, C 1-6 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 ;

[0030] R 3d is H or C 1-6 alkyl;

[0031] R 4 is H or C 1-6 alkyl;

[0032] R 5 is H, a halogen group, -NR 5a R 5b , C 1-6 alkyl or C 1-6 haloalkyl;

[0033] R 5a and R 5b are each independently H or C 1-6 alkyl;

[0034] provided that the pharmaceutical composition does not include a compound of the following formula:

[0035]

[0036] or a pharmaceutically acceptable salt thereof.

[0037] In a second embodiment, the present disclosure provides a pharmaceutical composition according to the first embodiment, wherein R 5 is -CH3; and the remaining variables are as described in the first embodiment.

[0038] In a third embodiment, the present disclosure provides a pharmaceutical composition according to the first or second embodiment, wherein R 1 is H, C1-6 alkyl, non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, phenyl group, or 5- or 6-membered monocyclic heteroaryl group, wherein said C 1-6 alkyl group is optionally substituted with one to three R 1a groups, wherein said non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, phenyl group, or 5- or 6-membered monocyclic heteroaryl group is each optionally substituted with one or two R 1c groups, or wherein R 1 and R 2 together with the carbon to which they are attached form a phenyl group optionally substituted with one or two R 1c groups; and the remaining variables in the first or second embodiment are as described in the first or second embodiment, respectively.

[0039] In a fourth embodiment, the present disclosure provides a pharmaceutical composition according to the first or second embodiment, wherein R 1 is a non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, phenyl group, or 5- or 6-membered monocyclic heteroaryl group, wherein said non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, phenyl group, or 5- or 6-membered monocyclic heteroaryl group is each optionally substituted with one or two R 1c groups; and the remaining variables are as described in the first or second embodiment.

[0040] In a fifth embodiment, the present disclosure provides a pharmaceutical composition according to the first or second embodiment, wherein R 1 is selected from the group consisting of bicyclo[1.1.1]pentyl, phenyl, pyridyl, thienyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, wherein each is optionally substituted with one or two R 1c groups; and the remaining variables are as described in the first or second embodiment.

[0041] In a sixth embodiment, the present disclosure provides a pharmaceutical composition according to the first or second embodiment, wherein R 1 is selected from the group consisting of bicyclo[1.1.1]pentyl, phenyl, thienyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, wherein each is optionally substituted with one or two R 1c groups; and the remaining variables are as described in the first or second embodiment.

[0042] In a seventh embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, or sixth embodiment, wherein R 1c is, each time it appears, C 1-6 alkyl, -OR 1b or halo, and wherein R 1bis -[CH2-CH2-O] z -CH3; and the remaining variables are as described in the first, second, third, fourth, fifth or sixth embodiment.

[0043] In the eighth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth or seventh embodiment, wherein R 3 is H, C 1-6 alkyl, a 6- to 10-membered bicyclic heterocyclic group, phenyl or a 5- or 6-membered monocyclic heteroaryl group, wherein the C 1-6 alkyl is optionally substituted with one to three R 3a substituents, and the 6- to 10-membered bicyclic heterocyclic group, phenyl or 5- or 6-membered monocyclic heteroaryl group are each optionally substituted with one to three R 3c substituents; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth or seventh embodiment.

[0044] In the ninth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth or seventh embodiment, wherein R 3 is a 6- to 10-membered bicyclic heterocyclic group, phenyl or a 5- or 6-membered monocyclic heteroaryl group, wherein the 6- to 10-membered bicyclic heterocyclic group, phenyl or 5- or 6-membered monocyclic heteroaryl group are each optionally substituted with one or two R 3c substituents; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth or seventh embodiment.

[0045] In the tenth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth or seventh embodiment, wherein R 3 is a 6- to 10-membered bicyclic heterocyclic group or a 5- or 6-membered monocyclic heteroaryl group, wherein the 6- to 10-membered bicyclic heterocyclic group or 5- or 6-membered monocyclic heteroaryl group are each optionally substituted with one or two R 3c substituents; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth or seventh embodiment.

[0046] In the eleventh embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment, wherein R 3 is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, benzodioxolyl, furyl, oxazolyl, oxadiazolyl, pyrazolyl or triazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, benzodioxolyl, furyl, oxazolyl, oxadiazolyl, pyrazolyl or triazolyl are each optionally substituted with one to two R 3cSubstituted; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0047] In a twelfth embodiment, the present disclosure provides a pharmaceutical composition according to the first embodiment, wherein the compound is represented by formula (II):

[0048]

[0049] or a pharmaceutically acceptable salt thereof, wherein:

[0050] m is from 0 to 2;

[0051] R 1c is independently a halogen group, C 1-6 alkyl or -OR 1b ;

[0052] R 1b is -[CH2-CH2-O] z -CH3;

[0053] R 3 is an optionally 5- or 6-membered monocyclic heteroaryl substituted by one or two R 3c ;

[0054] R 3c is a halogen group or C 1-6 alkyl; and the remaining variables are as described in the first embodiment.

[0055] 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, wherein 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.

[0056] 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, wherein R 3c is, each time it appears, a halogen group, 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.

[0057] 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, wherein R 3c is, each time it appears, -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.

[0058] 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, wherein 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.

[0059] In a seventeenth embodiment, the present disclosure provides a pharmaceutical composition according to the first, second, and third embodiments, wherein R 1a is -OR 1b and R 3a is, each time it appears, independently a halogen group, -OR 3b or a 5- or 6-membered monocyclic heteroaryl; and the remaining variables are as described in the first, second, or third embodiment.

[0060] 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, wherein R 1c is -F, -Cl, or -CH3 and 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.

[0061] In a nineteenth embodiment, the present disclosure provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of any one of Examples 1 to 81) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0062] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound selected from the group consisting of:

[0063] 6-Benzyl-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0064] 6-((5-Fluoropyridin-2-yl)methyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0065] 6-Benzyl-2-methyl-N-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0066] 6-Benzyl-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0067] 6-Benzyl-2-methyl-N-(3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0068] 6-Benzyl-2-methyl-N-((6-methylpyridin-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0069] 6-Benzyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0070] 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;

[0071] 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;

[0072] 6-Benzyl-2-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0073] N-(4-Chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0074] 6-Benzyl-2-methyl-5-oxo-N-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0075] 6-Benzyl-2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0076] 6-Benzyl-2-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0077] 6-Benzyl-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0078] 6-Benzyl-N-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0079] N,6-Dibenzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0080] 6-Benzyl-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0081] 6-Benzyl-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0082] N-(4-Chlorobenzyl)-6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0083] 6-(2-Methoxyethyl)-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0084] 6-Benzyl-N-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0085] 6-Benzyl-2-methyl-5-oxo-N-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0086] 6-Benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0087] 6-Benzyl-2-methyl-5-oxo-N-(4-(trifluoromethyl)benzyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0088] N-(4-Chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0089] N-(4-Chlorobenzyl)-2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0090] 6-Benzyl-2-methyl-5-oxo-N-(1-(pyridin-2-yl)ethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0091] 6-Benzyl-2-methyl-5-oxo-N-(pyrimidin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0092] 6-(2-Methoxyethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0093] 6-(4-Chlorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0094] 6-Benzyl-2-methyl-5-oxo-N-(pyrazin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0095] 6-Benzyl-2-methyl-5-oxo-N-(pyridazin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0096] 6-Benzyl-2-methyl-5-oxo-N-(pyrimidin-5-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0097] 6-Benzyl-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0098] 6-Benzyl-N-((3-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0099] 2-Methyl-5-oxo-6-(1-phenylethyl)-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0100] 6-Benzyl-N-((5-chloropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0101] 6-Benzyl-N-((4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0102] 6-(Cyclohexylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0103] 2-Methyl-5-oxo-N,6-bis(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0104] 6-Benzyl-N,2-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0105] 6-Benzyl-N-(4-carbamoylbenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0106] 6-((5-Fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0107] 6-Isopropyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0108] 2-Methyl-5-oxo-6-phenyl-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0109] 6-(4-Fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0110] 2-Methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0111] 2-Methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0112] 6-Benzyl-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0113] 6-(4-Chlorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0114] 2-Methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0115] 2,6-Dimethyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0116] 2-Methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0117] 6-(3-Fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0118] 6-(2-Fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0119] 6-Benzyl-N-((5-chloro-4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0120] 2-Methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0121] 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;

[0122] 6-(Bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0123] 6-(3,4-Difluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0124] 6-(3,4-Difluorobenzyl)-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0125] 6-(3,4-Difluorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0126] 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;

[0127] 6-Benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0128] 6-Benzyl-2-methyl-N-((4-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0129] 6-Benzyl-N-(4-isopropoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0130] 6-Benzyl-2-methyl-N-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0131] N-(Benzo[d][1,3]dioxol-5-ylmethyl)-6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0132] 2-Methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-6-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0133] 6-Benzyl-2-methyl-5-oxo-N-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0134] 6-(2-Methoxyethyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0135] 6-Benzyl-N-(2-(furan-2-yl)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0136] 2-Amino-6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0137] 6-(4-Chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0138] 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;

[0139] 6-(3,4-Difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0140] 6-(4-Fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0141] 6-(3-Fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0142] 6-(4-Chlorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide; and

[0143] 6-(3,5-Difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0144] or a pharmaceutically acceptable salt thereof.

[0145] In the twentieth embodiment, the present disclosure provides a compound represented by formula (II):

[0146]

[0147] or a pharmaceutically acceptable salt thereof, wherein:

[0148] R 2 is H or C 1-6 alkyl;

[0149] R 4 is H or C 1-6 alkyl;

[0150] R 1c is independently a halogen group or C 1-6 alkyl;

[0151] m is from 0 to 2;

[0152] When m is 0, R 3 is a 5-membered monocyclic heteroaryl or 6-membered monocyclic heteroaryl selected from the group consisting of oxazolyl, oxadiazolyl, pyrazolyl, and triazolyl, each of which is optionally substituted by one or two R 3c substituents; or

[0153] When m is 1 or 2, R 3 is a 5- or 6-membered monocyclic heteroaryl optionally substituted by one or two R 3c substituents;

[0154] R 3c is a halogen group or C 1-6 alkyl.

[0155] In the twenty-first embodiment, the present disclosure provides a compound according to the twentieth embodiment or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 are both H; and the remaining variables are as described in the twentieth embodiment.

[0156] In the twenty-second embodiment, the present disclosure provides a compound according to the twentieth or twenty-first embodiment or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, oxadiazolyl, pyrazolyl, or triazolyl, each of which is optionally substituted by one to two R 3c substituents; and the remaining variables are as described in the twentieth or twenty-first embodiment.

[0157] In the twenty-third embodiment, the present disclosure provides a compound according to the twentieth, twenty-first, or twenty-second embodiment or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridyl; and the remaining variables are as described in the twentieth, twenty-first, or twenty-second embodiment.

[0158] In the twenty-fourth embodiment, the present disclosure provides a compound according to the twentieth, twenty-first, twenty-second, or twenty-third embodiment or a pharmaceutically acceptable salt thereof, wherein each R 1c is independently H, -Cl, -F, or -CH3, and wherein 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.

[0159] In the twenty-fifth embodiment, the present disclosure provides a compound according to the twentieth, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1c is H, -Cl or -CH3, and wherein R 3c is -F; and the remaining variables are as described in the twentieth, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment.

[0160] In the twenty-sixth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0161] 6-((5-Fluoropyridin-2-yl)methyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0162] 6-Benzyl-2-methyl-N-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0163] 6-Benzyl-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0164] 6-Benzyl-2-methyl-N-(3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0165] 6-Benzyl-2-methyl-N-((6-methylpyridin-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0166] 6-Benzyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0167] 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;

[0168] 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;

[0169] 6-Benzyl-2-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0170] N-(4-Chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0171] 6-Benzyl-2-methyl-5-oxo-N-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0172] 6-Benzyl-2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0173] 6-Benzyl-2-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0174] 6-Benzyl-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0175] 6-Benzyl-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0176] 6-Benzyl-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0177] 6-(2-Methoxyethyl)-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0178] 6-Benzyl-2-methyl-5-oxo-N-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0179] 6-Benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0180] 6-Benzyl-2-methyl-5-oxo-N-(4-(trifluoromethyl)benzyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0181] N-(4-Chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0182] N-(4-Chlorobenzyl)-2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0183] 6-Benzyl-2-methyl-5-oxo-N-(1-(pyridin-2-yl)ethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0184] 6-Benzyl-2-methyl-5-oxo-N-(pyrimidin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0185] 6-(2-Methoxyethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0186] 6-(4-Chlorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0187] 6-Benzyl-2-methyl-5-oxo-N-(pyrazin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0188] 6-Benzyl-2-methyl-5-oxo-N-(pyridazin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0189] 6-Benzyl-2-methyl-5-oxo-N-(pyrimidin-5-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0190] 6-Benzyl-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0191] 6-Benzyl-N-((3-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0192] 2-Methyl-5-oxo-6-(1-phenylethyl)-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0193] 6-Benzyl-N-((5-chloropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0194] 6-Benzyl-N-((4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0195] 6-(Cyclohexylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0196] 2-Methyl-5-oxo-N,6-bis(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0197] 6-Benzyl-N,2-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0198] 6-Benzyl-N-(4-carbamoylbenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0199] 6-((5-Fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0200] 6-Isopropyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0201] 2-Methyl-5-oxo-6-phenyl-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0202] 6-(4-Fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0203] 2-Methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0204] 2-Methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0205] 6-Benzyl-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0206] 6-(4-Chlorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0207] 2-Methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0208] 2,6-Dimethyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0209] 2-Methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0210] 6-(3-Fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0211] 6-(2-Fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0212] 6-Benzyl-N-((5-chloro-4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0213] 2-Methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0214] 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;

[0215] 6-(Bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0216] 6-(3,4-Difluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0217] 6-(3,4-Difluorobenzyl)-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0218] 6-(3,4-Difluorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0219] 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;

[0220] 6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0221] 6-benzyl-2-methyl-N-((4-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0222] 2-amino-6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0223] 6-(4-chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0224] 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;

[0225] 6-(3,4-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0226] 6-(4-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0227] 6-(3-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0228] 6-(4-chlorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide; and

[0229] 6-(3,5-difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide;

[0230] or a pharmaceutically acceptable salt thereof.

[0231] In the 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0232] In the twenty-eighth embodiment, the present disclosure provides a method for treating a lysosomal storage disease, an infection, a metabolic disease, a muscle disease, a neurodegenerative disease, a kidney disease, a hematological disease or an ophthalmic disease, the method 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 pharmaceutically 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.

[0233] In the twenty-ninth embodiment, the present disclosure provides the method according to the twenty-eighth embodiment, wherein:

[0234] The lysosomal storage diseases are selected from Gaucher disease, Pompe disease, NPC, cystinosis, Krabbe disease, Sanfilipposyndrome, multiple sulfatase deficiency, alpha-mannosidosis, Fabry disease, Hunter syndrome, Scheie syndrome, Maroteaux-Lamy syndrome, hyaluronidase deficiency, sialidosis, mucolipidin 1deficiency, neuronal ceroidlipofuscinoses (Batten disease), type I, type II, type III, type IV, type VI, type VII and type IX mucopolysaccharidoses, Hurler-Scheie syndrome, Morquio syndrome, glycoproteinosis, glycogenstorage disease, metachromatic Leukodystrophy, Sly syndrome, I-cell disease, Danon disease, type A, type B, type C1 and type C2 Niemann-Pick disease, Sandhoff disease, lysosomal acid lipase deficiency, gangliosidoses, Tay-Sachs disease, Gaucher disease, Salla disease, cholesteryl ester storagedisease), aspartylglucosaminuria, cystinosis, mucolipidosis I-IV, Schindler disease type I and II, Wolman disease, fucosidosis, pycnodysostosis, and free sialic acid storage disease;

[0235] The infection is selected from bacterial infection, viral infection, and eukaryotic parasites;

[0236] The metabolic and muscle diseases are selected from α1-antitrypsin deficiency, polymyositis, and DMD;

[0237] The neurodegenerative diseases are selected from Parkinson's, Huntington's, Alzheimer's, and Lewy Body Dementia;

[0238] The kidney diseases are selected from PKD, AKI, renal interstitial fibrosis, and diabetic nephropathy;

[0239] The hematological disease is β-thalassemia; and

[0240] The ophthalmic diseases are selected from Macular Degeneration and Retinitis Pigmentosa.

[0241] In a thirtieth embodiment, the present disclosure provides a method for treating a TFEB-mediated disease or disorder, the method comprising administering to a subject an effective amount of the pharmaceutical composition or compound disclosed herein.

[0242] The compounds and intermediates described herein can be isolated and the compounds themselves can be used, i.e., in the neutral form. Alternatively, when moieties capable of forming salts are present, the compounds or intermediates can be isolated and used in their corresponding salt forms. As used herein, the term "salt / salts" refers to acid addition salts or base addition salts of the compounds described herein. "Salt" particularly encompasses "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 generally biologically or otherwise desirable. In many cases, the compounds of the present disclosure are capable of forming acidic and / or basic salts by virtue of the presence of amino and / or carboxyl or similar groups.

[0243] Pharmaceutically acceptable acid addition salts can be formed with inorganic or organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromides, bicarbonates / carbonates, bisulfates / sulfates, camphorsulfonates, chlorides / hydrochlorides, choline salts, citrates, edisylates, fumarates, glucoheptonates, gluconates, glucuronates, hippurates, hydroiodides / iodides, isethionates, lactates, lactobionates, lauryl sulfates, malates, maleates, malonates, mandelates, mesylates, methyl sulfates, naphthoates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, pamoates, phosphates / monohydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, stearates, succinates, sulfates, sulfosalicyclates, tartrates, toluenesulfonates, and trifluoroacetates.

[0244] Inorganic acids from which such salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0245] Organic acids from which such salts may 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.

[0246] Salts can be synthesized from compounds containing basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.) or by reacting the free base form of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or an organic solvent or a mixture of both. In general, if feasible, it is desirable to use a non-aqueous medium, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of other suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0247] Method of Use

[0248] The compounds disclosed herein have TFEB activation or stimulatory activity. As used herein, "TFEB activation activity" or "TFEB stimulatory activity" refers to the ability of a compound or composition to induce a detectable increase in TFEB activity (e.g., an increase in TFEB activity of at least 10% as measured by established assays such as the biological assays described in the examples and known in the art) in vivo or in vitro.

[0249] In certain embodiments, the present disclosure provides a method of treating a disease or disorder responsive to TFEB activity activation (referred to herein as a TFEB-mediated disease or disorder) in a subject in need thereof. The method comprises 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 pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0250] In certain embodiments, the present disclosure provides 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 pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a TFEB-mediated disease or disorder in a subject in need thereof.

[0251] In certain embodiments, the present 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 pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for treating a TFEB-mediated disease or disorder in a subject in need thereof.

[0252] In certain embodiments, the present disclosure provides a method of treating a lysosomal storage disease, an infection, a metabolic disease, a muscle disease, a neurodegenerative disease, a kidney disease, a hematological disease or an ophthalmic disease in a subject in need thereof. The method comprises 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 pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0253] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a pharmaceutical composition as in any one of the first to nineteenth or twenty-seventh embodiments or a compound as in any one of the twentieth to twenty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating a lysosomal storage disease, an infection, a metabolic disease, a muscle disease, a neurodegenerative disease, a kidney disease, a hematological disease or an ophthalmic disease in a subject in need of treatment.

[0254] In certain embodiments, the present disclosure provides a compound described herein (e.g., a pharmaceutical composition as in any one of the first to nineteenth or twenty-seventh embodiments or a compound as in any one of the twentieth to twenty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for treating a lysosomal storage disease, an infection, a metabolic disease, a muscle disease, a neurodegenerative disease, a kidney disease, a hematological disease or an ophthalmic disease in a subject in need of treatment.

[0255] In some embodiments, the lysosomal storage disease is selected from Gaucher disease, Pompe disease, NPC, cystinosis, Krabbe disease, Schindler disease, multiple sulfatase deficiency, alpha-mannosidosis, Fabry disease, Hunter syndrome, Scheie syndrome, Maroteaux-Lamy syndrome, hyaluronidase deficiency, sialidosis, mucolipin 1 deficiency, neuronal ceroid lipofuscinosis (Batten disease), types I, II, III, IV, VI, VII and IX mucopolysaccharidosis, Hurler-Scheie syndrome, Morquio syndrome, glycoprotein storage disease, glycogen storage disease, metachromatic leukodystrophy, Sly syndrome, I-cell disease, Danon disease, types A, B, C1 and C2 Niemann-Pick disease, Sandhoff disease, lysosomal acid lipase deficiency, GM2 gangliosidosis, Tay-Sachs disease, Gaucher disease, Salla disease, cholesterol ester storage disease, aspartylglucosaminuria, cystinosis, types I-IV mucolipidosis, types I and II Schindler disease, Wolman disease, fucosidosis, pycnodysostosis and free sialic acid storage disease.

[0256] In some embodiments, the infection is selected from bacterial infection, viral infection and eukaryotic parasites.

[0257] In some embodiments, the metabolic and muscle diseases are selected from alpha1-antitrypsin deficiency, polymyositis and Duchenne Muscular Dystrophy (DMD).

[0258] In some embodiments, the neurodegenerative disease is selected from Parkinson's disease, Huntington's disease, Alzheimer's disease and Lewy body dementia.

[0259] In some embodiments, the kidney disease is selected from polycystic kidney disease (PKD), acute kidney injury (AKI), renal interstitial fibrosis, and diabetic nephropathy.

[0260] In some embodiments, the hematological disease is β-thalassemia.

[0261] In some embodiments, the ophthalmic disease is selected from macular degeneration and retinitis pigmentosa.

[0262] In certain embodiments, the present disclosure relates to the foregoing method, wherein the subject is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

[0263] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. It means an amount effective to treat one or more diseases, disorders or conditions recited herein or to reduce their severity. In some embodiments, the effective dose can be between 10 μg and 500 mg.

[0264] The compounds and compositions of the methods according to the present disclosure can be administered in any amount and by any route of administration effective to treat one or more of the diseases, disorders or conditions recited above or to reduce their severity.

[0265] In certain embodiments, the present disclosure relates to the foregoing method, wherein the compound is administered parenterally. In certain embodiments, the present disclosure relates to the foregoing method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, by inhalation, rectally, intrathecally, topically, or intranasally. In certain embodiments, the present disclosure relates to the foregoing method, wherein the compound is administered systemically.

[0266] The compounds of the present invention can be used as pharmaceutical compositions (e.g., a compound of the present invention and at least one pharmaceutically acceptable carrier or diluent). As used herein, the term "pharmaceutically acceptable carrier or diluent" includes solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, pharmaceutical 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 that are generally recognized as safe (GRAS) by those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, Mack Printing Company, 1990, pp. 1289-1329). Except in cases where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. For the purposes of this disclosure, solvates and hydrates are considered to include pharmaceutical compositions of the compounds of the present invention and a solvent (i.e., solvate) or water (i.e., hydrate).

[0267] Formulations can be prepared using conventional dissolution and mixing procedures. For example, a bulk drug substance (i.e., a compound of the present invention or a stabilized form of said 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 excipients. The compounds of the present invention are generally formulated into pharmaceutical dosage forms to provide a readily controllable dosage of the drug and to provide an aesthetically pleasing and easily disposable product for the patient.

[0268] The pharmaceutical compositions (or formulations) for administration can be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for dispensing contains a container in which a suitable form of the pharmaceutical formulation is placed. 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-proof assembly to prevent easy access to the contents of the package. Additionally, a label describing the contents of the container is placed on the container. The label can also include appropriate warnings.

[0269] Pharmaceutical compositions comprising the compounds of the present disclosure are generally formulated for parenteral or oral administration or alternatively can be used as suppositories.

[0270] For example, the oral pharmaceutical compositions of the present disclosure can be made in solid forms (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or liquid forms (including but not limited to solutions, suspensions, or emulsions). Conventional pharmaceutical operations (such as sterilization) can be performed on the pharmaceutical compositions and / or they can contain conventional inert diluents, lubricants, or buffers as well as adjuvants (such as preservatives, stabilizers, wetting agents, emulsifying agents, and buffers, etc.).

[0271] Typically, a pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and the following substances:

[0272] a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0273] b) lubricants such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, also including:

[0274] c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary, including:

[0275] d) disintegrants such as starch, agar, alginic acid or its sodium salt or effervescent mixtures; and / or

[0276] e) absorbents, colorants, flavorants and sweeteners.

[0277] Tablets can be film-coated or enteric-coated by methods known in the art.

[0278] Compositions suitable for oral administration comprise a compound of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft gelatin capsules, or syrups or elixirs. Compositions intended for oral use are prepared by 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, flavorants, colorants and preservatives in order to provide a pharmaceutically elegant and palatable formulation. Tablets may contain a mixture of the active ingredient and non-toxic pharmaceutically acceptable excipients 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 may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, retard materials such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or in the form of soft gelatin capsules in which the active ingredient is mixed with a water or oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0279] A parenteral composition (e.g., an intravenous (IV) formulation) is an aqueous isotonic solution or suspension. The parenteral composition can be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubilizing agents, salts for adjusting osmotic pressure, and / or buffers. In addition, it can contain other substances of therapeutic value. The compositions are generally prepared according to conventional mixing, granulating, or coating methods, and contain from about 0.1% to 75% or from about 1% to 50% of the active ingredient.

[0280] The compounds or their pharmaceutical compositions of the present disclosure for use in a subject (e.g., a human) are generally administered orally or parenterally at a therapeutic dose. When administered intravenously via infusion, the dose can depend on the infusion rate of the IV formulation. Generally, the therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, body weight, age, and individual medical condition of the subject, the disorder or disease being treated, or the severity thereof. A generally skilled physician, pharmacist, clinician, or veterinarian can readily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of a disorder or disease.

[0281] It is advantageously possible to demonstrate the dose characteristics cited above in vitro and in vivo using mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and preparations. The compounds of the invention can be applied in vitro in the form of a solution (e.g., an aqueous solution) and, for example, in vivo enterally, parenterally, advantageously intravenously, in the form of a suspension or an aqueous solution. The in vitro dose can be in the range between about 10 -3 molar concentration and 10 -9 molar concentration.

[0282] Definitions

[0283] As used herein, the terms “patient,” “subject,” or “individual” are used interchangeably and refer to a human or non-human animal. The terms include mammals such as humans. Generally, the animal is a mammal. The subject also refers to, for example, a primate (e.g., a male or female human), bovine, ovine, caprine, equine, canine, feline, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

[0284] As used herein, the terms “inhibit,” “inhibition,” or “inhibiting” refer to alleviating or curbing an established medical condition, symptom, or disorder or disease, or significantly reducing the baseline activity of a biological activity or process.

[0285] 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.

[0286] As used herein, the terms "treat," "treating," or "treatment" of any disease refer to managing and caring for a patient for the purpose of combating the disease, condition, or disorder, and includes administering a compound of the invention to obtain the desired pharmacological and / or physiological effect. The treatment includes therapeutic treatment and prophylactic treatment. Therapeutic treatment includes partially or substantially achieving one or more of the following results: partially or completely reducing the degree of the disease, condition, or disorder; alleviating or improving the clinical symptoms, complications, or signs associated with the disease, condition, or disorder; or delaying, inhibiting the progression of the disease, condition, or disorder, or reducing the likelihood of its progression. Prophylactic treatment is reducing the likelihood of a subject with known risk factors developing a disease.

[0287] As used herein, a subject "needs" treatment if the subject (preferably, a human) would benefit biologically, medically, or in terms of quality of life from such treatment.

[0288] As used herein, the phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted." Generally, the term "optionally substituted" refers to replacing a hydrogen group in a given structure with a group of a specified substituent. Specific substituents are described in the definitions and descriptions of the compounds and their examples. Unless otherwise specified, 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 can be substituted with more than one substituent selected from the specified group, the substituents at each position may be the same or different.

[0289] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. The term "C 1-4 alkyl" refers to an alkyl having 1 to 4 carbon atoms. The terms "C 1-3 alkyl" and "C 1-2 alkyl" shall be interpreted accordingly. "C 1-4Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl portion of an alkoxy group (i.e., the alkyl moiety) has the same definition as above. When indicated as "optionally substituted", the alkane group or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally one to three substituents, unless in the case of perhalogenated (e.g., perhalo or perfluoroalkyl)).

[0290] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety linked by an oxygen bridge (i.e., -O-C 1-4 alkyl, where C 1-4 alkyl is as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. Preferably, the alkoxy has about 1 to 4 carbons, more preferably about 1 to 2 carbons. The term "C 1-2 alkoxy" should be interpreted accordingly.

[0291] As used herein, the term "C 1-4 alkoxyC 1-4 alkyl" refers to C 1-4 alkyl as defined herein, where at least one hydrogen atom is replaced by a C 1-4 alkoxy. The C 1-4 alkoxyC 1-4 alkane is linked via the alkyl to the remainder of the molecule described herein.

[0292] The number of carbon atoms in a group is specified herein by the prefix "C x-xx ", where x and xx are integers. For example, "C 1-3 alkyl" is an alkyl having 1 to 3 carbon atoms.

[0293] "Halogen" or "halo" can be fluorine, chlorine, bromine, or iodine.

[0294] As used herein, the term "halo-substituted C 1-4 alkyl" or "C 1-4 haloalkyl" refers to C 1-4 alkyl as defined herein, where at least one hydrogen atom is replaced by a halogen atom. The C 1-4 haloalkyl can be mono-halo-C 1-4 alkyl, di-halo-C 1-4 alkyl, or poly-halo-C 1-4 alkyl, including perhalo-C 1-4 alkyl. Mono-halo-C 1-4 alkyl can have one iodine, bromine, chlorine, or fluorine within the alkyl. Di-halo-C 1-4 alkyl or poly-halo-C1-4 The alkyl group may have two or more identical halogen atoms or a combination of different halogen groups within the alkyl group. Generally, the polyhalo-C 1-4 alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halogen groups. C 1-4 Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. Perhalo-C 1-4 alkyl group refers to a C 1-4 alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0295] The term "aryl" refers to an aromatic carbocyclic monocyclic ring or a bicyclic system having two aromatic carbocyclic rings containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0296] The term "heteroaryl" refers to a 5- to 12-membered aromatic group containing 1 to 4 heteroatoms selected from N, O, and S. In some examples, the nitrogen atom in the heteroaryl group may be quaternized. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". The heteroaryl group can be monocyclic or bicyclic. Monocyclic heteroaryl groups include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridyl, furyl, oxadiazolyl, thienyl, etc. Bicyclic heteroaryl groups include groups in which a monocyclic heteroaryl ring is fused to one or more aryl rings or heteroaryl rings. Non-limiting examples include pyrazolopyridyl, pyrazolopyridyl, benzotriazolyl, imidazopyridyl, and indolyl.

[0297] The term "non-aromatic carbocyclic" or "non-aromatic carbocyclic group" refers to a 3- to 12-membered saturated or partially unsaturated hydrocarbon ring system and can exist in monocyclic or polycyclic (e.g., bicyclic (including fused, spiro, or bridged carbocycles) or tricyclic) forms. Bicyclic non-aromatic carbocyclic groups include, for example, unsaturated carbocyclic groups fused to another unsaturated carbocyclic group, cycloalkyl group, or aryl group, such as 2,3-dihydroindenyl, decahydronaphthyl, and 1,2,3,4-tetrahydronaphthyl. Unless otherwise specified, non-aromatic carbocycles generally contain 4 to 10 ring members.

[0298] The term "C 3-6 cycloalkyl" refers to a completely saturated carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0299] The term "heterocyclic" or "heterocyclic group" refers to a 4- to 12-membered saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclic group can be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic). Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and piperidinyl. Bicyclic heterocyclic groups include, for example, an unsaturated heterocyclic group fused to another unsaturated heterocyclic group, 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 heterocyclic group is a 4- to 6-membered monocyclic heterocyclic group. In some embodiments, the heterocyclic group is a 4- to 6-membered monocyclic saturated heterocyclic group. In some embodiments, the heterocyclic group is an 8- to 10-membered bicyclic heterocyclic group. In some embodiments, the heterocyclic group is an 8- to 10-membered bicyclic saturated heterocyclic group.

[0300] As used herein, the term "spiro" ring means a bicyclic system in which two rings share a common ring atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptanyl and the like.

[0301] The term "fused" ring refers to a two-ring system that shares two adjacent ring atoms. A fused heterocycle has at least one ring system containing ring atoms that are heteroatoms selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0302] As used herein, the term "bridged" means a bicyclic system containing 5 to 10 ring atoms and sharing three or more ring atoms, 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).

[0303] The phrase "pharmaceutically acceptable" indicates that a substance, composition, or dosage form must be chemically compatible with the other ingredients in the formulation. Alternatively or additionally, the phrase "pharmaceutically acceptable" indicates that a substance, composition, or dosage form must be toxicologically compatible with the mammal being treated therewith.

[0304] 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. When moieties capable of forming salts are present, salts are also included, especially pharmaceutically acceptable salts.

[0305] As used herein, unless otherwise indicated herein or clearly contradicted by context, the terms "a", "an", "the", and similar terms as used in the context of the present invention (especially in the context of the claims) shall be construed to cover both the singular and the plural. The use of any and all examples or exemplary language (e.g., "such as") provided herein is merely intended to better illuminate the invention and does not impose a limitation on the scope of the invention otherwise claimed.

[0306] The intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve interconversion via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety where a proton can migrate between two ring nitrogens. Valence tautomers involve interconversion via reorganization of some of the bonding electrons.

[0307] In one embodiment, the present disclosure relates to a compound of formula (I) as defined herein in free form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in salt form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in acid addition salt form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in pharmaceutically acceptable salt form. In yet another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in pharmaceutically acceptable acid addition salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the examples in free form. In yet another embodiment, the present disclosure relates to any one of the compounds of the examples in salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the examples in acid addition salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the examples in pharmaceutically acceptable salt form. In still another embodiment, the present disclosure relates to any one of the compounds of the examples in pharmaceutically acceptable acid addition salt form.

[0308] The compounds of the present disclosure can be synthesized by synthetic routes that include processes similar to those well known in the chemical art, in particular in accordance with the instructions contained herein. The starting materials are generally obtained from commercial sources such as Sigma-Aldrich or are readily prepared using methods well known to those skilled in the art (e.g., by the methods generally described in Louis F. Fieser and Mary F. Fieser, Reagents for Organic Synthesis, Volumes 1 - 19, Wiley, New York (1967 - 1999 editions) or Beilsteins Handbuch der organischen Chemie, 4th Edition, Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0309] For illustrative purposes, the reaction schemes depicted below provide possible routes for synthesizing the compounds of the present disclosure and key intermediates. For a detailed description of each reaction step, see the Examples section below. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions.

[0310] Illustrative

[0311] Abbreviations:

[0312] DCM = dichloromethane

[0313] DIPEA = DIEA = diisopropylethylamine

[0314] DMF = dimethylformamide

[0315] DMSO = dimethyl sulfoxide

[0316] EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0317] ESI = electrospray ionization

[0318] EtOAc = EA = ethyl acetate

[0319] EtOH = ethanol

[0320] FA = formic acid

[0321] H2O = water

[0322] HCl = hydrochloric acid

[0323] HPLC = high performance liquid chromatography

[0324] HOBT = 1-Hydroxybenzotriazole

[0325] K2CO3 = Potassium carbonate

[0326] LCMS = Liquid chromatography mass spectrometry

[0327] MeCN = ACN = Acetonitrile

[0328] MeOH = Methanol

[0329] N2 = Nitrogen

[0330] Na2SO4 = Sodium sulfate

[0331] NaBH4 = Sodium borohydride

[0332] NaOH = Sodium hydroxide

[0333] NH3 = Ammonia

[0334] NH4HCO3 = Ammonium bicarbonate

[0335] NMR = Nuclear magnetic resonance spectroscopy

[0336] Pd(PCy3)2Cl2 = Dichloro bis(tricyclohexylphosphine)palladium(II)

[0337] THF = Tetrahydrofuran

[0338] Example 1: 6-Benzyl-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0339]

[0340] 1. Synthesis of Diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate

[0341]

[0342] 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 was detected by LCMS. The next step was carried out without any treatment. LCMS (ESI+): C 16 H 23 N2O4 [M+H] + Calculated m / z: 307; Observed: 307.

[0343] 2. Synthesis of Ethyl 6-Benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0344]

[0345] 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; Found: 323.

[0346] 3. Synthesis of 6-Benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic Acid

[0347]

[0348] 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; Found: 295.

[0349] 4. Synthesis of 6-Benzyl-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0350]

[0351] At 0 °C, EDC·HCl (276.9 mg, 1.784 mmol) and HOBT (241.0 mg, 1.784 mmol) were added 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), and then 1-(5-methylfuran-2-yl)methanamine (198.3 mg, 1.784 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C 18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 33% B to 43% B in 8 min, 43%) to give 6-benzyl-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (136 mg, yield: 29.4%) as a white solid. LCMS (ESI+): C 23 H 22 N3O3[M + H] + Calculated m / z value: 388; experimental value: 388. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.06 (t, J = 5.6 Hz, 1H), 8.43 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.36 - 7.27 (m, 5H), 6.72 (d, J = 7.6 Hz, 1H), 6.20 (d, J = 2.8 Hz, 1H), 6.02 (d, J = 1.6 Hz, 1H), 5.22 (s, 2H), 4.43 (d, J = 5.6 Hz, 2H), 2.65 (s, 3H), 2.26 (s, 3H).

[0352] 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

[0353]

[0354] 1. Synthesis of ethyl 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0355]

[0356] A solution of diethyl (E)-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 a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (3 × 10 mL) to give ethyl 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (100 mg, yield: 44.8%) as a yellow solid. LCMS (ESI+): C 18 H 17 FN3O3[M+H] + Calculated m / z for: 342.1; found: 342.1.

[0357] 2. Synthesis of ethyl 6-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0358]

[0359] 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 (80 mg, yield: 92.0%) as a yellow solid. LCMS (ESI+): C 16 H 13 FN3O3[M+H] + Calculated m / z for: 314.1; found: 314.1.

[0360] 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

[0361]

[0362] At 0 °C, EDC·HCl (38.9 mg, 0.203 mmol) and HOBT (27.5 mg, 0.204 mmol) were added 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), followed by the addition of 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 preparative HPLC using the following conditions (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH--HPLC; flow rate: 25 mL / min; gradient: 60% B to 60% B in 10 min, 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 (10 mg, yield: 18.1%) as a white solid. LCMS (ESI+): C 22 H 20 FN4O3[M+H] + Calculated m / z for: 407.1; found: 407.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.05 (t, J = 5.6 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H), 8.38 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.44 - 7.41 (m, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.18 (d, J = 2.8 Hz, 1H), 6.02 - 6.01 (m, 1H), 5.31 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 2.66 (s, 3H), 2.25 (s, 3H).

[0363] Example 3: 6-Benzyl-2-methyl-N-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0364]

[0365] 1. Synthesis of 6-benzyl-2-methyl-N-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0366]

[0367] At 0 °C, EDC·HCl (158.2 mg, 1.020 mmol) and HOBT (137.7 mg, 1.020 mmol) were added 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), followed by the addition of (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 by preparative HPLC using the following conditions (column: XBridgePrep OBD C 18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 33% B in 8 min, 33%) to give 6-benzyl-2-methyl-N-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (22.8 mg, yield: 8.58%) as a white solid. LCMS (ESI+): C 22 H 21 N4O3 [M + H] + Calculated m / z: 389.2; Found: 389.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.25 (t, J = 5.8 Hz, 1H), 8.49 (s, 1H), 7.91 (d, J = 7.6 Hz, 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 = 5.6 Hz, 2H), 2.68 (s, 3H), 2.30 - 2.29 (m, 3H).

[0368] Example 4: 6-Benzyl-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0369]

[0370] 1. Synthesis of 6-benzyl-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0371]

[0372] At 0 °C, EDC·HCl (195.4 mg, 1.020 mmol) and HOBT (137.7 mg, 1.020 mmol) were added 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), followed by the addition of (2-methyl-oxazol-5-yl)methylamine (114.3 mg, 1.020 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C 18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 32% B in 8 min, 32%) to give 6-benzyl-2-methyl-N-((2-methyl-oxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (86.6 mg, yield: 32.7%). LCMS (ESI+): C 22 H 21 N4O3 [M + H] + Calculated m / z: 389.2; found: 389.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.13 (t, J = 5.4 Hz, 1H), 8.44 (s, 1H), 7.91 (d, J = 7.6 Hz, 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 = 5.2 Hz, 2H), 2.65 (s, 3H), 2.39 (s, 3H).

[0373] Example 5: 6-Benzyl-2-methyl-N-(3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0374]

[0375] 1. Synthesis of 6-benzyl-2-methyl-N-(3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0376]

[0377] At 0 °C, EDC·HCl (195.4 mg, 1.020 mmol) and HOBT (137.7 mg, 1.020 mmol) were added 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), and then m-tolylmethylamine (56 mg, 0.518 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 55% B in 8 min, 55% B), to give 6-benzyl-2-methyl-N-(3-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (125.7 mg, yield: 46.1%). LCMS (ESI+): C 25 H 24 N3O2 [M + H] + Calculated m / z for: 398.2; found: 398.2. 1 1H NMR (300 MHz, DMSO-d6, δ): 9.12 (t, J = 5.9 Hz, 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 = 7.5 Hz, 1H), 5.21 (s, 2H), 4.45 (d, J = 6.0 Hz, 2H), 2.66 (s, 3H), 2.31 (s, 3H).

[0378] Example 6: 6-Benzyl-2-methyl-N-((6-methylpyridin-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0379]

[0380] 1. Synthesis of 6-Benzyl-2-methyl-N-((6-methylpyridin-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0381]

[0382] At 0 °C, EDC·HCl (197.8 mg, 1.273 mmol) and HOBT (172.1 mg, 1.273 mmol) were added 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), followed by the addition of (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 by preparative HPLC using the following conditions (column: XBridge Prep OBD C 18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 35% B in 8 min, 35% B) 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 (136.4 mg, yield: 40.2%). LCMS (ESI+): C 24 H 23 N4O2 [M + H] + Calculated m / z value: 399.2; experimental value: 399.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.20 (t, J = 6.0 Hz, 1H), 8.55 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.40 - 7.24 (m, 5H), 7.17 (dd, J = 15.4, 7.7 Hz, 2H), 6.73 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 4.54 (d, J = 6.0 Hz, 2H), 2.69 (s, 3H), 2.48 (s, 3H).

[0383] Example 7: 6-Benzyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0384]

[0385] 1. Synthesis of 6-benzyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0386]

[0387] At 0 °C, EDC·HCl (97.7 mg, 0.510 mmol) and HOBT (68.87 mg, 0.510 mmol) were added 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), followed by the addition of 2-pyridylmethylamine (55.1 mg, 0.510 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 385.2; Found: 385.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.23 (t, J = 6.0 Hz, 1H), 8.55 - 8.54 (m, 2H), 7.92 (d, J = 7.6 Hz, 1H), 7.83 - 7.79 (m, 1H), 7.42 - 7.28 (m, 7H), 6.73 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.59 (d, J = 5.6 Hz, 2H), 2.69 (s, 3H).

[0388] 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

[0389]

[0390] 1. Synthesis of 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

[0391]

[0392] At 0 °C, EDC·HCl (97.7 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol) were added 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), followed by the addition of (1-methyl-1H-1,2,3-triazol-4-yl)methanamine hydrochloride (76.2 mg, 0.515 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 50% MeOH H2O (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 (5.0 mg, yield: 3.8%) as a white solid. LCMS (ESI+): C 21 H 21 N6O2[M+H] + Calculated m / z for: 389; Found: 389. 1 1H NMR (400 MHz, 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 = 7.6 Hz, 1H), 5.27 (s, 2H), 4.18 - 4.13 (m, 2H), 2.68 (s, 3H), 2.76 (s, 3H).

[0393] 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

[0394]

[0395] 1. Synthesis of 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

[0396]

[0397] At 0 °C, EDC·HCl (98.2 mg, 0.514 mmol) and HOBT (70.1 mg, 0.519 mmol) were added 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), followed by the addition of (2-methyl-2H-1,2,3-triazol-4-yl)methanamine hydrochloride (78.5 mg, 0.528 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% MeOH / H2O (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 (6.6 mg, yield: 3.8%) as a white solid. LCMS (ESI+): C 21 H 21 N6O2[M+H] + Calculated m / z for: 389; Found: 389. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.17 - 9.11 (m, 1H), 8.46 (m, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.33 - 7.26 (m, 5H), 6.71 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.52 - 4.51 (m, 2H), 4.13 (s, 3H), 2.66 (s, 3H).

[0398] 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

[0399]

[0400] 1. Synthesis of 6-Benzyl-2-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0401]

[0402] At 0 °C, EDC·HCl (97.7 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol) were added 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), followed by the addition of (3-methyl-1,2,4-oxadiazol-5-yl)methanamine hydrochloride (70.1 mg, 0.469 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% MeCN / H2O (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 H 20 N5O3[M+H] + Calculated m / z for: 390.2, found: 390.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.47 (t, J = 5.6 Hz, 1H), 8.54 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.37 - 7.27 (m, 5H), 6.73 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 2.68 (s, 3H), 2.36 (s, 3H).

[0403] Example 11: N-(4-Chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0404]

[0405] 1. Synthesis of ethyl 2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0406]

[0407] A solution of diethyl (E)-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (3 × 10 mL) to give ethyl 2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydronaphthalene-1,6-dicarboxylate (457.0 mg, yield 44.1%) as a yellow solid. LCMS (ESI+): C 17 H 21 N2O4[M+H] + Calculated m / z for: 317, found: 317.

[0408] 2. Synthesis of 2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydronaphthalene-1,6-dicarboxylic acid

[0409]

[0410] A solution of ethyl 2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydronaphthalene-1,6-dicarboxylate (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-dihydronaphthalene-1,6-dicarboxylic acid (120 mg, yield: 65.8%) as a white solid. LCMS (ESI+): C 15 H 16 N2O4[M+H] + Calculated m / z for: 289, found: 289.

[0411] 3. Synthesis of N-(4-chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydrofuran-2-yl)methyl)-5,6-dihydronaphthalene-1,6-dicarboxamide

[0412]

[0413] At 0 °C, EDC·HCl (120 mg, 0.626 mmol) and HOBT (84 mg, 0.622 mmol) were added 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), followed by the addition of 1-(4-chlorophenyl)methanamine (88 mg, 0.621 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 (96.9 mg, yield: 56.3%) as a white solid. LCMS (ESI+): C 22 H 23 ClN3O3[M+H] + Calculated m / z for: 412, found: 412. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.19 (t, J = 5.9 Hz, 1H), 8.47 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.45 - 7.39 (m, 4H), 6.66 (d, J = 7.6 Hz, 1H), 4.48 (d, J = 6.0 Hz, 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).

[0414] Example 12: 6-Benzyl-2-methyl-5-oxo-N-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0415]

[0416] 1. Synthesis of 6-benzyl-2-methyl-5-oxo-N-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0417]

[0418] At 0 °C, EDC·HCl (98 mg, 0.511 mmol) and HOBT (69 mg, 0.511 mmol) were added 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), and then 4-pyridinemethanamine (56 mg, 0.518 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 385.2, found: 385.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.26 (t, J = 5.8 Hz, 1H), 8.55 (d, J = 4.0 Hz, 3H), 7.92 (d, J = 7.6 Hz, 1H), 7.37 - 7.27 (m, 7H), 6.72 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 4.52 (d, J = 6.0 Hz, 2H), 2.68 (s, 3H).

[0419] 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

[0420]

[0421] 1. Synthesis of 6-Benzyl-2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0422]

[0423] At 0 °C, EDC·HCl (195.4 mg, 1.020 mmol) and HOBT (137.7 mg, 1.020 mmol) were added 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), followed by the addition of (5-methyl-1,3,4-oxadiazol-2-yl)methanamine hydrochloride (115.3 mg, 0.774 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 35% B in 80 min, 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 (28.3 mg, yield: 10.7%). LCMS (ESI+): C 21 H 20 N5O3 [M + H] + Calculated m / z for: 390, found: 390. 1 1H NMR (300 MHz, DMSO-d6, δ): 9.37 (t, J = 6.2 Hz, 1H), 8.51 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.34 - 7.28 (m, 5H), 6.72 (d, J = 7.5 Hz, 1H), 5.22 (s, 2H), 4.67 (d, J = 5.7 Hz, 2H), 2.87 (s, 3H), 2.51 (s, 3H).

[0424] Example 14: 6-Benzyl-2-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0425]

[0426] 1. Synthesis of 6-benzyl-2-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0427]

[0428] At 0 °C, EDC·HCl (195.4 mg, 1.020 mmol) and HOBT (137.74 mg, 1.020 mmol) were added 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), followed by the addition of 1-(1-methyl-1H-pyrazol-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 by preparative HPLC using the following conditions (column: Xselect CSH C 18 OBD column, 30 * 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / 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 (45 mg, yield: 16.8%). LCMS (ESI+): C 22 H 22 N5O2[M + H] + Calculated m / z value: 388.2, experimental value: 388.2. 1 1H NMR (400 MHz, 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 = 5.6 Hz, 2H), 3.80 (s, 3H), 2.65 (s, 3H).

[0429] Example 15: 6-Benzyl-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0430]

[0431] 1. Synthesis of 6-benzyl-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0432]

[0433] At 0 °C, EDC·HCl (97.7 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol) were added 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), followed by the addition of 1-(1-methyl-1H-pyrazol-4-yl)methanamine (56.6 mg, 0.510 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (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 (31.4 mg, yield: 23.7%) as a white solid. LCMS (ESI+): C 22 H 22 N5O2[M+H] + Calculated m / z for: 388.2, found: 388.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 8.94 (t, J = 5.6 Hz, 1H), 8.41 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.65 (s, 1H), 7.40 - 7.26 (m, 6H), 6.70 (d, J = 7.6 Hz, 1H), 5.21 (s, 2H), 4.31 (d, J = 5.6 Hz, 2H), 3.81 (s, 3H), 2.65 (s, 3H).

[0434] Example 16: 6-Benzyl-N-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0435]

[0436] 1. Synthesis of 6-benzyl-N-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0437]

[0438] At 0 °C, EDC·HCl (79.1 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol) were added 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), and then 1-(2-fluorophenyl)methanamine (63.7 mg, 0.510 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 value: 402.2, experimental value: 402.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.15 (t, J = 5.8 Hz, 1H), 8.47 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.50 - 7.41 (m, 1H), 7.39 - 7.27 (m, 6H), 7.29 - 7.18 (m, 2H), 6.72 (d, J = 7.6 Hz, 1H), 5.21 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 2.65 (s, 3H).

[0439] Example 17: N,6-Dibenzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0440]

[0441] 1. Synthesis of N,6-dibenzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0442]

[0443] At 0 °C, EDC·HCl (97.7 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol) were added 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), followed by the addition of benzylamine (54.6 mg, 0.510 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (0.5% NH4HCO3)) to give N,6-dibenzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (32.7 mg, yield: 25%) as a white solid. LCMS (ESI+): C 24 H 22 N3O2 [M+H] + Calculated m / z for: 384.2, found: 384.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.16 (t, J = 5.8 Hz, 1H), 8.48 (s, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.40 - 7.26 (m, 10H), 6.72 - 6.71 (m, 1H), 5.22 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 2.67 (s, 3H).

[0444] Example 18: 6-Benzyl-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0445]

[0446] 1. Synthesis of 6-benzyl-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0447]

[0448] At 0 °C, EDC·HCl (79.1 mg, 0.510 mmol) and HOBT (70 mg, 0.518 mmol) were added 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), and then (2-methyloxazol-4-yl)methanamine (57.1 mg, 0.510 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (0.5% FA)) to obtain 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 for: 389, found: 389. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.02 (t, J = 5.6 Hz, 1H), 8.45 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.35 - 7.28 (m, 5H), 6.71 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.33 - 4.31 (m, 2H), 2.66 (s, 3H), 2.40 (s, 3H).

[0449] 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

[0450]

[0451] 1. Synthesis of 6-Benzyl-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0452]

[0453] At 0 °C, EDC·HCl (97.7 mg, 0.510 mmol) and HOBT (68.8 mg, 0.510 mmol) were added 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), followed by the addition of (5-methyl-1,2,4-oxadiazol-3-yl)methanamine hydrochloride (71 mg, 0.476 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% MeOH / H2O (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 (15.8 mg, yield: 11.8%) as a white solid. LCMS (ESI+): C 21 H 20 N5O3[M+H] + Calculated m / z for: 390.2, found: 390.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.29 (t, J = 5.8 Hz, 1H), 8.50 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.34 - 7.26 (m, 5H), 6.72 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.57 (d, J = 5.6 Hz, 2H), 2.68 (s, 3H), 2.51 (s, 3H).

[0454] Example 20: N-(4-Chlorobenzyl)-6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0455]

[0456] 1. Synthesis of Ethyl 6-(2-Methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0457]

[0458] A solution of diethyl (E)-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 for: 291.1, found: 291.0.

[0459] 2. Synthesis of 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0460]

[0461] 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) was stirred 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 for: 263, found: 263.

[0462] 3. Synthesis of N-(4-chlorobenzyl)-6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0463]

[0464] At 0 °C, EDC·HCl (219.2 mg, 1.145 mmol) and HOBT (154.5 mg, 1.145 mmol) were added 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), followed by the addition of 1-(4-chlorophenyl)methanamine (161.9 mg, 1.145 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 (121.2 mg, yield: 40.8%) as a white solid. LCMS (ESI+): C 20 H 21 ClN3O3[M + H] + Calculated m / z for: 386, found: 386. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.18 (t, J = 5.8 Hz, 1H), 8.47 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.45 - 7.39 (m, 4H), 6.66 (d, J = 7.6 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 4.18 - 4.15 (m, 2H), 3.64 - 3.62 (m, 2H), 3.25 (s, 3H), 2.66 (s, 3H).

[0465] Example 21: 6-(2-Methoxyethyl)-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0466]

[0467] 1. Synthesis of 6-(2-Methoxyethyl)-2-methyl-N-((2-methyloxazol-5-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0468]

[0469] At 0 °C, EDC·HCl (140.5 mg, 0.736 mmol) and HOBT (119.2 mg, 0.883 mmol) were added 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), and then (2-methyloxazol-5-yl)methanamine (76.1 mg, 0.679 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% MeOH / H2O (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 for: 357, found: 357. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.12 (t, J = 5.6 Hz, 1H), 8.44 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 6.93 (s, 1H), 6.67 - 6.65 (m, 1H), 4.51 (d, J = 5.6 Hz, 2H), 4.17 (t, J = 5.2 Hz, 2H), 3.63 (t, J = 5.2 Hz, 2H), 3.25 (s, 3H), 2.66 (s, 3H), 2.40 (s, 3H).

[0470] Example 22: 6-Benzyl-N-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0471]

[0472] 1. Synthesis of 6-benzyl-N-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0473]

[0474] At 0 °C, EDC·HCl (147 mg, 0.767 mmol) and HOBT (104 mg, 0.770 mmol) were added 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), followed by the addition of 1-(4-chlorophenyl)methanamine (108 mg, 0.763 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 (47.2 mg, yield: 22.09%) as a white solid. LCMS (ESI+): C 24 H 21 Calculated m / z for ClN3O2[M+H]: 418, found: 418. 1 1H NMR (400 MHz, 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).

[0475] Example 23: 6-Benzyl-2-methyl-5-oxo-N-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0476]

[0477] 1. Synthesis of 6-benzyl-2-methyl-5-oxo-N-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0478]

[0479] At 0 °C, EDC·HCl (98 mg, 0.511 mmol) and HOBT (69 mg, 0.511 mmol) were added 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), followed by the addition of 3-pyridinemethanamine (56 mg, 0.518 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (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 for: 385.2, found: 385.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.22 (t, J = 5.8 Hz, 1H), 8.59 (d, J = 1.2 Hz, 1H), 8.49 (d, J = 3.2 Hz, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.42 - 7.39 (m, 1H), 7.36 - 7.26 (m, 5H), 6.71 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.51 (d, J = 5.6 Hz, 2H), 2.66 (s, 3H).

[0480] Example 24: 6-Benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0481]

[0482] 1. Synthesis of 6-benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0483]

[0484] At 0 °C, EDC·HCl (98 mg, 0.631 mmol) and HOBT (69 mg, 0.511 mmol) were added 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), followed by the addition of (4-methoxyphenyl)methanamine (70 mg, 0.510 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (0.5% FA)) to give 6-benzyl-N-(4-methoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (47.2 mg, yield: 33.5%) as a white solid. LCMS (ESI+): C 25 H 24 N3O3 [M+H] + Calculated m / z for: 414.2, found: 414.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.10 (t, J = 5.8 Hz, 1H), 8.44 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.36 - 7.26 (m, 7H), 6.93 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 7.6 Hz, 1H), 5.21 (s, 2H), 4.42 (d, J = 6.0 Hz, 2H), 3.73 (s, 3H), 2.66 (s, 3H).

[0485] Example 25: 6-Benzyl-2-methyl-5-oxo-N-(4-(trifluoromethyl)benzyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0486]

[0487] 1. Synthesis of 6-benzyl-2-methyl-5-oxo-N-(4-(trifluoromethyl)benzyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0488]

[0489] At 0 °C, EDC·HCl (98 mg, 0.511 mmol) and HOBT (69 mg, 0.511 mmol) were added 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), followed by the addition of 1-[4-(trifluoromethyl)phenyl]methanamine (89 mg, 0.508 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (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 for: 452.2, found: 452.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.28 (t, J = 5.8 Hz, 1H), 8.53 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.34 - 7.26 (m, 5H), 6.72 (d, J = 7.2 Hz, 1H), 5.22 (s, 2H), 4.58 (d, J = 5.6 Hz, 2H), 2.68 (s, 3H).

[0490] Example 26: N-(4-Chlorobenzyl)-2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0491]

[0492] 1. Synthesis of ethyl 2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0493]

[0494] A solution of diethyl (E)-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 (392 mg, yield: 69.4%) as a yellow solid. LCMS (ESI+): C 18 H 23 N2O4[M+H] + Calculated m / z for: 331, found: 331.

[0495] 2. Synthesis of 2-methyl-5-oxo-6-((tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0496]

[0497] 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 (129 mg, yield: 40.8%) as a white solid. LCMS (ESI+): C 16 H 19 N2O4[M+H] + Calculated m / z for: 303, found: 303.

[0498] 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

[0499]

[0500] At 0 °C, EDC·HCl (185 mg, 0.965 mmol) and HOBT (86 mg, 0.636 mmol) were added 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) in DMF (1.2 mL), and then 1-(4-chlorophenyl)methanamine (88 mg, 0.621 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 (56.8 mg, yield: 33.60%) as a white solid. LCMS (ESI+): C 23 H 25 ClN3O3[M+H] + Calculated m / z for: 426, found: 426. 1 1H NMR (400 MHz, 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 = 7.6 Hz, 1H), 4.49 (d, J = 6 Hz, 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).

[0501] Example 27: N-(4-chlorobenzyl)-2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0502]

[0503] 1. Synthesis of ethyl 2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0504]

[0505] A solution of diethyl (E)-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (3 × 10 mL) to give ethyl 2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (350 mg, yield: 88.6%) as an orange solid. LCMS (ESI+): C 16 H 19 N2O4[M+H] + Calculated m / z for: 303.1, found: 303.1.

[0506] 2. Synthesis of 2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0507]

[0508] 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 overnight at 40 °C. 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 (200 mg, yield: 62.9%) as an orange oil. LCMS (ESI+): C 14 H 15 N2O4[M+H] + Calculated m / z for: 275.1, found: 275.1.

[0509] 3. Synthesis of N-(4-chlorobenzyl)-2-methyl-6-(oxetan-2-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0510]

[0511] At 0 °C, EDC·HCl (211 mg, 1.101 mmol) and HOBT (148 mg, 1.095 mmol) were added 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), followed by the addition of 1-(4-chlorophenyl)methanamine (155 mg, 1.095 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 (188.1 mg, yield: 63.4%) as a white solid. LCMS (ESI+): C 21 H 21 ClN3O3[M+H] + Calculated m / z for: 398.1, found: 398.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.19 (d, J = 5.6 Hz, 1H), 8.48 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.45 - 7.38 (m, 4H), 6.68 (d, J = 7.6 Hz, 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).

[0512] Example 28: 6-Benzyl-2-methyl-5-oxo-N-(1-(pyridin-2-yl)ethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0513]

[0514] 1. Synthesis of 6-benzyl-2-methyl-5-oxo-N-(1-(pyridin-2-yl)ethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0515]

[0516] At 0 °C, EDC·HCl (98 mg, 0.511 mmol) and HOBT (69 mg, 0.511 mmol) were added 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), followed by the addition of 1-(pyridin-2-yl)ethylamine (63 mg, 0.516 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 399.2, found: 399.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.08 (d, J = 8.0 Hz, 1H), 8.56 - 8.49 (m, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.82 - 7.78 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.37 - 7.27 (m, 6H), 6.71 (d, J = 7.6 Hz, 1H), 5.22 - 5.15 (m, 3H), 2.63 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H).

[0517] Example 29: 6-Benzyl-2-methyl-5-oxo-N-(pyrimidin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0518]

[0519] 1. Synthesis of 6-Benzyl-2-methyl-5-oxo-N-(pyrimidin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0520]

[0521] At 0 °C, EDC·HCl (98 mg, 0.511 mmol) and HOBT (69 mg, 0.511 mmol) were added 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), followed by the addition of 1-(pyrimidin-2-yl)methanamine (56 mg, 0.513 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-2-methyl-5-oxo-N-(pyrimidin-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 for: 386.2, found: 386.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.19 (t, J = 6.0 Hz, 1H), 8.82 (d, J = 4.8 Hz, 2H), 8.60 (d, J = 14.8 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.43 - 7.26 (m, 6H), 6.72 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 4.67 (d, J = 6.0 Hz, 2H), 2.70 (s, 3H).

[0522] Example 30: 6-(2-Methoxyethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0523]

[0524] 1. Synthesis of ethyl 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0525]

[0526] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (500 mg, 1.632 mmol) and 2-methoxyethylamine (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 for: 291, found: 291.

[0527] 2. Synthesis of 6-(2-methoxyethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0528]

[0529] 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 for: 263, found: 263.

[0530] 3. Synthesis of 6-(2-methoxyethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0531]

[0532] At 0 °C, EDC·HCl (124 mg, 0.674 mmol) and HOBT (88.0 mg, 0.651 mmol) were added 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) in DMF (2 mL), and then 2-pyridylmethylamine (72 mg, 0.666 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 353, found: 353. 1 1H NMR (400 MHz, 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 = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.32 - 7.29 (m, 1H), 6.68 (d, J = 7.6 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.19 - 4.16 (m, 2H), 3.65 - 3.62 (m, 2H), 3.35 (s, 3H), 2.68 (s, 3H).

[0533] Example 31: 6-(4-Chlorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0534]

[0535] 1. Synthesis of ethyl 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0536]

[0537] A solution of diethyl (E)-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 for: 357, found: 357.

[0538] 2. Synthesis of ethyl 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0539]

[0540] 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 for: 329, found: 329.

[0541] 3. Synthesis of 6-(4-chlorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0542]

[0543] At 0 °C, EDC·HCl (107 mg, 0.558 mmol) and HOBT (76 mg, 0.562 mmol) were added 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), and then 2-pyridinemethanamine (60 mg, 0.555 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 419.1, found: 419.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.24 - 9.22 (m, 1H), 8.55 - 8.53 (m, 2H), 7.94 (d, J = 7.6 Hz, 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 = 7.2 Hz, 1H), 5.21 (s, 2H), 4.59 (d, J = 6.0 Hz, 2H), 2.69 (s, 3H).

[0544] Example 32: 6-Benzyl-2-methyl-5-oxo-N-(pyrazin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0545]

[0546] 1. Synthesis of 6-benzyl-2-methyl-5-oxo-N-(pyrazin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0547]

[0548] At 0 °C, EDC·HCl (98 mg, 0.631 mmol) and HOBT (69 mg, 0.511 mmol) were added 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 (4 mL), and then 1-(pyrazin-2-yl)methanamine (56 mg, 0.513 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 386.2, found: 386.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.30 (t, J = 5.4 Hz, 1H), 8.71 (s, 1H), 8.63 (s, 1H), 8.56 (d, J = 13.2 Hz, 2H), 7.92 (d, J = 7.2 Hz, 1H), 7.36 - 7.28 (m, 5H), 6.72 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.64 (d, J = 5.6 Hz, 2H), 2.63 (s, 3H).

[0549] Example 33: 6-Benzyl-2-methyl-5-oxo-N-(pyridazin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0550]

[0551] 1. Synthesis of 6-Benzyl-2-methyl-5-oxo-N-(pyridazin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0552]

[0553] At 0 °C, EDC·HCl (51 mg, 0.266 mmol) and HOBT (35 mg, 0.259 mmol) were added 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), followed by the addition of 1-(pyridazin-3-yl)methanamine (30 mg, 0.275 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 for: 386.2, found: 386.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.37 - 9.25 (m, 1H), 9.17 (s, 1H), 8.56 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.72 - 7.71 (m, 2H), 7.36 - 7.28 (m, 5H), 6.73 (d, J = 6.4 Hz, 1H), 5.22 (s, 2H), 4.78 (d, J = 6.0 Hz, 2H), 2.67 (s, 3H).

[0554] Example 34: 6-Benzyl-2-methyl-5-oxo-N-(pyrimidin-5-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0555]

[0556] 1. Synthesis of 6-Benzyl-2-methyl-5-oxo-N-(pyrimidin-5-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0557]

[0558] At 0 °C, EDC·HCl (48 mg, 0.250 mmol) and HOBT (34 mg, 0.252 mmol) were added 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), followed by the addition of 4-pyridinecarboxamide (56 mg, 0.518 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 386.2, found: 386.2. 1 1H NMR (400 MHz, 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 = 7.6 Hz, 1H), 7.36 - 7.30 (m, 5H), 6.73 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H), 2.72 (s, 3H).

[0559] Example 35: 6-Benzyl-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0560]

[0561] 1. Synthesis of 6-Benzyl-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0562]

[0563] At 0 °C, EDC·HCl (48 mg, 0.250 mmol) and HOBT (35 mg, 0.259 mmol) were added 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), and then 1-(5-fluoropyridin-2-yl)methanamine (32 mg, 0.254 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 value: 403.2, experimental value: 403.2. 1 1H NMR (400 MHz, 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 = 7.6 Hz, 1H), 5.22 (s, 2H), 4.58 (d, J = 5.6 Hz, 2H), 2.68 (s, 3H).

[0564] Example 36: 6-Benzyl-N-((3-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0565]

[0566] 1. Synthesis of 6-benzyl-N-((3-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0567]

[0568] At 0 °C, EDC·HCl (102 mg, 0.532 mmol), HOBT (70 mg, 0.518 mmol), and DIEA (78 mg, 0.603 mmol) were added 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), followed by the addition of 1-(3-fluoropyridin-2-yl)methanamine (83 mg, 0.658 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 (52.6 mg, yield: 38.47%) as a white solid. LCMS (ESI+): C 23 H 20 FN4O2[M+H] + Calculated m / z for: 403.2, found: 403.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.17 - 9.14 (m, 1H), 8.50 (s, 1H), 8.43 (d, J = 3.6 Hz, 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 = 7.2 Hz, 1H), 5.22 (s, 2H), 4.67 (d, J = 5.6 Hz, 2H), 2.66 (s, 3H).

[0569] Example 37: 2-Methyl-5-oxo-6-(1-phenylethyl)-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0570]

[0571] 1. Synthesis of ethyl 2-methyl-5-oxo-6-(1-phenylethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0572]

[0573] A solution of diethyl (E)-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 for: 337.2, found: 337.1.

[0574] 2. Synthesis of 2-methyl-5-oxo-6-(1-phenylethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0575]

[0576] 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 overnight at 40 °C. 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 for: 309.1, found: 309.1.

[0577] 3. Synthesis of 2-methyl-5-oxo-6-(1-phenylethyl)-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0578]

[0579] At 0 °C, EDC·HCl (131 mg, 0.683 mmol) and HOBT (92 mg, 0.681 mmol) were added 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), followed by the addition of 2-pyridinemethanamine (74 mg, 0.684 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 for: 399.2, found: 399.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.24 (t, J = 5.8 Hz, 1H), 8.55 (d, J = 5.6 Hz, 2H), 7.82 (t, J = 7.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.42 - 7.31 (m, 5H), 7.29 (d, J = 6.4 Hz, 2H), 6.70 (d, J = 7.6 Hz, 1H), 6.29 - 6.23 (m, 1H), 4.59 (d, J = 5.6 Hz, 2H), 2.68 (s, 3H), 1.78 (d, J = 7.2 Hz, 3H).

[0580] Example 38: 6-Benzyl-N-((5-chloropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0581]

[0582] 1. Synthesis of 6-benzyl-N-((5-chloropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0583]

[0584] At 0 °C, EDC·HCl (49 mg, 0.316 mmol) and HOBT (35 mg, 0.259 mmol) were added to a solution of 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (50 mg, 0.170 mmol) in DMF (4 mL), followed by the addition of 1-(5-chloropyridin-2-yl)methanamine (37 mg, 0.259 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 419.1, found: 419.1. 1 1H NMR (400 MHz, 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 = 8.4 Hz, 1H), 7.35 - 7.28 (m, 5H), 6.72 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.57 (d, J = 6.0 Hz, 2H), 2.67 (s, 3H).

[0585] Example 39: 6-Benzyl-N-((4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0586]

[0587] 1. Synthesis of 6-benzyl-N-((4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0588]

[0589] At 0 °C, EDC·HCl (60 mg, 0.313 mmol), HOBT (42 mg, 0.311 mmol), and DIPEA (45 mg, 0.348 mmol) were added 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), followed by the addition of 1-(4-fluoropyridin-2-yl)methanamine (52 mg, 0.412 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 for: 403.2, found: 403.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.25 (m, 1H), 8.65 - 8.57 (m, 2H), 7.94 (s, 1H), 7.29 - 7.23 (m, 7H), 6.75 (s, 1H), 5.22 (s, 2H), 4.61 (d, J = 6.0 Hz, 2H), 2.80 (s, 3H).

[0590] Example 40: 6-(Cyclohexylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0591]

[0592] 1. Synthesis of ethyl 6-(cyclohexylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0593]

[0594] A solution of diethyl (E)-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 for: 329.2, found: 329.2.

[0595] 2. Synthesis of 6-(cyclohexylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0596]

[0597] 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 H2O (1 mL) was stirred overnight at 40 °C. 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-(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 for: 301.2, found: 301.1.

[0598] 3. Synthesis of 6-(cyclohexylmethyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0599]

[0600] At 0 °C, EDC·HCl (125 mg, 0.652 mmol) and HOBT (88 mg, 0.651 mmol) were added 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), followed by the addition of 2-pyridinemethanamine (71 mg, 0.657 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 for: 391.2, found: 391.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.22 (d, J = 6.0 Hz, 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 = 7.6 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.65 (d, J = 7.2 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 3.84 (d, J = 7.2 Hz, 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).

[0601] Example 41: 2-Methyl-5-oxo-N,6-bis(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0602]

[0603] 1. Synthesis of ethyl 2-methyl-5-oxo-6-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0604]

[0605] A solution of diethyl (E)-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 for: 324.1, found: 324.1.

[0606] 2. Synthesis of ethyl 2-methyl-5-oxo-6-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0607]

[0608] 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 overnight at 40 °C. 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 for: 296.1, found: 296.1.

[0609] 3. Synthesis of 2-methyl-5-oxo-N,6-bis(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0610]

[0611] At 0 °C, EDC·HCl (147 mg, 0.767 mmol) and HOBT (103 mg, 0.762 mmol) were added 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), followed by the addition of 2-pyridinemethanamine (83 mg, 0.767 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 for: 386.2, found: 386.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.22 (d, J = 6.0 Hz, 1H), 8.54 - 8.47 (m, 3H), 7.90 (d, J = 7.6 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.30 - 7.27 (m, 3H), 6.73 (d, J = 7.6 Hz, 1H), 5.31 (s, 2H), 4.58 (d, J = 6.0 Hz, 2H), 2.69 (s, 3H).

[0612] Example 42: 6-Benzyl-N,2-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0613]

[0614] 1. Synthesis of 6-benzyl-N,2-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0615]

[0616] At 0 °C, EDC·HCl (57 mg, 0.297 mmol), HOBT (45 mg, 0.333 mmol), and DIEA (58 mg, 0.449 mmol) were added 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), and then CH3NH2HCl (21 mg, 0.311 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 for: 308.1, found: 308.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 8.54 - 8.53 (m, 1H), 8.43 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.37 - 7.27 (m, 5H), 6.72 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 2.81 (d, J = 4.4 Hz, 3H), 2.68 (s, 3H).

[0617] Example 43: 6-Benzyl-N-(4-carbamoylbenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0618]

[0619] 1. Synthesis of 6-benzyl-N-(4-carbamoylbenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0620]

[0621] At 0 °C, EDC·HCl (50 mg, 0.261 mmol), HOBT (35 mg, 0.259 mmol), and DIEA (45 mg, 0.348 mmol) were added 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), followed by the addition of 4-(aminomethyl)benzamide hydrochloride (48 mg, 0.257 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 for: 427.2, found: 427.2. 1 1H NMR (400 MHz, 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 = 7.6 Hz, 1H), 5.22 (s, 2H), 4.54 (d, J = 6.0 Hz, 2H), 2.67 (s, 3H).

[0622] Example 44: 6-((5-Fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0623]

[0624] 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

[0625]

[0626] At 0 °C, EDC·HCl (83.0 mg, 0.44 mmol) and HOBT (57.0 mg, 0.44 mmol) were added 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) in DMF (2 mL), followed by the addition of 2-pyridinemethanamine (50.7 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude material was purified by a reverse-phase column (gradient: 0 to 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 (50.5 mg, yield: 43.58%) as a white solid. LCMS (ESI+): C 22 H 19 FN5O2[M+H] + Calculated m / z for: 404.1, found: 404.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.24 - 9.21 (m, 1H), 8.54 - 8.48 (m, 3H), 7.91 (d, J = 7.6 Hz, 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 = 7.6 Hz, 1H), 5.37 (s, 2H), 4.58 (d, J = 6.0 Hz, 2H), 2.85 (s, 3H).

[0627] Example 45: 6-Isopropyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0628]

[0629] 1. Synthesis of ethyl 6-isopropyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0630]

[0631] 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 H2O (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 for: 275, found: 275.

[0632] 2. Synthesis of 6-isopropyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0633]

[0634] 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), THF (0.9 mL), and H2O (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 Na2SO4 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 for: 247, found: 247.

[0635] 3. Synthesis of 6-isopropyl-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0636]

[0637] At 0 °C, EDC·HCl (66 mg, 0.344 mmol) and HOBT (51 mg, 0.377 mmol) were added 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), followed by the addition of 2-pyridylmethylamine (42 mg, 0.388 mmol). The reaction mixture was stirred at room temperature for 2 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 337.2, found: 337.3. 1 1H NMR (400 MHz, 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 = 8.0 Hz, 1H), 7.32 - 7.30 (m, 1H), 6.71 (s, 1H), 5.18 - 5.12 (m, 1H), 4.60 (d, J = 6.0 Hz, 2H), 2.68 (s, 3H), 1.37 - 1.35 (m, 6H).

[0638] Example 46: 2-Methyl-5-oxo-6-phenyl-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0639]

[0640] 1. Synthesis of ethyl 2-methyl-5-oxo-6-phenyl-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0641]

[0642] 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 a nitrogen atmosphere for 3 days. The reaction mixture was purified by a reverse-phase column (gradient: 0 to 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 for: 309, found: 309.

[0643] 2. Synthesis of 2-methyl-5-oxo-6-phenyl-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0644]

[0645] 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 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-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 for: 281.1, found: 281.0.

[0646] 3. Synthesis of 2-methyl-5-oxo-6-phenyl-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0647]

[0648] At 0 °C, EDC·HCl (31 mg, 0.16 mmol) and HOBT (22 mg, 0.16 mmol) were added 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), followed by the addition of 2-pyridinemethanamine (18 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 371.1, found: 371.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.25 (t, J = 5.9 Hz, 1H), 8.55 (d, J = 4.8 Hz, 2H), 7.85 - 7.77 (m, 2H), 7.57 (m, 2H), 7.53 - 7.47 (m, 3H), 7.42 (d, J = 7.8 Hz, 1H), 7.30 (m, 1H), 6.76 (d, J = 7.6 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H), 2.72 (s, 3H).

[0649] Example 47: 6-(4-Fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0650]

[0651] 1. Synthesis of ethyl 6-(4-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0652]

[0653] 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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 for: 341, found: 341.

[0654] 2. Synthesis of 6-(4-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0655]

[0656] 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), 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 for: 313, found: 313.

[0657] 3. Synthesis of 6-(4-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0658]

[0659] At 0 °C, EDC·HCl (111 mg, 0.579 mmol) and HOBT (71 mg, 0.525 mmol) were added 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), followed by the addition of 2-pyridinemethanamine (55 mg, 0.509 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 403.2, found: 403.3. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.25 - 9.21 (m, 1H), 8.56 - 8.54 (m, 2H), 7.95 (d, J = 7.6 Hz, 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 = 7.6 Hz, 1H), 5.20 (s, 2H), 4.59 (d, J = 6.0 Hz, 2H), 2.69 (s, 3H).

[0660] Example 48: 2-Methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0661]

[0662] 1. Synthesis of ethyl 2-methyl-6-((5-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0663]

[0664] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (50 mg, 0.16 mmol) and (5-methyl-oxazol-2-yl)methanamine hydrochloride (29 mg, 0.19 mmol) in EtOH (1 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (3 × 10 mL) to give ethyl 2-methyl-6-((5-methyl-oxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (50 mg, yield: 93.59%) as a yellow solid. LCMS (ESI+): C 17 H 18 N3O4[M+H] + Calculated m / z for: 328, found: 328.

[0665] 2. Synthesis of ethyl 2-methyl-6-((5-methyl-oxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0666]

[0667] A solution of ethyl 2-methyl-6-((5-methyl-oxazol-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 H2O (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-methyl-oxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (10 mg, yield: 21.03%) as a white solid. LCMS (ESI+): C 15 H 14 N3O4[M+H] + Calculated m / z for: 300.1, found: 300.1.

[0668] 3. Synthesis of 2-methyl-6-((5-methyl-oxazol-2-yl)methyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0669]

[0670] At 0 °C, EDC·HCl (10 mg, 0.05 mmol) and HOBT (7 mg, 0.05 mmol) were added to a solution of 2-methyl-6-((5-methyl-oxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (10 mg, 0.03 mmol) in DMF (1 mL), and then 2-pyridylmethylamine (6 mg, 0.05 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (0.5% NH4HCO3)) to give 2-methyl-6-((5-methyl-oxazol-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 for: 390.2, found: 390.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.23 (t, J = 6.0 Hz, 1H), 8.63 - 8.34 (m, 2H), 7.93 - 7.74 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.34 - 7.25 (m, 1H), 6.75 (d, J = 8.4 Hz, 2H), 5.30 (s, 2H), 4.59 (d, J = 5.9 Hz, 2H), 2.70 (s, 3H), 2.26 (s, 3H).

[0671] 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

[0672]

[0673] 1. Synthesis of ethyl 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0674]

[0675] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.81 mmol) and 1-(1-methyl-1H-pyrazol-4-yl)methanamine (109 mg, 0.98 mmol) in EtOH (3 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 (73 mg, yield: 27.41%) as a yellow solid. LCMS (ESI+): C 17 H 19 N4O3[M+H] + Calculated m / z for: 327.1, found: 327.1.

[0676] 2. Synthesis of 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0677]

[0678] 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 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 2-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (90 mg, yield: 32.39%) as a white solid. LCMS (ESI+): C 15 H 15 N4O3[M+H] + Calculated m / z for: 299.1, found: 299.1.

[0679] 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

[0680]

[0681] At 0 °C, EDC·HCl (107 mg, 0.55 mmol) and HOBT (75 mg, 0.55 mmol) were added 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), followed by the addition of 2-pyridinemethanamine (60 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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+): C 21 H 21 N6O2 [M+H] + Calculated m / z for: 389.2, found: 389.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.23 (t, J = 6.0 Hz, 1H), 8.58 - 8.47 (m, 2H), 7.89 (d, J = 7.6 Hz, 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 = 7.6 Hz, 1H), 5.02 (s, 2H), 4.59 (d, J = 5.9 Hz, 2H), 3.78 (s, 3H), 2.67 (s, 3H).

[0682] Example 50: 6-Benzyl-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0683]

[0684] 1. Synthesis of tert-butyl ((4,5-difluoropyridin-2-yl)methyl)carbamate

[0685]

[0686] A solution of 2-bromo-4,5-difluoropyridine (200 mg, 1.03 mmol), potassium N-[(trifluoro-λ4-boranediyl)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 H2O (2 mL) was stirred overnight at 90 °C under a 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 / petroleum ether (0 to 50%)), to give tert-butyl ((4,5-difluoropyridin-2-yl)methyl)carbamate (28 mg, yield: 11.12%) as a colorless oil. LCMS (ESI+): C 11 H 15 F2N2O2[M+H] + Calculated m / z for: 245.1, found: 245.1.

[0687] 2. Synthesis of (4,5-difluoropyridin-2-yl)methanamine hydrochloride

[0688]

[0689] A solution of tert-butyl ((4,5-difluoropyridin-2-yl)methyl)carbamate (28 mg, 0.11 mmol) in HCl (gas) / 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 for: 145.1, found: 145.0.

[0690] 3. Synthesis of 6-benzyl-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0691]

[0692] At 0 °C, EDC·HCl (24 mg, 0.12 mmol) and HOBT (17 mg, 0.12 mmol) were added 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), followed by the addition of (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 material was then purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (0.5% NH4HCO3)) to give 6-benzyl-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (16.5 mg, yield: 46%) as a white solid. LCMS (ESI+): C 23 H 19 F2N4O2[M + H] + Calculated m / z for: 421.1, found: 421.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.24 (t, J = 6.0 Hz, 1H), 8.73 (m, 1H), 8.57 (s, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.59 (m, 1H), 7.39 - 7.23 (m, 5H), 6.72 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 4.57 (d, J = 5.9 Hz, 2H), 2.68 (s, 3H).

[0693] Example 51: 6-(4-Chlorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0694]

[0695] 1. Synthesis of ethyl 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0696]

[0697] A solution of diethyl (E)-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 for: 357, found: 357.

[0698] 2. Synthesis of ethyl 6-(4-chlorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0699]

[0700] 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 for: 329, found: 329.

[0701] 3. Synthesis of 6-(4-chlorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0702]

[0703] At 0 °C, EDC·HCl (57 mg, 0.396 mmol) and HOBT (87 mg, 0.455 mmol) were added 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), followed by the addition of 1-(5-fluoropyridin-2-yl)methanamine (57 mg, 0.452 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 for: 437.1, found: 437.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.26 - 9.26 (m, 1H), 8.55 - 8.53 (m, 2H), 7.94 (d, J = 7.6 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.51 (d, J = 4.8 Hz, 1H), 7.49 - 7.48 (m, 2H), 7.43 - 7.41 (m, 2H), 6.74 (d, J = 7.6 Hz, 1H), 5.21 (s, 2H), 4.59 (d, J = 5.6 Hz, 2H), 2.68 (s, 3H).

[0704] Example 52: 2-Methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0705]

[0706] 1. Synthesis of ethyl 2-methyl-5-oxo-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0707]

[0708] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (300 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. Water (10 mL) was added to the mixture 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 for: 324, found: 324.

[0709] 2. Synthesis of 2-methyl-5-oxo-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0710]

[0711] 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 for: 296, found: 296.

[0712] 3. Synthesis of 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0713]

[0714] At 0 °C, EDC·HCl (78.2 mg, 0.405 mmol), HOBT (55.3 mg, 0.405 mmol), and DIPEA (70.5 mg, 0.54 mmol) were added 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) in DMF (5 mL), and then pyridin-2-ylmethanamine (43.7 mg, 0.405 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The crude product was purified by preparative HPLC using the following conditions (column: XBridgePrep OBD C 18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 33% B to 43% B in 8 min, 43%) to give 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-4-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide (8.4 mg, yield: 8%) as a white solid. LCMS (ESI+): C 22 H 20 N5O2[M + H] + Calculated m / z for: 386.2, found: 386.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.24 (t, J = 6.0 Hz, 1H), 8.58 - 8.50 (m, 4H), 7.93 (d, J = 7.6 Hz, 1H), 7.86 - 7.76 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.26 - 7.21 (m, 2H), 6.77 (d, J = 7.6 Hz, 1H), 5.26 (s, 2H), 4.58 (d, J = 5.9 Hz, 2H), 2.70 (s, 3H).

[0715] Example 53: 2,6-Dimethyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0716]

[0717] 1. Synthesis of ethyl 2,6-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0718]

[0719] 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 value: 247, experimental value: 247.

[0720] 2. Synthesis of 2,6-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0721]

[0722] 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), THF (0.9), and H2O (0.3 mL) was stirred at 40 °C for 4 h. The reaction mixture 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+): C 11 H 11 N2O3 [M+H] + Calculated m / z value: 219, experimental value: 219.

[0723] 3. Synthesis of 2,6-dimethyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0724]

[0725] At 0 °C, EDC·HCl (100 mg, 0.522 mmol) and HOBT (73 mg, 0.540 mmol) were added to a solution of 2,6-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid (80 mg, 0.367 mmol) in DMF (2 mL), followed by the addition of 2-pyridylmethylamine (62 mg, 0.573 mmol). The reaction mixture was stirred at room temperature for 2 h. Then the mixture was purified by a reverse-phase column (gradient: 0 to 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, found: 309.2. 1 1H NMR (400 MHz, 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 = 7.2 Hz, 1H), 4.60 (d, J = 6.0 Hz, 2H), 3.54 (s, 3H), 2.68 (s, 3H).

[0726] Example 54: 2-Methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0727]

[0728] 1. Synthesis of ethyl 2-methyl-6-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0729]

[0730] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.81 mmol) and p-tolylmethylamine (119 mg, 0.98 mmol) in EtOH (3 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the solid was collected by filtration and washed with H2O (3 × 5 mL) to give the crude product ethyl 2-methyl-6-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (290 mg, yield: 88.1%) as a yellow solid. LCMS (ESI+): C 20 H 21 N2O3[M+H] + Calculated m / z for: 337, found: 337.

[0731] 2. Synthesis of ethyl 2-methyl-6-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0732]

[0733] 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 overnight at 40 °C. The mixture 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 (150 mg, yield: 56.43%) as a yellow solid. LCMS (ESI+): C 18 H 17 N2O3[M+H] + Calculated m / z for: 309, found: 309.

[0734] 3. Synthesis of 2-methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0735]

[0736] At 0 °C, EDC·HCl (94.1 mg, 0.49 mmol) and HOBT (66.5 mg, 0.48 mmol) were added 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), and then 2-pyridinemethanamine (53.8 mg, 0.49 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h. Then the crude product was purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (0.5% NH4HCO3)) to obtain 2-methyl-6-(4-methylbenzyl)-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide (54 mg, yield: 41.74%) as a white solid. LCMS (ESI+): C 24 H 23 N4O2 [M+H] + Calculated m / z for: 399.2, found: 399.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.23 (t, J = 6.0 Hz, 1H), 8.59 - 8.47 (m, 2H), 7.89 (d, J = 7.6 Hz, 1H), 7.83 - 7.80 (m, 1H), 7.41 (m, 1H), 7.30 (m, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 6.71 (m, 1H), 5.17 (s, 2H), 4.58 (d, J = 5.9 Hz, 2H), 2.68 (s, 3H), 2.27 (s, 3H).

[0737] Example 55: 6-(3-Fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0738]

[0739] 1. Synthesis of ethyl 6-(3-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0740]

[0741] A solution of diethyl (E)-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] + The calculated m / z value is 341, experimental value: 341.

[0742] 2. Synthesis of 6-(3-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0743]

[0744] 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), 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] + The calculated m / z value: 313, experimental value: 313.

[0745] 3. Synthesis of 6-(3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0746]

[0747] At 0 °C, EDC·HCl (194 mg, 1.012 mmol) and HOBT (130 mg, 0.962 mmol) were added 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), and then 2-pyridinemethanamine (120 mg, 1.110 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 for: 403.2, found: 403.3. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.25 (d, J = 6.0 Hz, 1H), 8.55 (d, J = 5.2 Hz, 2H), 7.95 (d, J = 7.6 Hz, 1H), 7.83 - 7.80 (m, 1H), 7.41 - 7.37 (m, 2H), 7.31 (d, J = 5.2 Hz, 1H), 7.28 - 7.21 (m, 3H), 6.75 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 4.59 (d, J = 5.6 Hz, 2H), 2.69 (s, 3H).

[0748] Example 56: 6-(2-Fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0749]

[0750] 1. Synthesis of ethyl 6-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0751]

[0752] A solution of diethyl (E)-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 for: 341, found: 341.

[0753] 2. Synthesis of 6-(2-fluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0754]

[0755] 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 for 313, found: 313.

[0756] 3. Synthesis of 6-(2-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0757]

[0758] At 0 °C, EDC·HCl (240 mg, 1.25 mmol) and HOBT (124 mg, 0.91 mmol) were added 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), followed by the addition of 2-pyridinemethanamine (99 mg, 0.91 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 for: 403.2, found: 403.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.23 (t, J = 6.0 Hz, 1H), 8.60 - 8.45 (m, 2H), 7.94 - 7.75 (m, 2H), 7.44 - 7.09 (m, 6H), 6.75 (d, J = 7.6 Hz, 1H), 5.27 (s, 2H), 4.58 (d, J = 5.9 Hz, 2H), 2.69 (s, 3H).

[0759] Example 57: 6-Benzyl-N-((5-chloro-4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0760]

[0761] 1. Synthesis of tert-butyl ((5-chloro-4-fluoropyridin-2-yl)methyl)carbamate

[0762]

[0763] A solution of 2-bromo-5-chloro-4-fluoropyridine (50 mg, 0.23 mmol), potassium N-[(trifluoro-λ4-boranediyl)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 H2O (0.4 mL) was stirred overnight at 90 °C under a 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 / petroleum ether (0 to 50%)), to give tert-butyl ((5-chloro-4-fluoropyridin-2-yl)methyl)carbamate (10 mg, yield: 16.14%) as a colorless oil. LCMS (ESI+): C 11 H 15 ClFN2O2 [M+H] + Calculated m / z for: 261.1, found: 261.0.

[0764] 2. Synthesis of (5-chloro-4-fluoropyridin-2-yl)methanamine hydrochloride

[0765]

[0766] A solution of tert-butyl ((5-chloro-4-fluoropyridin-2-yl)methyl)carbamate (10 mg, 0.03 mmol) in HCl (gas) / 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 for: 161.0, found: 161.0.

[0767] 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

[0768]

[0769] At 0 °C, EDC·HCl (19 mg, 0.09 mmol) and HOBT (13 mg, 0.09 mmol) were added 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). Subsequently, (5-chloro-4-fluoropyridin-2-yl)methanamine hydrochloride (5 mg, 0.03 mmol) and DIEA (19 mg, 0.14 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (0.5% NH4HCO3)) to obtain 6-benzyl-N-((5-chloro-4-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (9.6 mg, yield: 46%) as a white solid. LCMS (ESI+): C 23 H 19 ClFN2O2[M+H] + Calculated m / z for: 437.1, found: 437.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.26 (t, J = 5.8 Hz, 1H), 8.74 (d, J = 9.7 Hz, 1H), 8.58 (s, 1H), 7.92 (m, 1H), 7.55 (d, J = 10.2 Hz, 1H), 7.40 - 7.25 (m, 5H), 6.72 (d, J = 7.5 Hz, 1H), 5.23 (s, 2H), 4.59 (d, J = 5.8 Hz, 2H), 2.68 (s, 3H).

[0770] Example 58: 2-Methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0771]

[0772] 1. Synthesis of ethyl 2-methyl-5-oxo-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0773]

[0774] A solution of diethyl (E)-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 (300.5 mg, yield: 94.8%) as a yellow solid. LCMS (ESI+): C 18 H 18 N3O3[M+H] + Calculated m / z for: 324, found: 324.

[0775] 2. Synthesis of ethyl 2-methyl-5-oxo-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0776]

[0777] 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 (123.3 mg, yield: 67.4%) as a white solid. LCMS (ESI+): C 16 H 14 N3O3[M+H] + Calculated m / z for: 296, found: 296.

[0778] 3. Synthesis of 2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-6-(pyridin-3-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0779]

[0780] At 0 °C, EDC·HCl (78.3 mg, 0.405 mmol), HOBT (55.6 mg, 0.405 mmol), and DIPEA (70.1 mg, 0.54 mmol) were added 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) in DMF (5 mL), followed by the addition of 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 by preparative HPLC using the following conditions (column: XBridgePrep OBD C 18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 33% B to 43% B in 8 min, 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 (20.3 mg, yield: 19%). LCMS (ESI+): C 22 H 20 N5O2[M + H] + Calculated m / z for: 386.2, found: 386.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.22 (t, J = 6.0 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.54 (d, J = 8.6 Hz, 2H), 8.51 - 8.49 (m, 1H), 8.00 (d, J = 7.6 Hz, 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 = 7.6 Hz, 1H), 5.25 (s, 2H), 4.58 (d, J = 6.0 Hz, 2H), 2.69 (s, 3H).

[0781] 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

[0782]

[0783] 1. Synthesis of ethyl 6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0784]

[0785] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (250 mg, 0.816 mmol) and 1-[2-(2-aminoethoxy)ethoxy]-2-methoxyethane (265 mg, 1.624 mmol) in EtOH (2.5 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 for: 379, found: 379.

[0786] 2. Synthesis of 6-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0787]

[0788] 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 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-(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 for: 351, found: 351.

[0789] 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

[0790]

[0791] At 0 °C, EDC·HCl (57 mg, 0.29 mmol) and HOBT (40 mg, 0.29 mmol) were added 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), followed by the addition of 1-(5-chloropyridin-2-yl)methanamine (42 mg, 0.295 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 (36.3 mg, yield: 38.2%) as a white solid. LCMS (ESI+): C 23 H 28 ClN4O5[M+H] + Calculated m / z for: 475.2, found: 475.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.28 - 9.25 (m, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.53 (s, 1H), 7.97 - 7.94 (m, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 4.59 (d, J = 6.0 Hz, 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).

[0792] 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

[0793]

[0794] 1. Synthesis of ethyl 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0795]

[0796] A solution of diethyl (E)-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 a nitrogen atmosphere. The crude material was then purified by a reverse-phase column (gradient: 0 to 50% ACN / H2O (0.5% NH4HCO3)) to afford 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 for: 313, found: 313.

[0797] 2. Synthesis of 6-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0798]

[0799] 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 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 afford 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 for: 285, found: 285.

[0800] 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

[0801]

[0802] At 0 °C, EDC·HCl (50 mg, 0.261 mmol) and HOBT (35 mg, 0.259 mmol) were added 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), followed by the addition of 2-pyridylmethylamine (28 mg, 0.259 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 23 N4O2 [M+H] + Calculated m / z for: 375.1, found: 375.1. 1 1H NMR (400 MHz, 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 = 7.5 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 2.6 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 4.08 (s, 2H), 2.69 (s, 3H), 2.47 (s, 1H), 1.69 (s, 6H).

[0803] Example 61: 6-(3,4-Difluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0804]

[0805] 1. Synthesis of ethyl 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0806]

[0807] A solution of diethyl (E)-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 for: 359, found: 359.

[0808] 2. Synthesis of ethyl 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0809]

[0810] 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 overnight at 40 °C. 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 for: 331, found: 331.

[0811] 3. Synthesis of 6-(3,4-difluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0812]

[0813] At 0 °C, EDC·HCl (88 mg, 0.45 mmol) and HOBT (62 mg, 0.45 mmol) were added to 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), and then 2-pyridinemethanamine (49 mg, 0.45 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h. Then the crude product was purified by a 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 as a white solid (67.2 mg, yield: 52.7%). LCMS (ESI+): C 23 H 19 F2N4O2[M + H] + Calculated m / z value: 421.1, experimental value: 421.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.22 (t, J = 6.0 Hz, 1H), 8.58 - 8.46 (m, 2H), 7.95 (d, J = 7.6 Hz, 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 = 7.6 Hz, 1H), 5.20 (s, 2H), 4.59 (d, J = 5.9 Hz, 2H), 2.69 (s, 3H).

[0814] Example 62: 6-(3,4-Difluorobenzyl)-N-((4,5-difluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0815]

[0816] 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

[0817]

[0818] At 0 °C, EDC·HCl (22 mg, 0.11 mmol), HOBT (15 mg, 0.11 mmol) and DIEA (22 mg, 0.17 mmol) were added to 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), followed by the 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 material was then purified by a reverse-phase column (gradient: 0 to 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 for: 457.1, found: 457.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.23 (t, J = 5.9 Hz, 1H), 8.74 - 8.71 (m, 1H), 8.56 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.49 - 7.36 (m, 2H), 7.23 - 7.15 (m, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 4.56 (d, J = 5.8 Hz, 2H), 2.67 (s, 3H).

[0819] Example 63: 6-(3,4-Difluorobenzyl)-N-((5-fluoropyridin-2-yl)methyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0820]

[0821] 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

[0822]

[0823] At 0 °C, EDC·HCl (88 mg, 0.45 mmol) and HOBT (62 mg, 0.45 mmol) were added to 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), and then 1-(5-fluoropyridin-2-yl)methanamine (58 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h. Then the crude material was purified by a 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 as a white solid (74.5 mg, yield: 55.0%). LCMS (ESI+): C 23 H 18 F3N4O2[M + H] + Calculated m / z for: 439.1, found: 439.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.25 (t, J = 6.0 Hz, 1H), 8.61 - 8.46 (m, 2H), 7.95 (d, J = 7.6 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.57 - 7.33 (m, 3H), 7.21 - 7.18 (m, 1H), 6.74 (d, J = 7.5 Hz, 1H), 5.20 (s, 2H), 4.58 (d, J = 5.9 Hz, 2H), 2.68 (s, 3H).

[0824] 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

[0825]

[0826] 1. Synthesis of tert-butyl (4-(2-(2-methoxyethoxy)ethoxy)benzyl)carbamate

[0827]

[0828] 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 under a nitrogen atmosphere for 2 h. The reaction was quenched with water (3 mL). The mixture was extracted with EtOAc (3 × 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 for: 326, found: 326.

[0829] 2. Synthesis of (4-(2-(2-methoxyethoxy)ethoxy)phenyl)methanamine hydrochloride

[0830]

[0831] A solution of tert-butyl (4-(2-(2-methoxyethoxy)ethoxy)benzyl)carbamate (324 mg, 0.996 mmol) in HCl (gas) / 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 for: 226, found: 226.

[0832] 3. Synthesis of ethyl 6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0833]

[0834] Under a nitrogen atmosphere at room temperature, (4-(2-(2-methoxyethoxy)ethoxy)phenyl)methanamine hydrochloride (220 mg, 0.980 mmol) was added to a stirred solution of diethyl (E)-2-(2-(dimethylamino)vinyl)-6-methylpyridine-3,5-dicarboxylate (150 mg, 0.490 mmol) in EtOH (1.6 mL). 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 for: 441, found: 441.

[0835] 4. Synthesis of ethyl 6-(4-(2-(2-methoxyethoxy)ethoxy)benzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0836]

[0837] 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:H2O = 3:1 (2 mL) was stirred at 40 °C overnight. The mixture was acidified to pH 5 with HCl (aqueous solution). The residue was purified by reverse flash chromatography (MeOH / water (0.1% HCl), 15% to 45% in 20 min) 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 for: 413, found: 413.

[0838] 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

[0839]

[0840] Under a nitrogen atmosphere at room temperature, 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 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. The reaction mixture was stirred at room temperature for 1 h. The reaction product was purified by reverse flash chromatography (using MeOH / H2O (10 mmol / L NH4HCO3), 30% to 60% in 30 min) to obtain 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 for: 537.1, found: 537.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.30 - 9.24 (m, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.54 (s, 1H), 7.97 - 7.88 (m, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 7.6 Hz, 1H), 5.14 (s, 2H), 4.58 (d, J = 5.9 Hz, 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).

[0841] Example 65: 6-Benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0842]

[0843] 1. Synthesis of diethyl 2-methylpyridine-3,5-dicarboxylate

[0844]

[0845] Under a nitrogen atmosphere, Et3N (0.77 g, 7.61 mmol) was added dropwise to a mixture of ethyl 2-formyl-3-oxopropionate (1 g, 6.93 mmol) in Et2O (7 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h and then the solvent was evaporated under reduced pressure. The residue was diluted with DMF (5 mL), and DMF (6 mL) containing methanesulfonyl (1.45 g, 7.606 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 4 h. At 25 °C, 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) was added to the mixture. 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 × 20 mL). The combined organic layers were washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, 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 as a yellow solid (950 mg, yield: 57.7%). LCMS (ESI+): C 12 H 16 NO4[M+H] + Calculated m / z for: 238, found: 238.

[0846] 2. Synthesis of diethyl (E)-2-(2-(dimethylamino)vinyl)pyridine-3,5-dicarboxylate

[0847]

[0848] 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 used directly in the next step. LCMS (ESI+): C 15 H 21 N2O4[M+H] + Calculated m / z for: 293, found: 293.

[0849] 3. Synthesis of ethyl 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0850]

[0851] 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 value: 309, experimental value: 309.

[0852] 4. Synthesis of 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0853]

[0854] 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 × 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 value: 281, experimental value: 281.

[0855] 5. Synthesis of 6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0856]

[0857] At 0 °C, EDC·HCl (61.5 mg, 0.321 mmol) and HOBT (43.4 mg, 0.321 mmol) were added 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), followed by the addition of 2-pyridylmethanamine (34.7 mg, 0.321 mmol). The reaction mixture was stirred at room temperature for 2 h. Then the crude material was purified by a 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 as a white solid (24.6 mg, yield: 31.0%). LCMS (ESI+): C 22 H 19 N4O2[M+H] + Calculated m / z for: 371.1, found: 371.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.63 - 9.49 (m, 1H), 9.37 (d, J = 2.3 Hz, 1H), 9.09 (d, J = 2.3 Hz, 1H), 8.58 - 8.48 (m, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.41 - 7.24 (m, 7H), 6.83 (d, J = 7.6 Hz, 1H), 5.25 (s, 2H), 4.62 (d, J = 5.9 Hz, 2H).

[0858] Example 66: 6-Benzyl-2-methyl-N-((4-methyloxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0859]

[0860] 1. Synthesis of (4-methyloxazol-2-yl)methanamine hydrochloride

[0861]

[0862] To a solution of 4-methyl-oxazole-2-carbaldehyde (20.0 mg, 0.181 mmol) in MeOH (0.5 mL) was added NH₃ ammonia (g) / MeOH (0.5 mL, 3.50 mmol), and the mixture was 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. Subsequently, HCl (gas) / 1,4-dioxane (1 mL, 4.0 mmol) was added, and the mixture was stirred at 0 °C for 5 min. The resulting mixture was concentrated under reduced pressure to give (4-methyl-oxazol-2-yl)methanamine hydrochloride as a yellow oil (22 mg, yield: 82.1%). LCMS (ESI+): C₅H₉N₂O [M+H] + Calculated m / z for: 113, found: 113.

[0863] 2. Synthesis of 6-benzyl-2-methyl-N-((4-methyl-oxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0864]

[0865] 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-methyl-oxazol-2-yl)methanamine hydrochloride (20.5 mg, 0.138 mmol). The residue was purified by reverse flash chromatography (eluting with MeCN / water (0.5% NH₄HCO₃), 10% to 100% gradient in 30 min) to give 6-benzyl-2-methyl-N-((4-methyl-oxazol-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (3.6 mg, yield: 6.7%). LCMS (ESI+): C 22 H 21 N₄O₃ [M+H] + Calculated m / z for: 389.2, found: 389.2. 1HNMR (400 MHz, DMSO-d6, δ): 9.39 (t, J = 6.0 Hz, 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 = 5.6 Hz, 2H), 2.67 (s, 3H), 2.20 (s, 3H).

[0866] Example 67: 6-Benzyl-N-(4-isopropoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0867]

[0868] 1. Synthesis of 6-benzyl-N-(4-isopropoxybenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0869]

[0870] 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) at 0 °C was added EDC·HCl (98 mg, 0.51 mmol), HOBT (69 mg, 0.51 mmol) and DIEA (88 mg, 0.68 mmol), followed by addition of 1-(4-isopropoxyphenyl)methanamine hydrochloride (103 mg, 0.51 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 as a white solid (81.3 mg, yield: 54.03%). LCMS (ESI+): C 27 H 28 N3O3[M + H] + Calculated m / z for: 442.2, found: 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).

[0871] Example 68: 6-Benzyl-2-methyl-N-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0872]

[0873] 1. Synthesis of 6-Benzyl-2-methyl-N-(4-methylbenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0874]

[0875] 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 was added EDC·HCl (65.1 mg, 0.340 mmol) and HOBT (68.8 mg, 0.510 mmol), followed by the addition of 4-methyl-benzylamine (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 to 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 as a white solid (58.8 mg, yield: 42.7%). LCMS (ESI+): C 25 H 24 N3O2 [M + H] + Calculated m / z for: 398.2, found: 398.1. 1HNMR (400 MHz, DMSO-d6, δ): 9.12 - 9.10 (m, 1H), 8.45 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.36 - 7.32 (m, 7H), 7.18 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.45 (d, J = 6.0 Hz, 2H), 2.67 (s, 3H), 2.30 (s, 3H).

[0876] Example 69: N-(Benzo[d][1,3]dioxol-5-ylmethyl)-6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0877]

[0878] 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

[0879]

[0880] 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 was added EDC·HCl (97.7 mg, 0.510 mmol) and HOBT (68.9 mg, 0.510 mmol), followed by addition of 1-(2H-1,3-benzodioxol-5-yl)methanamine (77.0 mg, 0.510 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude material was purified by a reverse-phase column (gradient: 0 to 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 as a white solid (60.9 mg, yield: 41.1%). LCMS (ESI+): C 25 H 22 N3O4 [M + H] + Calculated m / z for: 428.2, found: 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).

[0881] Example 70: 2-Methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-6-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0882]

[0883] 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

[0884] 2-Methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-6-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide (13.7 mg) as a white solid was synthesized in a manner similar to Example 1. LCMS(ESI+): C 21 H 20 N3O3S [M + H] + Calculated m / z: 394.1, Found: 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 - 6.98 (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).

[0885] Example 71: 6-Benzyl-2-methyl-5-oxo-N-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0886]

[0887] 1. Synthesis of 6-benzyl-2-methyl-5-oxo-N-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0888] 6-Benzyl-2-methyl-5-oxo-N-(thiophen-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide (74.1 mg) as a white solid was synthesized in a similar manner to Example 1. LCMS (ESI+): C 22 H 20 N3O2S [M+H] + Calculated m / z value: 390.1, experimental value: 390.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.28 - 9.26 (m, 1H), 8.45 (s, 1H), 7.92 (d, J = 7.6 Hz, 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 = 7.6 Hz, 1H), 5.22 (s, 2H), 4.66 (d, J = 6.0 Hz, 2H), 2.67 (s, 3H).

[0889] Example 72: 6-(2-Methoxyethyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0890]

[0891] 1. Synthesis of 6-(2-Methoxyethyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0892] 6-(2-Methoxyethyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (14.9 mg) as a white solid was synthesized in a similar manner to Example 20. LCMS (ESI+): C 19 H 22 N3O4 [M+H] + Calculated m / z value: 356.1, experimental value: 356.1. 1HNMR (400 MHz, DMSO-d6, δ): 9.06 - 9.05 (m, 1H), 8.42 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.20 (d, J = 2.4 Hz, 1H), 6.03 (s, 1H), 4.43 (d, J = 5.2 Hz, 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).

[0893] Example 73: 6-Benzyl-N-(2-(furan-2-yl)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0894]

[0895] 1. Synthesis of 6-benzyl-N-(2-(furan-2-yl)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0896] 6-Benzyl-N-(2-(furan-2-yl)ethyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide (65.0 mg) as a white solid was synthesized in a manner similar to Example 1. LCMS (ESI+): C 23 H 22 N3O3[M + H] + Calculated m / z for: 388.1, Found: 388.1. 1 HNMR (400 MHz, DMSO-d6, δ): 8.72 - 8.69 (m, 1H), 8.41 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.37 - 7.29 (m, 5H), 6.71 (d, J = 7.6 Hz, 1H), 6.39 - 6.38 (m, 1H), 6.21 (d, J = 3.2 Hz, 1H), 5.22 (s, 2H), 3.56 - 3.51 (m, 2H), 2.92 - 2.89 (m, 2H), 2.62 (s, 3H).

[0897] Example 74: 2-Amino-6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0898]

[0899] 1. Synthesis of diethyl 2-methylpyridine-3,5-dicarboxylate

[0900]

[0901] At 0 °C, Et3N (7.7 g, 76.09 mmol) was added dropwise to a solution of ethyl 2-formyl-3-oxopropionate (10.0 g, 69.38 mmol) in diethyl ether (100 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure and dissolved in DMF (150 mL), and then 4-methylbenzene-1-sulfonyl chloride (14.6 g, 76.58 mmol) was added dropwise at 0 °C. 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 mixture was stirred at 80 °C under a nitrogen atmosphere overnight. The reaction mixture was quenched with H2O at 0 °C and extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluted with EtOAc / petroleum ether (0 to 50%)), to give diethyl 2-methylpyridine-3,5-dicarboxylate as a yellow solid (8.4 g, yield: 51.0%). LCMS (ESI+): C 12 H 16 NO4[M+H] + Calculated m / z for: 238, found: 238.

[0902] 2. Synthesis of diethyl (E)-2-(2-(dimethylamino)vinyl)pyridine-3,5-dicarboxylate

[0903]

[0904] 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 at 100 °C under a nitrogen atmosphere overnight. The reaction solution was used for the next step without further treatment. LCMS (ESI+): C 15 H 21 N2O4[M+H] + Calculated m / z for: 293, found: 293.

[0905] 3. Synthesis of ethyl 6-benzyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0906]

[0907] A solution of diethyl (E)-2-(2-(dimethylamino)vinyl)pyridine-3,5-dicarboxylate (from the previous step, 20 mL DMF solution) and benzylamine (1.1 g, 10.26 mmol) in EtOH (10 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O 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 material was used in the next step without further purification. LCMS (ESI+): C 18 H 17 N2O3[M+H] + Calculated m / z for: 309, found: 309.

[0908] 4. Synthesis of ethyl 6-benzyl-3-(ethoxycarbonyl)-5-oxo-5,6-dihydro-1,6-naphthyridine 1-oxide

[0909]

[0910] 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 portionwise to m-CPBA (2.7 g, 15.6 mmol) at 0 °C, and the solution was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was diluted with H2O and quenched by adding Na2SO3 at 0 °C. The resulting mixture was extracted with CH2Cl2, 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 MeCN / CH2Cl2 (0 to 10%)) to give 880 mg (crude) of ethyl 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 for: 325, found: 325.

[0911] 5. Synthesis of ethyl 6-benzyl-2-chloro-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0912]

[0913] 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 under a nitrogen atmosphere for 4 h. The reaction was quenched by adding water at 0 °C and extracted with EtOAc, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by reverse flash chromatography (eluting with MeCN / H2O (0.1% FA), 5% to 100%) to give ethyl 6-benzyl-2-chloro-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (400 mg, yield: 47.3%). LCMS (ESI+): C 18 H 16 ClN2O3 [M+H] + Calculated m / z for: 343, found: 343.

[0914] 6. Synthesis of ethyl 6-benzyl-2-((tert-butoxycarbonyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0915]

[0916] 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 under a nitrogen atmosphere for 2 h. The resulting mixture was filtered, extracted with EtOAc, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by reverse flash chromatography (eluting with MeCN / H2O (0.1% FA), 5% to 100%) to give ethyl 6-benzyl-2-((tert-butoxycarbonyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as a yellow solid (200 mg, yield: 40.4%). LCMS (ESI+): C 23 H 26 N3O5 [M+H] + Calculated m / z for: 424, found: 424.

[0917] 7. Synthesis of 6-benzyl-2-((tert-butoxycarbonyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid

[0918]

[0919] 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 H2O (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 / water (0.1% FA), 5% to 100%) to give 6-benzyl-2-((tert-butoxycarbonyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid as a yellow solid (55 mg, yield: 29.4%). LCMS (ESI+): C 21 H 22 N3O5[M+H] + Calculated m / z for: 396, found: 396.

[0920] 8. Synthesis of tert-butyl (6-benzyl-5-oxo-3-((pyridin-2-ylmethyl)carbamoyl)-5,6-dihydro-1,6-naphthyridin-2-yl)carbamate

[0921]

[0922] 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) at 0 °C 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). The reaction mixture was stirred at room temperature for 0.5 h. The crude material was then purified by reverse flash chromatography (eluting with MeCN / 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 as a yellow solid (45 mg, yield: 66.6%). LCMS (ESI+): C 27 H 28 N5O4[M+H] + Calculated m / z for: 486, found: 486.

[0923] 9. Synthesis of 2-amino-6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0924]

[0925] 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) / 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 / water (0.5% NH4HCO3), 5% to 100%) to give 2-amino-6-benzyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide as a white solid (5.9 mg, yield: 16.4%). LCMS (ESI+): C 22 H 20 N5O2[M+H] + Calculated m / z for: 386.1, found: 386.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.43 (t, J = 5.8 Hz, 1H), 8.76 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 7.79 - 7.74 (m, 4H), 7.37 - 7.26 (m, 7H), 6.31 (d, J = 7.6 Hz, 1H), 5.14 (s, 2H), 4.54 (d, J = 5.6 Hz, 2H).

[0926] Example 75: 6-(4-Chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0927]

[0928] 1. Synthesis of 6-(4-Chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0929] 6-(4-Chloro-3-fluorobenzyl)-2-methyl-5-oxo-N-(pyridin-2-ylmethyl)-5,6-dihydro-1,6-naphthyridine-3-carboxamide (20.5 mg) was synthesized in a similar manner to Example 61 as a white solid. LCMS (ESI+): C 23 H 19 ClFN4O2[M+H] + Calculated m / z for: 437.1, found: 437.1. 1HNMR(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).

[0930] Example 76: 6-(3,4-Difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0931]

[0932] 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

[0933]

[0934] 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) at 0 °C was added EDC·HCl (57.4 mg, 0.300 mmol) and HOBT (40.5 mg, 0.300 mmol), followed by the addition of (2-methyloxazol-4-yl)methylamine (33.6 mg, 0.300 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 as a white solid (49.1 mg, yield: 57%). LCMS (ESI+): C 22 H 19 F2N4O3[M + H] + Calculated m / z for: 425.1, found: 425.1. 1HNMR(400MHz, DMSO-d6, δ): 9.04 - 9.01 (m, 1H), 8.44 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.46 - 7.37 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.18 (s, 2H), 4.32 (d, J = 5.6 Hz, 2H), 2.65 (s, 3H), 2.40 (s, 3H).

[0935] 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

[0936]

[0937] 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 (42.0 mg) as a white solid was synthesized in a similar manner to Example 51. LCMS (ESI+): C 28 H 30 ClN4O5 [M + H] + Calculated m / z value: 537.2, Experimental value: 537.2.

[0938] Example 78: 6-(4-Fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0939]

[0940] 1. Synthesis of 6-(4-Fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0941]

[0942] At 0 °C, EDC·HCl (50 mg, 0.261 mmol) and HOBT (34 mg, 0.252 mmol) were added 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), followed by the addition of (2-methyloxazol-4-yl)methanamine (60 mg, 0.535 mmol). The reaction mixture was stirred at room temperature for 2 h. The residue was purified by reverse flash chromatography (eluting with MeCN / H2O (0.5% NH4HCO3), 10% to 100% gradient 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 for: 407.1, found: 407.2. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.03 - 9.00 (m, 1H), 8.45 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.42 - 7.38 (m, 2H), 7.20 - 7.15 (m, 2H), 6.72 (d, J = 7.2 Hz, 1H), 5.19 (s, 2H), 4.33 - 4.31 (m, 2H), 2.64 (s, 3H), 2.40 (s, 3H).

[0943] Example 79: 6-(3-Fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0944]

[0945] 1. Synthesis of 6-(3-fluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0946]

[0947] At 0 °C, EDC·HCl (46.0 mg, 0.240 mmol) and HOBT (12.9 mg, 0.096 mmol) were added 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) in DMF (2 mL), and then (2-methyloxazol-4-yl)methanamine (26.9 mg, 0.240 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The residue was purified by reverse flash chromatography (eluting with MeCN / H2O (0.5% NH4HCO3), 10% to 100% gradient 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 (22.3 mg, yield: 34.2%) as a white solid. LCMS (ESI+): C 22 H 20 FN4O3[M+H] + Calculated m / z for: 407.1, found: 407.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.02 - 9.01 (m, 1H), 8.45 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.42 - 7.38 (m, 1H), 7.24 - 7.11 (m, 3H), 6.72 (d, J = 7.2 Hz, 1H), 5.23 (s, 2H), 4.32 (d, J = 5.6 Hz, 2H), 2.66 (s, 3H), 2.40 (s, 3H).

[0948] Example 80: 6-(4-Chlorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0949]

[0950] 1. Synthesis of 6-(4-chlorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0951]

[0952] At 0 °C, EDC·HCl (87 mg, 0.456 mmol) and HOBT (61 mg, 0.456 mmol) were added 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), followed by the addition of (2-methyloxazol-4-yl)methanamine (51 mg, 0.456 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the crude material was purified by a reverse-phase column (gradient: 0 to 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 (55.9 mg, yield: 45.9%) as a white solid. LCMS (ESI+): C 22 H 20 ClN4O3[M+H] + Calculated m / z for: 423.1, found: 423.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.02 - 8.99 (m, 1H), 8.44 (s, 1H), 7.92 (d, J = 7.6 Hz, 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 = 4.8 Hz, 2H), 2.66 (s, 3H), 2.40 (s, 3H).

[0953] Example 81: 6-(3,5-Difluorobenzyl)-2-methyl-N-((2-methyloxazol-4-yl)methyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxamide

[0954]

[0955] 1. Synthesis of ethyl 6-(3,5-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0956]

[0957] A solution of diethyl (E)-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 overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the precipitated solid was collected by filtration and washed with H2O (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 for: 359, found: 359.

[0958] 2. Synthesis of ethyl 6-(3,5-difluorobenzyl)-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate

[0959]

[0960] 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 for: 331, found: 331.

[0961] 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

[0962]

[0963] At 0 °C, EDC·HCl (46 mg, 0.240 mmol) and HOBT (32 mg, 0.237 mmol) were added 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), followed by the addition of (2-methyloxazol-4-yl)methanamine (64 mg, 0.571 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude material was then purified by a reverse-phase column (gradient: 0 to 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 for: 425.1, found: 425.1. 1 1H NMR (400 MHz, DMSO-d6, δ): 9.02 - 9.01 (m, 1H), 8.45 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 1.1 Hz, 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).

[0964] Biological Example

[0965] TFEB-translocation analysis of HEK-293T-oEX-TFEB-GFP cell line

[0966] 1. Experimental Materials

[0967]

[0968]

[0969] 2. Cell Culture and Compound Dilution

[0970] 2.1. Culture of HEK-293T-oEX-TFEB-GFP Cell Line

[0971] 1). 2×10 6 cells were added to a 15 mL DMEM medium (containing 10%

[0972] in a T75 flask containing FBS, 1% PS, 1× GLUTAMAX, 1× MEM NEAA, 1× HEPES buffer solution and 5 μg / mL blasticidin).

[0973] 2). Incubate for 48 to 72 hours. Obtain cells in the logarithmic growth phase for experiments. Passage other cells as described in step 1.

[0974] 3). Seed 1×10 4 cells / 30 μL / well into a 384-well plate (BD 356663). Incubate overnight at 37℃

[0975] and 5% CO2 incubator.

[0976] 4). Note: The cells used are <10 passages

[0977] 2.2. Compound dilution and treatment

[0978] 1). First, dilute the compound to the required stock solution (10 mM) with DMSO, aliquot and store at -20℃.

[0979] 2). Take one aliquot each time and perform 3-fold or 2-fold dilutions as indicated, for a total of 10 doses plus 1 DMSO control well in the source plate.

[0980] 3). Add 150 or 90 nL / well of the compound solution to the assay plate by ECHO and incubate at 37℃ and 5% CO2 incubator for 6 or 18 hours respectively.

[0981] 3. Translocation analysis

[0982] 3.1. Cell fixation

[0983] 1). Add 30 μL of 8% PFA to the wells and incubate at room temperature for 20 min.

[0984] 2). Discard the medium and wash the wells twice with DPBS to remove foam and bubbles in the wells.

[0985] 3.2. Nuclear staining

[0986] 1). Dilute Hoechest-333824 in DPBS to obtain a 2 μg / mL solution and add 30 μL /

[0987] well to the assay plate and incubate at room temperature for 20 min.

[0988] 2). Discard the supernatant, wash the wells twice with DPBS to remove foam and bubbles in the wells. Then add 20 μL / well of DPBS.

[0989] 3). Through the Operetta scanning plate.

[0990] 3.3. Plate map for TFEB translocation analysis

[0991] 1). Reference compound: Torin 1

[0992] 2). Test compounds: C1, C2, C3, C4, C5, C6.

[0993] 3). Dilute the compounds in the 384 LDV dilution plate according to the dilution plate map

[0994] 4). Starting compound concentrations: Torin 1: 300 nM and test compounds: 50 μM.

[0995] 4. Data analysis: Ratio of TFEB translocation positive cells

[0996] 1). Select all cell nuclei as 'all cells' through the Operetta

[0997] 2). Calculate the average EGFP intensity inside the cell nucleus area.

[0998] 3). Select the population with an average EGFP intensity > background inside the cell nucleus area as EGFP positive cells

[0999] 4). Select the surrounding area of the cell nucleus and calculate the average EGFP intensity of said area

[1000] 5). Inside the EGFP-positive cell population, select the average EGFP intensity inside the cell nucleus area

[1001] / average EGFP intensity inside the surrounding area = 1.2 (this ratio can be slightly adjusted over time) of the cells as translocation positive cells.

[1002] 6). Output the ratio of translocation positive cells / EGFP-positive cells as the translocation positive ratio.

[1003] 7). Set the ratio of the DMSO group (control group) to approximately 15% each time, and then normalize the compound groups to the DMSO group.

[1004] EC of reference compound Torin 1 50 is 28.34 nM.

[1005] Data of the examples

[1006] Table 1. TFEB translocation EC values of exemplary compounds 50 Value

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017] *NT = Not Tested; "++++" = EC 50 <0.1 μM; "+++" = EC 50 ≥ 0.1 μM and < 1 μM; "++" = EC 50 ≥ 1 μM and < 10 μM; "+" = EC 50 ≥ 10 μM

[1018] In vitro hepatic microsomal metabolic stability analysis of different species

[1019] 1. Store the hepatic microsomes at -80 °C before use. The hepatic microsome information is listed in Table 2.

[1020] Table 2. Hepatic microsome information

[1021]

[1022] 2. Prepare the stock solution according to Table 3.

[1023] Table 3. Preparation of the stock solution

[1024]

[1025] 3. Add 40 μL of 10 mM NADPH solution to each well. The final concentration of NADPH is 1 mM. Preheat the mixture at 37 °C for 5 minutes. Prepare the negative control sample by replacing the NADPH solution with 40 μL of ultrapure H2O. Use the negative control to exclude misleading factors caused by the instability of the chemical itself. Prepare the samples with NADPH in duplicate. Prepare a single negative control.

[1026] 4. The reaction was initiated by adding 2 μL of 200 μM control compound or test compound solution. Verapamil was used as the positive control in this study. The final concentration of the test compound or control compound was 1 μM.

[1027] 5. Aliquots of 50 μL were taken from the reaction solution at 0 and 30 minutes. The reaction was stopped by adding 4 volumes of cold acetonitrile with 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 minutes. An aliquot of 90 μL of the supernatant was mixed with 90 μL of ultrapure H2O and then used for LC-MS / MS analysis.

[1028] 6. Data analysis

[1029] All calculations were performed using Microsoft Excel.

[1030] Peak areas were determined from the extracted ion chromatograms. The slope value k was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug versus incubation time curve.

[1031] The in vitro half-life (in vitro t 1 / 2 ) was determined based on the slope value:

[1032] In vitro t 1 / 2 = -(0.693 / k)

[1033] The in vitro t 1 / 2 (min) was converted to in vitro intrinsic clearance (in vitro CL int , in μL / min / mg protein) using the following equation (average of repeated determinations):

[1034]

[1035] The in vitro t 1 / 2 (min) was converted to scaled unbound intrinsic clearance (scaled CL int , in mL / min / mg) using the following equation (average of repeated determinations):

[1036]

[1037] Table 4. Scaling factors for the prediction of intrinsic clearance in liver microsomes

[1038]

[1039] a. Davies and Morris, 1993, Pharmaceutical Research, 10(7), pp. 1093-1095.

[1040] b. Barter et al., 2007, Current Drug Metabolism, 8(1), pp. 33-45; Iwatsubo et al., 1997, Journal of Pharmacology and Experimental Therapeutics, 283(2), pp. 462-469.

[1041] Table 5. Clearance data of selected compounds

[1042]

[1043]

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 is H, a halogen group, C 1-6 alkyl, non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein the C 1-6 alkyl is optionally substituted by one to three R 1a substituents, wherein the non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl are each optionally substituted by one to three R 1c substituents; R 1a independently at each occurrence is a halogen group, -OR 1b , non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl group, naphthyl group, 5- or 6-membered monocyclic heteroaryl group or 9- or 10-membered bicyclic heteroaryl group, wherein the non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl group, naphthyl group, 5- or 6-membered monocyclic heteroaryl group and 9- or 10-membered bicyclic heteroaryl group are each optionally substituted by one to three R 1c substituents; R 1b is H, C 1-6 alkyl or -[CH2-CH2-O] z -CH3; z is from 1 to 3; R 1c independently at each occurrence is a halogen group, 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 ; R 1d is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or R 1 and R 2 forms, together with the carbon to which it is attached, a non-aromatic C 3-8 carbocyclic group, a 4- to 6-membered monocyclic heterocyclic group, a 6- to 10-membered bicyclic heterocyclic group, a phenyl group, a naphthyl group, a 5- or 6-membered monocyclic heteroaryl group or a 9- or 10-membered bicyclic heteroaryl group, each of which is optionally substituted by one to three R 1c substituents; R 3 is H, a halogen group, C 1-6 alkyl, non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein the C 1-6 alkyl is optionally substituted by one to three Rs 3a wherein the non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl are each optionally substituted by one to three Rs 3c substituted; R 3a independently at each occurrence is a halogen group, -OR 3b , non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl group, naphthyl group, 5- or 6-membered monocyclic heteroaryl group or 9- or 10-membered bicyclic heteroaryl group, wherein the non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered bicyclic heterocyclic group, phenyl group, naphthyl group, 5- or 6-membered monocyclic heteroaryl group and 9- or 10-membered bicyclic heteroaryl group are each optionally substituted by one to three R 3c substituents; R 3b is H, C 1-6 alkyl or -[CH2-CH2-O] y -CH3; y is from 1 to 3; R 3c is independently, at each occurrence, a halogen group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, -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 ; R 3d is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is H, a halogen group, -NR 5a R 5b , C 1-6 alkyl or C 1-6 haloalkyl; R 5a and R 5b each independently is H or C 1-6 alkyl; provided that the pharmaceutical composition does not include a compound of the following formula: or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein R 5 is -CH3.

3. The pharmaceutical composition according to claim 1 or 2, wherein R 1 is H, C 1-6 alkyl, non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, phenyl or 5- or 6-membered monocyclic heteroaryl, wherein the C 1-6 alkyl is optionally substituted by one to three R 1a substituents, wherein the non-aromatic C 3-8 carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, phenyl or 5- or 6-membered monocyclic heteroaryl is each optionally substituted by one or two R 1c substituents, or wherein R 1 and R 2 together with the carbon to which they are attached form a phenyl optionally substituted by one or two R 1c substituents.

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

5. The pharmaceutical composition according to claim 1 or 2, wherein R 1 is selected from the group consisting of bicyclo[1.1.1]pentyl, phenyl, pyridyl, thienyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, wherein each is optionally substituted with one or two R 1c substituents.

6. The pharmaceutical composition according to claim 1 or 2, wherein R 1 is selected from the group consisting of bicyclo[1.1.1]pentyl, phenyl, thienyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, wherein each is optionally substituted with one or two R 1c substituents.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein R 1c is, each time it appears, C 1-6 alkyl, -OR 1b or a halogen group, and wherein R 1b is -[CH2-CH2-O] z -CH3.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein R 3 is H, C 1-6 alkyl, a 6- to 10-membered bicyclic heterocyclic group, a phenyl group, or a 5- or 6-membered monocyclic heteroaryl group, wherein the C 1-6 alkyl is optionally substituted with one to three R 3a substituents, and wherein the 6- to 10-membered bicyclic heterocyclic group, phenyl group, or 5- or 6-membered monocyclic heteroaryl group is each optionally substituted with one to three R 3c substituents.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein R 3 is a 6- to 10-membered bicyclic heterocyclic group, a phenyl group, or a 5- or 6-membered monocyclic heteroaryl group, wherein the 6- to 10-membered bicyclic heterocyclic group, phenyl group, or 5- or 6-membered monocyclic heteroaryl group is each optionally substituted with one or two R 3c substituents.

10. The pharmaceutical composition according to any one of claims 1 to 7, wherein R 3is a 6- to 10-membered bicyclic heterocyclic group or a 5- or 6-membered monocyclic heteroaryl group, wherein said 6- to 10-membered bicyclic heterocyclic group or 5- or 6-membered monocyclic heteroaryl group is each optionally substituted with one or two R 3c substituents.

11. The pharmaceutical composition according to any one of claims 1 to 9, wherein R 3 is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, benzodioxolyl, furyl, oxazolyl, oxadiazolyl, pyrazolyl or triazolyl, wherein said phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, benzodioxolyl, furyl, oxazolyl, oxadiazolyl, pyrazolyl or triazolyl is each optionally substituted with one to two R 3c substituents.

12. The pharmaceutical composition according to claim 1, wherein the compound is represented by formula (II): or a pharmaceutically acceptable salt thereof, wherein: m is from 0 to 2; R 1c independently a halogen group, C 1-6 alkyl or -OR 1b ; R 1b -[CH2-CH2-O] z -CH3; R 3 is an optionally one- or two-R 3c substituted 5- or 6-membered monocyclic heteroaryl; R 3c is a halogen group or a C 1-6 alkyl group.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein R 3 is pyridyl.

14. The pharmaceutical composition according to any one of claims 1 to 11, wherein R 3c is, each time it appears, a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, -OR 3b or -C(O)NR 3d R 3d .

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein R 3c is, each time it appears, -CH3, -CF3, -Cl, -F, -OCH3, -OCH(CH3)2 or -C(O)NH2.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein R 2 and R 4 are both H.

17. The pharmaceutical composition according to any one of claims 1 to 3, wherein R 1a is -OR 1b , and R 3a is, each time it appears independently, a halogen group, -OR3b a 5- or 6-membered monocyclic heteroaryl.

18. The pharmaceutical composition according to any one of claims 1 to 16, wherein R 1c is -F, -Cl or -CH3, and R 3c is -F, Cl or -CH3.

19. The pharmaceutical composition according to claim 1, wherein the compound is selected from: 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 pharmaceutically acceptable salt thereof.

20. A compound represented by formula (II): or a pharmaceutically acceptable salt thereof, wherein: R 2 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 1c independently a halogen group or a C 1-6 alkyl group; m is from 0 to 2; When m is 0, R 3 is a 5-membered monocyclic heteroaryl or 6-membered monocyclic heteroaryl selected from the group consisting of oxazolyl, oxadiazolyl, pyrazolyl and triazolyl, each of which is optionally substituted by one or two R 3c substituents; or When m is 1 or 2, R 3 is an optionally one- or two-R 3c substituted 5- or 6-membered monocyclic heteroaryl; R 3c is a halogen group or C 1-6 alkyl.

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

22. The compound according to claim 20 or 21 or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, oxadiazolyl, pyrazolyl or triazolyl, each of which is optionally substituted with one or two R 3c substituents.

23. The compound according to any one of claims 20 to 22 or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridyl.

24. The compound according to any one of claims 20 to 23 or a pharmaceutically acceptable salt thereof, wherein each R 1c is independently H, -Cl, -F or -CH3, and wherein each R 3c is independently -F, -Cl or -CH3.

25. The compound according to any one of claims 20 to 24 or a pharmaceutically acceptable salt thereof, wherein R 1c is H, -Cl or -CH3, and wherein R 3c is -F.

26. A method for treating a disease mediated by transcription factor EB, the method comprising administering to a subject an effective amount of the compound according to any one of claims 20 to 25 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 1 to 19.

27. A method for treating a lysosomal storage disease, an infection, a metabolic disease, a muscle disease, a neurodegenerative disease, a kidney disease, a hematological disease or an ophthalmic disease, the method comprising administering to a subject an effective amount of the compound according to any one of claims 20 to 25 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 1 to 19.

28. The method according to claim 27, wherein: the lysosomal storage disease is selected from Gaucher disease, Pompe disease, NPC, cystinosis, Krabbe disease, Schiefferdecker syndrome, multiple sulfatase deficiency, α-mannosidosis, Fabry disease, Hunter syndrome, Scheie syndrome, Maroteaux-Lamy syndrome, hyaluronidase deficiency, sialidosis, mucolipin 1 deficiency, neuronal ceroid lipofuscinosis (Batten disease), type I, type II, type III, type IV, type VI, type VII and type IX mucopolysaccharidosis, Hurler-Scheie syndrome, Morquio syndrome, glycoprotein storage disease, glycogen storage disease, metachromatic leukodystrophy, Sly syndrome, I-cell disease, Danon disease, type A, type B, type C1 and type C2 Niemann-Pick disease, Sandhoff disease, lysosomal acid lipase deficiency, GM2 gangliosidosis, Tay-Sachs disease, Gaucher disease, Sara disease, cholesterol ester storage disease, aspartylglucosaminuria, cystinosis, type I-IV mucolipidosis, type I and type II Schindler disease, Wolman disease, fucosidosis, pycnodysostosis and free sialic acid storage disease; the infection is selected from bacterial infection, viral infection and eukaryotic parasites; the metabolic and muscle diseases are selected from α1-antitrypsin deficiency, polymyositis and DMD; the neurodegenerative diseases are selected from Parkinson's disease, Huntington's disease, Alzheimer's disease and Lewy body dementia; the kidney diseases are selected from PKD, AKI, renal interstitial fibrosis and diabetic nephropathy; the hematological disease is β-thalassemia; and the ophthalmic diseases are selected from macular degeneration and retinitis pigmentosa.

Images