1,6-naphthiridine compounds as SMARCA2 inhibitors useful in the treatment of SMARCA4-deficient cancers

Abstract

The present invention relates to pharmaceutical compounds and pharmaceutical compositions containing said compounds, processes for preparing said compounds, the use of said compounds as inhibitors of the SMARCA2 protein, and the use thereof in the treatment of SMARCA4-deficient cancers, such as SMARCA4-deficient non-small cell lung cancer (NSCLC). [Formula 1] TIFF2026523245001031.tif16128

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compounds and pharmaceutical compositions containing said compounds, processes for preparing said compounds, the use of said compounds as inhibitors of the SMARCA2 protein, and the use thereof in the treatment of SMARCA4-deficient cancers, such as SMARCA4-deficient non-small cell lung cancer (NSCLC). [Background technology]

[0002] The Switch / Sucrose Non-Fermenting (SWI / SNF) complex, also known as the BAF complex, is a multi-subunit complex that regulates chromatin structure through the activity of two mutually exclusive helicase / ATPase catalytic subunits: SWI / SNF-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2 (SMARCA2, BRAHMA, or BRM) and SWI / SNF-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4, or BRG1). The core and regulatory subunits link ATP hydrolysis to histone-DNA contact perturbations, thereby providing access points to transcription factors and congeneral DNA elements that promote gene activation and repression.

[0003] Mutations in the genes encoding 20 standard SWI / SNF subunits are observed in nearly 20% of all cancers, with the highest frequency mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical, and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, and clear cell carcinomas of the esophagus and kidney. Despite having a high degree of homology and presumed overlapping functions, SMARCA2 and SMARCA4 have been reported to have different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is rare in tumorigenesis. Indeed, numerous types of cancer, including lung cancer (non-small cell lung cancer or NSCLC, etc.), have been shown to be SMARCA4-related (e.g., cancers with SMARCA4 mutations or SMARCA4 deficiencies, e.g., lack of expression).

[0004] SMARCA2 has been demonstrated as one of the most important genes in SMARCA4-related or mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells are exclusively dependent on SMARCA2 activity; that is, there is greater uptake of SMARCA2 into the complex to compensate for the SMARCA4 deficiency. Therefore, SMARCA2 can be targeted in SMARCA4-related / deficient cancers. The simultaneous occurrence of deficiencies in the expression of two (or more) genes that lead to cell death is known as synthetic lethality. Therefore, synthetic lethality can be utilized in the treatment of certain SMARCA2 / SMARCA4-related cancers.

[0005] There is a continuing need for effective treatments for diseases treatable by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, nonspecific effects and the inability to selectively target and modulate SMARCA2 remain obstacles to the development of effective therapies. Therefore, small molecule therapies targeting SMARCA2 are highly valuable.

[0006] The object of the present invention is to provide a compound that is more selective to SMARCA2 than to SMARCA4.

[0007] The objective of the present invention is to provide a SMARCA2 inhibitor that is effective in treating SMARCA4-deficient cancer.

[0008] The object of the present invention is to provide a SMARCA2 inhibitor compound that is effective in treating SMARCA4-deficient NSCLC. [Overview of the project] [Means for solving the problem]

[0009] Embodiments of the present invention relate to 1,6-naphthyrizine chemicals having SMARCA2 regulatory properties, as described in the claims, specific uses and methods of use of pharmaceutical compositions containing these chemicals, the use of these chemicals as inhibitors of the SMARCA2 protein, and methods for treating or use in the treatment of SMARCA4-deficient cancer.

[0010] Additional embodiments, features, and advantages of the present invention will become apparent from the following "Modes for Carrying Out the Invention" and through the practice of the present invention.

[0011] Embodiments of the present invention are compounds of formula (I),

[0012] [ka] During the ceremony, R 1 This is a phenyl compound that is optionally substituted, selected from the following: (a) 2-chlorophenyl, 2-methyl-5-(1H-tetrazole-1-yl)phenyl, 5-(tert-butyl)-2-methoxyphenyl, 3-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl, 2-fluoro-5-(1-hydroxyethyl)-4-methylphenyl,

[0013] [ka] and wherein R a is independently selected from one or two substituents selected from H, halo, C 1~4 alkyl, OH, cyclopropyl, CN, and CH2CO2C 1~4 alkyl substituted with one or two substituents independently selected from each of C 1~4 alkyl, C[[ID=1)4]] 1~4 haloalkyl, C substituted with one or two OH groups 1~4 haloalkyl, CN, OC 1~4 alkyl, OC 1~4 haloalkyl, (P=O)(CH3)2, CO2C 1~4 alkyl, NH(SO2-C 2~3 alkenyl), and NH(C=O)C 2~3 alkynyl, and is selected from R b is selected from Cl, F, Br, C 1~4 alkyl, OC 1~4 alkyl, cyclopropyl, and 4-methyl-1H-imidazol-1-yl R c is selected from Cl, Br, I, C 1~4 alkyl, C 1~4 haloalkyl, OC 1~4 alkyl, O-CH2CH2OH, C(OH)(CH3)2, (C=O)CF3, CN, C(CH3)2CN, N(CH3)(CH2CH2OH), N(SO2CH3)(CH2CH2OH), CH(OH)(CH3), CH(OH)(OCH3), halo, OH, CH3, CH2CH2OH, OC 1~4 alkyl, and CO2C 1~4 alkyl, and is selected from one or two substituents independently selected from each of optionally substituted heterocycloalkyl R d is Cl or CH3 R e is C substituted with one or two OH groups 1~4 alkyl, and 1H-tetrazole R f is I, B(OH)2, CH2NH2, CH2N(CH2CH3)2, and

[0014] [ka] Selected from, or (b)

[0015] [ka] And, During the ceremony, R g This is a C atom that is optionally substituted with one OH group. 1~4 It is alkyl, R h C 1~4 Alkyl or C 1~4 It is a haloalkyl, R j OH, CN, OC 1~4 Alkyl, CN, NH2, N(C 1~4 Alkyl)2, O-tetrahydropyranyl, C(OH)(CH3)2-substituted piperidine, and NH(CO2C 1~4 Alkyl) and NH(C 1~4 Alkyl) and N(C 1~4 Alkyl)2, NH(CH2CH2OH), tetrahydropyranyl, and C 1~4 Haloalkyl and C 2~4 C is independently substituted with one, two, or three atoms selected from alkenyls, azetidines optionally substituted with OH groups, and (cis)-2,6-dimethylmorpholinyl. 1~4 Selected from alkyl groups, Each R k Hello, C 1~4 Alkyl, OC 1~4 Alkyl, NH2, OC 1~4 Haloalkyl, CN, CH2OH, C 3~6 Cycloalkyl, and C 2~4 Selected independently from Alkenil, R m C 1~4 Selected from haloalkyl, CH2CH2OH, and CH2CN, n is 0, 1, 2, or 3. X is O, NH, or N-CH3. R 3 C is optionally substituted with H and one selected from OH, NH2, N(CH3)2, NH(C=O)CH3, and morpholine. 1~4 Alkyl and selected from, R 5 This group consists of the following: i), ii), iii), iv), v), and vi): I C 5~7 Cycloalkyl or C 5~7 A 5-membered or 6-membered heteroaryl obtained by optional condensation with a heterocycloalkyl group, wherein the following: (cis)-2,6-dimethyl-4-(5,6,7,8-tetrahydro-2,6-naphthyrizin-1-yl)morpholine, 7-((cis)-2,6-dimethylmorpholino)-2,3-dihydrofl[2,3-c]pyridine, 4-((cis)-2,6-dimethylmorpholino)-1,3-dihydrofl[3,4-c]pyridine, (cis)-2,6-dimethyl-4-(5,6,7 ,8-tetrahydroisoquinoline-1-yl)morpholine, 3-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-6-yl, (cis)-2,6-dimethyl-4-(pyrimidine-4-yl)morpholine, (cis)-2,6-dimethyl-4-(1H-pyrazole-3-yl)morpholine, (1H-pyrazole-1-yl),

[0016] [ka] Selected from, In the formula, R n The following group is selected:

[0017] [ka] and R p The following group is selected from (a), (b), (c), (d), and (e): (a) An 8- to 10-membered nitrogen-bonded spirocyclic heterocycloalkyl ring system, in which each ring optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, and S, and OH, C 1~4 Alkyl, C 1~4 Haloalkyl, oxo, CO2C 1~4 Alkyl, NH2, N(H)(C 1~4 Alkyl), N(C 1~4 Alkyl)2, N(H)(CO2C 1~4 Alkyl, and OC 1~4 An 8- to 10-membered nitrogen-bonded spirocyclic heterocycloalkyl ring system, optionally substituted with one, two, or three atoms independently selected from the alkyl group. (b)

[0018] [ka] (c) CH3, NH2, and NH(CO2C 1~4 Nitrogen-bonded azetidines, which are optionally substituted with one or two atoms independently selected from alkyl groups. Hello, C 1~4 Alkyl, CH2OH, CH2OCH3, C 1~4 Haloalkyl, OH, NH2, oxo, NH(CO2C 1~4 Optionally substituted nitrogen-bonded pyrrolidine, deuterium, halo, or C, each independently selected from alkyl, morpholinyl, and CH2-morpholinyl, with one, two, three, or four atoms. 1~4 Alkyl, CH2OH, CH2CH2OH, OH, NH2, NH(c 1~4 Alkyl, and OC 1~4 Nitrogen-bonded piperidines are optionally substituted with one, two, three, or four atoms independently selected from the alkyl group. Hello, C 1~4 Alkyl, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, CH2CN, (C=O)NH2, CH2(C=O)NH2, CO2C 1~4 Alkyl, CH2SO2CH3, C 1~4 Haloalkyl, OH, oxo, C3~6 Cycloalkyl, and CH2-C 3~6 One, two, three, or four nitrogen-linked piperazines independently selected from cycloalkyl, and optionally substituted with C 1~4 Alkyl, C 1~4 Haloalkyl, CO2OH, oxo, (CH2) 4~6 -NH2, (CH2) 4~6 -NH(C=O)CH3, and (CH2) 4~6 -NH(CO2C 1~4 Alkyl), one, two, three, or four nitrogen-linked morpholines independently selected from, and optionally substituted with One or two C 1~4 Alkyl groups, nitrogen-linked diazepane optionally substituted with One or two C 1~4 Alkyl groups, nitrogen-linked oxazepane optionally substituted with, and nitrogen-linked thiomorpholine 1,1-dioxide (d) A 5- to 10-member fused or bridged ring, where each ring optionally contains 1, 2, or 3 heteroatoms independently selected from N, S, or O, and halo, C 1~4 Alkyl, OH, NH2, NH(C 1~4 Alkyl), N(C 1~4 Alkyl)2, NH(CO2C 1~4 Alkyl), CO2C 1~4 Alkyl, and oxo, one, two, or three independently selected from, and optionally substituted with, a 5- to 10-member fused or bridged ring, and (e)

[0019]

Chemical formula

[0020] [Chemical formula] independently selected from R s is H or halo, R t is C 1~4 alkyl, oxetan-3-yl, a carbon-bonded azetidine optionally substituted with (CO2-tBu), tetrahydropyran, 1,3-oxazinane-2-one, 2,2,6,6-tetramethylpiperidin-4-yl, and 2,2,6,6-tetramethyltetrahydro-2H-pyran, selected from ii)

[0021] [Chemical formula] where in the formula, R u is H, pyridin-3-yl, or pyridin-4-yl, R<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ [ka] iv)

[0025] [ka] v)

[0026] [ka] and vi)C 1~4 Haloalkyl or -CH2-R aa Selected from, R aa CH(CH3)2, CH2CH2OCH3, cyclopentyl,

[0027] [ka] Phenyl,

[0028] [ka] This refers to the use and therapeutic methods of compounds selected from, as well as their pharmaceutically acceptable salts, stereoisomers, and isotopic variants.

[0029] In one embodiment of the present invention, the compound is not 3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide or 3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide.

[0030] Built-in by reference All publications, patents, patent applications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referenced herein are incorporated by reference to the same extent that each individual publication, patent, patent application, or published nucleotide and amino acid sequence is specifically and individually indicated as being incorporated by reference. [Modes for carrying out the invention]

[0031] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood in relation to the subject matter claimed. Where URLs or other such identifiers or addresses are referenced, it is understood that such identifiers may change, and certain information on the Internet may shift, but equivalent information can be found by searching the Internet. References to these are evidence of the existence and public dissemination of such information.

[0032] Please understand that the general description above and the detailed description below are illustrative and descriptive only and do not limit any subject matter claimed.

[0033] In this application, unless otherwise specifically stated, the use of the singular form includes the plural. Note that, as used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple objects unless otherwise clearly indicated by the surrounding context. In this application, unless otherwise specifically stated, the use of "or" means "and / or."

[0034] When a value is expressed as an approximation using the antecedent "about," it should be understood that the particular value forms another embodiment. As used herein, "about X" (where X is a numerical value) preferably encompasses ±10% of the stated value. For example, the phrase "about 8" encompasses values ​​from 7.2 to 8.8, and as an alternative, the phrase "about 8%" encompasses values ​​from 7.2% to 8.8%. All ranges, where present, are inclusive and combinable. For example, when listing the range "1 to 5," the listed range should be interpreted as including ranges such as "1 to 4," "1 to 3," "1 to 2," "1 to 2 and 4 to 5," "1 to 3 and 5," etc. Furthermore, when a list of substitutes is explicitly provided, such a list may also include embodiments in which any of the substitutes may be excluded. For example, when describing the range "1 to 5," such description may support situations in which 1, 2, 3, 4, or 5 is excluded. Therefore, the statement "1-5" may support the interpretation of "1 and 3-5, but not 2" or simply "2 is not included."

[0035] Some of the quantitative expressions given herein are not modified by the term “approximately.” Whether or not the term “approximately” is explicitly used, all quantities shown herein mean the actual values ​​shown, and are understood to also mean approximations of such shown values ​​that can be reasonably estimated based on the ordinary skill in the art, including approximations of such shown values ​​based on experimental and / or measurement conditions and permissible errors.

[0036] As used herein, the expression "one or more" means, whenever possible, at least one, for example, one, two, three, four, five or more, depending on the context.

[0037] Furthermore, the use of the term "include," as well as other forms such as "include," "includes," and "included," is not limited to these.

[0038] The chapter headings used herein are for structural purposes only and should not be interpreted as limiting the subjects described.

[0039] The standard definitions of chemical terms are found in Carey and Sundberg's "Advanced Organic Chemistry 4". th This can be found in references including, but not limited to, "Ed." Vols. A (2000) and B (2001), Plenum Press, New York.

[0040] Unless otherwise specified, the nomenclature, experimental procedures, and techniques used in relation to analytical chemistry, synthetic organic chemistry, and pharmaceutical and pharmaceutical chemistry described herein are recognized in the art. Standard methods can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and for the treatment of patients. Standard methods can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reaction and purification techniques can be carried out using kits specified by the manufacturer, or as commonly achieved in the art, or as described herein. The aforementioned techniques and procedures can generally be carried out by conventional methods, as described in the various general and more specific references cited and discussed throughout this specification.

[0041] The methods and compositions described herein are not limited to the specific methodologies, protocols, cell lines, constructs, and reagents described herein, and should therefore be understood to be subject to change. Furthermore, the terms used herein are solely for the purpose of describing specific embodiments and are not intended to limit the scope of the methods, compounds, and compositions described herein.

[0042] In the above and below, the term "compound of formula (I)" is meant to include its addition salts and stereoisomers.

[0043] As used herein, "C x~y "(where x and y are integers) refers to the number of carbon atoms constituting the moiety it designates (excluding optional substituents). Thus, C 1~6 alkyl groups contain 1 to 6 carbon atoms, C 3~6 cycloalkyl groups contain 3 to 6 carbon atoms, and so on.

[0044] The term "halo", or "halogen", means fluoro, chloro, bromo and iodo.

[0045] Alkyl groups can have 1 to 6 carbon atoms (whenever it appears herein, numerical ranges such as "1 to 6" always refer to each integer within the given range. For example, "1 to 6 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 6 carbon atoms, and this definition also includes the case of the term "alkyl" where no numerical range is specified). The alkyl groups of the compounds described herein can be designated as "C 1~6 alkyl" or similar designations.

[0046] By way of example, the term "C 1~4 alkyl" or "C[[ID=​​​​​​"Haloalkyl", "C" 1~6 "Haloalkyl", monohalo C 1~4 Alkyl, monohalo C 1~6 Alkyl, polyhalo C 1~4ア Lucyl, and polyhalo C 1~6 alkyl is included. C1-4 haloalkyl or C 1~6 One, two, or more hydrogen atoms may be replaced by halogen so that the haloalkyl may have one, two, or more halogens. Examples of the "haloalkyl" group include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and groups that are considered equivalent to any one of the foregoing examples based on ordinary skill in the art and the teachings provided herein.

[0048] The term "alkenyl" refers to an alkyl group of the type in which at least two atoms of the alkyl group form a double bond that is not part of an aromatic group. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2, and -C(CH3)=CHCH3. The alkenyl moiety may be branched or straight-chain. The alkenyl group may have 2 to 6 carbons. The alkenyl group may be substituted or unsubstituted. Depending on the structure, the alkenyl group may be a monoradical or a diradical (i.e., an alkenylene group). Examples of "alkenyl" include "C" 2~4 alkenyl" or "C" 2~6 alkenyl" are also included.

[0049] The term "alkynyl" refers to an alkyl group of the type in which at least two atoms of the alkyl group form a triple bond. Non-limiting examples of alkynyl groups include

[0050]

Chemical formula

[0051] "Amino" refers to the -NH2 group.

[0052] The terms "alkylamine" or "alkylamino" refer to -N(alkyl) x H y "Dialkylamino" refers to a -N(alkyl)2 group, where alkyl is as defined herein, and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups can optionally form a cyclic ring system together with the nitrogen to which they are bonded. "Dialkylamino" refers to a -N(alkyl)2 group, where alkyl is as defined herein.

[0053] The terms "carboxy" or "carboxyl" refer to -CO2H. In some embodiments, the carboxyl moiety may be replaced with a "carboxylic acid bioequivalent," which refers to a functional group or moiety exhibiting similar physical and / or chemical properties to the carboxylic acid moiety. The carboxylic acid bioequivalent has similar biological properties to the carboxylic acid group. A compound having a carboxylic acid moiety can have the carboxylic acid moiety replaced with a carboxylic acid bioequivalent and will have similar physical and / or biological properties when compared to a carboxylic acid-containing compound. For example, in one embodiment, the carboxylic acid bioequivalent ionizes to approximately the same extent as the carboxylic acid group at physiological pH. Examples of carboxylic acid bioequivalents include, but are not limited to,

[0054] [ka] These are some examples.

[0055] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. Aromatic rings can be formed from 5, 6, 7, 8, 9, or 10 or more atoms. Aromatics may be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0056] The term "non-aromatic group" encompasses unsaturated, partially saturated, and fully saturated heterocycloalkyl ring systems that do not possess aromatic properties, unless the context indicates otherwise.

[0057] The terms "unsaturated" and "partially saturated" refer to ring structures containing atoms that share two or more valence bonds, i.e., rings with at least one multiple bond, e.g., C=C.

[0058] [ka] Alternatively, it refers to a ring containing an N=C bond.

[0059] The term "fully saturated" refers to a ring in which there are no multiple bonds between ring atoms. Examples of saturated heterocycloalkyl groups include piperidine, morpholine, thiomorpholine, and piperazine. Examples of partially saturated heterocycloalkyl groups include pyrazolines, such as 2-pyrazoline and 3-pyrazoline.

[0060] The term "aryl" refers to a monocyclic aromatic carbocyclic ring (a ring structure with all carbon atoms) that has six atoms per ring (the carbon atoms in the aryl group are sp2 hybridized).

[0061] The term "phenyl" refers to the following part:

[0062] [ka]

[0063] The term "cycloalkyl" or "cycloalkenyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., the skeletal atoms) is a carbon atom. "Cycloalkyl" or "cycloalkenyl" may be saturated or partially unsaturated. Examples of "cycloalkyl" are " 3~6 cycloalkyl". Cycloalkyl may be fused to an aromatic ring (in which case, cycloalkyl is attached via a non-aromatic ring carbon atom). Examples of cycloalkyl groups include groups having 3 to 10 ring atoms. Exemplary examples of cycloalkyl groups or cycloalkenyl groups include,

[0064] but are not limited to, the following moieties:

[0065]

Chemical formula

[0066] As used herein, the term "heterocyclyl" or "heterocycloalkyl" typically contains at least one heteroatom selected from nitrogen, oxygen or sulfur, and in particular contains up to 5, up to 4, up to 3, up to 2, or a single heteroatom. When reference is made herein to a heterocyclyl ring system or a heterocycloalkyl ring system, the heterocyclyl ring or heterocycloalkyl ring may be optionally substituted by one or more substituents considered herein (i.e., unsubstituted or substituted) unless the context indicates otherwise. These radicals may be fused to an aryl or heteroaryl. It is understood that a heterocyclyl group or a heterocycloalkyl group may be attached, where chemically possible, via a heteroatom in the ring or via one of the carbons constituting the heterocycloalkyl ring. Specific examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include the following:

[0067] [ka]

[0068] A heterocyclyl ring system or heterocycloalkyl ring system may be a heteroaryl ring system having 5 to 12 ring members, more generally 5 to 10 ring members.

[0069] Heterocyclyl or heterocycloalkyl rings also include spiro, condensed, and crosslinked ring systems. Examples include crosslinked cycloalkanes, e.g., norbornane (1,4-endomethylene-cyclohexane), adamantane, oxa-adamantane; crosslinked morpholine rings, e.g., 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane; crosslinked piperazine rings, e.g., 3,6-diazabicyclo[3.1.1]heptane; and crosslinked piperidine rings, e.g., 1,4-ethylenepiperidine. For an explanation of the distinction between condensed and crosslinked ring systems, see Advanced Organic Chemistry, by Jerry March, 4. th See Edition, Wiley Interscience, pages 131–133, 1992.

[0070] The term "heteroaryl" is used herein to describe a heterocyclyl ring system having aromatic properties. The term "heteroaryl" encompasses polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system may be bonded to the remainder of the compound by aromatic or non-aromatic rings.

[0071] Examples of heteroaryl groups include monocyclic and bicyclic groups containing 5 to 12 ring members, more commonly 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings, or bicyclic structures formed from fused 5- and 6-membered rings, or two fused 6-membered rings or two fused 5-membered rings. Heteroaryl ring systems may typically contain up to about 5 heteroatoms selected from nitrogen, oxygen, and sulfur. Typically, heteroaryl rings contain up to 4 heteroatoms, more typically up to 3 heteroatoms, and more commonly up to 2, for example, a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. Nitrogen atoms in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or they may be essentially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, is less than 5. It is understood that heteroaryl groups can be bonded via heteroatoms in the ring, or via one of the carbon atoms constituting the heteroaryl ring, where chemically possible. Specific examples of heterocycloalkyl groups, also called non-aromatic heterocycles, include:

[0072] [ka] These are some examples.

[0073] A nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. Each ring may further contain up to about four other heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring contains up to three heteroatoms, e.g., one, two, or three, and more generally up to two nitrogen atoms, e.g., a single nitrogen atom. The nitrogen atoms in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or they may be essentially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, is less than five.

[0074] Examples of non-aromatic heterocyclyl groups are those having 3 to 12 ring members, more commonly 5 to 10 ring members. Such groups may be monocyclic or bicyclic, for example, and typically have 1 to 5 heteroatom ring members (more commonly 1, 2, 3, or 4 heteroatom ring members), usually selected from nitrogen, oxygen, and sulfur. Heterocyclyl groups may contain, for example, cyclic ether moieties (such as those in tetrahydrofuran and dioxane), cyclic thioether moieties (such as those in tetrahydrothiophene and dithiane), cyclic amine moieties (such as those in pyrrolidine), and combinations thereof (e.g., thiomorpholine).

[0075] Heterocyclyl rings and cycloalkyl rings also include cross-linked ring systems, such as cross-linked cycloalkanes, e.g., norbornane (1,4-endo-methylene-cyclohexane), adamantane, oxa-adamantane, etc.; cross-linked morpholine rings, e.g., 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane, etc.; cross-linked piperazine rings, e.g., 3,6-diazabicyclo[3.1.1]heptane, etc.; and cross-linked piperidine rings, e.g., 1,4-ethylenepiperidine, etc. For an explanation of the distinction between condensed ring systems and cross-linked ring systems, see Advanced Organic Chemistry, by Jerry March, 4 th See Edition, Wiley Interscience, pages 131–133, 1992.

[0076] The lines drawn within the ring system indicate that a bond can be attached to any of the appropriate and available ring atoms. The term "variable bond point" means that a group is bonded at two or more alternative positions within the structure. This bond always substitutes a hydrogen atom for one of the ring atoms. In other words, all arrangements of bonds are represented by a single diagram, as shown in the diagram below.

[0077] [ka]

[0078] Those skilled in the art will recognize that, if two or more such substituents exist on a given ring, the bonding of each substituent is independent of all the others. The groups listed or illustrated above are not exhaustive.

[0079] The terms "optional" or "optional" mean that the event described thereafter may or may not occur. This term encompasses both cases where the event occurs and cases where it does not.

[0080] In the compounds disclosed herein, in the depicted formula, * The carbon atom indicated by " is a chiral center. * When a carbon atom is indicated as "(S)", it means it is a pure enantiomer, but it is unclear whether it is an R or S enantiomer. Similarly, when a carbon atom is indicated as "(S * When indicated by )", it means it is a pure enantiomer, but it is unclear whether it is an R or S enantiomer.

[0081] The terms "bond" or "single bond" refer to a chemical bond between two atoms, or a chemical bond between two parts when the atoms linked by the bond are considered part of a larger substructure.

[0082] The term "part" refers to a specific segment or functional group of a molecule. Chemical parts are often perceived as chemical entities embedded within or attached to a molecule.

[0083] As used herein, the term “therapeutic dose” means the amount of active compound or medicinal product that, when administered to a mammal in need, is effective in at least partially improving or at least partially preventing the disease, disorder, or condition described herein.

[0084] As used herein, the term “composition” is intended to encompass products containing a particular component in a specific amount, as well as any products resulting directly or indirectly from a combination of a particular amount of a particular component.

[0085] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0086] As used herein, the term “antagonist” refers to a small molecule drug that binds to a receptor and subsequently reduces the receptor’s agonist-induced transcriptional activity.

[0087] As used herein, the term “agonist” refers to a small molecule drug that binds to a receptor and subsequently increases receptor transcriptional activity in the absence of a known agonist.

[0088] As used herein, the term “inverse agonist” refers to a small molecule drug that binds to a receptor and subsequently reduces the baseline level of receptor transcriptional activity present in the absence of a known agonist.

[0089] As used herein, the term “modulate” means to interact with a target directly or indirectly in such a way as to alter its activity, including, for example, enhancing, inhibiting, limiting, or prolonging the activity of the target.

[0090] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human. Those skilled in the art will recognize that therapies that reduce the severity of a condition in one species of mammal may predict the effect of the same therapy in another species of mammal.

[0091] As used herein, the terms “treat,” “treating,” and “treatment” include alleviating, reducing or improving at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, for example, stopping the onset of a disease or condition, reducing a disease or condition, causing a regression of a disease or condition, reducing a condition caused by a disease or condition, or preventing and / or therapeutically cessating the symptoms of a disease or condition.

[0092] "Proliferative disorders" refer to diseases resulting from abnormal growth or expansion due to cell proliferation. Proliferative disorders may be associated with 1) pathological proliferation of cells that are normally quiescent, 2) pathological migration of cells from normal sites (e.g., neoplastic cell metastasis), 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase), or 4) pathological angiogenesis, such as in proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0093] The terms “neoplasm” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue whose growth exceeds and does not coordinate with the growth of normal tissue. Neoplasms or tumors may be “benign” or “malignant” depending on the following characteristics: degree of cellular differentiation (including morphology and function), growth rate, local invasion, and metastasis. “Benign neoplasms” are generally highly differentiated, grow more slowly than malignant neoplasms, and remain localized to the site of origin. In addition, benign neoplasms do not have the ability to invade, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromes, adenomas, filamentous fibromas, senile angiomas, seborrheic keratosis, lentigo, and sebaceous gland hyperplasia. In some cases, certain “benign” tumors may later develop into malignant neoplasms, which may be due to additional genetic changes in a subpopulation of neoplastic cells in the tumor; these tumors are called “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and characterized by rapid growth accompanied by progressive invasion, infiltration, and destruction of surrounding tissues. Furthermore, malignant neoplasms generally have the ability to metastasize to distant sites.

[0094] As used herein, the term "cancer" refers to a malignant neoplasm.

[0095] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in a healthy body for wound healing and restoring blood flow to damaged tissue. A healthy body controls angiogenesis through several means, such as angiogenic growth factors and angiogenic inhibitors. Many pathological conditions, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal angiogenesis (i.e., increased or excessive). Abnormal angiogenesis refers to angiogenesis that is greater than that in a normal body, especially in adults unrelated to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels that nourish diseased tissue and / or destroy normal tissue, and in the case of cancer, new blood vessels can allow tumor cells to escape into the circulatory system and remain in other organs (tumor metastasis).

[0096] The term “biological specimen” refers to any specimen including tissue specimens (such as tissue sections and needle biopsies), cell specimens (e.g., cytological smears (e.g., Pap or blood smears) or specimens of cells obtained by microscopic dissection), specimens of whole organisms (e.g., specimens of yeast or bacteria), or cell fractions, fragments or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological specimens include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., cheek swabs), or any substance containing biomolecules derived from the first biological specimen. Biological specimens also include transgenic biological specimens such as transgenic oocytes, spermatids, blastocysts, embryos, fetuses, donor cells, or cell nuclei.

[0097] Isomers, salts, N-oxides, isotope-labeled derivatives In the above and below, “compound of formula (I),” “compound of the present disclosure or the present invention,” “compound presented herein,” or similar terms mean including its addition salts and stereoisomers.

[0098] In certain embodiments, the compounds presented herein have one or more stereocenters, each independently existing in either an R or S configuration. The compounds presented herein include all diastereomers, enantiomers, atropisomers, and epimer forms, as well as suitable mixtures thereof. Stereoiomers are obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography column. In some embodiments, the compounds of the disclosure are used as single enantiomers. In some embodiments, the compounds of the disclosure are used as racemic mixtures. In some embodiments, the compounds of the disclosure have rotational hindrance around a single bond resulting in atropisomers.

[0099] Under certain circumstances, compounds may exist as tautomers. All tautomers fall within the range of compounds presented herein.

[0100] To avoid misunderstanding, a compound may exist in one of several geometric isomers or tautomers, and if only one is specifically described or shown, all others are nevertheless encompassed. Examples of tautomers include, for example, the following tautomer pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / endiamine, nitroso / oxime, thioketone / enthiol, and nitro / ac-nitro, such as the keto, enol, and enolate forms.

[0101] [ka]

[0102] Such forms are intended to be included within the range of compounds presented herein, to the extent that they exist. Thus, a single compound may exist in both stereoisomer and tautomer forms.

[0103] If a compound described herein contains one or more chiral centers and may exist in the form of two or more optical isomers, references to such compounds herein include all optical isomeric forms (e.g., enantiomers, epimers, and diastereoisomers) either as individual optical isomers or as a mixture of two or more optical isomers (e.g., a racemic mixture), unless the context requires otherwise. If a compound has two or more chiral centers and one chiral center is indicated to have absolute configuration, the other chiral centers include all optical isomeric forms either as individual optical isomers or as a mixture of two or more optical isomers (e.g., a racemic mixture), unless the context requires otherwise. Optical isomers may be characterized and identified by their optical activity (i.e., as + and - isomers or d and l isomers depending on the direction in which they rotate plane-polarized light), or they may be characterized in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog (Advanced Organic Chemistry by Jerry March, 4). th See Edition, John Wiley & Sons, New York, 1992, pages 109–114, and also see Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385–415. For example, decomposed enantiomers whose absolute configuration is unknown may be designated as (+) or (-) depending on the direction in which they rotate plane-polarized light.

[0104] Optical isomers can be separated by many techniques, including chiral chromatography (chromatography on a chiral support), and such techniques are well known to those skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomer salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-ditoluyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, separating the diastereoisomers by preferential crystallization, and then dissociating the salts to obtain individual enantiomers of the free bases.

[0105] When a compound exists in two or more isomeric forms, one isomeric form, for example, one enantiomer in a pair of enantiomers, may exhibit superiority over the other isomer, for example, in terms of biological activity. Therefore, in certain situations, it may be desirable to use only one of a pair of enantiomers, or only one of multiple diastereoisomers, as a therapeutic agent.

[0106] When a specific stereoisomer is identified, this means that the stereoisomer is substantially free from other stereoisomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1% of other stereoisomers. Therefore, when a compound described herein is identified, for example, as (S), this means that the compound is substantially free from the (R) isomer.

[0107] When a compound described herein is identified, for example, as E, this means that the compound is substantially free of the Z isomer, and when a compound described herein is identified, for example, as cis, this means that the compound is substantially free of the trans isomer.

[0108] As used herein, any chemical formula having a bond that is shown only as a solid line and not as a solid wedge bond or hashed wedge bond, or otherwise shown as having a specific arrangement (e.g., R, S) around one or more atoms, is intended to represent each possible stereoisomer or a mixture of two or more stereoisomers.

[0109] The terms "stereoisomer," "stereoisomeric form," and "stereochemical isomer form" used above and below are interchangeable.

[0110] Enantiomers are stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0111] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers; that is, they are not related as mirror images. If a compound contains a double bond, the substituent can be in an E or Z configuration. Substituents on a divalent cyclic (partially) saturated radical can have either a cis or trans configuration; for example, if a compound contains a disubstituted cycloalkyl group, the substituent can be in either a cis or trans configuration.

[0112] Disubstituted cycloalkyl and heterocycloalkyl stereoisomers may be designated by nomenclature prefixes such as cis and trans. Cis and trans isomers are also called "geometric isomers." When a compound described herein is identified, for example, as "cis," this means that the two groups point in the same direction with respect to the plane of the ring. In the "trans" isomer, they point in opposite directions. The "cis" and "trans" isomers of 2,6-dimethylmorpholine are illustrated below. Two possible relative configurations exist, based on the relative positions of the two substituents and whether they are on the same side or opposite side of the cyclic structure.

[0113] [ka]

[0114] for example,

[0115] [ka]

[0116] In the present invention, the trisubstituted piperidine moiety having a stereocenter is defined as (3α, 4α, 5α) or (3α, 4β, 5α).

[0117] [ka]

[0118] Therefore, the disclosure includes, whenever chemically possible, enantiomers, atrop isomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof.

[0119] The meanings of all terms, namely enantiomer, atropisomer, diastereomer, racemate, E isomer, Z isomer, cis isomer, trans isomer, and mixtures thereof, are known to those skilled in the art.

[0120] The methods and formulations described herein involve the use of N-oxides (where appropriate), pharmaceutically acceptable salts, and combinations thereof of compounds having the structure and the same type of activity as presented herein.

[0121] The salt forms of the compounds presented herein are typically pharmaceutically acceptable salts, examples of which are discussed in Berge et al. (1977), "Pharmaceutically Acceptable Salts," J.Pharm.Sci, Vol. 66, pp. 1-19. However, pharmaceutically unacceptable salts may also be prepared as intermediate forms and subsequently converted to pharmaceutically acceptable salts. For example, such non-pharmaceutically acceptable salt forms, which may be useful in the purification or separation of the compounds of the present invention, also form part of the present invention.

[0122] A pharmaceutically acceptable salt means that it includes pharmaceutically acceptable acids and base addition salts, and includes therapeutically active, non-toxic acid and base addition salt forms in which the compounds described herein can be formed.

[0123] The salts of this disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods, such as those described in "Pharmaceutical Salts: Properties, Selection, and Use," edited by P. Heinrich Stahl and Camille G. Wermuth, ISBN: 3-90639-026-8, hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base of these compounds with a suitable base or acid in water, an organic solvent, or a mixture thereof, typically using non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. The compounds of the present invention may exist as monosaltes or disaltes, depending on the pKa of the acid in which the salt is formed.

[0124] Pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the salt form with a suitable inorganic acid in an anionic form (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or an organic acid (e.g., acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, etc.).

[0125] Suitable anions include, for example, acetate, 2,2-dichloroacetate, adipine, alginate, ascorbate (e.g., L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4-acetamidebenzoate, butanoate, bicarbonate, bicarbonate, bromide, (+) camphorate, camphor sulfonate, (+)-(1S)-camphor-10-sulfonate, calcium edetate, cansilate, caprine, caproate, caprylate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecyl sulfate, edetate, estrate, esylate, ethane-1,2-disulfonate, ethanesulfonate, formate, fumarate, galactalate, gentisinate, glucoheptone, gluceptate, gluconate. Salts, D-gluconates, glucuronates (e.g., D-glucuronates), glutamates (e.g., L-glutamates), α-oxoglutarates, glycolates, glycolyl arsanilates, hexyl resorcinates, hippurates, hydravamin, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonates, hydroxynaphthoates, iodides, isethionates, lactates (e.g., (+)-L-lactate, (±)-DL-lactate), lactobionates, malates, (-)-L-malates, maleates, malons, mandelates, (±)-DL-mandelates, mesylates, methanesulfonates, methyl bromide, methyl nitrate, methyl sulfate, mucinates, naphthalene sulfonates (e.g., naphthalene-2-sulfonates), naphthalene-1,This includes 5-disulfonates, 1-hydroxy-2-naphthoates, napsylates, nicotinates, nitrates, oleates, orotates, oxalates, palmitates, pamoates (embonates), pantothenates, phosphates / diphosphates, propionates, polygalacturonates, L-pyroglutamates, pyruvates, salicylates, 4-aminosalicylates, sebacinates, stearates, acetates, succinates, sulfates, tannates, tartrates, (+)-L-tartrates, theoclates, thiocyans, toluenesulfonates (e.g., p-toluenesulfonates), tosylates, triethiozides, undecylenates, valeric acids, as well as acylated amino acids and cation exchange resins. Conversely, the above salt forms can be converted to free salt forms by treatment with a suitable base.

[0126] Compounds of the present disclosure containing acidic protons may be converted to non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases in cationic form. Suitable basic salts are those formed with organic cations such as arginine, benzathine, benzylamine, butylamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, diethanolamine, diethylamine, ethanolamine, ethylamine, ethylenediamine, lysine, meglumine, phenylbenzylamine, piperazine, procaine, triethylamine, and tromethamine, and ammonium ions (i.e., NH4) + ), quaternary ammonium ion N(CH3)4 + , and substituted ammonium ions (e.g., NH3R + NH2R2 + NHR3 + NR4 +This includes compounds formed from ) and compounds formed from metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. If the compounds described herein contain amine functional groups, they can form quaternary ammonium salts by reaction with alkylating agents, for example, according to methods known to those skilled in the art. Such quaternary ammonium compounds are within the range of compounds presented herein.

[0127] Conversely, the salt form can be converted back to the free form by treatment with an appropriate acid.

[0128] In some embodiments, the sites on the compounds disclosed herein are susceptible to various metabolic reactions. Therefore, incorporating appropriate substituents at the sites of metabolic reactions reduces, minimizes, or eliminates metabolic pathways. In certain embodiments, suitable substituents for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions are, to name just a few, halogens, deuterium, or alkyl groups.

[0129] The compounds of this disclosure include isotope-labeled compounds, i.e., compounds having one or more isotopic substitutions. These compounds are identical to those enumerated in the various formulas and structures presented herein, but in practice, one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. References to specific elements include, within their scope, all isotopes of the element that exist naturally or are synthetically produced, either in natural abundance or in isotopic enrichment forms. For example, references to hydrogen include, within their scope... 1 H, 2 H(D), and 3 H(T) is included. Similarly, references to carbon and oxygen are within their respective ranges. 12 C, 13 C and 14 C, and 16 O and 18Each contains O. These isotopes may be radioactive or non-radioactive. In one embodiment, the compound does not contain radioactive isotopes. In another embodiment, the compound may contain one or more radioactive isotopes. Compounds containing such radioactive isotopes may be useful in diagnostic settings. The radiolabeled compounds described herein are 2 H, 3 H, 11 C, 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 It may contain radioactive isotopes selected from the group including Br. Preferably, the radioactive isotopes are 2 H, 3 H, 11 C, and 18 Selected from the group F. More preferably, the radioactive isotope is 2 It is H. In particular, deuterium compounds are intended to be included within the scope of the present invention. In some embodiments, the metabolic sites on the compounds described herein are deuterated.

[0130] Throughout this specification, groups and their substituents can be selected to provide stable moieties and compounds.

[0131] The embodiments of the 1,6-naphthyridine compounds for use described herein are compounds of formula (I):

[0132] [ka] During the ceremony, R 1 This is a phenyl compound that is optionally substituted, selected from the following: (a) 2-chlorophenyl, 2-methyl-5-(1H-tetrazole-1-yl)phenyl, 5-(tert-butyl)-2-methoxyphenyl, 3-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl, 2-fluoro-5-(1-hydroxyethyl)-4-methylphenyl,

[0133] [ka] And, During the ceremony, R a H, Haro, and C 1~4 Alkyl, OH, cyclopropyl, CN, and CH2CO2C 1~4 C substituted with one or two atoms independently selected from the alkyl group 1~4 Alkyl and C 1~4 Haloalkyls, C1-4 haloalkyls substituted with one or two OH groups, CN, and OC 1~4 Alkyl and OC 1~4 Haloalkyl, (P=O)(CH3)2, and CO2C 1~4 Alkyl and NH(SO2-C 2~3 Alkenyl, and NH(C=O)C 2~3 Alkinyl and selected from, R b Cl, F, Br, C 1~4 Alkyl, OC 1~4 Selected from alkyl, cyclopropyl, and 4-methyl-1H-imidazole-1-yl, R c Cl, Br, I, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl, O-CH2CH2OH, C(OH)(CH3)2, (C=O)CF3, CN, C(CH3)2CN, N(CH3)(CH2CH2OH), N(SO2CH3)(CH2CH2OH), CH(OH)(CH3), CH(OH)(OCH3) and halo, OH, CH3, CH2CH2OH, OC 1~4 Alkyl and CO2C 1~4A heterocycloalkyl group that is optionally substituted with one or two alkyl groups, each independently selected from the alkyl groups, and selected from the alkyl groups. R d is Cl or CH3, R e C is a carbon atom substituted with one or two OH groups. 1~4 Selected from alkyl and 1H-tetrazole, R f These are I, B(OH)2, CH2NH2, CH2N(CH2CH3)2, and

[0134] [ka] Selected from, or (b)

[0135] [ka] And, During the ceremony, R g This is a C atom that is optionally substituted with one OH group. 1~4 It is alkyl, R h C 1~4 Alkyl or C 1~4 It is a haloalkyl, R j OH, CN, OC 1~4 Alkyl, CN, NH2, N(C 1~4 Alkyl)2, O-tetrahydropyranyl, C(OH)(CH3)2-substituted piperidine, and NH(CO2C 1~4 Alkyl) and NH(C 1~4 Alkyl) and N(C 1~4 Alkyl)2, NH(CH2CH2OH), tetrahydropyranyl, and C 1~4 Haloalkyl and C 2~4 C is independently substituted with one, two, or three atoms selected from alkenyls, azetidines optionally substituted with OH groups, and (cis)-2,6-dimethylmorpholinyl. 1~4 Selected from alkyl groups, Each R k Hello, C 1~4 Alkyl, OC 1~4 Alkyl, NH2, OC 1~4 Haloalkyl, CN, CH2OH, C 3~6 Cycloalkyl, and C 2~4 Selected independently from Alkenil, R m C 1~4 Selected from haloalkyl, CH2CH2OH, and CH2CN, n is 0, 1, 2, or 3. X is O, NH, or N-CH3. R 3 C is optionally substituted with H and one selected from OH, NH2, N(CH3)2, NH(C=O)CH3, and morpholine. 1~4 Alkyl and selected from, R 5 This group consists of the following: i), ii), iii), iv), v), and vi): I C 5~7 Cycloalkyl or C 5~7 A 5-membered or 6-membered heteroaryl obtained by optional condensation with a heterocycloalkyl group, wherein the following: (cis)-2,6-dimethyl-4-(5,6,7,8-tetrahydro-2,6-naphthyrizin-1-yl)morpholine, 7-((cis)-2,6-dimethylmorpholino)-2,3-dihydrofl[2,3-c]pyridine, 4-((cis)-2,6-dimethylmorpholino)-1,3-dihydrofl[3,4-c]pyridine, (cis)-2,6-dimethyl-4-(5,6,7 ,8-tetrahydroisoquinoline-1-yl)morpholine, 3-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-6-yl, (cis)-2,6-dimethyl-4-(pyrimidine-4-yl)morpholine, (cis)-2,6-dimethyl-4-(1H-pyrazole-3-yl)morpholine, (1H-pyrazole-1-yl),

[0136] [ka] Selected from, In the formula, R n The following group is selected:

[0137] [ka] and R p The following group is selected from (a), (b), (c), (d), and (e): (a) An 8- to 10-membered nitrogen-bonded spirocyclic heterocycloalkyl ring system, in which each ring optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, and S, and OH, C 1~4 Alkyl, C 1~4 Haloalkyl, oxo, CO2C 1~4 Alkyl, NH2, N(H)(C 1~4 Alkyl), N(C 1~4 Alkyl)2, N(H)(CO2C 1~4 Alkyl, and OC 1~4 An 8- to 10-membered nitrogen-bonded spirocyclic heterocycloalkyl ring system, optionally substituted with one, two, or three atoms independently selected from the alkyl group. (b)

[0138] [ka] (c) CH3, NH2, and NH(CO2C 1~4 Nitrogen-bonded azetidines, which are optionally substituted with one or two atoms independently selected from alkyl groups. Hello, C 1~4 Alkyl, CH2OH, CH2OCH3, C 1~4 Haloalkyl, OH, NH2, oxo, NH(CO2C 1~4 Optionally substituted nitrogen-bonded pyrrolidine, deuterium, halo, or C, each independently selected from alkyl, morpholinyl, and CH2-morpholinyl, with one, two, three, or four atoms. 1~4 Alkyl, CH2OH, CH2CH2OH, OH, NH2, NH(c 1~4Alkyl, and OC 1~4 Nitrogen-bonded piperidines are optionally substituted with one, two, three, or four atoms independently selected from the alkyl group. Hello, C 1~4 Alkyl, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, CH2CN, (C=O)NH2, CH2(C=O)NH2, CO2C 1~4 Alkyl, CH2SO2CH3, C 1~4 Haloalkyl, OH, oxo, C 3~6 Cycloalkyl and CH2-C 3~6 A nitrogen-bonded piperazine, C, which is optionally substituted with one, two, three, or four atoms independently selected from cycloalkyl groups. 1~4 Alkyl, C 1~4 Haloalkyl, CO2OH, oxo, (CH2) 4~6 -NH2, (CH2) 4~6 -NH(C=O)CH3 and (CH2) 4~6 Nitrogen-bonded morpholine, which is optionally substituted with one, two, three, or four atoms independently selected from -NH(CO2C1-4 alkyl), 1 or 2 C 1~4 A nitrogen-bonded diazepane optionally substituted with an alkyl group, 1 or 2 C 1~4 A nitrogen-bonded oxazepane optionally substituted with an alkyl group, and a nitrogen-bonded thiomorpholine 1,1-dioxide, (d) 5-membered to 10-membered condensed or crosslinked rings, where each ring optionally contains 1, 2, or 3 heteroatoms independently selected from N, S, or O, and a halo, C 1~4 Alkyl, OH, NH2, NH(C 1~4 Alkyl), N(C 1~4 Alkyl)2, NH(CO2C 1~4 Alkyl), CO2C 1~4 A 5-membered to 10-membered condensed or crosslinked ring, optionally substituted with one, two, or three elements independently selected from alkyl and oxo, and (e)

[0139] [ka] During the ceremony, Each R q H, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, CN, CO2C 1~4 Alkyl, CO2H, (C=O)NH2, CH2OH, CH(OH)(CH3),

[0140] [ka] Selected independently from, R s H or halo, R t C 1~4 Selected from alkyl, oxetan-3-yl, carbon-bonded azetidine optionally substituted with (CO2-tBu), tetrahydropyran, 1,3-oxazinan-2-one, 2,2,6,6-tetramethylpiperidine-4-yl, and 2,2,6,6-tetramethyltetrahydro-2H-pyran, ii)

[0141] [ka] And, During the ceremony, R u is H, pyridine-3-yl, or pyridine-4-yl, R v is (cis)-2,6-dimethylmorpholinyl, pyridine-3-yl, or pyridine-4-yl, and R w is H, F, or OCH3, iii)

[0142] [ka] And, During the ceremony, R xIt is pyridine-3-yl or pyridine-4-yl, R y teeth,

[0143] [ka] Selected from pyridine-3-yl and pyridine-4-yl, and R z teeth,

[0144] [ka] iv)

[0145] [ka] v)

[0146] [ka] and vi)C 1~4 Haloalkyl or -CH2-R aa Selected from, R aa CH(CH3)2, CH2CH2OCH3, cyclopentyl,

[0147] [ka] Phenyl,

[0148] [ka] Compounds, as well as their pharmaceutically acceptable salts, stereoisomers, and isotopic variants, are selected from the above.

[0149] In one embodiment of the present invention, the compound is not 3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide or 3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide.

[0150] In some embodiments, R 1 teeth,

[0151] [ka] That is the case.

[0152] In some embodiments, R 1 teeth,

[0153] [ka] That is the case.

[0154] In some embodiments, R 1 teeth,

[0155] [ka] That is the case.

[0156] In some embodiments, R 1 teeth,

[0157] [ka] That is the case.

[0158] In some embodiments, R 1 teeth,

[0159] [ka]

[0160] [ka] That is the case.

[0161] In some embodiments, R 1 teeth,

[0162] [ka] That is the case.

[0163] In some embodiments, R 1 teeth,

[0164] [ka] That is the case.

[0165] In some embodiments, R 3 H, CH3,

[0166] [ka] That is the case.

[0167] In some embodiments, R 5 teeth,

[0168] [ka] That is the case.

[0169] In some embodiments, R 5 teeth,

[0170] [ka]

[0171] In some embodiments, R 5 teeth,

[0172] [ka] That is the case.

[0173] In some embodiments, (i)R 5 teeth,

[0174] [ka] is, or (ii)R 5 teeth,

[0175] [ka] is, or (iii)R 5 teeth,

[0176] [ka] That is the case.

[0177] In some embodiments, R 5 teeth,

[0178] [ka] And here, (i)R p teeth,

[0179] [ka] is, or (ii)R p teeth,

[0180] [ka] is, or (iii)R p teeth,

[0181] [ka]

[0182] [ka]

[0183] [ka] is, or (iv)R p teeth,

[0184] [ka] is, or (v)R p teeth,

[0185] [ka] That is the case.

[0186] In some embodiments, R q are H, Cl, F, I, CH3, CN, CH2OH, CH(OH)(CH3), CO2H, (C=O)NH2, CHF2, CF3, CO2CH3,

[0187] [ka] That is the case.

[0188] In some embodiments, R 5 teeth, (i)R 5 teeth,

[0189] [ka] is, or (ii)R 5 teeth,

[0190] [ka] is, or (iii)R 5 teeth,

[0191] [ka] That is the case.

[0192] In some embodiments, the compound of formula (I) is one of the compounds shown in Table 1 below.

[0193] [Table 1-1]

[0194] [Table 1-2]

[0195] [Table 1-3]

[0196] [Table 1-4]

[0197] [Table 1-5]

[0198] [Table 1-6]

[0199] Table 1-7

[0200] Table 1-8

[0201] Table 1-9

[0202] Table 1-10

[0203] Table 1-11

[0204] Table 1-12

[0205] Table 1-13

[0206] Table 1-14

[0207] Table 1-15

[0208] Table 1-16

[0209] Table 1-17

[0210] Table 1-18

[0211] Table 1-19

[0212] Table 1-20

[0213] Table 1-21

[0214] Table 1-22

[0215] Table 1-23

[0216] Table 1-24

[0217] Table 1-25

[0218] Table 1-26

[0219] Table 1-27

[0220] Table 1-28

[0221] Table 1-29

[0222] Table 1-30

[0223] Table 1-31

[0224] Table 1-32

[0225] Table 1-33

[0226] Table 1-34

[0227] Table 1-35

[0228] Table 1-36

[0229] Table 1-37

[0230] Table 1-38

[0231] Table 1-39

[0232] Table 1-40

[0233] Table 1-41

[0234] Table 1-42

[0235] Table 1-43

[0236] Table 1-44

[0237] Table 1-45

[0238] Table 1-46

[0239] Table 1-47

[0240] Table 1-48

[0241] Table 1-49

[0242] Table 1-50

[0243] Table 1-51

[0244] Table 1-52

[0245] Table 1-53

[0246] Table 1-54

[0247] Table 1-55

[0248] Table 1-56

[0249] Table 1-57

[0250] Table 1-58

[0251] Table 1-59

[0252] Table 1-60

[0253] Table 1-61

[0254] Table 1-62

[0255] Table 1-63

[0256] Table 1-64

[0257] Table 1-65

[0258] Table 1-66

[0259] Table 1-67

[0260] Table 1-68

[0261] Table 1-69

[0262] Table 1-70

[0263] Table 1-71

[0264] Table 1-72

[0265] Table 1-73

[0266] Table 1-74

[0267] Table 1-75

[0268] Table 1-76

[0269] Table 1-77

[0270] Table 1-78

[0271] Table 1-79

[0272] Table 1-80

[0273] Table 1-81

[0274] Table 1-82

[0275] Table 1-83

[0276] Table 1-84

[0277] Table 1-85

[0278] Table 1-86

[0279] Table 1-87

[0280] Table 1-88

[0281] Table 1-89

[0282]

Table 1-90

[0283] Table 1-91

[0284] Table 1-92

[0285] Table 1-93

[0286] Table 1-94

[0287] Table 1-95

[0288] Table 1-96

[0289] Table 1-97

[0290] Table 1-98

[0291] Table 1-99

[0292] Table 1-100

[0293] Table 1-101

[0294] Table 1-102

[0295] Table 1-103

[0296] Table 1-104

[0297] Table 1-105

[0298] Table 1-106

[0299] Table 1-107

[0300] Table 1-108

[0301] [Table 1-109]

[0302] [Table 1-110]

[0303] [Table 1-111]

[0304] [Table 1-112]

[0305] [Table 1-113]

[0306] [Table 1-114]

[0307] [Table 1-115]

[0308] [Table 1-116]

[0309] [Table 1-117] These are compounds, as well as their pharmaceutically acceptable salts, isotopic variants, and stereoisomers.

[0310] In some embodiments, the 1,6-naphthyridine compound is selected from the group consisting of: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(2-hydroxyethyl)-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-5-methylbenzamide, N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(4-Fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide, 3-Chloro-5-(( * S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Chloro-5-(( * R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((2R,6S)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( * S)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( * R)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, 3-(( * R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(( * S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-fluorobenzamide, 3-Chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-hydroxy-6-methyl-2-azaspiro[3,3]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Chloro-5-(( * R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, and 3-Chloro-5-(( * S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, These are compounds, as well as their pharmaceutically acceptable salts, isotopes, and stereoisomers.

[0311] Further embodiments of the present invention include a method for treating cancer or non-small cell lung cancer (NSCLC) in a subject, comprising administering an effective amount of a pharmaceutical composition, or the use of a pharmaceutical composition for treating cancer or non-small cell lung cancer (NSCLC), or a pharmaceutical composition for such use, comprising (B) a compound of formula (I), and at least one compound selected from pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of the compound of formula (I), and (B) at least one pharmaceutically acceptable excipient.

[0312] In some embodiments, such a pharmaceutical composition comprises a therapeutically effective amount of at least one compound from Table 1, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, or a pharmaceutically acceptable prodrug of at least one compound from Table 1, or at least one pharmaceutically active metabolite from Table 1; and at least one pharmaceutically acceptable excipient.

[0313] Compound synthesis In this section, unless otherwise indicated by context, references to formula (I) in all other sections of this application include all other subgroups and their embodiments as defined herein.

[0314] The synthesis of the compounds described herein is achieved by means of the chemical literature, by the methods described herein, or by a combination thereof. In addition, the solvents, temperatures, and other reaction conditions presented herein may vary. Techniques and materials recognized in the art include, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4. th Ed.,(Wiley 1992);Carey and Sundberg,Advanced Organic Chemistry 4 th Ed.,Vols.A and B(Plenum 2000,2001), and Green and Wuts,Protective Groups in Organic Synthesis 3 rd The details are described in Ed., (Wiley 1999) (both of these documents are incorporated by reference to their disclosures). General methods for preparing the compounds disclosed herein may be derived from reactions to introduce the various parts found in the formulas provided herein, and the reactions may be modified using appropriate reagents and conditions.

[0315] The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or obtained from commercial sources, including but not limited to Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0316] In the reactions described herein, it may be necessary to protect reactive functional groups, such as hydroxyl groups, amino groups, imino groups, thio groups, or carboxyl groups, if desired in the final product, to avoid their undesirable involvement in the reaction. Protecting groups are used to block some or all of the reactive moieties, preventing such groups from participating in the chemical reaction until the protecting group is removed. Preferably, each protecting group can be removed by different means. Protecting groups that are cleaved under completely different reaction conditions satisfy different removal requirements.

[0317] Protecting groups can be removed by acids, bases, reducing conditions (e.g., hydrolysis), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl can be used to protect carboxy and hydroxy-reactive moieties in the presence of amino groups protected by acid-unstable and hydrolytically removable Cbz groups and base-unstable Fmoc groups. Carboxylic acid and hydroxy-reactive moieties can be blocked by acid-unstable groups such as t-butyl carbamate, or by base-unstable groups such as methyl, ethyl, and acetyl, in the presence of amines blocked by carbamates that are stable to both acids and bases but hydrolytically removable.

[0318] The carboxylic acid and hydroxyl-reactive moieties may also be blocked with hydrolytically removable protecting groups, such as benzyl groups, while amine groups that can hydrogenate with acids may be blocked with base-unstable groups, such as acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The carboxylic acid-reactive moieties may be protected by conversion to simple ester compounds, such as those exemplified herein, including conversion to alkyl esters, or they may be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be blocked with fluoride-unstable silylcarbamates.

[0319] Allyl blocking groups are useful in the presence of acid protecting groups and base protecting groups because the former are stable and can then be removed with a metal or π-acid catalyst. For example, allyl-blocked carboxylic acids can be protected in the presence of acid-unstable t-butyl carbamate or base-unstable amine acetate protecting groups, and Pd 0 Deprotection can be achieved using catalytic reactions. Another form of protecting group is a resin to which a compound or intermediate can be bound. As long as the residue is bound to the resin, its functional group is blocked and cannot react. Once released from the resin, the functional group becomes available for reaction.

[0320] Typically, blocking / protecting groups can be selected from the following:

[0321] [ka]

[0322] A detailed description of other protecting groups, as well as techniques applicable to the fabrication and removal of protecting groups, is provided in TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007, which is incorporated herein by reference for such disclosures.

[0323] General synthesis route Scheme 1

[0324] [ka]

[0325] Preferably substituted ester compounds of formula (II) are commercially available or can be obtained synthetically. An aryl iodide compound of formula (II), for example methyl 3-chloro-5-iodo-4-methylbenzoate, is reacted with triphenylphosphine by palladium-catalyzed sulfination, and in the presence of 1,10-phenanthroline, K2S2O5, and sodium formate, using a palladium catalyst such as tert-butylammonium bromide or palladium acetate, followed by in-situ alkylation with 2-(2-bromoethoxy)tetrahydro-2H-pyran in a suitable solvent such as DMSO or ACN at a temperature in the range of room temperature to 100°C to obtain methyl 3-chloro-4-methyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonyl)benzoate. Deprotection of pyrane is achieved under acidic conditions well known to those skilled in the art, such as HCl / MeOH, to provide methyl 3-chloro-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzoate.

[0326] An ester compound represented by formula (II), in which ring B has a halide such as I, for example, methyl 3-chloro-5-iodobenzoate, can be further functionalized by reaction with i-PrMgCl and acetone in a suitable solvent such as THF at a temperature in the range of -78°C to room temperature to obtain a compound of formula (II) in which I is replaced with C(OH)(CH3)2.

[0327] A commercially available or synthetically obtained ester compound of formula (II) (wherein ring B is preferably substituted with phenyl) can be reacted under basic conditions such as NaOH, LiOH, or KOH in a suitable solvent such as methanol (MeOH), ethanol (EtOH), THF, ACN, H2O, or a mixture thereof, at a temperature in the range of approximately 60°C to 80°C for 1 to 6 hours to obtain an acid compound of formula (III).

[0328] Acid compounds of formula (III) in which ring B has a halogen such as Br (bromide) can be further functionalized by reaction with a suitable boronic acid or boronic acid derivative, such as potassium cyclopropyl trifluoroborate (CAS [1065010-87-8]), which is carried out in a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature such as 80°C, in the presence of a suitable base such as Na2CO3 and a suitable catalyst such as Pd(dppf)Cl2.DCM (CAS [95464-05-4]).

[0329] Acid compounds of formula (III) (wherein ring B has a halide such as Br [bromide]), such as 3-bromo-4-cyclopropylbenzoic acid, can be further functionalized by reacting them with BuLi and acetaldehyde in a suitable solvent such as THF. By carrying out this reaction at a temperature of about -78°C for 1 hour, a compound of formula (III) in which Br is replaced with CH(OH)CH3 can be obtained.

[0330] Scheme 2

[0331] [ka]

[0332] According to Scheme 2, the compound of formula (IV) is such that Hal is Br or Cl, and R 5 When is a suitably substituted heteroaryl, borylation can be carried out using conditions well known to those skilled in the art, such as Miyaura borylation conditions. For example, when Hal is Br or Cl, the compound of formula (IV) can be obtained by reacting it at a temperature in the range of 80°C to 100°C for 2 to 8 hours in the presence of a transition metal catalyst such as 1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium (XIX) (Pd(dppf)Cl2), a suitable solvent such as dimethyl sulfoxide (DMSO) or 1,4-dioxane, a base such as potassium acetate, and a boron source such as bis(pinacolato)diboron or pinacolborane.

[0333] Scheme 3

[0334] [ka]

[0335] According to Scheme 3, R 3Compounds of formula (XXIII) where is H can be prepared by metal-mediated coupling reaction of a commercially available or synthetically obtainable compound of formula (VII) (wherein H is a suitable halogen such as Br (bromine)) with a boronic acid or boronic acid ester, such as potassium trifluoro(vinyl)borate, in the presence of a catalyst such as bis(triphenylphosphine)palladium(XIX) dichloride and a base such as Cs2CO3, in a suitable solvent such as THF, 1,4-dioxane, toluene, water, or a mixture thereof, at a temperature range of 70°C to 100°C for a period of 12 to 18 hours. Compounds of formula (VIII) can also be obtained by halogenating a compound of formula (VI) using a chlorinating agent such as POCl3 at a temperature range of 70 to 90°C in a suitable solvent such as 1,2-dichloroethane or chloroform. The compound of formula (VIII) can be oxidized to the compound of formula (XXI) by treatment with osmium tetroxide and NaIO4 in a suitable solvent such as 1,4-dioxane, THF, water, or a mixture thereof. The compound of formula (IX) can be reduced to the compound of formula (X) in a suitable solvent such as MeOH or EtOH using a suitable reducing agent such as NaBH4. The subsequent mesylation of the hydroxy compound of formula (X) can be achieved in a suitable solvent such as DCM using a suitable base such as methanesulfonyl chloride (mesyl chloride) or triethylamine (TEA) to obtain the compound of formula (XI). The azide compound of formula (XII) can be prepared from the compound of formula (XI) using azide conditions known to those skilled in the art. In a preferred method, the compound of formula (XI) can be reacted with sodium azide in a suitable solvent such as DMF at room temperature for 18 hours to obtain the compound of formula (XII). The compound of formula (XIII) can be prepared by reacting the intermediate of formula (XII) with a suitable reducing agent, such as triphenylphosphine, in a suitable solvent, such as THF, at a suitable temperature, such as room temperature.The compound of formula (XIII) can be protected with a Boc protecting group by reacting the compound of formula (XIII) with Boc anhydride at room temperature for about 4-7 hours under conditions known to those skilled in the art, for example, in the presence of a suitable base such as Et3N, and P. 1 We can provide compounds of formula (XIV) where is Boc.

[0336] Scheme 4

[0337] [ka]

[0338] According to Scheme 4, the compound of formula (VII) (wherein Hal is Cl) can be subjected to palladium-catalyzed cyanation using conditions well known to those skilled in the art. For example, the compound of formula (VII) can be reacted with a palladium catalyst such as Pd(dppf)Cl2·CH2Cl2 and zinc cyanide as a nucleophile in a suitable solvent such as DMA or N,N-dimethylformamide (DMF) at a temperature of about 100°C for 2 to 6 hours to obtain the cyano compound of formula (XV). The halogenation of the compound of formula (XV) can be achieved using previously described methods, such as using POCl3, to obtain the compound of formula (XVI). The compound of formula (XVI) can be reduced using a suitable reducing agent such as DIBAL-H in a suitable solvent such as DCM or toluene at a temperature from -78°C to room temperature, and then reacted with a suitable protecting group precursor such as Boc anhydride in a suitable solvent such as DCM at a suitable temperature such as room temperature to obtain the compound of formula (XIV).

[0339] Scheme 5

[0340] [ka]

[0341] According to Scheme 5, the compound of formula (XIV) (wherein P 1is Boc, R 3 The compound of formula (XVIII) can be reacted in a metal-mediated cross-coupling reaction with a commercially available or synthetically available boronic acid of formula R5'-B(OH)2 or a boronate derivative of formula (XLIa) (wherein R5' is an optionally substituted heteroaryl) using methods well known to those skilled in the art. For example, the compound of formula (XVIII) can be reacted in the presence of a suitable base such as 6-fluoropyridine-2-boronic acid, Cs2CO3, K2CO3, K3PO4, K2HPO4, KHCO3, Na2CO3, NaHCO3, and a palladium catalyst such as bis(triphenylphosphine)palladium(XIX) dichloride in a suitable solvent such as 1,4-dioxane, DMF, acetonitrile (ACN), ethanol, water, or a mixture thereof, at a temperature range of 50-100°C for about 16-24 hours to produce the compound of formula (XVII) (wherein R5' is an optionally substituted heteroaryl). 3 H is R 5’ A compound (which is 6-fluoropyridyl) can be obtained.

[0342] Compound (XVII) (wherein R5' is a suitable heteroaryl such as 2-pyridyl, substituted with a suitable halogen leaving group such as F (fluorine), for example) is reacted in a suitable solvent such as DMSO or ACN at a temperature range of 50 to 130°C for 12 to 24 hours in the presence of a base such as cis-2,6-dimethylmorpholine, or a heterocycloalkyl (including but not limited to 4-membered to 8-membered heterocycloalkyls, condensed, spiro, and bridged 8-membered to 10-membered heterocycloalkyls, each containing one or two heteroatoms independently selected from N, S, and O, respectively), in a suitable solvent such as DMSO or ACN, in the presence of a base such as DIPEA, to produce compound (XVIII) (wherein R5' is a suitable heteroaryl such as 2-pyridyl, substituted with a suitable halogen leaving group such as F (fluorine), for example) 5 Compounds can be obtained (where is a preferred heteroaryl substituted with a nitrogen-bonded heterocycloalkyl group).

[0343] Deprotection of the compound of formula (XVIII) (wherein P 1The compound (where is Boc) can be achieved using established methodologies following procedures well known to those skilled in the art, such as the method described in TW Greene and PGMWuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999, pp. 518-525. For example, the compound of formula (XIX) can be obtained by reacting under acidic conditions such as TFA / CH2Cl2 or HCl / dioxane at room temperature for about 2 hours.

[0344] Scheme 6

[0345] [ka]

[0346] According to Scheme 6, in the formula R 3 A compound of formula (XIX), where is H (hydrogen), can be reacted with a suitable ketone, such as benzophenone, in the presence of a suitable catalyst, such as pTsOH, in a suitable solvent, such as toluene, at a suitable temperature, such as the reflux temperature of the solvent, to obtain an imine derivative compound of formula (XX). The compound of formula (XX) is a suitable alkylating agent R 3 It can be reacted with Hal, and here, R 3 R3 is as defined in the claims, and Hal is a suitable halogen leaving group, such as an iodide. The reaction is carried out in a suitable solvent, such as THF or DMF, in the presence of a suitable base, such as potassium tert-butoxide, at a suitable temperature, such as room temperature, to obtain a compound of formula (XXI) (wherein R3 is as defined in the claims). Deprotection of the imine compound of formula (XXI) is achieved at room temperature for 30 minutes to 2 hours using acidic conditions well known to those skilled in the art, such as HCl / dioxane, to obtain a compound of formula (XIX).

[0347] Scheme 7

[0348] [ka]

[0349] According to Scheme 7, the compound of formula (XIV) (wherein R 3 H is H, Hal is Cl, and P 1 (where is Boc) can be reacted with a suitable sulfinate, such as sodium 1-methyl-3-sulfinopropanoate (CAS[90030-48-1]), in the presence of a suitable catalyst, such as CuI, in a suitable solvent, such as DMSO, at a suitable temperature, such as 110°C, to obtain the compound of formula (XXII). The compound of formula (XXII) can be obtained from commercially available or synthetically substituted 2-halogeno-R 5 Compounds of formula (XVIII) can be obtained by reacting (for example, (cis)-4-(6-bromo-4-fluoropyridine-2-yl)-2,6-dimethylmorpholine) with a suitable phosphonium salt such as di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3]), a suitable base such as K2CO3, and a suitable catalyst such as Pd(OAc)2, in a suitable solvent such as 1,4-dioxane, at a suitable temperature such as 150°C. Deprotection of the Boc protecting group on compound (XVIII) can be achieved using acidic conditions known to those skilled in the art or the aforementioned acidic conditions, to obtain compound (XIX).

[0350] Scheme 8

[0351] [ka]

[0352] According to Scheme 8, R 3 H, P 1 Boc, R 5’Compound (XXIII) can be obtained by deprotecting a compound of formula (XVII), which is a halogenated heteroaryl in which ring B is suitably substituted, using a method well known to those skilled in the art or the method described above. Compound (XXIII) can be converted by reacting it with a suitably substituted commercially available or synthetically obtainable carboxylic acid and using conventional amide bond formation techniques such as coupling reactions well known to those skilled in the art. For example, compound (XXIII) can be obtained by reacting a carboxylic acid of formula (III), in which ring B is a suitably substituted phenyl ring, with a compound of formula (XXIV) in the presence of a suitable coupling agent such as HATU, HBTU, or 1-propanephosphonic anhydride, in the presence of a suitable base such as TEA or DIPEA, in a suitable solvent such as DCM or DMF, at a suitable temperature such as room temperature.

[0353] Alternatively, the compound of formula (XXIV) can be prepared in two steps from the compound of formula (XIII). In the first step, the compound of formula (XIII) is reacted with the carboxylic acid of formula (III), which has a phenyl ring in which ring B is preferably substituted, by an amide bond formation reaction, and the compound of formula (XXV) can be obtained by a method well known to those skilled in the art or by the method described above. Alternatively, the compound of formula (XXV) can be obtained by reacting an acid chloride derived from the acid of formula (III) with the compound of formula (XIII) in the presence of a base such as DIPEA in a suitable solvent such as DCM. In the second step, the compound of formula (XXV) is reacted with R in a coupling reaction. 5The compound of formula (XXIV) can be obtained by reacting it with a suitable boronic acid such as -B(OH)2, for example, a boronate derivative such as 6-fluoropyridine-2-boronic acid or 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, in the presence of a suitable base such as Na2CO3 or NaHCO3, a suitable catalyst such as bis(triphenylphosphine)palladium(II) chloride (CAS[13965-03-2]) or Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4]), in a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature such as 85°C.

[0354] A compound of formula (XXIV) or similarly a compound of formula (I), where R 1 Those having halides such as Br can be further functionalized by reaction with a suitable boronic acid or boron derivative, such as potassium cyclopropyl trifluoroborate (CAS[1065010-87-8]), which is carried out in a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature such as 80°C, in the presence of a suitable base such as Na2CO3 and a suitable catalyst such as Pd(dppf)Cl2.DCM (CAS[95464-05-4]).

[0355] Scheme 9

[0356] [ka]

[0357] According to Scheme 9, a compound of formula (XXV) (wherein R3 is H, Hal is Cl, and R1 is the suitably substituted phenyl described in claim 1) can be reacted with a suitable sulfinate, such as sodium 1-methyl-3-sulfinopropanoate (CAS[90030-48-1]), in the presence of a suitable catalyst such as CuI, in a suitable solvent such as DMSO, at a temperature in the range of 90 to 110°C, to obtain a compound of formula (XXVI).

[0358] The compound of formula (XXVI) is of formula R 5 -Hal(where Hal is Br or Cl, R 5 Compounds of formula (I) can be obtained by reacting a preferably substituted heteroaryl halide (as defined in claim 1) with a suitable phosphonium salt such as di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3]), a suitable base such as K2CO3, and a suitable catalyst such as Pd(OAc)2.

[0359] Scheme 10

[0360] [ka]

[0361] According to Scheme 10, the compound of formula (XVI) is a suitable boronic acid or boronate derivative R 5Compound (XXVII) can be obtained by reacting -B(OR)2 (e.g., 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine) with a suitable base (e.g., NaHCO3), a suitable catalyst (e.g., Pd(dppf)Cl2·DCM), a suitable solvent (e.g., a mixture of 1,4-dioxane and water), and a suitable temperature (e.g., 90°C). Compound (XVII) can be obtained by reacting compound (XXVII) with a suitable reducing agent (e.g., NaBH4), a suitable catalyst (e.g., NiCl2), a suitable protecting group precursor (e.g., di-tert-butyl dicarbonate), a suitable solvent (e.g., MeOH), and a suitable temperature (e.g., room temperature).

[0362] Scheme 11

[0363] [ka]

[0364] According to Scheme 11, R 3 A compound of formula (X) in which is H and Hal is Cl can be coupled using a coupling method well known to those skilled in the art, or as described above, with a suitable boronic acid R 5 -B(OH2) or boronate derivatives of formula (V) can be reacted. For example, R 3 The compound of formula (X) in which is H and Hal is Cl is R 5 '-B(OH)2(R here 5 '-B(OH)2 is 6-fluoropyridine-2-boronic acid' reacts with a suitable base (e.g., Cs2CO3, K2CO3, K3PO4, K2HPO4, KHCO3, Na2CO3, NaHCO3, etc.) and a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride (CAS[13965-03-2])) in a suitable solvent such as 1,4-dioxane, DMF, acetonitrile (ACN), ethanol, water, or a mixture thereof, at a temperature in the range of 80-100°C, thereby producing formula (XXVIII) (wherein R 5Compounds of formula (XXVIII) can be obtained by reacting phthalimide with a suitable solvent such as a suitable phosphine (e.g., triphenylphosphine), a suitable azodicarboxylic acid ester (e.g., DIAD, DEAD, etc.), or THF at a suitable temperature, for example, room temperature, to obtain compounds of formula (XXIX).

[0365] In an alternative method, the compound of formula (XXIX) can be prepared in two steps from the compound of formula (x). In the first step, the compound of formula (X) (wherein R 3 A compound of formula (XXXII) can be obtained by reacting phthalimide with a suitable phosphine (e.g., triphenylphosphine), a suitable azodicarboxylic acid ester (e.g., DIAD, DEAD), and a suitable solvent (e.g., THF, toluene, or a mixture thereof) at a suitable temperature, for example, room temperature. In the second step, a compound of formula (XXIX) can be obtained by reacting the compound of formula (XXXII) under coupling conditions well known to those skilled in the art or as described above.

[0366] The compound of formula (XXIX) can be reacted with a suitable deprotection agent, such as hydrazine hydrate, in a suitable solvent, such as EtOH, at a suitable temperature, such as 65°C, to obtain the compound of formula (X).

[0367] Scheme 12

[0368] [ka]

[0369] According to Scheme 12, the compound of formula (XIV) (wherein Hal is Cl and P 1 is a suitable nitrogen protecting group such as Boc, and R 3A compound of formula (XXXI) can be obtained by reacting a suitable hydrolysis reagent (e.g., a 37% aqueous solution) with a suitable solvent (e.g., H) in a suitable solvent (e.g., 1,4-dioxane) at a suitable temperature (e.g., 60°C) and a suitable hydrolysis reagent (e.g., a 37% aqueous solution). A compound of formula (XXXII) can be obtained by reacting a suitably substituted acid of formula (III) (available commercially or by synthesis) in a suitable solvent (e.g., ACN) at a suitable temperature (e.g., room temperature) in the presence of a suitable coupling agent (e.g., HATU) and a suitable base (e.g., DIPEA). A compound of formula (XXXII) can be reacted with a suitable amine or heteroaryl R 5 The compound of formula (I) can be obtained by reacting H with a suitable activator (e.g., BOP (CAS[56602-33-6])), a suitable base (e.g., DBU), and a suitable solvent (e.g., ACN) at a suitable temperature (e.g., 80°C).

[0370] Scheme 13

[0371] [ka]

[0372] According to Scheme 13, the compound of formula (XXV) (wherein Hal is Cl) can be reacted with a commercially available or synthetically available, preferably substituted heterocycle, such as 2-piperidone, using standard Buchwald coupling conditions, in a suitable base (e.g., cesium carbonate), a suitable catalyst (e.g., XantPhos Pd G4 (CAS[1621274-19-8])), a suitable solvent (e.g., 1,4-dioxane), at a suitable temperature (e.g., 100°C), thereby obtaining the compound of formula (I), where R 5 It is defined as an N-bonded heteroaryl group or an N-bonded heterocycloalkyl group, as defined in the general range.

[0373] Compound (XXV) can be reacted with a commercially available or synthetically available suitably substituted boronic acid or boronate derivative, for example, (cis)-4-(3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)-2,6-dimethylmorpholine, for example, using standard Suzuki coupling conditions, in the presence of a suitable base, for example, sodium carbonate, in the presence of a suitable catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS[72287-26-4]), in a suitable solvent, for example, a mixture of water and 1,4-dioxane, at a suitable temperature, for example, 100°C, to obtain compound (I), where R 5 It is defined as a C-bonded heteroaryl, aryl, or heterocycloalkyl group.

[0374] According to Scheme 13, the compound of formula (XXV) can be obtained by reacting a suitable stannane derivative such as [4-(6-trimethylstannyl)-4-pyrimidinyl]-2,6-dimethylmorpholine with a suitable Pd source (e.g., tetrakis(triphenylphosphine)palladium(0)) and a suitable solvent such as 1,4-dioxane at a suitable temperature (e.g., 110°C), where R 5 It is defined as a C-linked heteroaryl.

[0375] Scheme 14

[0376] [ka]

[0377] According to Scheme 14, the compound of formula (XIX) can be reacted with a suitable commercially available or synthesizable carboxylic acid using conventional amide bond formation techniques such as coupling reactions well known to those skilled in the art. For example, as described in claim 1, R 3 and R 5The compound of formula (XIX) can be obtained by reacting a suitable carboxylic acid with a suitable base, such as N-ethyldiisopropylamine (DIPEA) or triethylamine (TEA), in a suitable solvent, such as DCM, THF, or DMF, at a suitable temperature, such as between 0°C and room temperature, in the presence of a suitable coupling reagent such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU, or 1-propanephosphonic anhydride, in the presence of a suitable base such as N-ethyldiisopropylamine (DIPEA) or triethylamine (TEA), at a suitable temperature such as between 0°C and room temperature.

[0378] Alternatively, the compound of formula (I) can be prepared by reacting the compound of formula (XIX) with a suitable activated form of a carboxylic acid, such as acyl chloride, or its corresponding anhydride, in the presence of a suitable base, such as DIPEA or Et3N, in a suitable solvent, such as DCM or DMF, at a suitable temperature, such as 0°C to room temperature.

[0379] R 5 However, a compound of formula (XXIV), which is a suitable heteroaryl such as 2-pyridyl and in which Hal is a suitable halogen leaving group such as F (fluorine), is converted in a suitable solvent such as DMSO in the presence of a suitable base such as DIPEA, at a suitable temperature such as 90°C or up to 150°C, to a suitable amine HNR 9a R 9b By reacting it with the compound of formula (I), the compound of formula (I) can be obtained.

[0380] Alternatively, the compound of formula (I) is R 5However, defined as a C-bonded heteroalkyl group as defined in a general range, it can be prepared according to Scheme 14: A compound of formula (XXIV) can be reacted with a suitable heteroalkyl organozinc derivative R5-Zn-Hal, where Hal is a suitable halide, e.g., an iodide, and the reaction can be carried out in the presence of a suitable catalyst, e.g., palladium(II) acetate (CAS[3375-31-3]), a suitable ligand, e.g., RuPhos (CAS[787618-22-8]), a suitable solvent, e.g., THF or a mixture of THF and DMF, at a suitable temperature, e.g., 100°C.

[0381] If the compound of formula (I) has a protecting group such as Boc, the protecting group can be removed using conditions well known to those skilled in the art. For example, the reaction with a reagent such as pTsOH (p-toluenesulfonic acid), TFA, or HCl is carried out in a suitable solvent (e.g., DCM or 1,4-dioxane) and at a suitable temperature (e.g., room temperature or 40°C).

[0382] If the compound of formula (I) has a protecting group such as TBDMS, the protecting group can be removed by reaction with a suitable deprotecting agent such as TBAF in a suitable solvent such as THF at a suitable temperature such as room temperature or 50°C.

[0383] The compound of formula (I) has a protecting group such as Boc or THP, for example, R 1 If present on a group, the protecting group can be removed, for example, at a suitable temperature such as room temperature, in a suitable solvent such as 1,4-dioxane or EtOH, by reaction with a suitable reagent such as HCl, pTsOH, or pyridinium p-toluenesulfonate. If the protecting group is an ester, the compound of formula (I) can be reacted with a suitable hydrolyzing agent such as LiOH or NaOH, for example, at a suitable temperature such as room temperature, in a suitable solvent such as THF, MeOH, water, or a mixture thereof.

[0384] Those skilled in the art will understand that another series of chemical reactions shown in the following scheme can also yield the desired compound of formula (I).

[0385] Those skilled in the art will understand that the intermediates and final compounds shown in the following scheme can be further functionalized according to methods well known to those skilled in the art.

[0386] Compounds of formula (I) can also be converted to each other through reactions or functional group transformations known in the art. For example, -C(=O)-OC 1~6 Alkyl substituents can be converted to carboxylic acids in the presence of lithium hydroxide, for example, tetrahydrofuran, or an alcohol, such as methanol, or other suitable solvents.

[0387] Those skilled in the art will recognize that in some cases, it may be recommended or necessary to carry out the reactions described in the scheme under an inert atmosphere, such as an N2 gas atmosphere.

[0388] It will be apparent to those skilled in the art that cooling of the reaction mixture may be necessary before the reaction is carried out (meaning a series of operations necessary to isolate and purify the products of the chemical reaction, such as quenching, column chromatography, or extraction).

[0389] Those skilled in the art will understand that heating a reaction mixture under stirring can enhance the reaction outcome. In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

[0390] The compounds of the present invention, prepared by the processes described below, may be synthesized in the form of enantiomer mixtures, particularly racemic mixtures of enantiomers, which can be separated from each other by decomposition procedures known in the art. A racemic compound of formula (I) containing a basic nitrogen atom may be converted to the corresponding diastereomer salt form by reaction with a suitable chiral acid. The diastereomer salt form is then separated, for example, by selective or fractional crystallization, and the enantiomer is liberated therefrom by alkali. Alternative methods for separating the enantiomer forms of the compound of formula (I), and its pharmaceutically acceptable addition salts, include liquid chromatography using a chiral stationary phase, such as supercritical fluid chromatography. The pure stereochemical isomer form may also be derived from the corresponding pure stereochemical isomer form of a suitable starting material, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by a stereospecific preparation method. These methods will advantageously use enantiomerically pure starting materials.

[0391] In all of these preparations, the reaction product may be isolated from the reaction medium and, if necessary, further purified according to methodologies commonly known in the art (e.g., extraction, crystallization, tritulation, and chromatography). The purity of the reaction product can be determined according to methods commonly known in the art, such as LC-MS, TLC, and HPLC.

[0392] Treatment methods and medical uses, pharmaceutical compositions, and combinations The present invention also provides a method for treating or preventing proliferative disorders (e.g., cancer, benign neoplasms, angiogenesis) in a subject. Such a method comprises administering to a subject in need an effective amount of the compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or isotope-labeled derivative thereof, or a pharmaceutically acceptable composition thereof.

[0393] The subjects of treatment are mammals. The subjects may be humans. The subjects may be domestic animals such as dogs, cats, cattle, pigs, horses, sheep, or goats. The subjects may be companion animals such as dogs or cats. The subjects may be domesticated animals such as cattle, pigs, horses, sheep, or goats. The subjects may be zoo animals. The subjects may be research animals such as rodents, dogs, or non-human primates. The subjects may be non-human transgenic animals such as transgenic mice or transgenic pigs.

[0394] Proliferative disorders treated or prevented with compounds of formula (I) are typically associated with abnormal activity of SMARCA2. Abnormal activity of SMARCA2 may be elevated and / or inappropriate (e.g., abnormal) activity of SMARCA2. In certain embodiments, SMARCA2 is not overexpressed, and its activity is elevated and / or inappropriate. In certain other embodiments, SMARCA2 is overexpressed, and its activity is elevated and / or inappropriate. The compounds of this disclosure, as well as their pharmaceutically acceptable salts, tautomers, stereoisomers, isotope-labeled derivatives, and compositions, may be useful in inhibiting SMARCA2 activity and treating and / or preventing proliferative disorders.

[0395] Proliferative disorders may also be associated with the inhibition of apoptosis in cells in biological specimens or subjects. All types of biological specimens described herein or known in the art are intended to be within the scope of the present invention. Inhibition of SMARCA2 activity is expected to cause cytotoxicity through the induction of apoptosis. The compounds of this disclosure, as well as their pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, may be useful in inducing apoptosis and, consequently, in treating and / or preventing proliferative disorders.

[0396] In certain embodiments, the proliferative disorder treated or prevented using the compounds of this disclosure is cancer.

[0397] The cells described herein may be abnormal cells. The cells may be in vitro or in vivo. The cells may be proliferative cells.

[0398] In another embodiment, the present invention provides a method for downregulating the expression of SMARCA2 in a biological sample or subject.

[0399] In yet another embodiment, the present invention provides compounds of the present disclosure, as well as pharmaceutically acceptable salts, tautomers, stereoisomers, isotope-labeled derivatives, and compositions thereof, for use in the treatment of proliferative disorders in subjects. The compounds described herein, as well as their pharmaceutically acceptable salts and compositions, may be used in the inhibition of cell proliferation. The compounds described herein, as well as their pharmaceutically acceptable salts and compositions, may be used in the induction of apoptosis in cells. The compounds described herein, as well as their pharmaceutically acceptable salts and compositions, may be used in the inhibition of transcription.

[0400] Those skilled in the art will recognize that a therapeutically effective amount of the compound of the present invention is sufficient to have therapeutic activity, and that this amount varies, among other things, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the patient's condition. Generally, the amount of the compound of the present invention to be administered as a therapeutic agent for treating the disorders referred to herein is determined on a case-by-case basis by the attending physician.

[0401] Those skilled in the art in the treatment of such diseases may determine an effective therapeutic daily dose from the test results shown below. The effective therapeutic daily dose may be approximately 0.005 mg / kg to 50 mg / kg body weight. The amount of the compound according to the present invention, also referred to herein as the active ingredient, required to achieve a therapeutic effect may vary on a case-by-case basis, for example, depending on the specific compound, route of administration, the age and condition of the recipient, and the specific disorder or disease being treated. The treatment method may also involve administering the active ingredient in a regimen of 1 to 4 doses per day. In these treatment methods, the compound according to the present invention is preferably formulated before administration. As described below herein, suitable pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients.

[0402] While the active ingredient can be administered alone, it is preferable to provide it as part of a pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition comprising the compound according to the present invention together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense that it is compatible with the other components of the composition and is not harmful to its recipient.

[0403] The pharmaceutical compositions of the present invention are, for example, described in Gennaro et al. Remington's Pharmaceutical Sciences (18 thPharmaceutical compositions can be prepared by any method well known in the field of pharmacy, such as those described in (see, in particular, Part 8: Pharmaceutical preparations and their Manufacture) of Mack Publishing Company, 1990. A therapeutically effective amount of a specific compound in base form or salt form, as the active ingredient, is closely mixed and combined with a pharmaceutically acceptable carrier, and can take on a wide variety of forms depending on the form of formulation preferred for administration. These pharmaceutical compositions are preferably in unit dosage forms suitable for systemic administration, such as oral, transdermal, or parenteral administration, or in topical administration, such as inhalation or nasal spray. For example, when preparing an oral dosage form composition, any of the usual pharmaceutical media can be used, such as water, glycol, oil, or alcohol in the case of oral liquid formulations such as suspensions, syrups, elixirs, and solutions, or in the case of powders, pills, capsules, and tablets, such as starch, sugar, kaolin, lubricants, binders, or disintegrants. Tablets and capsules are the most advantageous oral unit dosage forms because they are easy to administer, in which case it is clear that a solid pharmaceutical carrier is used. In the case of parenteral compositions, the carrier usually contains at least a large portion of sterile water, but may also contain other components (e.g., to aid solubility). For example, an injectable solution may be prepared in which the carrier contains physiological saline, glucose solution, or a mixture of physiological saline and glucose solution. An injectable suspension may also be prepared, in which case a suitable liquid carrier, suspending agent, etc., may be used. In compositions suitable for transdermal administration, the carrier optionally contains a penetration enhancer and / or a suitable wetting agent, optionally in combination with some suitable additive that does not cause significant adverse effects on the skin in small amounts. Such additives can facilitate administration to the skin and / or may be useful in preparing the desired composition. These compositions can be administered in various ways, for example, as transdermal patches, spot-on treatments, or ointments.

[0404] The above-mentioned pharmaceutical compositions are particularly advantageous when formulated as unit dosage forms to facilitate administration and ensure uniformity of the dosage. As used herein and in the claims, a unit dosage form refers to a physically separated unit suitable as a single dose, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, together with the necessary pharmacological carrier. Examples of such unit dosage forms include tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons, and multiple portions thereof.

[0405] The precise dosage and frequency of administration depend, as is well known to those skilled in the art, on the specific compound of the present invention used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, degree of disability and overall health of the specific patient, and any other medications the individual may be taking. Furthermore, it is evident that the effective daily dose may be increased or decreased depending on the response of the subject being treated and / or on the assessment of the physician prescribing the compound of the present invention.

[0406] The methods described herein may also include a further step of administering one or more additional pharmaceuticals in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition comprising such compound or a pharmaceutically acceptable salt thereof. Thus, combinations of the compound or composition of the present invention with additional pharmaceuticals may be useful for treating proliferative disorders that are resistant to treatment using additional pharmaceuticals without the compound or composition of the present invention.

[0407] Combination therapy includes administering a single drug formulation containing the compound according to the present invention and one or more additional therapeutic agents, as well as administering the compound according to the present invention and each additional therapeutic agent in its own separate drug formulation. For example, the compound and therapeutic agent according to the present invention may be administered together to the patient in a single oral formulation such as a tablet or capsule, or each agent may be administered in a separate oral formulation.

[0408] Accordingly, one embodiment of the present invention relates to a product comprising a compound according to the present invention as a first active ingredient and one or more anticancer agents as further active ingredients, as a combination preparation for simultaneous, separate, or sequential use in the treatment of a patient suffering from cancer.

[0409] One or more other drugs and compounds according to the present invention may be administered simultaneously (e.g., separately or in a single composition) or sequentially in any order. In the latter case, the two or more compounds are administered for a period of time and in a quantity and manner sufficient to ensure that a favorable or synergistic effect is achieved. It will be understood that the preferred method and order of administration, as well as the respective dosages and regimens, for each component of the combination will depend on the specific other drugs and compounds of the present invention being administered, their routes of administration, the specific tumor being treated, and the specific host being treated. The optimal method and order of administration, as well as the dosages and administration plans, can be readily determined by those skilled in the art using conventional methods and taking into account the information described herein.

[0410] The weight ratio of the compound according to the present invention to one or more other anticancer agents when administered in combination can be determined by those skilled in the art. The ratio, as well as the exact dosage and frequency of administration, depends, as is well known to those skilled in the art, on the specific compound according to the present invention and the other anticancer agents used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, administration time and general physical condition of the specific patient, the mode of administration, and other medications the individual may take. Furthermore, it is evident that the effective daily dose may be increased or decreased depending on the response of the subject being treated and / or the assessment of the physician prescribing the compound according to the present invention. Specific weight ratios of the compound of formula (I) and other anticancer agents may range from 1 / 10 to 1 / 10, more specifically from 1 / 5 to 1 / 5, and even more specifically from 1 / 3 to 1 / 3. [Examples]

[0411] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. These examples and all references to the literature throughout this specification are incorporated herein by reference for all legal purposes provided herein. The starting materials and reagents used in the synthesis of the compounds described herein may be synthesized or may be obtained from commercial sources such as Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific, but are not limited to these.

[0412] When the stereocenter is indicated by "RS," it means that a racemic mixture has been obtained.

[0413] For intermediates that may be used in the next reaction step as crude or partially purified intermediates, the theoretical molar amounts may be shown in the reaction protocol described below.

[0414] Below, "DCM" and "CH2Cl2" mean dichloromethane. "rt" means room temperature. "Boc" means tert-butoxycarbonyl. "CH3CN" and "ACN" mean acetonitrile. "MeOH" means methanol, "EtOH" means ethanol, and "iPrOH" means isopropanol. "DMF" means dimethylformamide. "iPrNH2" means isopropylamine. "SOCl2" means thionyl chloride. "Et3N" means triethylamine. "NH4OAc" means ammonium acetate, NH4OH means ammonium hydroxide, and "NH4Cl" means ammonium chloride. "NaBH(OAc)3" means sodium triacetoxyborohydride. "POCl3" means phosphorus oxychloride. "RuPhos Pd G3" means (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. "Na2CO3" means sodium carbonate. "KHSO4" means potassium bisulfate, and "HBTU" means 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. "EA" means ethylamine. "NH4HCO3" means ammonium bicarbonate. "TFA" means trifluoroacetic acid, and "THF" means tetrahydrofuran. "h" means time. "RM" means reaction mixture. "SFC" means supercritical fluid chromatography. "Bredereck's "Reagent" means tert-butoxybis(dimethylamino)methane. "AcOEt" means ethyl acetate. "K2CO3" means potassium carbonate. "MgSO4" means magnesium sulfate. "Boc2O" means di-tert-butyl decarbonate.

[0415] Example A: Preparation of intermediate and final compounds, and their characterization. Several methods for preparing the compounds of the present invention are shown in the following examples. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purification, or can be synthesized by those skilled in the art using well-known methods.

[0416] [Table 2]

[0417] As will be understood by those skilled in the art, compounds synthesized using the indicated protocol may contain residual solvent or small amounts of impurities.

[0418] Those skilled in the art will understand, even if not explicitly mentioned in the following experimental protocol, that typically, after column chromatography purification, the desired fraction is collected and the solvent is evaporated.

[0419] If the stereochemistry is not shown, this means that it is a mixture of stereoisomers, unless otherwise specified or evident from the context. [Examples]

[0420] In obtaining the compounds and corresponding analytical data described in the following examples, the following experimental and analytical protocols were followed unless otherwise specified.

[0421] Unless otherwise specified, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. When solutions were “dried,” they were generally dried with a drying agent such as Na2SO4 or MgSO4. When mixtures, solutions, and extracts were “concentrated,” they were typically concentrated in a rotary evaporator under reduced pressure.

[0422] High-performance liquid chromatography (HPLC) measurements were performed using the LC pump, diode array (DAD), or UV detector and column specified for each method. Additional detectors were included as needed (see the table of methods below). The flow from the column was brought to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Setting adjustment parameters (e.g., scanning range, residence time, etc.) to obtain ions that enable the identification of the nominal monoisotopic molecular weight (MW) of the compound is within the knowledge of those skilled in the art. Data acquisition was performed with appropriate software. The compounds were analyzed based on their experimental retention time (R t ) and ions are described. Unless otherwise specified in the data table, the reported molecular ions are [M+H] + (protonated molecules) and / or [MH] - This corresponds to a (deprotonated molecule). If a compound cannot be directly ionized, its adduct form is identified (i.e., [M+NH4]). + [M+HCOO] - (etc.). For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are those obtained with respect to the lowest isotopic mass. All results are obtained with experimental uncertainty generally associated with the methods used.

[0423] Some NMR experiments were performed using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe head with a z-gradient, operating at 500 MHz for protons and 125 MHz for carbon. Some NMR experiments were performed using a Bruker Avance III 400 spectrometer with internal deuterium locking and inverse double resonance with a z-gradient. 1 H, 13The experiments were performed using a C,SEI) probe head, operating at 400 MHz for protons. Experiments were conducted at ambient temperature (298.6 K) unless otherwise specified. Chemical shifts (d) are reported in parts per million (ppm). J values ​​are expressed in Hz. The definitions of multiplicity are as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, hept = heptet, dd = doublet of doublets, dt = doublet of triplets, dq = doublet of quartets, dp = doublet of pentets, td = triplet of doublets, tt = triplet of triplets, ddd = doublet of doublets, m = multiplet, br = broad. For compounds containing interchangeable protons, it will be understood that these protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to perform the NMR spectroscopy and the concentration of the compound in solution.

[0424] Preparation of intermediates For intermediates used in subsequent reaction steps, either as crude or partially purified intermediates, the molar amount of such intermediate in the subsequent reaction step may not be mentioned, or an estimated or theoretical molar amount of such intermediate in the subsequent reaction step may be indicated in the reaction protocol described below.

[0425] Compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0426] * R or * Compounds denoted as S are enantiomers that are pure compounds whose absolute configuration has not been determined.

[0427] Intermediate 1: (2-chloro-1,6-naphthyridine-7-yl)methaneamine.

[0428] [ka]

[0429] Step A: 7-Vinyl-1,6-naphthyrizine-2(1H)-one. 7-Bromo-1,6-naphthyrizine-2(1H)-one (CAS[1574395-48-4], 2.32 g, 10.309 mmol), potassium trifluoro(vinyl)borate (CAS[13682-77-4], 1.657 g, 12.371 mmol, 1.2 equivalents), bis(triphenylphosphine)palladium(II) chloride (CAS[13965-03-2], 434 mg, 0.619 mmol, 0.06 equivalents), and Cs2CO3 (10.077 g, 30.928 mmol, 3 equivalents) were dissolved in THF (40 mL) and water (10 mL) under a nitrogen atmosphere. The mixture was stirred at 80°C for 16 hours. After cooling, the reaction mixture was diluted with toluene and water was added. The layers were separated, the organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography (80 g, SiO2, toluene / heptane 10 / 90-100:0) to obtain the title compound (1150 mg, yield: 64%) as a white solid.

[0430] Step B: 2-Chloro-7-vinyl-1,6-naphthiridine. POCl3 (1.86 mL, 20.037 mmol, 3 equivalents) was added to a suspension of 7-vinyl-1,6-naphthiridine-2(1H)-one (1.15 g, 6.679 mmol) in 1,2-dichloroethane (34 mL). The mixture was stirred at 80°C for 16 hours. The mixture was diluted with aqueous Na2CO3 and SiO2. The layers were separated, and the aqueous layer was extracted with SiO2 (3×). The combined organic layers were dried over (MgSO4), filtered, and evaporated to obtain the title compound (1.16 g, yield: 90%) as an orange solid, which was used without further purification.

[0431] Step C: 2-Chloro-1,6-naphthiridine-7-carbaldehyde. 2-Chloro-7-vinyl-1,6-naphthiridine (1.16 g, 6.064 mmol) and 2,6-lutidine (1.41 mL, 12.128 mmol, 2 equivalents) were dissolved in water (6 mL) and 1,4-dioxane (23 mL). NaIO4 (5.19 g, 24.257 mmol, 4 equivalents) and OsO4 (38 mg, 0.152 mmol, 0.025 equivalents) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted several times with DCM. The combined organic layer was dried over MgSO4, filtered, and evaporated to obtain the title compound (820 mg, yield: 63%) as a dark brown solid, which was used without further purification.

[0432] Step D: (2-chloro-1,6-naphthirizine-7-yl)methanol. A solution of 2-chloro-1,6-naphthirizine-7-carbaldehyde (820 mg, 3.832 mmol) in EtOH (30 mL) was cooled to 0°C, and NaBH4 (72 mg, 1.916 mmol, 0.5 equivalents) was added. The reaction mixture was stirred at room temperature for 20 minutes. The mixture was diluted with water and extracted with siRNA. The organic layer was dried over (Na2SO4), filtered, and evaporated. The residue was purified by flash column chromatography (80 g SiO2, DCM in DCM: DCM in DCM / MeOH (9:1) 0 / 100~20 / 80) to obtain the title compound (387 mg, yield: 51%) as a white solid.

[0433] Step E: (2-chloro-1,6-naphthirizin-7-yl)methylmethanesulfonate. Et3N (114 μL, 0.832 mmol, 1.2 equivalents) was added at room temperature to a solution of (2-chloro-1,6-naphthirizin-7-yl)methanol (135 mg, 0.694 mmol) in DCM (5 mL). MsCl (59 μL, 0.763 mmol, 1.1 equivalents) was then added gradually at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to obtain the title compound (190 mg, yield: 95%) as a brown oily substance, which was used without further purification.

[0434] Step F: 7-(azidomethyl)-2-chloro-1,6-naphthiridine. Sodium azide (59 mg, 0.906 mmol, 1.3 equivalents) was added to a solution of (2-chloro-1,6-naphthiridine-7-yl)methylmethanesulfonate (190 mg, 0.697 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under vacuum to obtain the title compound as a brown liquid. The product was used directly in the next step.

[0435] Step G: (2-chloro-1,6-naphthirizine-7-yl)methaneamine. Triphenylphosphine (252 mg, 0.963 mmol, 1.4 equivalents) was added to a solution of 7-(azidomethyl)-2-chloro-1,6-naphthirizine (151 mg, 0.688 mmol) in dry THF (5 mL). The mixture was stirred at room temperature for 1 hour. Additional triphenylphosphine (90 mg, 0.343 mmol, 0.5 equivalents) was added, and the mixture was stirred at room temperature for 1.5 hours. Water (2 mL) was added, and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography (12 g silica, DCM / MeOH / NH39 / 1 / 0.25 in DCM, 0-60% gradient) to obtain the title compound (50 mg, yield: 38%) as a brown oil.

[0436] Intermediate 2: Tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate.

[0437] [ka]

[0438] Method 1: Anhydrous Boc (7.486 g, 34.301 mmol, 1.1 equivalents), followed by Et3N (13 mL, 93.548 mmol, 3 equivalents), was gradually added to a suspension of (2-chloro-1,6-naphthyridine-7-yl)methaneamine (intermediate 1, HCl salt, 7.175 g, 31.183 mmol) in 200 mL of dry DCM under a nitrogen atmosphere at room temperature. The resulting solution was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with DCM and water, and the layers were separated. The aqueous layer was extracted again with DCM. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g, eluate: heptane: siRNA 1 / 3 100:0~20:80) to obtain the title compound (6.1 g, yield: 67%) as a white solid.

[0439] Method 2: Step A: 2-Oxo-1,2-dihydro-1,6-naphthiridine-7-carbonitrile. In a 3 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, DMA (2.24 L), Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 22.4 g, 0.1 equivalent), 7-chloro-1H-1,6-naphthiridine-2-one (CAS[1345091-18-0], 224 g, 1240.37 mmol), zinc (16.22 g, 248.07 mmol, 0.2 equivalent), and zinc cyanide (145.65 g, 1240.37 mmol, 1 equivalent) were added. The resulting solution was stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature. The solid was filtered off and washed with 2 × 100 mL of DMA. The reaction was then quenched by adding 5 L of water / ice. The solid was collected by filtration, and the title compound (147 g, yield: 69%) was obtained as a brown solid.

[0440] Step B: 2-Chloro-1,6-naphthirizine-7-carbonitrile. In a 2 L three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, phosphorus oxychloride (1.47 L) and 2-oxo-1,2-dihydro-1,6-naphthirizine-7-carbonitrile (147.00 g, 858.85 mmol) were added. The resulting solution was stirred at 80°C for 3 hours. The reaction mixture was concentrated. The resulting solution was diluted with 2 L of DCM. The reaction was then quenched by adding 4 L of water / ice. The resulting solution was extracted with 3 × 3 L of DCM, the organic layer was dried over Na₂SO₄, and concentrated to obtain the title compound (58 g, yield: 36%) as a yellow solid.

[0441] Step C: tert-butyl((2-chloro-1,6-naphthirizine-7-yl)methyl)carbamate. In a 5 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, 1.74 L of DCM and 58 g of 2-chloro-1,6-naphthirizine-7-carbonitrile (305.90 mmol) were added. Subsequently, DIBAL-H (1 N, 765 mL, 2.5 equivalents) was added dropwise over 30 minutes while stirring at -78°C. The resulting solution was stirred at -78°C for 2 hours. Potassium sodium tartrate (Rochelle salt) (257 g, 1224 mmol, 4 equivalents) was added at -78°C. The resulting solution was stirred at room temperature for 1 hour. Subsequently, di-tert-butyl dicarbonate (73.3 g, 336.50 mmol, 1.1 equivalents) was added. The resulting solution was stirred overnight at room temperature. The solid was filtered off and washed with 3 × 300 mL of DCM. The filtrate was concentrated. The residue was purified by column chromatography (siRNA / petroleum ether 1 / 3 to 1 / 2) on silica gel to obtain the title compound (60.9 g, yield: 68%) as a yellow solid.

[0442] Intermediate 9: tert-butyl((2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0443] [ka]

[0444] A suspension of tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2) (9900 mg, 33.702 mmol), 6-fluoropyridine-2-boronic acid (CAS [916176-61-9], 5699 mg, 40.442 mmol, 1.2 equivalents), and sodium carbonate (10716 mg, 101.105 mmol, 3 equivalents) in 1,4-dioxane (90 mL) and water (30 mL) was degassed by bubbling nitrogen for 5 minutes. Bis(triphenylphosphine)palladium(II) chloride (CAS [13965-03-2], 1183 mg, 1.685 mmol, 0.05 equivalents) was added, and the mixture was further degassed with nitrogen for 5 minutes. The reaction mixture was stirred overnight at 90°C under a nitrogen atmosphere. The reaction mixture was diluted with siRNA and water. The layers were separated, and the aqueous layer was extracted again with siRNA. The combined organic layers were dried over MgSO4, filtered, and evaporated. The solid residue was ground in Et2O and filtered. The white solid was washed with a small amount of Et2O to obtain intermediate 9 (7.47 g, yield: 58%) as a white solid.

[0445] Intermediate 10: tert-butyl((2-(6-((cis)-2,6-dimethylmorpholino)-pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0446] [ka]

[0447] A suspension of intermediate 9 (5208 mg, 11.169 mmol), cis-2,6-dimethylmorpholine (CAS[6485-55-8], 5.7 mL, 44.676 mmol, 4 equivalents), and DIPEA (5.8 mL, 33.507 mmol, 3 equivalents) in dry DMSO (20 mL) was divided into two thick-walled vials. The vials were sealed and the reaction mixture was stirred overnight at 130 °C. The reaction mixture was diluted with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was ground in DCM / Et2O 1 / 1. The solid was filtered and washed with a small amount of Et2O. This solid was combined with the filtrate and purified by column chromatography (Biotage Sfar 200g, eluate: heptane:EtOH / SiO2 1 / 3 100:0~20:80) to obtain intermediate 10 (5.1g, quantitative).

[0448] Intermediate 11: (2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0449] [ka]

[0450] HCl (37% in H2O, 40 mL, 484.24 mmol, 20 equivalents) was added dropwise to a yellow suspension of intermediate 10 (10.85 g, 24.135 mmol) in 1,4-dioxane (100 mL) at room temperature (1 drop / second, slightly exothermic). The reaction mixture turned red, then yellow again, and was stirred at room temperature for 16 hours. The yellow suspension was evaporated to dryness, and the residue was co-evaporated several times with toluene to obtain intermediate 11 (HCl salt, 12 g, quantitative) as an orange solid, which was dried under vacuum at 50°C.

[0451] Intermediate 15: 4-methyl-3-((3-((tetrahydro-2H-pyran-2-yl)oxypropyl)sulfonyl)benzoic acid.

[0452] [ka]

[0453] Step A: Methyl 4-methyl-3-((3-((tetrahydro-2H-pyran-2-yl)oxypropyl)sulfonyl)benzoate. 1,10-phenanthroline (CAS[66-71-7], 55 mg, 0.308 mmol, 0.17 equivalents), PPh3 (81 mg, 0.29 mmol, 0.16 equivalents), K2S2O5 (906 mg, 4.075 mmol, 2.25 equivalents), sodium formate (308 mg, 4.528 mmol, 2.5 equivalents), and tetrabutylammonium bromide (730 mg, 2.264 mmol, 1.25 equivalents) were added to a solution of methyl 3-iodo-4-methylbenzoate (CAS[90347-66-3], 500 mg, 1.811 mmol) in DMSO (8 mL). The reaction mixture was degassed by bubbling nitrogen for 20 minutes. Pd(OAc)2 (23 mg, 0.101 mmol, 0.06 equivalents) was added, and the reaction mixture was stirred at 100°C for 3 hours. After cooling to room temperature, 2-(3-bromopropoxy)tetrahydro-2H-pyran (394 μL, 2.21 mmol, 1.2 equivalents) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (25 g SiO2, ethyl acetate / heptane 0 / 100~50 / 50) to obtain the title compound (1.359 g, yield: 43%) as an orange oil.

[0454] Step B: 4-Methyl-3-((3-((tetrahydro-2H-pyran-2-yl)oxypropyl)sulfonyl)benzoic acid. NaOH (1 M in water, 1.35 mL, 1.347 mmol, 2 equivalents) was added to a solution of methyl 4-methyl-3-((3-((tetrahydro-2H-pyran-2-yl)oxypropyl)sulfonyl)benzoate (240 mg, 0.673 mmol) in EtOH (4 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL). KHSO4 (1 M in water, 2.1 mL) was added dropwise over 10 minutes under vigorous stirring. The pH reached 2-3. Ether was added and the mixture was stirred for 2 minutes. The layers were separated, the organic layer was dried on MgSO4, filtered, and concentrated under vacuum to obtain intermediate 15 (125 mg, yield: 54%) as a white oily substance, which was used without further purification.

[0455] Intermediate 19: 3-chloro-4-methyl-5-(methylsulfonyl)benzoic acid.

[0456] [ka]

[0457] Step A: Methyl 3-chloro-4-methyl-5-(methylsulfonyl)benzoate. 1,10-Phenanthroline (CAS[66-71-7], 197 mg, 1.095 mmol, 0.17 equivalents), PPh3 (287 mg, 1.031 mmol, 0.16 equivalents), K2S2O5 (3222 mg, 14.492 mmol, 2.25 equivalents), sodium formate (1095 mg, 16.102 mmol, 2.5 equivalents), and tetrabutylammonium bromide (2595 mg, 8.051 mmol, 1.25 equivalents) were added to a solution of methyl 3-chloro-5-iodo-4-methylbenzoate (CAS[21324-01-6], 2 g, 6.441 mmol) in DMSO (40 mL). The reaction mixture was degassed by bubbling nitrogen for 20 minutes. Pd(OAc)2 (81 mg, 0.361 mmol, 0.06 equivalents) was added, and the reaction mixture was stirred at 100°C for 3 hours. After cooling to room temperature, methyl iodide (489 μL, 7.858 mmol, 1.2 equivalents) was added. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (25 g SiO2, ethyl acetate / heptane 0 / 100~50:50) to obtain the title compound (638 mg, yield: 38%) as a white solid.

[0458] Step B: 3-Chloro-4-methyl-5-(methylsulfonyl)benzoic acid. NaOH (1M in water, 3.8 mL, 3.808 mmol, 1.6 equivalents) was added at room temperature to a solution of methyl 3-chloro-4-methyl-5-(methylsulfonyl)benzoate (638 mg, 2.38 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, and KHSO4 (1M in water) was added to adjust the pH to approximately 2-3. The mixture was extracted with RINKAN. The combined organic layers were dried over (MgSO4), filtered, and evaporated to obtain the title compound (546 mg, yield: 83%) as a white solid, which was used without further purification.

[0459] Intermediate 28: 3-(1,1-difluoroethyl)-4-fluorobenzoic acid.

[0460] [ka]

[0461] NaOH (5M in water, 0.61 mL, 3.049 mmol, 5.6 equivalents) was added at room temperature to a stirred solution of 3-(1,1-difluoroethyl)-4-fluorobenzonitrile (CAS[1253792-43-6], 100 mg, 0.54 mmol) in EtOH (2 mL). The mixture was stirred under reflux for 17 hours. Na2CO3 (1M in water) was added, and the mixture was extracted with DCM. The aqueous layer was acidified with HCl (37% in water) to pH=2-3 and extracted with DCM. The organic layer was dried with (MgSO4), filtered, and the solvent was evaporated under vacuum to obtain a 1:1 mixture (112 mg) of 3-(1,1-difluoroethyl)-4-fluorobenzoic acid (intermediate 28) and 3-(1,1-difluoroethyl)-4-ethoxybenzoic acid (intermediate 29) as an oily substance, which was used without further purification.

[0462] Intermediate 29: 3-(1,1-difluoroethyl)-4-ethoxybenzoic acid.

[0463] [ka]

[0464] The title compound was isolated as an oily substance from the reaction mixture (112 mg) of intermediate 28 and used without further purification.

[0465] Intermediate 37: 4-Cyclopropyl-3-(1-hydroxyethyl)benzoic acid.

[0466] [ka]

[0467] Under a nitrogen atmosphere, 350 mg, 1.452 mmol of 3-bromo-4-cyclopropylbenzoic acid was dissolved in 9 mL of dry THF, and the reaction mixture was cooled to -78°C. After 10 minutes, n-BuLi (2.5 M in hexane, 1.16 mL, 2.904 mmol, 2 equivalents) was added dropwise, and the reaction mixture was stirred at -78°C for 20 minutes. Next, a solution of acetaldehyde (163 μL, 2.904 mmol, 2 equivalents) in 1 mL of dry THF was added dropwise, and the reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl solution, and the mixture was diluted with DCM and water. The layers were separated, and the organic layer was concentrated to dryness under vacuum. The residue was purified by flash column chromatography (silica, DCM:MeOH(9:1) 0 / 100~20 / 80 in DCM) to obtain intermediate 37 (179 mg, yield: 57%) as a white solid.

[0468] Intermediate 41: (2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0469] [ka]

[0470] HCl (37% in H2O, 47 mL, 588.7 mmol, 20 equivalents) was added dropwise at room temperature to a pale brown solution of intermediate 9 (10 g, 27.94 mmol) in 1,4-dioxane (300 mL) (1 drop / second, slightly exothermic). The reaction mixture was stirred at room temperature for 30 minutes. The precipitate that appeared during the reaction was filtered, and the solid was washed with dioxane to obtain intermediate 41 (HCl salt, 8.3 g, quantitative) as a gray solid, which was dried under vacuum at 50°C and used without further purification.

[0471] Intermediate 43: 3-Chloro-5-(2-hydroxypropan-2-yl)benzoic acid.

[0472] [ka]

[0473] Step A: Methyl 3-chloro-5-(2-hydroxypropan-2-yl)benzoate. Under a nitrogen atmosphere, methyl 3-chloro-5-iodobenzoate (CAS [289039-85-6], 500 mg, 1.686 mmol) was dissolved in dry THF (5 mL), and the reaction mixture was cooled to -50°C and stirred for 10 minutes. i-PrMgCl (2 M in THF, 1.212 mL, 2.425 mmol, 1.44 equivalents) was added dropwise, and the reaction mixture was stirred at -50°C for 2 hours. After cooling to -78°C, a solution of acetone (250 μL, 3.373 mmol, 2 equivalents) in dry THF (1 mL) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature and stirred for 1 hour. The solvent was removed under vacuum, DCM was added, and the reaction mixture was washed with saturated NaHCO3 aqueous solution. The organic layer was concentrated under vacuum, and the residue was purified by flash column chromatography (alkyl silica, heptane, Â100~30 / 70) to obtain the impure title compound (350 mg, purity: 25%, yield: 23%) as a colorless oil, which was used without further purification.

[0474] Step B: 3-Chloro-5-(2-hydroxypropan-2-yl)benzoic acid. NaOH (1M in water, 765 μL, 0.765 mmol, 2 equivalents) was added at room temperature to a solution of methyl 3-chloro-5-(2-hydroxypropan-2-yl)benzoate (25% pure, 350 mg, 0.383 mmol) in MeOH (4 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and 1M aqueous KHSO4 solution was added dropwise over 10 minutes with vigorous stirring. The pH reached 2-3. Ether was added, and the mixture was stirred for 2 minutes. The layers were separated, the organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (25 g SiO2, DCM:methanol (9:1), 0 / 100-40 / 60) to obtain intermediate 43 (80 mg, yield: 96%) as a white solid.

[0475] Intermediate 44: 3-Chloro-N-((2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(2-hydroxypropan-2-yl)benzamide

[0476] [ka]

[0477] Method AA Intermediate 43 (126 mg, 0.588 mmol, 1.15 equivalents) and DIPEA (267 μL, 1.534 mmol, 3 equivalents) were added to a solution of intermediate 41 (130 mg, 0.511 mmol) in DMF (5 mL). The reaction mixture was stirred for 1 minute, after which HATU (243 mg, 0.639 mmol, 1.25 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was recrystallized over ACN, filtered, washed with Et2O, and dried under vacuum to obtain intermediate 44 (184 mg, yield: 79%) as a white solid.

[0478] The compounds in Table 3 were prepared from intermediate 41 and the corresponding acid following a procedure similar to the method shown in Table 3. * The post-treatment conditions for the reaction mixture may vary.

[0479] [Table 3]

[0480] The intermediates in Table 4 were prepared from intermediate 11 and the corresponding acid following a procedure similar to the method shown in Table 4. * The post-treatment conditions for the reaction mixture may vary.

[0481] [Table 4]

[0482] Intermediate 45: N-((2-chloro-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0483] [ka]

[0484] A solution of 4-methyl-3-(methylsulfonyl)benzoyl chloride (CAS[1146702-14-8], 4477 mg, 19.24 mmol, 1 equivalent) in 50 mL of dry DCM was added to a solution of (2-chloro-1,6-naphthyrizin-7-yl)methaneamine (intermediate 1) (5129 mg, 19.24 mmol, 1 equivalent) in 200 mL of dry DCM at 0°C under a nitrogen atmosphere. After 5 minutes, DIPEA (11.730 mL, 67.34 mmol, 3.5 equivalents) was added dropwise at 0°C under a nitrogen atmosphere. The dark brown reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and water, and the layers were separated. The aqueous layer was extracted again with DCM. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was ground in warm DCM. After cooling, the solid was filtered and washed with cold DCM to obtain intermediate 45 (4485 mg, yield: 60%) as an off-white solid, which was dried under vacuum at 50°C.

[0485] Intermediate 46: N-((2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0486] [ka]

[0487] Intermediate 45 (1.1 g, 2.596 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS [842136-58-7], 0.81 g, 3.634 mmol, 1.4 equivalents), and Na2CO3 (825 mg, 7.787 mmol, 3 equivalents) were dissolved in 1,4-dioxane (10 mL) and water (5 mL) in a thick-walled vial at room temperature. After degassing by bubbling nitrogen gas for 10 minutes, bis(triphenylphosphine)palladium(II) chloride (CAS [13965-03-2], 91 mg, 0.13 mmol, 0.05 equivalents) was added, and the mixture was stirred overnight at 85°C. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated under vacuum to obtain intermediate 46 (810 mg, purity: 68%, yield: 47%), which was used without further purification.

[0488] Intermediate 49: 3-Chloro-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzoic acid.

[0489] [ka]

[0490] Process A: Methyl 3-chloro-4-methyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxyethyl)sulfonyl)benzoate. 1,10-Phenanthroline (CAS[66-71-7], 392 mg, 2.175 mmol, 0.17 equivalents), triphenylphosphine (570 mg, 2.047 mmol, 0.16 equivalents), potassium metabisulfite (6.4 g, 28.78 mmol, 2.25 equivalents), sodium formate (2.175 g, 31.98 mmol, 2.5 equivalents), and tert-butylammonium bromide (5.15 g, 15.99 mmol, 1.25 equivalents) were added to a solution of methyl 3-chloro-5-iodo-4-methylbenzoate (CAS[21324-01-6], 3.97 g, 12.792 mmol) in DMSO (65 mL). The reaction mixture was degassed by bubbling nitrogen into the solution for 20 minutes. Palladium(II) acetate (161 mg, 0.716 mmol, 0.06 equivalents) was added, and the reaction mixture was heated at 100°C for 3 hours. After cooling to room temperature, 2-(2-bromoethoxy)tetrahydro-2H-pyran (CAS[17739-45-6], 2.36 mL, 1.22 equivalents) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (80 g SiO2, ethyl acetate / heptane 0 / 100~60 / 40) to obtain the title compound (1.92 g, yield: 39%) as an oil.

[0491] Step B: Methyl 3-chloro-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzoate. HCl (37% in water, 0.4 mL, 5.1 mmol, 1 equivalent) was added to a solution of methyl 3-chloro-4-methyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonyl)benzoate (1.92 g, 5.1 mmol) in MeOH (15 mL). The reaction mixture was stirred at room temperature for 30 minutes. Na2CO3 (1 M in water) was added, and the mixture was extracted with DCM (75 mL). The aqueous layer was extracted again with DCM / MeOH (9 / 1). The combined organic layers were dried over MgSO4, filtered, and evaporated to obtain the title compound (1.49 g, yield: 93%) as a solid, which was used without further purification.

[0492] Process C: 3-Chloro-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzoic acid. LiOH·H2O (278 mg, 6.625 mmol, 10 equivalents) was added at room temperature to a solution of intermediate 48 (198 mg, 0.66 mmol) in THF (2 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 16 hours, and 1 M HCl was added to adjust the pH to <2. The aqueous layer was then extracted with SiO(3×). The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain the title compound (120 mg, yield: 65%), which was used without further purification.

[0493] Intermediate 50: 3-chloro-5-((2-hydroxyethyl)sulfonyl)benzoic acid.

[0494] [ka]

[0495] The title compound was prepared in the same manner as for intermediate 49, by using methyl 3-chloro-5-iodo-benzoate (CAS[289039-85-6]) instead of methyl 3-chloro-5-iodo-4-methylbenzoate in step A.

[0496] Intermediate 61: N-((2-(6-((cis)-4-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0497] [ka]

[0498] Intermediate 61 was prepared starting from intermediate 46 and rel-(3R,4S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-methylpiperidine (CAS[1610033-91-4]) by a method similar to that of method J for compound 45.

[0499] Intermediate 65: 4-Cyclopropyl-N-((2-(6-Fluoropyridine-2-yl)-1,6-Naphthyridine-7-yl)methyl)-3-(Methylsulfonyl)benzamide.

[0500] [ka]

[0501] A mixture of intermediate 53 (140 mg, 0.272 mmol), potassium cyclopropyl trifluoroborate (CAS [1065010-87-8], 121 mg, 0.815 mmol, 3 equivalents), and Na2CO3 (115 mg, 1.087 mmol, 4 equivalents) in 1,4-dioxane (6 mL) and water (1.5 mL). The mixture was degassed by bubbling nitrogen for 15 minutes. Pd(dppf)Cl2.DCM (CAS [95464-05-4], 24 mg, 0.027 mmol, 0.1 equivalent) was added, and the reaction mixture was stirred under nitrogen flow at 80°C for 16 hours. Further potassium cyclopropyl trifluoroborate (60 mg, 0.407 mmol, 1.5 equivalents) and Na2CO3 (57 mg, 0.543 mmol, 2 equivalents) were added to the reaction mixture. The mixture was degassed again with nitrogen for 10 minutes, and Pd(dppf)Cl2.DCM (24 mg, 0.027 mmol, 0.1 equivalent) was added. The mixture was stirred at 80°C for 16 hours. After cooling, the reaction mixture was diluted with RINKAN, and water was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (12 g silica, DCM: MeOH (9:1) in DCM 0%~30%) to obtain intermediate 65 (47 mg, yield: 36%) as a yellow solid.

[0502] Intermediate 67: N-((2-chloro-1,6-naphthyridine-7-yl)methyl)-3,4-dimethyl-5-(methylsulfonyl)benzamide.

[0503] [ka]

[0504] Intermediate 67 was prepared using a method similar to that for intermediate 44, starting from (2-chloro-1,6-naphthyridine-7-yl)methaneamine (intermediate 1) and 3-methanesulfonyl-4,5-dimethylbenzoic acid (CAS[15110466-4]).

[0505] Intermediate 68: N-((2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethyl-5-(methylsulfonyl)benzamide.

[0506] [ka]

[0507] 2-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS [842136-58-7], 503 mg, 2.255 mmol, 1.8 equivalents) and Na2CO3 (1 M in water, 3.8 mL, 3.8 mol, 3 equivalents) were added at room temperature to a solution of intermediate 67 (506 mg, 1.253 mmol) in 1,4-dioxane (50 mL) that had been pre-degassed by bubbling nitrogen. Pd(dppf)Cl2.CH2Cl2 (CAS [95464-05-4], 51 mg, 0.063 mmol, 0.1 equivalents) was added, and the mixture was stirred at 90°C under a nitrogen stream for 16 hours. After cooling, water was added, the mixture was extracted with ethyl acetate, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (25g silica column, siRNA 0 / 100~100 / 0 in heptane) to obtain intermediate 68 (263mg, yield: 45%) as a brown solid.

[0508] Intermediate 69: 2-((2-chloro-1,6-naphthyridine-7-yl)methyl)isoindoline-1,3-dione.

[0509] [ka]

[0510] (2-chloro-1,6-naphthyridine-7-yl)methanol (intermediate 1, product from step D, 1.14 g, 5.858 mmol), phthalimide (948 mg, 6.443 mmol, 1.1 equivalents), and triphenylphosphine (1.844 g, 7.029 mmol, 1.2 equivalents) were dissolved in dry THF (45 mL) and degassed by bubbling nitrogen. DIAD (1.384 mL, 7.029 mmol, 1.2 equivalents) dissolved in toluene (2 mL) was added dropwise to the reaction mixture. Stirring was continued at room temperature for 2 hours. The mixture was diluted with water and SiO2. The organic phase was separated, dried, filtered, and the solvent evaporated under vacuum. The residue was ground with ACN, the solid was filtered, washed with Et2O, and dried under vacuum to obtain intermediate 69 (1.46 g, yield: 73%) as a white solid.

[0511] Intermediate 70: 2-(((2-(6-fluoro-4-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)benzoic acid.

[0512] [ka]

[0513] Intermediate 69 (130 mg, 0.402 mmol), 6-fluoro-4-methylpyridine-2-boronic acid (CAS [1897428-49-7], 93 mg, 0.602 mmol, 1.5 equivalents), and Na2CO3 (128 mg, 1.205 mmol, 3 equivalents) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) at room temperature. The mixture was degassed by bubbling nitrogen for 10 minutes. Bis(triphenylphosphine)palladium(II) chloride (CAS [13965-03-2], 14 mg, 0.020 mmol, 0.05 equivalents) was added, and the reaction mixture was stirred at 85°C for 3 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified with HCl 1N until the pH was 4-5. A beige solid precipitated, which was filtered, washed with DCM and Et2O, and vacuum-dried to obtain intermediate 70 (104 mg, yield: 58%) as a beige solid.

[0514] Intermediate 71: (2-(6-fluoro-4-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0515] [ka]

[0516] To a solution of intermediate 70 (104 mg, 0.25 mmol) in EtOH (2 mL), hydrazine hydrate (182 μL, 3.746 mmol, 15 equivalents) was added and the mixture was stirred at 65°C for 16 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted by DCM (x3). The combined organic layers were dried in (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (25 g SiO2, 0% to 40% of DCM / MeOH / NH3 (9 / 1 / 0.25) in DCM) to obtain intermediate 71 (27 mg, yield: 36%) as a white solid.

[0517] Intermediate 72: N-((2-(6-fluoro-4-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0518] [ka]

[0519] Intermediate 72 was formed starting from intermediate 71 and 3-methanesulfonyl-4-methylbenzoic acid (CAS[51522-22-6]) and followed the process of intermediate 44.

[0520] Intermediate 90: 2-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

[0521] [ka]

[0522] A mixture of 6-bromo-2-fluoro-3-methylpyridine (CAS[1211536-81-0], 800 mg, 4.21 mmol), bis(pinacorato)diboron (CAS[73183-34-3], 1283 mg, 5.052 mmol, 1.2 equivalents), Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 86 mg, 0.105 mmol, 0.02 equivalents), and KOAc (1.24 g, 12.631 mmol, 3 equivalents) in 1,4-dioxane (12 mL) was degassed by bubbling nitrogen gas for 15 minutes, and then stirred under nitrogen gas at 90°C for 6 hours. After cooling, the mixture was filtered through a Celite® pad, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (330 g silica column; alkyl heptane with alkyl sulfate in 0 / 100 to 60 / 40 solutions) to obtain intermediate 90 (1.2 g, purity: 80%, yield: 86%) as a yellow oily substance.

[0523] Intermediate 91: N-((2-(6-fluoro-5-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0524] [ka]

[0525] Intermediate 45 (90 mg, 0.231 mmol), intermediate 90 (105 mg, 0.332 mmol, 1.44 equivalents), and Na2CO3 (73 mg, 0.693 mmol, 3 equivalents) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) in a pressure flask at room temperature. The mixture was degassed by bubbling with nitrogen for 10 minutes. Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 9 mg, 0.011 mmol, 0.05 equivalents) was added, and the reaction mixture was stirred at 85°C for 3 hours. The mixture was diluted with water and extracted twice with SiO2. The aqueous phase was acidified to pH 4-5 with HCl aqueous solution (1N). The precipitated beige solid was filtered, washed with DCM and Et2O, and vacuum-dried to obtain intermediate 91 (87 mg, yield: 77%) as a beige solid.

[0526] Intermediate 93: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-((3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)sulfonyl)benzamide.

[0527] [ka]

[0528] The title compound was prepared using intermediates 11 and 15 as starting materials, by a method similar to that used for intermediate 44.

[0529] Intermediate 94: Methyl 3-((7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)sulfonyl)propanoate.

[0530] [ka]

[0531] tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2) (1.03 g, 3.506 mmol) was added to a solution of sodium 1-methyl-3-sulfinopropanoate (CAS[90030-48-1], 1.22 g, 7.013 mmol, 2 equivalents) and copper iodide (1.34 g, 7.013 mmol, 2 equivalents) in DMSO (10 mL). The reaction mixture was stirred at 110 °C for 1 hour under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with phenylethylamine and washed with water (1 mL) containing aqueous NH3 solution. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (25g column, siRNA / heptane gradient of 0 / 100 to 100 / 0) to obtain intermediate 94 (801 mg, yield: 53%) as an orange solid.

[0532] Intermediate 96: (cis)-4-(6-bromo-4-fluoropyridine-2-yl)-2,6-dimethylmorpholine.

[0533] [ka]

[0534] Step A: (cis)-4-(6-bromo-4-nitropyridine-2-yl)-2,6-dimethylmorpholine. 2,6-dibromo-4-nitropyridine (CAS[175422-04-5], 5g, 17.737 mmol) and cis-2,6-dimethylmorpholine (CAS[6485-55-8], 2.42 mL, 19.511 mmol, 1.1 equivalents) were dissolved in toluene (140 mL), and the solution was degassed by bubbling with nitrogen for 15 minutes. Next, Cs2CO3 (8.67 g, 26.606 mmol, 1.5 equivalents), rac-BINAP (CAS[98327-87-8], 1.10 g, 1.774 mmol, 0.1 equivalent), and Pd(OAc)2 (CAS[3375-31-3], 398 mg, 1.774 mmol, 0.1 equivalent) were added, and the resulting mixture was refluxed under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 × 250 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (120 g column, 0 / 100 to 40 / 60 siRNA / heptane gradient) to obtain the title compound (3.2 g, yield: 56%) as an orange solid.

[0535] Step B: (cis)-4-(6-bromo-4-fluoropyridine-2-yl)-2,6-dimethylmorpholine. Tetramethylammonium fluoride (CAS[373-68-2], 663 mg, 7.117 mmol, 1.5 equivalents) was added to a solution of (cis)-4-(6-bromo-4-nitropyridine-2-yl)-2,6-dimethylmorpholine (1500 mg, 4.745 mmol) in DMF (40 mL) in a sealed tube. The mixture was stirred at 65°C for 3 hours. The reaction was quenched by the addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (80g column with an siRNA / heptane gradient from 0 / 100 to 30 / 70) to obtain intermediate 96 (1139mg, yield: 81%) as an orange solid.

[0536] Intermediate 97: tert-butyl((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0537] [ka]

[0538] Intermediate 94 (950 mg, 2.32 mmol), intermediate 96 (1006 mg, 3.48 mmol, 1.5 equivalents), and K2CO3 (481 mg, 3.48 mmol, 1.5 equivalents) were dissolved in 1,4-dioxane (24 mL) in a sealed tube under a nitrogen stream. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 58 mg, 0.232 mmol, 0.1 equivalents) and Pd(OAc)2 (CAS[3375-31-3], 26 mg, 0.116 mmol, 0.05 equivalents) were added, and the reaction mixture was stirred at 150°C for 4 hours. The mixture was cooled to room temperature, diluted with SiO2, and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (25g column, siRNA / heptane gradient of 0 / 100 to 100 / 0) to obtain intermediate 97 (428mg, yield: 39%) as a yellow solid.

[0539] Intermediate 98: (2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0540] [ka]

[0541] Intermediate 97 (428 mg, 0.906 mmol) was dissolved in a solution of HCl (4 M in 1,4-dioxane, 2.27 mL, 9.063 mmol, 10 equivalents) and 1,4-dioxane (40 mL), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum, and the residue was ground in Et2O to obtain intermediate 98 (HCl salt, 406 mg, quantitative) as an orange solid.

[0542] Intermediate 102: 3-Chloro-5-((2-hydroxyethyl)sulfonyl)benzoic acid.

[0543] [ka]

[0544] Intermediate 102 was prepared in the same manner as intermediate 49, starting with methyl 3-chloro-5-iodo-benzoate (CAS[289039-85-6]) instead of methyl 3-chloro-5-iodo-4-methylbenzoate.

[0545] Intermediate 103: 3-((2-hydroxyethyl)sulfonyl)-5-methylbenzoic acid.

[0546] [ka]

[0547] Intermediate 103 was prepared in the same manner as intermediate 49, starting with methyl 3-iodo-5-methylbenzoate (CAS[597563-45-6]) instead of methyl 3-chloro-5-iodo-4-methylbenzoate.

[0548] Intermediate 104: 3-(hydroxymethyl)-5-(methylsulfonyl)benzoic acid.

[0549] [ka]

[0550] LiOH (150 mg, 3.58 mmol) was added at room temperature to a solution of methyl 3-(hydroxymethyl)-5-(methylsulfonyl)benzoate (CAS[1358967-53-9]) (175 mg, 0.72 mmol) in THF (5 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 16 hours, and the pH was adjusted to 3 by adding 1MKHSO4 aqueous solution. The aqueous layer was then extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain intermediate 104 (98 mg, yield: 55%), which was used without further purification.

[0551] Intermediate 105: 3-chloro-5-(1-hydroxyethyl)benzoic acid.

[0552] [ka]

[0553] Intermediate 105 was prepared in the same manner as intermediate 15, starting with 3-chloro-5-(1-hydroxyethyl)-methyl benzoic acid (CAS[2438162-92-4]) instead of intermediate 15 and the product of step A.

[0554] Intermediate 121: tert-butyl((2-(6-fluoro-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0555] [ka]

[0556] Intermediate 121 was prepared in the same manner as intermediate 97, using 2-bromo-6-fluoro-3-methylpyridine (CAS[1211536-01-4]) instead of intermediate 96.

[0557] Intermediate 123: (2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0558] [ka]

[0559] Step A: tert-butyl((2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. The title compound was prepared according to Method I, starting from intermediate 121 and cis-2,6-dimethylmorpholine (CAS[6485-55-8]).

[0560] Step B: (2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine. TFA (604 μL, 7.895 mmol, 30 equivalents) was added at 0°C to a solution of tert-butyl((2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate (122 mg, 0.263 mmol) in DCM (1.2 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated to obtain intermediate 123 (TFA salt, 126 mg, estimated quantitative) as a brown oily substance, which was used without further purification.

[0561] Intermediate 124: 3-((7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)sulfonyl)propanoate methyl.

[0562] [ka]

[0563] Intermediate 124 was prepared in the same manner as intermediate 94, starting from intermediate 45 instead of tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2).

[0564] Intermediate 127: 5-chloro-7-((cis)-2,6-dimethylmorpholino)-2,3-dihydrofl[2,3-c]pyridine.

[0565] [ka]

[0566] Step A: 7-chloro-2,3-dihydrofluoro[2,3-c]pyridine 6-oxide. m-CPBA (946 mg, 4.111 mmol, 1.3 equivalents) was gradually added over 15 minutes to a solution of 7-chloro-2,3-dihydrofluoro[2,3-c]pyridine (CAS[193605-53-7], 1200 mg, 3.162 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM (50 mL) and washed with 1 M Na2CO3 aqueous solution (50 mL). The aqueous layer was re-extracted with DCM (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (25 g, MeOH / DCM 0 / 100~6 / 94) to obtain the title compound (334 mg, yield: 59%) as a white solid.

[0567] Step B: 5,7-Dichloro-2,3-dihydrofl[2,3-c]pyridine. Phosphorus oxychloride (1.8 mL, 19.466 mmol, 10 equivalents) was added to intermediate 125 (334 mg, 1.947 mmol) at room temperature. The reaction mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to room temperature and poured onto ice. Solid Na2CO3 was added until the pH > 7. The mixture was extracted by DCM, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (silica gel, 25 g, siRNA / heptane 0 / 100~80 / 20) to obtain the title compound (260 mg, purity: 90%, yield: 63%) as a white solid.

[0568] Step C: 5-Chloro-7-((cis)-2,6-dimethylmorpholino)-2,3-dihydrofl[2,3-c]pyridine. Cis-2,6-dimethylmorpholine (CAS[6485-55-8], 3.4 mL, 27.365 mmol, 20 equivalents) was added at room temperature to a stirred solution of 5,7-dichloro-2,3-dihydrofl[2,3-c]pyridine (260 mg, 1.368 mmol) in DMSO (4 mL). The reaction mixture was stirred at 120 °C for 3 hours. The mixture was cooled to room temperature, diluted with Na2CO3 aqueous solution (1 M), and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (80 g silica, acetone / heptane 0 / 100~100 / 0) to obtain intermediate 127 (81 mg, yield: 22%) as a yellow solid.

[0569] Intermediate 129: (2-(6-(2,2,6,6-tetramethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0570] [ka]

[0571] Step A: tert-butyl((2-(6-(2,2,6,6-tetramethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. Starting with intermediate 9 and 2,2,6,6-tetramethylmorpholine (CAS[19151-69-0]), the title compound was prepared according to Method J.

[0572] Step B: (2-(6-(2,2,6,6-tetramethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine. HCl (4M in 1,4-dioxane, 4.3 mL, 17.127 mmol, 10 equivalents) was added to a stirred solution of tert-butyl((2-(6-(2,2,6,6-tetramethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate (409 mg, 0.856 mmol) in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature for 16 hours. To complete the reaction, further HCl (4M in 1,4-dioxane, 4.3 mL, 17.127 mmol, 10 equivalents) was added, and the mixture was stirred at 50°C for 16 hours. The solvent was evaporated under vacuum to obtain intermediate 129 (HCl salt, 448 mg, 86% purity, quantitative) as an orange solid.

[0573] The compounds in Table 5 were prepared using intermediate 9 and the corresponding amine, following the same procedure as shown in the table, in the same manner as intermediate 129.

[0574] [Table 5]

[0575] Intermediate 135: 4-Cyclopropyl-3-(methylsulfonyl)benzoic acid.

[0576] [ka]

[0577] A solution of 4-bromo-3-(methylsulfonyl)benzoic acid (CAS[158608-01-6], 2.8 g, 10.032 mmol), potassium cyclopropyl trifluoroborate (CAS[1065010-87-8], 4.453 g, 30.096 mmol, 3 equivalents), and Na2CO3 (6.38 g, 60.192 mmol, 6 equivalents) in 1,4-dioxane (40 mL) and water (10 mL). The mixture was degassed by bubbling nitrogen for 15 minutes. Pd(dppf)Cl2.DCM (CAS[95464-05-4], 904 mg, 1.003 mmol, 0.1 equivalent) was added, and the reaction mixture was stirred under a nitrogen atmosphere at 80°C for 16 hours. To complete the reaction, additional potassium cyclopropyl trifluoroborate (2.226 g, 15.048 mmol, 1.5 equivalents) and Na2CO3 (2.13 g, 20.064 mmol, 2 equivalents) were added to the reaction mixture, and the mixture was degassed with nitrogen for 10 minutes. Then, Pd(dppf)Cl2.DCM (904 mg, 1.003 mmol, 0.1 equivalents) was added, and the mixture was stirred at 80°C for 16 hours. The mixture was diluted with water and extracted with butyl. The organic layer was separated, and the aqueous layer was acidified with HCl (1N in water) to pH 4-5, and then extracted with butyl. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under vacuum to obtain intermediate 135 (3.2 g, purity: 75%, quantitative) as a brown solid.

[0578] Intermediate 138: 3-((2-hydroxyethyl)(methyl)amino)-4-methylbenzoic acid.

[0579] [ka]

[0580] Step A: Methyl 3-((2-((tert-butyldimethylsilyl)oxyethyl)amino)-4-methylbenzoate. A solution of methyl 3-amino-4-methylbenzoate (CAS[18595-18-1], 100 mg, 0.605 mmol) and tert-butyldimethylsilyloxy)acetaldehyde (CAS[102191-92-4], 154 μL, 0.726 mmol, 1.2 equivalents) in DCM (2 mL) and AcOH (38 μL, 0.666 mmol, 1.1 equivalents) was stirred at room temperature for 30 minutes. Then, NaBH(OAc)3 (257 mg, 1.211 mmol, 2 equivalents) was added, and the reaction mixture was stirred at room temperature for 72 hours. The mixture was diluted with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (12 g silica, siRNA / heptane gradient 0 / 100 to 8 / 92) to obtain the title compound (95 mg, yield: 46%) as a colorless oil.

[0581] Step B: Methyl 3-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-4-methylbenzoate. A solution of methyl 3-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-4-methylbenzoate (95 mg, 0.279 mmol), formaldehyde (37% in water, 208 μL, 2.79 mmol, 10 equivalents), and AcOH (18 μL, 0.307 mmol, 1.1 equivalents) in DCM (1.5 mL) was stirred at room temperature for 30 minutes. Then, NaBH3CN (53 mg, 0.837 mmol, 3 equivalents) was added, and the mixture was stirred at room temperature for 16 hours. To complete the reaction, an additional amount of formaldehyde (37% in water, 104 μL, 1.395 mmol, 5 equivalents) was added, and the mixture was stirred at room temperature for 30 minutes. NaBH3CN (35 mg, 0.558 mmol, 2 equivalents) was added, and the mixture was stirred at room temperature for 4 hours. Again, another batch of formaldehyde (37% in water, 104 μL, 1.395 mmol, 5 equivalents) was added, and the mixture was stirred at room temperature for 30 minutes. Finally, NaBH3CN (35 mg, 0.558 mmol, 2 equivalents) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (25 g silica, toluene / heptane 0 / 100~10 / 90) to obtain the title compound (57 mg, yield: 57%) as a colorless oil.

[0582] Step C: 3-((2-hydroxyethyl)(methyl)amino)-4-methylbenzoic acid. NaOH (276 mg, 6.899 mmol, 12 equivalents) was added to a solution of methyl 3-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-4-methylbenzoate (198 mg, 0.575 mmol) in MeOH (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was neutralized with HCl (1 M in water). This aqueous solution was then washed with ethyl acetate (×3). The aqueous layer was evaporated, and the residue was washed with DCM:MeOH (9:1). The washing solution was evaporated to obtain intermediate 138 (100 mg, purity 89%, yield: 74%) as a yellow solid, which was used without further purification.

[0583] Intermediate 140: 3-(N-(2-hydroxyethyl)methylsulfonamide)-4-methylbenzoic acid.

[0584] [ka]

[0585] Step A: Methyl 3-(N-(2-hydroxyethyl)methylsulfonamide)-4-methylbenzoate. NaH (60% in mineral oil, 154 mg, 3.847 mmol, 4 equivalents) was gradually added to a solution of methyl 4-methyl-3-[(methylsulfonyl)amino]benzoate (CAS[432500-90-8], 234 mg, 0.962 mmol) in dry DMF (6 mL) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 5°C for 30 minutes, then 2-bromoethoxy-tert-butyldimethylsilane (CAS[86864-60-0], 1.24 mL, 5.771 mmol, 6 equivalents) was added at 5°C under a nitrogen stream, and the reaction mixture was stirred at room temperature for 16 hours. Further NaH (60% in mineral oil, 77 mg, 1.924 mmol, 2 equivalents) was added to the mixture at 0°C and stirred at 0°C for 30 minutes. Then, 2-bromoethoxy-tert-butyldimethylsilane (619 μL, 2.886 mmol, 3 equivalents) was added under nitrogen flow at 5°C and the reaction mixture was stirred at 60°C for 21 hours. The mixture and the residue were dissolved in HCl (4M in 1,4-dioxane, 4.8 mL, 19.24 mmol, 20 equivalents) and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum and the residue was purified by flash column chromatography (25 g silica, MeOH in DCM, 0 / 100~1 / 99) to obtain the title compound (226 mg, purity: 81%, yield: 66%) as a yellow oil.

[0586] Step B: 3-(N-(2-hydroxyethyl)methylsulfonamide)-4-methylbenzoic acid. NaOH (428 mg, 10.691 mmol, 12 equivalents) was added to a stirred solution of methyl 3-(N-(2-hydroxyethyl)methylsulfonamide)-4-methylbenzoate (256 mg, 0.891 mmol) in MeOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and the pH was adjusted to 2-3 with HCl (1 M in water). The mixture was evaporated under vacuum, and the residue was washed with DCM:MeOH (9:1). The washing solution was evaporated under vacuum to obtain intermediate 140 (154 mg, purity: 92%, yield: 58%), which was used without further purification.

[0587] Intermediate 141: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-iodo-4-(trifluoromethyl)benzamide.

[0588] [ka]

[0589] HATU ([148893-10-1], 56 mg, 0.148 mmol, 1.3 equivalents) was added at room temperature to a red suspension of intermediate 11 (48 mg, 0.114 mmol) and 3-iodo-4-(trifluoromethyl)benzoic acid (43 mg, 0.136 mmol, 1.2 equivalents) in dry DMF (1 mL). DIPEA (69 μL, 0.398 mmol, 3.5 equivalents) was then added dropwise to the suspension at room temperature. The reaction mixture became clear yellow and was stirred at room temperature for 3 hours. The reaction mixture was diluted with HCl and water, and the layers were separated. The aqueous layer was extracted twice again with HCl. The combined organic layers were dried by filtration on Extrelut NT3 and evaporated to obtain intermediate 141 (70 mg, purity: 52%, yield: 49%) as a black solid, which was used without further purification.

[0590] Intermediate 142: (cis)-4-(3-chloro-5,6,7,8-tetrahydroisoquinoline-1-yl)-2,6-dimethylmorpholine and Intermediate 143: (cis)-4-(1-chloro-5,6,7,8-tetrahydroisoquinoline-3-yl)-2,6-dimethylmorpholine.

[0591] [ka]

[0592] 12 mL, 96.688 mmol, 23 equivalents of cis-2,6-dimethylmorpholine (CAS[6485-55-8]) was added to a solution of 1,3-dichloro-5,6,7,8-tetrahydroisoquinoline (CAS[38969-63-0]) at room temperature (848 mg, 4.196 mmol). The reaction mixture was stirred at 100°C for 72 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried with MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (25 g silica column, ethyl acetate / heptane 0 / 100~15 / 85) to obtain intermediate 142 (128 mg, yield: 11%) and intermediate 143 (236 mg, yield: 20%), both as solids.

[0593] Intermediate 144: 6-chloro-4-((cis)-2,6-dimethylmorpholino)-1,3-dihydrofl[3,4-c]pyridine, and intermediate 145: 4-chloro-6-((cis)-2,6-dimethylmorpholino)-1,3-dihydrofl[3,4-c]pyridine.

[0594] [ka]

[0595] Intermediate 144 and intermediate 145 were prepared in the same manner as intermediate 142 and intermediate 143, starting with 4,6-dichloro-1,3-dihydrofl[3,4-c]pyridine (CAS[754992-21-7]) instead of 1,3-dichloro-5,6,7,8-tetrahydroisoquinoline.

[0596] Intermediate 152: 3,4-dimethyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxyethyl)sulfonyl)benzoic acid.

[0597] [ka]

[0598] Step A: Methyl 3,4-dimethyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxyethyl)sulfonyl)benzoate. The title compound was prepared in the same manner as intermediate 49 (Step A), starting with methyl 3-iodo-4,5-dimethylbenzoate (CAS[1529736-58-0]) instead of methyl 3-chloro-5-iodo-4-methylbenzoate.

[0599] Step B: 3,4-dimethyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonyl)benzoic acid. NaOH (1M in water, 614 μL, 0.614 mmol, 1 equivalent) was added at room temperature to a solution of methyl 3,4-dimethyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonyl)benzoate (219 mg, 0.614 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL). KHSO4 (1M in water, 0.7 mL) was added dropwise over 10 minutes with vigorous stirring (pH 2-3). The reaction mixture was extracted with ELISA. The organic layer was dried over MgSO4, filtered, and concentrated to obtain intermediate 152 (132 mg, purity: 70%, yield: 44%) as a white solid.

[0600] Intermediate 153: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonyl)benzamide.

[0601] [ka]

[0602] Intermediate 153 was prepared using intermediates 11 and 152 as starting materials, according to the procedure for intermediate 44.

[0603] Intermediate 154: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.

[0604] [ka]

[0605] The solutions of N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-iodo-4,5-dimethylbenzamide (compound 27) (117 mg, 0.193 mmol), bis(pinacorato)diboron (CAS[73183-34-3], 147 mg, 0.578 mmol, 3 equivalents), and KOAc (57 mg, 0.578 mmol, 3 equivalents) in dry DMF (3 mL) were degassed for 5 minutes. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (CAS[95464-05-4,] 31 mg, 0.038 mmol, 0.2 equivalents) were added, and the solution was degassed for a further 5 minutes. The vial was sealed and stirred in a microwave oven at 100°C for 2 hours. The reaction mixture was diluted with RINKAN and water. The layers were separated, and the aqueous layer was extracted twice again with RINKAN. The combined organic layers were dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g, eluate: heptane:RINKAN / RINKAN 1 / 3 100:0~20:80) to obtain intermediate 154 (108 mg, yield: 87%) as a yellow solid.

[0606] Intermediate 158: tert-butyl((2-(3,6-difluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0607] [ka]

[0608] Intermediate 158 was prepared in the same manner as intermediate 97, using 2-bromo-3,6-difluoropyridine (CAS[1382786-22-2]) instead of intermediate 96.

[0609] Intermediate 159: tert-butyl((2-(6-((cis)-2,6-dimethylmorpholino)-3-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0610] [ka]

[0611] Intermediate 158 (94 mg, 0.25 mmol) was added to a solution of cis-2,6-dimethylmorpholine [CAS RN 6485-55-8] (37 μL, 0 mmol) and DIPEA [7087-68-5] (0.7 mmol) in DMSO (1 mL), and the reaction mixture was stirred at 130 °C for 16 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. Purification was performed (flash column chromatography, 12 g column, gradient of B (DCM / methanol 9:1) in A (DCM) [B from 0% to 35%]). The desired fraction was collected, concentrated under vacuum, and the impure product (250 mg) was purified by reverse-phase chromatography using a Gilson 1 column equipped with Brand Phenomenex; Gemini type; product number 00D-4435-EO-AX; ID (mm) 100x30; particle size 5 μm (C18) 110A; method: MMP4BIC 81:19~45:55 [25 mM NH4HCO3] / [ACN:MeOH (1:1)]). The fractions were combined and evaporated under vacuum to obtain the title compound and tert-butyl((2-(3-((cis)-2,6-dimethylmorpholino)-6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0612] Intermediate 160: (2-(6-((cis)-2,6-dimethylmorpholino)-3-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0613] [ka]

[0614] Intermediate 160 (TFA salt) was prepared in the same manner as intermediate 123, starting from intermediate 159 instead of intermediate 123 and the product of step A.

[0615] Intermediate 165: 4-Cyclopropyl-3-(N,N-dimethylsulfamoyl)benzoic acid.

[0616] [ka]

[0617] Step A: 3-(chlorosulfonyl)-4-cyclopropylbenzoic acid. 4-cyclopropylbenzoic acid (CAS[1798-82-9], 150 mg, 0.925 mmol) was gradually added to chlorosulfonic acid (385 μL, 5.79 mmol, 6.3 equivalents) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then at 100°C for 1 hour. The mixture was poured onto ice. The precipitate was filtered, washed with water, and dried to obtain the title compound (113 mg, yield: 46%) as a brown solid, which was used without further purification.

[0618] Step B: 4-Cyclopropyl-3-(N,N-dimethylsulfamoyl)benzoic acid. Dimethylamine (2M in THF, 13.16 mL, 26.314 mmol, 7 equivalents) was added at 0°C to a solution of 3-(chlorosulfonyl)-4-cyclopropylbenzoic acid (980 mg, 3.759 mmol) in THF (25 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated under vacuum. The pH of the resulting crude mixture was adjusted to 2 with HCl (1M in water). The mixture was extracted with ELISA (3×). The organic layer was concentrated under vacuum to obtain intermediate 165 (650 mg, purity: 90%, yield: 58%), which was used without further purification.

[0619] Intermediate 167: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1-hydroxyethyl)-4-methylbenzamide.

[0620] [ka]

[0621] Intermediate 167 was prepared starting from intermediate 166 and cis-2,6-dimethylmorpholine (CAS[6485-55-8]) in the same manner as compound 45, method J.

[0622] Intermediate 171:( * R)-N-((2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1-hydroxyethyl)-4-methylbenzamide and intermediate 172:( * S)-N-((2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1-hydroxyethyl)-4-methylbenzamide.

[0623] [ka]

[0624] Intermediate 166 was separated by SFC (i-cellulose-c column; isoconcentration elution mode: 60% [EtOH + 0.1% DEA] - 40% [CO2]), yielding intermediate 171, a pure stereoisomer with an uncertain absolute stereochemistry. * R)-N-((2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1-hydroxyethyl)-4-methylbenzamide) and intermediate 172, which are pure stereoisomers but have an indeterminate absolute stereochemistry (( * Both S)-N-((2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1-hydroxyethyl)-4-methylbenzamide were obtained as yellow solids.

[0625] Intermediate 174: (cis)-4-(6-chloro-3-fluoro-4-methylpyridine-2-yl)-2,6-dimethylmorpholine.

[0626] [ka]

[0627] Step A: 6-Chloro-2-((cis)-2,6-dimethylmorpholino)-4-methylpyridine-3-amine. 3-amino-2,6-dichloro-4-methylpyridine (CAS[129432-25-3], 1 g, 5.65 mmol) and cis-2,6-dimethylmorpholine (CAS[6485-55-8], 10 mL, 81.182 mmol, 14.4 equivalents) were placed in a stainless steel pressure reactor, and the reaction mixture was stirred at 170°C for 48 hours. After cooling, the reaction mixture was diluted with ELISA (100 mL). The solution was washed twice with water (2 × 100 mL) and once with brine (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (80 g, siRNA / heptane 0 / 100~75 / 25), followed by preparative reverse-phase chromatography (Gemini 5 μm C18 column (100 × 30 mm); medium gradient (19~64%) of 0.1% formic acid aqueous solution of MeOH / ACN mixture (1 / 1, v / v)) to obtain the title compound (1183 mg, yield: 81%) as an oil, which crystallized upon standing.

[0628] Step B: (cis)-4-(6-chloro-3-fluoro-4-methylpyridine-2-yl)-2,6-dimethylmorpholine. 6-chloro-2-((cis)-2,6-dimethylmorpholino)-4-methylpyridine-3-amine (750 mg, 2.933 mmol) dissolved in DCM (7 mL) was added at 0°C to a suspension of nitrosyltetrafluoroborate (CAS[14635-75-7], 377 mg, 3.226 mmol, 1.1 equivalents) in DCM (8 mL). The reaction mixture was stirred at 0°C for 30 minutes, then returned to room temperature, diluted with xylene, and stirred at 130°C for 1 hour. After cooling, the suspension was diluted with saturated NaHCO3 aqueous solution and extracted with ethylethanol. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g silica; acetone / heptane 0 / 100~10 / 90) to obtain intermediate 174 (580 mg, yield: 76%) as a yellow oil.

[0629] Intermediate 175: (cis)-4-(6-chloro-4,5-dimethylpyridine-2-yl)-2,6-dimethylmorpholine.

[0630] [ka]

[0631] cis-2,6-dimethylmorpholine (CAS[6485-55-8], 16.24 mL, 130.883 mmol, 23 equivalents) was added to 2,6-dichloro-3,4-dimethylpyridine (CAS[72605-55-1], 1 g, 5.68 mmol) in a sealed tube at room temperature. The mixture was stirred at 100°C for 48 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was subjected to flash column chromatography (25g silica, siRNA / heptane 0 / 100~15 / 85), followed by preparative SFC (Lux Amylose-1 250×30mm 5μm column, isoconcentration elution mode: 50%[iPrOH+0.1% DEA]-50%[CO2]) to obtain intermediate 175 (400mg, yield: 27%) as a white solid.

[0632] Intermediate 183: (3α,4β,5α)-4-methoxy-3,5-dimethylpiperidine.

[0633] [ka]

[0634] Step A: tert-butyl(3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidine-1-carboxylate and tert-butyl(3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-carboxylate. Et3N (84 mL, 604 mmol, 5 equivalents) was added to a 500 mL solution of 3,5-dimethylpiperidine-4-ol (HCl salt, CAS [1822604-07-8], 20.02 g, 120.848 mmol) and di-tert-butyl dicarbonate (32.97 g, 151.06 mmol, 1.25 equivalents) in dry DCM (500 mL) under a nitrogen atmosphere at 0°C. After addition, a thick white slurry was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and the layers were separated. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography (silica, 330 g, siRNA / heptane 0 / 100~35 / 65, 2 batches) to obtain tert-butyl(3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidine-1-carboxylate (11.61 g, yield: 42%) and (3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-carboxylate (10.29 g, yield: 37%), both as white solids.

[0635] Step B: tert-butyl(3α,4β,5α)-4-methoxy-3,5-dimethylpiperidine-1-carboxylate. Sodium hydride (60% in mineral oil, 418 mg, 10.9 mmol, 5 equivalents) was added to an ice-cold solution of (3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-carboxylate (500 mg, 2.18 mmol) in THF (20 mL). The reaction mixture was stirred at 0°C for 30 minutes, then stirred at room temperature for another 30 minutes. The reaction mixture was cooled to 0°C, and methyl iodide (163 μL, 2.62 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with RINKAN (100 mL), water (20 mL), and brine (50 mL). The organic layer was separated, and the aqueous layer was extracted with RINKAN (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain the title compound (676 mg, purity: 78%, yield: 99%), which was used without further purification.

[0636] Step C: (3α,4β,5α)-4-methoxy-3,5-dimethylpiperidine. HCl (4M in 1,4-dioxane, 5.42 mL, 21.67 mmol, 10 equivalents) was added to a solution of tert-butyl(3α,4β,5α)-4-methoxy-3,5-dimethylpiperidine-1-carboxylate (676 mg, 2.167 mmol) in 1,4-dioxane (5 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was dried to obtain intermediate 183 (HCl salt, 657 mg, quantitative).

[0637] Intermediate 184: tert-butyl 3-hydroxy-3-(5-(methoxycarbonyl)-2-methylphenyl)azetidine-1-carboxylate.

[0638] [ka]

[0639] Under a nitrogen atmosphere, methyl 3-iodo-4-methylbenzoate [90347-66-3] (0.5 g, 1.81 mmol) was dissolved in dry THF (5 mL). The reaction mixture was cooled to -50°C and stirred for 10 minutes. Isopropyl magnesium chloride solution (2 M in THF) [1068-55-9] (1.3 mL, 2.6 mmol) was added dropwise, and the reaction mixture was stirred at -50°C for 2 hours. The reaction mixture was cooled to -78°C, and a solution of N-Boc-3-oxoazetidine [398489-26-4] (0.62 g, 3.62 mmol) in dry THF (1 mL) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature and stirred for 1 hour. The solvent was removed under vacuum, DCM was added, and the reaction mixture was washed with saturated NaHCO3 aqueous solution. The combined organic layers were concentrated to dryness and purified by flash column chromatography (25 g, silica, DCM in DCM, DCM / MeOH (9:1) [0%~100%]). The desired fraction was collected and concentrated to obtain intermediate 184 (249 mg, yield: 42%) as a colorless oil.

[0640] Intermediate 188: 3-(1-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-yl)-4-methylbenzoic acid.

[0641] [ka]

[0642] Intermediate 188 was prepared in the same manner as intermediate 506 (step E), but using intermediate 184 instead of methyl 3-((3,3-difluoropropyl)sulfonyl)-4-methylbenzoate.

[0643] Intermediate 189: tert-butyl 3-(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)-2-methylphenyl)-3-hydroxyazetidine-1-carboxylate.

[0644] [ka]

[0645] Intermediate 189 was prepared starting from intermediates 11 and 188, following the same procedure as for intermediate 44.

[0646] Intermediate 190: tert-butyl 4-hydroxy-4-(5-(methoxycarbonyl)-2-methylphenyl)piperidine-1-carboxylate.

[0647] [ka]

[0648] Intermediate 190 was prepared in the same manner as intermediate 184, using N-Boc-4-piperidone (CAS[79099-07-3]) instead of N-Boc-3-oxoazetidine.

[0649] Intermediate 191: 3-(1-(tert-butoxycarbonyl)-4-hydroxypiperidine-4-yl)-4-methylbenzoic acid.

[0650] [ka]

[0651] Intermediate 191 was prepared using intermediate 190 instead of intermediate 186, in the same manner as intermediate 187.

[0652] Intermediate 193: tert-butyl 4-(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate.

[0653] [ka]

[0654] Intermediate 193 was prepared according to Method L, starting from intermediate 192 and cis-2,6-dimethylmorpholine (CAS[6485-55-8]).

[0655] Intermediate 194: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-1,1-diphenylmethanymine.

[0656] [ka]

[0657] A solution of intermediate 11 (free base, 282 mg, 0.71 mmol), benzophenone (131 mg, 0.71 mmol, 1 equivalent), and p-toluenesulfonic acid monohydrate (CAS[6192-52-5], 7 mg, 0.0355 mmol, 0.05 equivalents) in toluene (60 mL) was refluxed overnight in a flask equipped with a Dean-Stark trap. The solvent was evaporated to obtain intermediate 194 (350 mg, purity: 49%, yield: 47%) as a brown solid, which was used directly in the next step.

[0658] Intermediate 195: N-(1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)ethyl)-1,1-diphenylmethanymine.

[0659] [ka]

[0660] Potassium tert-butoxide (59 mg, 0.501 mmol, 1.5 equivalents) was added all at once to a solution of intermediate 194 (350 mg, 0.334 mmol) in dry DMF (5 mL) under a nitrogen atmosphere at room temperature. The reaction mixture immediately turned dark black. After 2 minutes, iodomethane (31 μL, 0.501 mmol, 1.5 equivalents) was added dropwise, and the brown reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and ethyl acetate, and the layers were separated. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and the solvent was evaporated to obtain intermediate 195 (354 mg, purity: 63%, assumed to be quantitative) as a brown solid, which was used directly in the next step.

[0661] Intermediate 196: 1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)ethane-1-amine.

[0662] [ka]

[0663] HCl (37% in water, 0.7 mL, 8.453 mmol, 20 equivalents) was added dropwise to a solution of intermediate 195 (354 mg, purity: 63%, 0.423 mmol) in 1,4-dioxane (3 mL) at room temperature (1 drop / second). The reaction mixture was stirred at room temperature for 30 minutes. The brown suspension was evaporated to dryness, and the residue was co-evaporated several times with toluene to obtain intermediate 196 (HCl salt, 383 mg, purity 22%) as a brown solid, which was dried under vacuum at 50°C and used without further purification.

[0664] Intermediate 201: 4-((trans)-4-benzyl-6-methylmorpholine-2-yl)butan-1-ol and intermediate 202: 4-((cis)-4-benzyl-6-methylmorpholine-2-yl)butan-1-ol and intermediate 203: 4-((2 * S,6 * R)-4-benzyl-6-methylmorpholin-2-yl)butan-1-ol and intermediate 204:4-((2 * R,6* S)-4-benzyl-6-methylmorpholin-2-yl)butan-1-ol.

[0665] [ka]

[0666] Step A: 1-(benzylamino)-6-((tert-butyldimethylsilyl)oxy)hexane-2-ol. 2-[4-[tert-butyl)dimethylsiloxy]butyl]oxirane (CAS[103791-53-3], 3.03 g, 13.15 mmol) and benzylamine (4.31 mL, 39.45 mmol, 3 equivalents) were combined in iPrOH (10 mL), and the mixture was stirred under reflux for 16 hours. After cooling, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (120 g, siRNA / heptane 0 / 100~100 / 0) to obtain the title compound (3.41 g, yield: 76%).

[0667] Step B: N-benzyl-N-(6-((tert-butyldimethylsilyl)oxy)-2-hydroxyhexyl)-2-chloropropanamide. 1-(benzylamino)-6-((tert-butyldimethylsilyl)oxy)hexane-2-ol (3.4 g, 10.072 mmol) and Et3N (2.81 mL, 20.144 mmol, 2 equivalents) were dissolved in DCM (20 mL), and the solution was cooled in an ice bath. Then, a solution of 2-chloropropionyl chloride (1.07 mL, 11.079 mmol, 1.1 equivalents) in DCM (10 mL) was added dropwise over 5-10 minutes. The reaction mixture was stirred at 0°C for 1 hour, and then allowed to reach room temperature over 1 hour. The reaction mixture was quenched by adding 1 M Na2CO3 aqueous solution (50 mL). The reaction mixture was extracted with DCM (2 × 50 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (80 g column, toluene / heptane gradient 0 / 100 to 40 / 60) to obtain the title compound (3.83 g, yield: 88%) as a clear oily substance (mixture of diastereomers).

[0668] Step C: 4-benzyl-6-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-methylmorpholine-3-one. NaH (60% in mineral oil, 422 mg, 10.54 mmol, 1.2 equivalents) was added to an ice-cold solution of N-benzyl-N-(6-((tert-butyldimethylsilyl)oxy)-2-hydroxyhexyl)-2-chloropropanamide (3.76 g, 8.783 mmol) in DMF (80 mL) under a nitrogen atmosphere. The mixture was stirred for 16 hours and the temperature was slowly raised to room temperature. The reaction was quenched by adding saturated NaHCO3 aqueous solution (20 mL). Water (20 mL) was added and the mixture was extracted with ELISA (2 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (80g column, toluene / heptane 0 / 100~35 / 65) to obtain the title compound (3.13g, yield: 90%) as a colorless oily substance (a mixture of diastereomers).

[0669] Step D: 4-Benzyl-6-(4-hydroxybutyl)-2-methylmorpholine-3-one. HCl (35% in water, 1.4 mL, 16.985 mmol, 2 equivalents) was added at room temperature to a solution of 4-benzyl-6-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-methylmorpholine-3-one (3.13 g, 7.992 mmol) in MeOH (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM (200 mL) and saturated NaHCO3 aqueous solution (100 mL) was added. The layers were separated, and the aqueous layer was extracted again with DCM (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (80g column, MeOH / DCM 0 / 100~10 / 90) to obtain the title compound (2.27g, quantitative) as a clear oily substance (a mixture of diastereoisomers).

[0670] Step E: A solution of 4-benzyl-6-(4-hydroxybutyl)-2-methylmorpholine-3-one (2.27 g, 8.184 mmol) in THF (30 mL) was added dropwise to a suspension of LiAlH4 (373 mg, 9.821 mmol, 1.2 equivalents) in THF (20 mL) at room temperature. The reaction mixture was then stirred at 60°C for 2 hours. After cooling, the reaction was quenched by adding acetone (5 mL) and water (20 mL). Then, NaOH (1 M in water, 20 mL) and DCM (100 mL) were added. The mixture was filtered through a Celite® pad and further rinsed with DCM (2 × 50 mL). The layers were separated, and the aqueous layer was extracted again with DCM (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (80g column, siRNA / heptane 0 / 100~100 / 0) to obtain intermediate 201 (975mg, yield: 45%) and intermediate 202 (930mg, yield: 43%), both as colorless oils. Intermediate 202 was subjected to preparative SFC (column: Amylose-1; method: isoconcentration elution mode 7% MeOH + 0.1% DEA) to obtain intermediate 203 (380mg, yield: 17%) and intermediate 204 (376mg, yield: 17%), both as oils.

[0671] Intermediate 208: tert-butyl(4-((2 * S,6 * R)-6-methylmorpholine-2-yl)butyl)carbamate.

[0672] [ka]

[0673] Process A:2-(4-((2 * S,6 * R)-4-benzyl-6-methylmorpholine-2-yl)butyl)isoindoline-1,3-dione. 4-((2 * S,6 *R)-4-benzyl-6-methylmorpholine-2-yl)butan-1-ol (intermediate 203, 378 mg, 1.435 mmol), phthalimide (253 mg, 1.722 mmol, 1.2 equivalents), and PPh (3565 mg, 2.153 mmol, 1.5 equivalents) were dissolved in dry THF (10 mL) under a nitrogen atmosphere. A solution of DIAD (CAS[2446-83-5], 424 μL, 2.153 mmol, 1.5 equivalents) in dry THF (5 mL) was then added dropwise over 5 minutes at room temperature. The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel (80g column, Ã / heptane 0 / 100~40 / 60) to obtain the title compound (958mg, purity 50%, yield: 85%) as an oily substance, which solidified upon standing.

[0674] Process B:4-((2 * S,6 * R)-4-benzyl-6-methylmorpholine-2-yl)butan-1-amine. Hydrazine monohydrate (321 μL, 3.631 mmol, 3 equivalents) is dissolved in 2-(4-((2) of EtOH (10 mL) at room temperature. * S,6 * The reaction was added to a solution of R)-4-benzyl-6-methylmorpholine-2-yl)butyl)isoindoline-1,3-dione (950 mg, 50% purity, 1.21 mmol). The reaction mixture was stirred at 70°C for 3 hours. After cooling, the white precipitate was filtered off and washed with EtOH (3 × 10 mL). The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography (25 g column, DCM / MeOH / NH4OH, 90 / 9 / 1, v / v / v, gradient from 0 to 100% in DCM) to obtain the title compound (313 mg, yield: 99%) as a colorless oil.

[0675] Process C: tert-butyl(4-((2 * S,6 * R)-4-benzyl-6-methylmorpholine-2-yl)butyl)carbamate. Boc anhydrous (310 mg, 1.422 mmol, 1.2 equivalents) in DCM (5 mL) * S,6 *The reaction mixture was added to a solution of R)-4-benzyl-6-methylmorpholine-2-yl)butan-1-amine (311 mg, 1.185 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (12 g column, siRNA / heptane 0 / 100~50 / 50) to obtain the title compound (421 mg, yield: 97%) as a clear oil.

[0676] Process D: tert-butyl(4-((2 * S,6 * R)-6-methylmorpholine-2-yl)butyl)carbamate. Pd / C 10% (100 mg, 0.094 mmol, 0.08 equivalents) is tert-butyl(4-((2 * S,6 * The suspension was added to a solution of R)-4-benzyl-6-methylmorpholine-2-yl)butyl)carbamate (408 mg, 1.125 mmol) in MeOH (15 mL), and the suspension was placed under a hydrogen atmosphere (1 atm). The reaction mixture was stirred at room temperature for 16 hours. The catalyst was filtered through a Celite® pad, and the filter cake was further rinsed with MeOH (3 × 10 mL). The filtrate was concentrated to obtain intermediate 208 (292 mg, yield: 95%) as a colorless oil, which was used without further purification.

[0677] Intermediate 209: tert-butyl(4-((2 * R,6 * S)-6-methylmorpholine-2-yl)butyl)carbamate.

[0678] [ka]

[0679] The title compound was prepared by starting with intermediate 204 instead of intermediate 203, using the same method as for intermediate 208.

[0680] Intermediate 210: Methyl 2-fluoro-6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl) isonicotinate.

[0681] [ka]

[0682] Methyl 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-pyridinecarboxylate (CAS [1622217-30-4], 1.139 g, 4.051 mmol, 3 equivalents) and NaHCO3 (1 M in water, 2.70 mL, 2.701 mmol, 2 equivalents) were added at room temperature to a solution of intermediate 45 (0.65 g, 1.35 mmol) in 10 mL of 1,4-dioxane, which had been degassed beforehand by bubbling nitrogen. Subsequently, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (CAS [95464-05-4], 110 mg, 0.135 mmol, 0.1 equivalent) was added, and the mixture was stirred at 90°C for 5 hours under the protection of nitrogen gas. After cooling, water was added and the mixture was extracted with siRNA. The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (25 g SiO2, DCM / MeOH(9 / 1) with 0 / 100 to 20 / 80 in DCM) to obtain intermediate 210 (250 mg, yield: 33%) as a light brown solid.

[0683] Intermediate 215: tert-butyl((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0684] [ka]

[0685] Intermediate 215 was prepared according to Method I using intermediate 9 and (3α,4β,5α)-3,5-dimethyl-4-piperidinol (CAS[374067-78-4]).

[0686] Intermediate 217: 3-(4-(tert-butoxycarbonyl)morpholin-2-yl)-4-methylbenzoic acid.

[0687] [ka]

[0688] Step A: Methyl 3-(1-hydroxy-2-((2-hydroxyethyl)amino)ethyl)-4-methylbenzoate. Ethanolamine (CAS[141-43-5], 139 μL, 2.295 mmol, 3 equivalents) was added to a solution of 4-methyl-3-(2-oxyranyl)-methyl benzoate (CAS[2344806-63-7], 147 mg, 0.765 mmol) in EtOH (6 mL). The reaction mixture was stirred at 45°C for 14 hours. The solvent was removed under vacuum, the residue was diluted with ethyl acetate, and washed with water. The aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (24 g silica, alkyl / heptane 0 / 100~80 / 20) to obtain the title compound (323 mg, purity: 60%, quantitative) as a yellow oily substance.

[0689] Step B: Methyl 3-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)-1-hydroxyethyl)-4-methylbenzoate. Di-tert-butyl dicarbonate (CAS[24424-99-5], 176 μL, 0.765 mmol, 1 equivalent) was added at room temperature to a solution of methyl 3-(1-hydroxy-2-((2-hydroxyethyl)amino)ethyl)-4-methylbenzoate (194 mg, 0.765 mmol) and Et3N (107 μL, 0.765 mmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography (80 g silica; SiO / heptane 0 / 100~50 / 50) to obtain the title compound (300 mg, purity: 90%, quantitative) as a colorless oil.

[0690] Step C: tert-butyl 2-(5-(methoxycarbonyl)-2-methylphenyl)morpholine-4-carboxylate. A solution of DIAD (CAS[2446-83-5], 226 μL, 1.148 mmol, 1.5 equivalents) in toluene (4 mL) was added dropwise to a solution of methyl 3-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)-1-hydroxyethyl)-4-methylbenzoate (270 mg, 0.765 mmol), Et3N (320 μL, 2.295 mmol, 3 equivalents), and triphenylphosphine (301 mg, 1.148 mmol, 1.5 equivalents) in toluene (20 mL) under a nitrogen atmosphere at 45°C. After addition, stirring was continued at 45°C for 1 hour. The mixture was concentrated under reduced pressure, the residue was diluted with water, and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (80 g silica, SiO2 / 100~90 / 10) to obtain the title compound (98 mg, purity 81%, yield: 31%) as a colorless solid, and the remaining starting material (100 mg, purity 80%, yield: 29%).

[0691] Step D: 3-(4-(tert-butoxycarbonyl)morpholine-2-yl)-4-methylbenzoic acid. NaOH (4N in water, 178 μL, 0.711 mmol, 3 equivalents) was added at room temperature to a solution of tert-butyl 2-(5-(methoxycarbonyl)-2-methylphenyl)morpholine-4-carboxylate (79 mg, 0.237 mmol) in EtOH (2 mL). The mixture was stirred at room temperature for 12 hours, followed by 4 hours at 60°C. The reaction mixture was diluted with water (20 mL), and KHSO4 (1M in water, 3 mL) was added dropwise over 10 minutes with vigorous stirring to adjust the pH to 2-3. Ether was added, and the mixture was stirred for 2 minutes. The layers were separated, the organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (25 g silica, MeOH / DCM0 / 100~10 / 90) to obtain intermediate 217 (67 mg, purity: 89%, yield: 78%) as a brown oily substance.

[0692] Intermediate 220: 3-(3-hydroxypyrrolidine-1-yl)-4-methylbenzoic acid.

[0693] [ka]

[0694] Step A: 3-(3-hydroxypyrrolidine-1-yl)-4-methylbenzoate methyl Pd3(dba)2 (CAS[51364-51-3], 29 mg, 0.031 mmol, 0.05 equivalents) and Xphos (CAS[564483-18-7], 30 mg, 0.063 mmol, 0.1 equivalents) were added to a solution of 3-pyrrolidinol (CAS[40499-83-0], 55 μL, 0.688 mmol, 1.1 equivalents), methyl 3-bromo-4-methylbenzoate (CAS[104901-43-01], 100 μL, 0.626 mmol), and Cs2CO3 (611 mg, 1.877 mmol, 3 equivalents) in 1,4-dioxane (15 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at 90°C for 16 hours. The mixture was diluted with toluene and water and extracted with toluene (×3). The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (25 g silica, toluene / heptane 0 / 100~75:25) to obtain the title compound (22 mg, yield: 14%) as a white solid.

[0695] Step B: 3-(3-hydroxypyrrolidine-1-yl)-4-methylbenzoic acid. Intermediate 220 was prepared in the same manner as intermediate 43, starting with methyl 3-(3-hydroxypyrrolidine-1-yl)-4-methylbenzoate instead of intermediate 42.

[0696] Intermediate 223: (3α,4β,5α)-1-(6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-5-methylpyridine-2-yl)-3,5-dimethylpiperidine-4-ol.

[0697] [ka]

[0698] Step A: tert-butyl((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-iodopyridine-2-yl)-1,6-naphthiridine-7-yl)methyl)carbamate. N-iodosuccinimide (199 mg, 0.884 mmol, 1 equivalent) was added at 0°C to a solution of tert-butyl((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthiridine-7-yl)methyl)carbamate (intermediate 215 mg, 410 mg, 0.884 mmol) in hexafluoroisopropanol (10 mL). The reaction mixture was stirred at 0°C for 30 minutes, then at room temperature for 1 hour. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with ELISA. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (silica, alkyl / heptane 0 / 100~50 / 50) to obtain the title compound (450 mg, purity: 66%, yield: 57%) as a yellow oil.

[0699] Process B: tert-butyl((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. A solution of tert-butyl((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-iodopyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate (450 mg, 66% purity, 0.504 mmol), trimethylboroxine (CAS[823-96-1], 423 μL, 3.023 mmol, 6 equivalents), and K2CO3 (418 mg, 3.023 mmol, 6 equivalents) in 1,4-dioxane (0.5 mL) and water (0.3 mL) was degassed with nitrogen for 5 minutes. Xanthophos Pd G3 (CAS [1445085-97-1], 48 mg, 0.050 mmol, 0.1 equivalent) was added to the solution at room temperature, and the mixture was stirred at 80°C for 12 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (25 g silica, ethyl acetate / heptane 0 / 100~100 / 0), followed by reversed-phase column chromatography (Phenomenex Gemini C18 30 × 100 mm 5 μm column, 81% [0.1% HCOOH]-19% ACN~45% [0.1% HCOOH]-55% ACN) to obtain the title compound (77 mg, yield: 32%) as a yellow solid.

[0700] Step C: (3α,4β,5α)-1-(6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-5-methylpyridine-2-yl)-3,5-dimethylpiperidine-4-ol. HCl (4M in 1,4-dioxane, 419 μL, 1.675 mmol, 20 equivalents) was added to a solution of tert-butyl((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate (40 mg, 0.084 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated to obtain intermediate 223 (HCl salt, 42 mg, purity 90%, quantitative) as an orange solid.

[0701] Intermediate 225: tert-butyl(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)-2,3-dimethylbenzyl)carbamate.

[0702] [ka]

[0703] Tetrakis(triphenylphosphine)palladium(0) (CAS[14221-01-3], 27 mg, 0.023 mmol, 0.1 equivalent) was added to a suspension of compound 27 (140 mg, 0.230 mmol) in 1,4-dioxane (3 mL), potassium ((tert-butoxycarbonyl)amino)methyl) trifluoroborate (CAS[1314538-55-0], 82 mg, 0.346 mmol, 1.5 equivalent) and Na2CO3 in water (1.15 mL, 1 M, 1.152 mmol, 5 equivalents), while degassing with nitrogen. After further degassing with nitrogen for 2 minutes, the vial was sealed and the reaction mixture was stirred in a microwave oven at 110°C for 3 hours. Further potassium (((tert-butoxycarbonyl)amino)methyl) trifluoroborate (164 mg, 0.691 mmol, 3 equivalents) and tetrakis(triphenylphosphine)palladium (0) (27 mg, 0.023 mmol, 0.1 equivalent) were added, and the reaction mixture was degassed with nitrogen for 5 minutes. After sealing the vial, the reaction mixture was stirred in a microwave oven at 120°C for 2 hours. Again, further potassium (((tert-butoxycarbonyl)amino)methyl) trifluoroborate (164 mg, 0.691 mmol, 3 equivalents) and tetrakis(triphenylphosphine)palladium (0) (27 mg, 0.023 mmol, 0.1 equivalent) were added, and the reaction mixture was degassed with nitrogen for 5 minutes. After sealing the vial, the reaction mixture was stirred at 120°C overnight. After cooling, the reaction mixture was diluted with water and RINKAN. The layers were separated, and the aqueous layer was extracted again with RINKAN. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25g, eluate: heptane: siRNA / EtOH 3 / 1 100:0~0:100) to obtain intermediate 225 (45mg, purity: 66%, yield: 21%) as a yellow solid, which was used without further purification.

[0704] Intermediate 231: 6-methyl-7-(methylsulfonyl)isochroman-1-one.

[0705] [ka]

[0706] Chlorosulfonic acid (2.25 mL, 1.75 g / mL, 33.665 mmol, 10 equivalents) was added to 3,4-dihydro-6-methyl-1H-2-benzopyran-1-one (CAS[74786-78-0], 546 mg, 3.366 mmol) at room temperature. The reaction mixture was then stirred overnight at 100°C. The reaction mixture was carefully poured onto ice. The resulting mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. A solution of this solid in THF (12 mL) was added dropwise over 15 minutes at 70°C to a solution of sodium sulfite (513 mg, 4.073 mmol, 1.2 equivalents) and NaHCO3 (1225 mg, 14.577 mmol, 4.3 equivalents) in water (12 mL). The reaction mixture was stirred at 70°C for 1 hour. After cooling to room temperature, methyl iodide (0.91 ml, 14.577 mmol, 4.3 equivalents) was added, and the reaction mixture was stirred overnight at 50°C. Further MeI (0.91 ml, 14.577 mmol, 4.3 equivalents) was added, and the mixture was stirred overnight at 60°C. Water was added, followed by aqueous HCl (1N). The resulting precipitate was filtered and dried to obtain intermediate 231 (349 mg, yield: 43%).

[0707] Intermediate 232: 2-(2-chloroethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide.

[0708] [ka]

[0709] SOCl2 (1.66 mL, 22.89 mmol, 50 equivalents) and DMF (5 μL, 0.071 mmol, 0.15 equivalents) were added to 6-methyl-7-(methylsulfonyl)isochroman-1-one (intermediate 231, 110 mg, 0.458 mmol), and the mixture was stirred overnight at 80°C. The excess SOCl2 was evaporated, and the residue was dissolved in DCM (7 mL). DIPEA (0.79 mL, 4.58 mmol, 10 equivalents) and intermediate 11 (193 mg, 0.405 mmol, 0.88 equivalents) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and it was extracted with DCM. The organic layer was dried (MgSO4), filtered, and evaporated to obtain intermediate 232 (253 mg, yield: 91%), which was used without further purification.

[0710] Intermediate 235: tert-butyl 7-(6-chloro-3-fluoropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

[0711] [ka]

[0712] DIPEA (2.1 mL, 12.05 mmol, 4 equivalents) was added at room temperature to a solution of 2,6-dichloro-3-fluoropyridine (CAS[52208-50-1], 500 mg, 3.012 mmol), 4,7-diazaspiro[2.5]octane-4-carboxylate tert-butyl (CAS[674792-08-6], 671 mg, 3.163 mmol, 1.05 equivalents), and DMSO (5 mL). The reaction mixture was stirred at 120 °C for 18 hours. The reaction mixture was diluted with water and ethyl acetate, and the layers were separated. The organic layer was washed with brine (3 ×), dried, and concentrated in (MgSO4). The residue was purified by silica gel column chromatography (40 g silica, ethyl acetate / heptane 0 / 100~100 / 0) to obtain intermediate 235 (830 mg, yield: 81%) as an oil.

[0713] Intermediate 237: (cis)-4-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-dimethylmorpholine.

[0714] [ka]

[0715] Step A: (cis)-4-(3-bromo-2-fluorophenyl)-2,6-dimethylmorpholine. A suspension of 1-bromo-2-fluoro-3-iodobenzene (CAS[958458-89-4], 552 mg, 1.835 mmol), cis-2,6-dimethylmorpholine (CAS[6485-55-8], 228 μL, 1.835 mmol, 1 equivalent), and Cs2CO3 (1195 mg, 3.669 mmol, 2 equivalents) in 1,4-dioxane (6 mL) was degassed by bubbling nitrogen for 15 minutes. Palladium(II) acetate (CAS[3375-31-3], 41 mg, 0.183 mmol, 0.1 equivalent) and xanthophos (CAS[161265-03-8], 106 mg, 1.183 mmol, 0.1 equivalent) were added, and the reaction mixture was stirred at 100°C for 4 hours. After cooling, the mixture was diluted with saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The organic phase was dried with MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (25 g SiO2, ethyl acetate / heptane 0 / 100~50:50) to obtain the title compound (196 mg, yield: 37%) as a yellow solid.

[0716] Step B: (cis)-4-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-dimethylmorpholine. (cis)-4-(3-bromo-2-fluorophenyl)-2,6-dimethylmorpholine (196 mg, 0.68 mmol), bis(pinacorato)diboron (CAS[73183-34-3], 224 mg, 0.884 mmol, 1.3 equivalents), and KOAc (200 mg, 2.041 mmol, 3 equivalents) were suspended in 1,4-dioxane (5 mL). The mixture was degassed by bubbling nitrogen for 15 minutes. Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 33 mg, 0.041 mmol, 0.06 equivalents) was added, and the reaction mixture was stirred overnight at 90°C. A degassed solution of bis(pinacorato)diboron (172 mg, 0.680 mmol, 1 equivalent) and Pd(dppf)Cl2.CH2Cl2 (16 mg, 0.020 mmol, 0.03 equivalents) in 1,4-dioxane (2 mL) was added to the reaction mixture, and it was stirred at 90°C for 5 hours. After cooling, the reaction mixture was partitioned between an aqueous solution of Na2CO3 (1 M) and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by flash column chromatography (25 g SiO2, siRNA / heptane 0 / 100~40 / 60) to obtain intermediate 237 (107 mg, yield: 47%) as a yellow oil.

[0717] Intermediate 238: (cis)-4-(3-bromo-2,6-difluorophenyl)-2,6-dimethylmorpholine.

[0718] [ka]

[0719] Intermediate 238 was prepared by starting with 1-bromo-2,4-difluoro-3-iodobenzene (CAS[1208075-99-3]) instead of 1-bromo-2-fluoro-3-iodobenzene, and using the same method as for intermediate 237 and step A.

[0720] Intermediate 262: tert-butyl7-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

[0721] [ka]

[0722] Intermediate 262 was prepared according to Method J, starting from intermediate 46 and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (CAS[674792-08-6]).

[0723] Intermediate 263: (cis)-4-(6-bromopyrazine-2-yl)-2,6-dimethylmorpholine.

[0724] [ka]

[0725] DIPEA (1.48 mL, 8.476 mmol, 3 equivalents) was added to a solution of 2-bromo-6-fluoropyrazine (CAS[1209458-12-7], 500 mg, 2.825 mmol) and cis-2,6-dimethylmorpholine (CAS[6485-55-8], 348 μL, 2.825 mmol, 1 equivalent) in DMSO (3 mL), and the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was diluted with DCM (100 mL), water (50 mL), and brine (50 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica, 40 g, alkyl / heptane 0 / 100~100 / 0) to obtain intermediate 263 (693 mg, purity: 92%, yield: 83%).

[0726] Intermediate 273: 3-(1-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-yl)-4-chlorobenzoic acid

[0727] [ka]

[0728] Under a nitrogen atmosphere, 3-bromo-4-chlorobenzoic acid (CAS[42860-10-6], 1 g, 4.247 mmol) was dissolved in dry THF (10 mL), and the reaction mixture was cooled to -78°C. n-butyllithium (2.5 M in hexane, 3.4 mL, 8.5 mmol, 2 equivalents) was added dropwise, and the reaction mixture was stirred at -78°C for 20 minutes. Next, a solution of 1-Boc-3-azetidinone (CAS[398489-26-4], 1.5 g, 8.762 mmol, 2.06 equivalents) in dry THF (5 mL) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature and stirred for 1 hour. The reaction was quenched by adding saturated aqueous solution NH4Cl, and 1 M KHSO4 aqueous solution was added dropwise over 10 minutes with vigorous stirring to reach a pH of 2-3. DCM and water were added, and the layers were separated. The organic layer was vacuum concentrated to obtain intermediate 273 (520 mg, purity 80%, yield: 30%) as a yellow oil, which was used without further purification.

[0729] Intermediate 275: 3-(1-(tert-butoxycarbonyl)-3-hydroxypiperidine-3-yl)-4-methylbenzoic acid.

[0730] [ka]

[0731] 3-Bromo-4-methylbenzoic acid (CAS[7697-26-9], 2g, 9.3 mmol) was dissolved in dry THF (5 mL), and the reaction mixture was cooled to -78°C under a nitrogen atmosphere. n-BuLi (2.5 M in hexane, 7.44 mL, 18.601 mmol, 2 equivalents) was added dropwise, and the reaction mixture was stirred at -78°C for 20 minutes. Next, a solution of 1-Boc-3-piperidone (CAS[98977-36-7], 3.7 g, 18.601 mmol, 2 equivalents) in dry THF (1 mL) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature and stirred for 1 hour. The reaction was quenched by adding saturated NH4Cl aqueous solution, and then 1 M KHSO4 aqueous solution was added dropwise over 10 minutes with high stirring to bring the pH to 2-3. DCM and water were added, and the layers were separated. The organic layer was concentrated under vacuum, and the residue was purified by flash column chromatography (80 g silica, DCM / MeOH(9 / 1), 0 / 100~40 / 60) to obtain intermediate 275 (377 mg, yield: 12%) as a yellow solid.

[0732] Intermediate 283: (2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0733] [ka]

[0734] Step A: (cis)-4-(6-bromo-3-nitropyridine-2-yl)-2,6-dimethylmorpholine. A mixture of 2,6-dibromo-3-nitropyridine (CAS[55304-80-8], 2.15 g, 7.627 mmol), cis-2,6-dimethylmorpholine (CAS[6485-55-8], 0.94 mL, 7.627 mmol, 1 equivalent), and K2CO3 (1.05 g, 7.627 mmol, 1 equivalent) in toluene (25 mL) was stirred at 50°C for 3 hours. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography (12 g SiO2; siRNA / heptane 0 / 100~10 / 90) to obtain the title compound (1.81 g, yield: 74%) as a yellow solid.

[0735] Step B: 6-Bromo-2-((cis)-2,6-dimethylmorpholino)pyridine-3-amine. Iron powder (2.65 g, 47.484 mmol, 10 equivalents) was added to a solution of (cis)-4-(6-bromo-3-nitropyridine-2-yl)-2,6-dimethylmorpholine (1.5 g, 4.748 mmol) and NH4Cl (1.27 g, 23.742 mmol, 5 equivalents) in water (13 mL) and EtOH (48 mL). The reaction mixture was stirred at 70°C for 1.5 hours. After cooling, the mixture was filtered through Celite® and the filter was washed with EtOH and ethyl acetate. The filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 aqueous solution. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated under vacuum to obtain the title compound (860 mg, yield: 63%) as a yellow solid, which was used without further purification.

[0736] Step C: (cis)-4-(6-bromo-3-fluoropyridine-2-yl)-2,6-dimethylmorpholine. 6-bromo-2-((cis)-2,6-dimethylmorpholino)pyridine-3-amine (784 mg, 2.74 mmol) dissolved in DCM (4 mL) was added at 0°C to a slurry of nitrosyltetrafluoroborate (CAS[14635-75-7], 352 mg, 3.014 mmol, 1.1 equivalents) in DCM (4 mL). The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was allowed to reach room temperature, diluted with xylene (12 mL), and stirred at 130°C for 1.5 hours. After cooling, the mixture was extracted with saturated NaHCO3 aqueous solution and the reaction mixture with ethyl acetate. The layers were separated, the organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g silica; acetone / heptane 0 / 100~10 / 90) to obtain the title compound (710 mg, yield: 85%) as a colorless oil.

[0737] Step D: tert-butyl((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. The title compound was prepared in a similar manner to intermediate 97, starting from (cis)-4-(6-bromo-3-fluoropyridine-2-yl)-2,6-dimethylmorpholine instead of intermediate 96.

[0738] Step E: (2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridine-2-yl)-1,6-naphthiridine-7-yl)methaneamine. TFA (565 μL, 7.379 mmol, 30 equivalents) was added at 0°C to a solution of tert-butyl((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridine-2-yl)-1,6-naphthiridine-7-yl)methyl)carbamate (115 mg, 0.246 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM (x3). The combined organic layers were dried in (MgSO4), filtered, and the solvent was evaporated under vacuum to obtain intermediate 283 (TFA salt, 86 mg, yield: 72%), which was used without further purification.

[0739] Intermediate 291: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-formylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0740] [ka]

[0741] Despiltan periodinane (CAS[87413-09-0], 172 mg, 0.393 mmol, 1.5 equivalents) was added to a solution of compound 182 (151 Mg, 0.262 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 3 hours. An aqueous solution of Na2CO3 (1 M) was added, and the mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (SiO2 25 g, MeOH in DCM:DCM(9:1) 0 / 100~50 / 50) to obtain intermediate 291 (105 mg, purity: 86%, yield: 60%) as a yellow solid.

[0742] Intermediate 300: (2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0743] [ka]

[0744] Step A: tert-butyl 7-(6-bromo-4-nitropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. Nitrogen was purged into a solution of 2,6-dibromo-4-nitropyridine (CAS[175422-04-5], 2 g, 7.095 mmol) in 1,4-dioxane (10 mL). Then, Cs2CO3 (5.086 g, 15.609 mmol, 2.2 equivalents), DavePhos (CAS[213697-53-1], 279 mg, 0.709 mmol, 0.1 equivalent), and Pd2dba3 (CAS[51364-51-3], 325 mg, 0.355 mmol, 0.05 equivalents) were added to the reaction mixture at room temperature while bubbling nitrogen. 4-Boc-4,7-diazaspiro[2.5]octane (CAS[674792-08-6], 1.732 g, 8.159 mmol, 1.15 equivalents) was added, and the vial was sealed. The reaction mixture was stirred at 90°C for 3 hours. The reaction was quenched by adding saturated NaHCO3 aqueous solution (1 M). The mixture was extracted with siRNA (3 × 20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g silica, siRNA / heptane 0 / 100~25 / 75) to obtain the title compound (2.4 g, yield: 74%) as an orange solid.

[0745] Step B: tert-butyl 7-(6-bromo-4-fluoropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. Tetramethylammonium fluoride (CAS[373-68-2], 584 mg, 6.275 mmol, 1.2 equivalents) was added in a sealed tube to a solution of tert-butyl 7-(6-bromo-4-nitropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (2161 mg, 5.229 mmol) in dry DMF (15 mL). The reaction mixture was stirred at 65 °C for 3 hours. After cooling, the reaction mixture was diluted with siRNA (30 mL) and water (30 mL). The layers were separated. The organic layer was washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (80 g silica, siRNA / heptane 0 / 100~20 / 80) to obtain the title compound (1.23 g, yield: 59%) as an orange solid.

[0746] Step C: tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)-4-fluoropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. Intermediate 94 (459 mg, 1.121 mmol), tert-butyl 7-(6-bromo-4-fluoropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (650 mg, 1.682 mmol, 1.5 equivalents), and K2CO3 (232 mg, 1.682 mmol, 1.5 equivalents) were dissolved in 1,4-dioxane (3 mL). The reaction mixture was degassed by bubbling nitrogen for 10 minutes. Next, Pd(OAc)2 (CAS[3375-31-3], 13 mg, 0.056 mmol, 0.05 equivalents) and di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 28 mg, 0.112 mmol, 0.1 equivalents) were added, and the mixture was stirred at 150°C for 4 hours. The mixture was diluted with water, extracted with siRNA, and washed twice with brine. The organic layer was separated, filtered, and the solvent evaporated under vacuum. The residue was purified by flash column chromatography (24 g silica, siRNA / heptane 0 / 100~100 / 0) to obtain the title compound (232 mg, yield: 36%) as a yellow solid.

[0747] Step D: (2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthiridine-7-yl)methaneamine. HCl (4M in 1,4-dioxane, 1.08 mL, 4.34 mmol, 10 equivalents) was added at room temperature to a solution of tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthiridine-2-yl)-4-fluoropyridine-2-yl)-4,7-diazaspiro[2.5]octan-4-carboxylate (245 mg, 0.434 mmol) in 1,4-dioxane (1.1 mL). The mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the solid was washed with 1,4-dioxane (20 mL) to obtain intermediate 300 (HCl salt, 159 mg, yield: 83%) as a red solid. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The pH of the aqueous layer was adjusted to 10 with Na₂CO₃ (1 M in water, 2 mL), and the mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over (MgSO₄), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (24 g silica, MeOH / DCM 0 / 100~20 / 80) to obtain the title compound (free base, 11 mg, yield: 7%) from another batch as a green solid.

[0748] Intermediate 304: 4-methyl-3-(tetrahydrofuran-2-yl)benzoic acid.

[0749] [ka]

[0750] Process A: 4-methyl-3-(tetrahydrofuran-2-yl)methyl benzoate. Tetrahydro-2-furoic acid (CAS [16874-33-2], 472 μL, 4.911 mmol, 1.2 equivalents), methyl 3-bromo-4-methylbenzoate (CAS [104901-43-1], 654 μL, 4.092 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (CAS [29046-78-4], 90 mg, 0.409 mmol, 0.1 equivalent), 4,4'-di-tert- A 50 mL solution of til-2,2'-dipyridyl (CAS[72914-19-3], 165 mg, 0.614 mmol, 0.15 equivalents), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (CAS[870987-63-6], 46 mg, 0.041 mmol, 0.01 equivalents), and Cs2CO3 (4 g, 12.277 mmol, 3 equivalents) in DMF was degassed by bubbling nitrogen for 15 minutes. The reaction mixture was stirred and irradiated with a blue LED (internal temperature = 55-60°C) for 6 hours. The reaction mixture was diluted with ethyl acetate. The combined organic layers were washed twice with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (25 g silica, alkyl / heptane 0 / 100~70 / 30) to obtain the title compound (70 mg, yield: 8%) as a yellow oil.

[0751] Step B: 4-Methyl-3-(tetrahydrofuran-2-yl)benzoic acid. Sodium hydroxide (1 M in water, 1 mL, 1 mmol, 3 equivalents) was added at room temperature to a solution of methyl 4-methyl-3-(tetrahydrofuran-2-yl)benzoate (76 mg, 0.345 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 72 hours. The mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was acidified to pH=1 with HCl (1 M in water) and then extracted twice with ethyl acetate. This organic layer was dried over MgSO4, filtered, and concentrated under vacuum to obtain intermediate 304 (56 mg, yield: 78%) as a white powder.

[0752] Intermediate 323: 3-methyl-5-(1H-tetrazole-1-yl)benzoic acid.

[0753] [ka]

[0754] Step A: Methyl 3-methyl-5-(1H-tetrazole-1-yl)benzoate. A mixture of methyl 3-amino-5-methylbenzoate (1.5 g, 9.1 mmol) and triethyl orthoformate (6 mL, 36 mmol, 4 equivalents) in AcOH (8 mL) was stirred at room temperature for 2 hours. The solvent was then evaporated. AcOH (8 mL), followed by NaN3 (2.3 g, 35 mmol, 3.8 equivalents), was added. The mixture was stirred at 70°C for 1 hour. An additional AcOH (4 mL) was added, and the mixture was stirred further at 70°C for 1 hour. After cooling, water was added and the mixture was stirred for 30 minutes. The precipitate was filtered, washed with water, and dried to obtain the title compound (1.82 g, yield: 91%).

[0755] Step B: 3-Methyl-5-(1H-tetrazole-1-yl)benzoic acid. A mixture of methyl 3-methyl-5-(1H-tetrazole-1-yl)benzoate (1.82 g, 8.3 mmol) and NaOH (1N in water, 8.34 mL, 8.3 mmol, 1 equivalent) in MeOH (150 mL) was stirred at room temperature for 48 hours and then evaporated. The residue was collected with water. The solution was washed with DCM, acidified with aqueous HCl, and extracted with phenylethylamine. The organic layer was dried with (MgSO4), filtered, and evaporated to obtain intermediate 323 (1.6 g, yield: 94%).

[0756] Intermediate 327: 2-(((2-(3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)benzoic acid.

[0757] [ka]

[0758] Intermediate 69 (175 mg, 0.541 mmol, 1 equivalent), 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine (CAS[1009033-83-3], 243 mg, 0.778 mmol, 1.44 equivalents), and Na2CO3 (172 mg, 1.62 mmol, 3 equivalents) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) in a pressure flask. Nitrogen was bubbling into the reaction mixture for 10 minutes, and then Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 22 mg, 0.027 mmol, 0.05 equivalents) was added. The reaction vessel was sealed, and the reaction mixture was stirred at 85°C for 3 hours. The reaction mixture was diluted with water and extracted twice with siRNA. The aqueous layer was acidified with an aqueous HCl solution (1N) until the pH reached 4-5. The precipitate was filtered, washed with DCM and Et2O, and dried under vacuum to obtain intermediate 327 (251 mg, yield: 70%) as a beige solid.

[0759] Intermediate 328: (2-(3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methaneamine.

[0760] [ka]

[0761] Intermediate 327 (175 mg, 0.38 mmol, 1 equivalent) was added to a solution of hydrazine hydrate (CAS[10217-52-4], 92 μL, 1.9 mmol, 5 equivalents) in EtOH (6 mL), and the reaction mixture was stirred at 65 °C for 16 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM (×3). The combined organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography (25 g, DCM / MeOH, 100 / 0~90 / 10) on silica gel to obtain intermediate 328 (92 mg, yield: 77%) as a white solid.

[0762] Intermediate 329: 2-(((2-(3-(pyridine-3-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)benzoic acid.

[0763] [ka]

[0764] Intermediate 329 was synthesized in a similar manner to intermediate 327, using 3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine (CAS[939430-30-5]) instead of 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine (CAS[1009033-83-3]).

[0765] Intermediate 330: (2-(3-(pyridine-3-yl)phenyl)-1,6-naphthyridine-7-yl)methaneamine.

[0766] [ka]

[0767] Intermediate 330 was synthesized in the same manner as intermediate 328, using intermediate 329 instead of intermediate 327.

[0768] Intermediate 332: (2-(4-fluoro-3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methaneamine.

[0769] [ka]

[0770] Step A: 2-(((2-(4-fluoro-3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)benzoic acid. The title compound was prepared in the same manner as intermediate 327, using 3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine (CAS[425378-79-6]) instead of 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine (CAS[1009033-83-3]).

[0771] Step B: (2-(4-fluoro-3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methaneamine. The title compound was synthesized in a similar manner to intermediate 328, using 2-(((2-(4-fluoro-3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)benzoic acid instead of intermediate 327.

[0772] Intermediate 333: 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-7-yl)pyridine.

[0773] [ka]

[0774] 4-(5-bromo-2,3-dihydro-7-benzofuranyl)pyridine (CAS[923297-52-3], 301 mg, 1.09 mmol, 1 equivalent), bis(pinacorato)diboron (CAS[73183-34-3], 360 mg, 1.417 mmol, 1.3 equivalents), Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 27 mg, 0.033 mmol, 0.03 equivalents), and KOAc (321 mg, 3.27 mmol, 3 equivalents) were dissolved in 10 mL of 1,4-dioxane and reacted with nitrogen gas for 15 minutes. The reaction mixture was stirred at 90°C for 2 hours. The mixture was diluted with 1 M Na2CO3 aqueous solution and DCM, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography (heptane / Â100 / 0~50 / 50) on silica gel to obtain intermediate 333 (298 mg, yield: 83%) as a white oily substance.

[0775] Intermediate 334: 4-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine.

[0776] [ka]

[0777] Intermediate 334 was prepared in the same manner as intermediate 333, using 4-(3-bromo-4-methoxyphenyl)pyridine (CAS[191602-60-5]) instead of 4-(5-bromo-2,3-dihydro-7-benzofuranyl)pyridine (CAS[923297-52-3]).

[0778] Intermediate 335: 4-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine.

[0779] [ka]

[0780] Intermediate 335 was prepared in the same manner as intermediate 333, using 4-(3-bromo-5-fluorophenyl)pyridine (CAS[1247883-59-5]) instead of 4-(5-bromo-2,3-dihydro-7-benzofuranyl)pyridine (CAS[923297-52-3]).

[0781] Intermediate 339: tert-butyl((2-(6-(5,6-dihydro-2H-pyran-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0782] [ka]

[0783] Step A: 2-bromo-6-(5,6-dihydro-2H-pyran-3-yl)pyridine. 3,6-dihydropyran-5-boronic acid ester (CAS[212127-81-6], 265 mg, 1.26 mmol, 1 equivalent), 2,6-dibromopyridine (CAS[626-05-1], 1.20 g, 5.05 mmol, 4 equivalents), and K2CO3 (349 mg, 2.52 mmol, 2 equivalents) were suspended in 1,4-dioxane (4 mL) and water (1 mL), and the mixture was bubbling with a nitrogen stream for 1 minute. Then, Pd(PPh3)4 (CAS[14221-01-3], 73 mg, 0.063 mmol, 0.05 equivalents) was added, and the mixture was slowly heated to 80°C and maintained at this temperature for 16 hours. The reaction mixture was extracted with a saturated NaHCO3 aqueous solution and toluene. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (25 g, heptane / toluene 100 / 0~90 / 10) to obtain the title compound (223 mg, yield: 73%) as a colorless oil.

[0784] Step B: tert-butyl((2-(6-(5,6-dihydro-2H-pyran-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. The title compound was prepared in the same manner as intermediate 97, using 2-bromo-6-(5,6-dihydro-2H-pyran-3-yl)pyridine instead of intermediate 96.

[0785] Intermediate 340: (2-(6-(5,6-dihydro-2H-pyran-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0786] [ka]

[0787] Intermediate 339 was dissolved in TFA (274 μL) and DCM (1 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. The TFA salt of intermediate 340 was obtained by evaporation (purity 87%, quantitative) and used without further purification.

[0788] Intermediate 343: (6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)(cyclopropyl)methanone.

[0789] [ka]

[0790] Step A: (6-bromo-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)(cyclopropyl)methanone. DIPEA (948 μL, 5.443 mmol, 5 equivalents) was added to a suspension of 6-bromo-1',2',3',6'-tetrahydro-2,4'-bipyridine (CAS[478366-38-0], 300 mg, 1.089 mmol, 1 equivalent) and cyclopropane carbonyl chloride (CAS[4023-34-1], 198 μL, 2.177 mmol, 2 equivalents) in DCM (4 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM (x3). The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (12 g, heptane / acetate 100 / 0~60 / 40) to obtain the title compound (200 mg, yield: 58%) as a yellow oil.

[0791] Step B: tert-butyl((2-(1'-(cyclopropanecarbonyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. The title compound was prepared in the same manner as intermediate 97, using (6-bromo-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)(cyclopropyl)methanone instead of intermediate 96.

[0792] Step C: (6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)(cyclopropyl)methanone. The marked compound (TFA salt) was prepared in the same manner as for intermediate 340, using tert-butyl((2-(1'-(cyclopropanecarbonyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl)-1,6-naphthyridine-7-yl)methyl)carbamate instead of intermediate 339.

[0793] Intermediate 346: 4-methyl-3-(methylsulfonyl)-N-((2-oxo-1,2-dihydro-1,6-naphthyridine-7-yl)methyl)benzamide.

[0794] [ka]

[0795] Step A: 7-(aminomethyl)-1,6-naphthyridine-2(1H)-one. HCl (37% in H2O, 3.41 mL, 40.85 mmol, 6 equivalents) was added at room temperature to a solution of tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2) (2 g, 6.81 mmol, 1 equivalent) in 1,4-dioxane (34 mL), and the mixture was heated at 60°C for 30 minutes. The reaction mixture was cooled to room temperature, and ACN (10 mL) was added. The solid was isolated by filtration and dried under vacuum to obtain the title compound (HCl salt, 1.44 g, yield: 85%) as a light brown solid.

[0796] Step B: 4-methyl-3-(methylsulfonyl)-N-((2-oxo-1,2-dihydro-1,6-naphthyrizin-7-yl)methyl)benzamide. A suspension of 3-methanesulfonyl-4-methylbenzoic acid (CAS[51522-22-6], 115 mg, 0.537 mmol, 1.3 equivalents) in ACN (5 mL) was treated with DIPEA (0.4 mL, 2.32 mmol, 5.6 equivalents). HATU (200 mg, 0.526 mmol, 1.27 equivalents) was added, and the reaction mixture was stirred at room temperature for 10 minutes. 7-(aminomethyl)-1,6-naphthyrizin-2(1H)-one (103 mg, 0.415 mmol, 1 equivalent) was added, and the reaction mixture was stirred for a further 10 minutes. The product was isolated by filtration, washed with ACN, and dried under vacuum to obtain intermediate 346 (136 mg, yield: 88%) as a beige solid.

[0797] Intermediate 350: (2-(3-(pyridine-3-yl)pyrrolidine-1-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0798] [ka]

[0799] Step A: tert-butyl((2-(3-(pyridine-3-yl)pyrrolidine-1-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2) (150 mg, 0.511 mmol, 1 equivalent) was dissolved in THF (2.5 mL), then DIPEA (0.176 mL, 1.021 mmol, 2 equivalents) and 3-(3-pyrrolidinyl)pyridine (CAS [150281-46-2], 151 mg, 1.021 mmol, 2 equivalents) were added, and the reaction mixture was stirred at 100°C for 3 hours. The solvent was evaporated, and the residue was purified by flash column chromatography on silica gel (40 g, DCM / MeOH 100 / 0~95 / 5) to obtain the title compound (180 mg, yield: 87%).

[0800] Step B: (2-(3-(pyridine-3-yl)pyrrolidine-1-yl)-1,6-naphthyridine-7-yl)methaneamine. The title compound was prepared in the same manner as intermediate 340 using tert-butyl((2-(3-(pyridine-3-yl)pyrrolidine-1-yl)-1,6-naphthyridine-7-yl)methyl)carbamate instead of intermediate 339. The crude product was purified by reverse-phase chromatography (Kinetex 5 umEVO c18 100; 0.1% TFA aqueous solution, ACN, 10% ACN~100% ACN) to obtain intermediate 350 as a solid.

[0801] Intermediate 352: (2-(4-(pyridine-4-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0802] [ka]

[0803] The title compound was prepared in the same manner as intermediate 350, using 1-(4-pyridyl)piperazine (CAS[1008-91-9]) instead of 3-(3-pyrrolidinyl)pyridine in step A, and the resulting crude product was purified by reverse-phase chromatography (Kinetex 5um EVO c18 100; 0.1% TFA aqueous solution, ACN, 10% ACN to 100% ACN).

[0804] Intermediate 354: (2-(4-(pyridine-3-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0805] [ka]

[0806] The title compound was prepared in the same manner as intermediate 350, except that 1-(3-pyridinyl)piperazine (CAS[67980-77-2]) was used instead of 3-(3-pyrrolidinyl)pyridine in step A.

[0807] Intermediate 357: 1-(6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)-4-fluorobutan-1-one.

[0808] [ka]

[0809] Step A: 1-(6-bromo-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)-4-fluorobutan-1-one. DIPEA (1.39 mg, 7.983 mmol, 5 equivalents) was added to a suspension of 6-bromo-1',2',3',6'-tetrahydro-2,4'-bipyridine (CAS[478366-38-0], 440 mg, 1.597 mmol, 1 equivalent), 4-fluorobutanoic acid (CAS[462-23-7], 186 mg, 1.756 mmol, 1.1 equivalents), and HATU (759 mg, 2.00 mmol, 1.25 equivalents) in DCM (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM (x3). The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (25 g, DCM / MeOH 100 / 0~90 / 10) to obtain the title compound (350 mg, yield: 64%) as a yellow oil.

[0810] Step B: tert-butyl((2-(1'-(4-fluorobutanoyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. The title compound was prepared in the same manner as intermediate 97, using 1-(6-bromo-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)-4-fluorobutan-1-one instead of intermediate 96.

[0811] Step C: 1-(6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)-4-fluorobutan-1-one. The marked compound (TFA salt) was prepared in the same manner as for intermediate 340, using tert-butyl((2-(1'-(4-fluorobutanoyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl)-1,6-naphthyridine-7-yl)methyl) carbamate instead of intermediate 339.

[0812] Intermediate 359: (2-(4-(pyridine-3-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0813] [ka]

[0814] Step A: tert-butyl((2-(4-(pyridine-3-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)carbamate. The title compound was prepared in the same manner as intermediate 9, using (4-(pyridine-3-yl)phenyl)boronic acid (CAS[170230-28-1]) instead of 6-fluoropyridine-2-boronic acid, but purified by flash column chromatography (heptane / siRNA 100 / 0~0 / 100) on silica gel instead of precipitation.

[0815] Step B: (2-(4-(pyridine-3-yl)phenyl)-1,6-naphthyridine-7-yl)methaneamine. The marked compound (TFA salt) was prepared in the same manner as for intermediate 340, using tert-butyl((2-(4-(pyridine-3-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)carbamate instead of intermediate 339.

[0816] Intermediate 361: (2-(1-(pyridine-3-yl)piperidine-4-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0817] [ka]

[0818] Process A: Methyl 4-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)-1-(pyridine-3-yl)piperidine-4-carboxylate. tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2) (100 mg, 0.34 mmol, 1 equivalent), 4-piperidinecarboxylic acid, 1-(3-pyridinyl)-,methyl ester (CAS [1823499-87-1], 90 mg, 0.409 mmol, 1.2 equivalents), P(t-Bu)3 paradacyclegen. 4 (CAS[1621274-11-0], 14 mg, 0.0238 mmol, 0.1 equivalent) and toluene (2.5 mL) were combined in a vial, the mixture was evacuated, and the vial was refilled three times with nitrogen. LiHMDS (1.06 M in THF, CAS[4039-32-1], 0.963 mL, 1.021 mmol, 3 equivalents) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours, concentrated, and purified by flash column chromatography on silica gel (24 g, DCM / MeOH 100 / 0~90 / 10) to obtain the title compound (80 mg, yield: 49%).

[0819] Step B: (2-(1-(pyridine-3-yl)piperidine-4-yl)-1,6-naphthiridine-7-yl)methaneamine. Methyl 4-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthiridine-2-yl)-1-(pyridine-3-yl)piperidine-4-carboxylate (80 mg, 0.168 mmol, 1 equivalent) was dissolved in THF (277 μL) and MeOH (553 μL). NaOH (50% in water, 35 μL, 0.67 mmol, 5 equivalents) was added, and the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and DCM (1 mL) was added. TFA (0.128 mL, 1.675 mmol, 10 equivalents) was added dropwise, and the mixture was stirred at room temperature for 2 hours, then evaporated to obtain intermediate 361, which was used without further purification.

[0820] Intermediate 362: (2-(4-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methaneamine.

[0821] [ka]

[0822] The title compound was prepared in step A using (4-(pyridine-4-yl)phenyl)boronic acid (CAS[1045332-30-6]) in the same manner as intermediate 359.

[0823] Intermediate 366: 4-methyl-3-(methylsulfonyl)-N-((2-(piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide.

[0824] [ka]

[0825] Step A: Benzyl 4-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)piperazine-1-carboxylate. Tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2) (1500 mg, 4.7 mmol, 1 equivalent), 1-cbz-piperazine (CAS[31166-44-6], 1.09 mL, 5.64 mmol, 1.2 equivalents), and Cs2CO3 (3061 mg, 9.4 mmol, 2 equivalents) were dissolved in ACN (31 mL). The reaction mixture was stirred at 80°C for 4 hours, then 1-cbz-piperazine (CAS[31166-44-6], 45 μL, 0.5 equivalents) and Cs2CO3 (1.53 g, 4.7 mmol, 1 equivalent) were added, and stirring was continued overnight. The reaction mixture was diluted with water, and the organic phase was extracted with SiO(x3). The combined organic layers were washed with HCl aqueous solution (1 M) and brine, dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (24 g, heptane / SiO2 100 / 0~0 / 100) to obtain the title compound (1742 mg, yield: 78%) as a pale yellow solid.

[0826] Step B: Benzyl 4-(7-(aminomethyl)-1,6-naphthyridine-2-yl)piperazine-1-carboxylate. The marked compound (TFA salt) was prepared in the same manner as intermediate 340, using benzyl 4-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)piperazine-1-carboxylate instead of intermediate 339.

[0827] Step C: Benzyl 4-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)piperazine-1-carboxylate. Starting with benzyl 4-(7-(aminomethyl)-1,6-naphthyridine-2-yl)piperazine-1-carboxylate instead of intermediate 359, the title compound was prepared similarly to compound 233.

[0828] Step D: 4-methyl-3-(methylsulfonyl)-N-((2-(piperazin-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide. Benzyl 4-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)piperazin-1-carboxylate (56 mg, 0.098 mmol, 1 equivalent) was dissolved in 1.95 mL of butyl, and Pd / C (10%, 56 mg, 0.46 mmol, 1 equivalent) was added. A hydrogen balloon was attached to the vial and spurged for 5 minutes, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through a short pad of Celite®, washed with butyl, and the filtrate was evaporated to obtain intermediate 366, which was used without further purification.

[0829] Intermediate 367: (2-(4-(pyridazin-3-yl)piperazin-1-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0830] [ka]

[0831] tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2) (400 mg, 1.362 mmol, 1 equivalent) and 1-(6-pyridazinyl)piperazine (CAS[51047-56-4], 447 mg, 2.723 mmol, 2 equivalents) were dissolved in THF (7 mL), and DIPEA (469 μL, 2.723 mmol, 2 equivalents) was added. The reaction mixture was stirred at 100 °C for 18 hours. The reaction mixture was adsorbed onto silica and purified by flash column chromatography on silica gel (DCM / MeOH 100 / 0~90 / 10). The obtained product was dissolved in DCM (1 mL) and treated with TFA (1 mL, 13.617 mmol, 10 equivalents) at room temperature for 2 hours. The reaction mixture was evaporated to obtain intermediate 367 (TFA salt, 424 mg, yield: 35%), which was used without further purification.

[0832] Intermediate 368: (2-(4-(6-methoxypyridine-3-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0833] [ka]

[0834] Intermediate 368 (TFA salt) was prepared in the same manner as intermediate 367, using 1-(6-methoxypyridine-3-yl)piperazine (CAS[158399-76-9]) instead of 1-(6-pyridazinyl)piperazine (CAS[51047-56-4]).

[0835] Intermediate 369: (2-(4-(pyrazine-2-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0836] [ka]

[0837] Intermediate 369 (TFA salt) was prepared in the same manner as intermediate 367, using 2-(piperazin-1-yl)pyrazine (CAS[34803-68-4]) ​​instead of 1-(6-pyridazinyl)piperazine (CAS[51047-56-4]).

[0838] Intermediate 372: (2-(1-(pyridine-3-yl)piperidine-3-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0839] [ka]

[0840] Step A: tert-butyl((2-(3-butyryl-1-(pyridin-3-yl)piperidine-3-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2) (148 mg, 0.504 mmol, 1 equivalent), ethyl 1-(3-pyridinyl)-3-piperidine carboxylate (CAS [1369241-44-0], 177 mg, 0.755 mmol, 1.5 equivalents), P(t-Bu)3 paradacyclegen, 4 (CAS [1621274-11-0], 30 mg, 0.050 mmol, 0.1 equivalents), and toluene (2 mL) were combined in a vial, and the mixture was sparged with nitrogen for 10 minutes. LiHMDS (1.06 M in THF, CAS[4039-32-1], 1.51 mL, 1.51 mmol, 3 equivalents) was added dropwise. The reaction mixture was stirred overnight at room temperature, then DCM (0.5 mL) and MeOH (0.5 mL) were added, and the reaction mixture was stirred for 5 minutes. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (24 g, heptane / siRNA (10% in EtOA) 100 / 0~30 / 70) to obtain the title compound (98 mg, yield: 40%) as a yellow oil.

[0841] Step B: (2-(1-(pyridine-3-yl)piperidine-3-yl)-1,6-naphthyridine-7-yl)methaneamine. Tert-butyl((2-(3-butyryl-1-(pyridine-3-yl)piperidine-3-yl)-1,6-naphthyridine-7-yl)methyl)carbamate (98.4 mg, 0.2 mmol, 1 equivalent) was dissolved in THF (0.5 mL) and MeOH (1 mL), then NaOH (50% in H2O, 53 μL, 1.00 mmol) was added, and the reaction mixture was stirred at 70°C for 30 minutes. The residue was dissolved in DCM (1 mL) and TFA (1 mL), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated, the residue was diluted with DCM, and washed with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with DCM, and then extracted twice with 10% trifluoroethanol / DCM. The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain intermediate 372 (63 mg, yield: 99%).

[0842] Intermediate 376: 3-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)cyclohexa-2-ene-1-carboxylic acid.

[0843] [ka]

[0844] Step A: Ethyl 3-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)cyclohexa-2-ene-1-carboxylate. A vial containing tert-butyl((2-chloro-1,6-naphthyrizin-7-yl)methyl)carbamate (intermediate 2) (400 mg, 1.362 mmol, 1 equivalent), 2-cyclohexen-1-carboxylic acid, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-ethyl ester (CAS [1536395-80-8], 496 mg, 1.77 mmol, 1.3 equivalents), PdCl2 (dppf) (CAS [72287-26-4], 50 mg, 0.0681 mmol, 0.05 equivalents), and K2CO3 (565 mg, 4.085 mmol, 3 equivalents) was evacuated three times and refilled with nitrogen. Next, 1,4-dioxane (5 mL) and water (2 mL) were added, and the reaction mixture was sparged with nitrogen for 10 minutes. The reaction mixture was stirred at 100°C for 18 hours. After evaporation of the solvent, the crude mixture was directly purified by flash column chromatography on silica gel (40 g, DCM / siRNA 100:0~0:100) to obtain the title compound (525 mg, yield: 94%).

[0845] Step B: Ethyl 3-(7-(aminomethyl)-1,6-naphthyridine-2-yl)cyclohexa-2-ene-1-carboxylate. The marked compound (TFA salt) was prepared in the same manner as intermediate 340, using ethyl 3-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)cyclohexa-2-ene-1-carboxylate instead of intermediate 339.

[0846] Step C: Ethyl 3-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)cyclohexa-2-ene-1-carboxylate. Starting with ethyl 3-(7-(aminomethyl)-1,6-naphthyridine-2-yl)cyclohexa-2-ene-1-carboxylate instead of intermediate 350, the title compound was prepared similarly to compound 224.

[0847] Step D: 3-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)cyclohexa-2-ene-1-carboxylic acid. Ethyl 3-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)cyclohexa-2-ene-1-carboxylate (20 mg, 0.0394 mmol, 1 equivalent) was dissolved in MeOH (133 μL) and THF (133 μL), then NaOH (50% in H2O, 32 μL, 0.394 mmol, 10 equivalents) was added, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was purified by reverse-phase chromatography (Kinetex 5 um EVOc 18 100; 0.1% TFA aqueous solution, ACN, 10% ACN to 100% ACN) to obtain intermediate 376 (TFA salt, 34 mg, quantitative).

[0848] Intermediate 378: Ethyl 1-(7-(aminomethyl)-1,6-naphthyridine-2-yl)piperidine-3-carboxylate.

[0849] [ka]

[0850] Step A: Ethyl 1-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthiridine-2-yl)piperidine-3-carboxylate. tert-butyl((2-chloro-1,6-naphthiridine-7-yl)methyl)carbamate (intermediate 2) (800 mg, 2.723 mmol, 1 equivalent) was added to a 50 mL vial, evacuated, and refilled with nitrogen, followed by anhydrous ACN (12 mL). Ethyl nipecotinate (CAS[25137-01-3], 0.50 mL, 3.132 mmol, 1.15 equivalents) was added, the vial was evacuated, refilled twice with nitrogen, and then DIPEA (1.08 mL, 6.264 mmol, 2.3 equivalents) was added. The reaction mixture was stirred at 70°C for 5 hours. Ethyl nipecotinate (CAS[25137-01-3], 0.5 mL) was added, and the mixture was stirred overnight. The reaction mixture was diluted with Âly and water / brine 1 / 1. The organic layer was separated, washed with brine, then with water, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography (40 g, heptane / MeOH (10% in Âly) 80 / 20~30 / 70) to obtain the marked compound (780 mg, yield: 69%) as a sticky off-white solid.

[0851] Step B: Ethyl 1-(7-(aminomethyl)-1,6-naphthiridine-2-yl)piperidine-3-carboxylate. The marked compound (TFA salt) was prepared in the same manner as intermediate 340, using ethyl 1-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthiridine-2-yl)piperidine-3-carboxylate instead of intermediate 339.

[0852] Intermediate 379: Methyl 4-(1-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)piperidine-3-yl)benzoate.

[0853] [ka]

[0854] Intermediate 379 was prepared in the same manner as in step A, using 4-(piperidine-3-yl)methyl benzoate hydrochloride (CAS[1187173-13-2]) instead of ethyl nipecotinate, and intermediate 45 instead of tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2).

[0855] Intermediate 380: N-((2-(3-bromo-1H-pyrazole-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0856] [ka]

[0857] Intermediate 346 (163 mg, 0.439 mmol, 1 equivalent), 3-bromopyrazole (CAS[14521-80-3], 101 mg, DBU (CAS[6674-22-2], 0.25 mL, 1.64 mmol, 3.7 equivalents), and BOP (CAS[56602-33-6], 221 mg, 0.5 mmol, 1.14 equivalents) were dissolved in ACN (5 mL), and the reaction mixture was stirred at 80°C for 16 hours. The product was isolated by filtration, washed with ACN, and dried under vacuum to obtain intermediate 380 (164 mg, yield: 75%) as a light brown solid.

[0858] Intermediate 381: Methyl 3-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)-1-(pyridine-4-yl)piperidine-3-carboxylate.

[0859] [ka]

[0860] Intermediate 381 was prepared in the same manner as intermediate 372 (step A), but using methyl 1-(4-pyridinyl)-3-piperidinecarboxylate (CAS[1550628-47-1]) instead of ethyl 1-(3-pyridinyl)-3-piperidinecarboxylate.

[0861] Intermediate 382: (2-(1-(pyridine-4-yl)piperidine-3-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0862] [ka]

[0863] Intermediate 382 was prepared in the same way as intermediate 372, starting from intermediate 381 instead of intermediate 371.

[0864] Intermediate 384: (2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0865] [ka]

[0866] Step A: tert-butyl((2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. N-chlorosuccinimide (CAS[128-09-6], 73 mg, 0.55 mmol, 1.5 equivalents) was added at 0°C to a solution of intermediate 97 (170 mg, 0.36 mmol, 1 equivalent) in 1,1,1,3,3,3-hexafluoro-2-propanol (11 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ELISA (×3). The organic layer was separated, dried over MgSO4, filtered, and evaporated. The residue was purified by flash chromatography on silica gel (24 g, heptane / acetaldehyde 100 / 0~10 / 90) to obtain the title compound (107 mg, 46%) as a brown solid.

[0867] Step B: (2-(3-chloro-6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthiridine-7-yl)methaneamine. Hydrochloric acid (4M in 1,4-dioxane, 0.53 mL, 2.13 mmol, 10 equivalents) was added to a solution of tert-butyl((2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthiridine-7-yl)methyl)carbamate (107 mg, 0.21 mmol, 1 equivalent) in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 12 hours. Hydrochloric acid (4M in 1,4-dioxane, 0.027 mL, 1.07 mmol, 5 equivalents) was added, and stirring was continued for 24 hours. The reaction mixture was diluted with water and extracted with phenylethylamine. The aqueous layer was basicized to pH 10 with Na2CO3 (1M in water), and the product was extracted twice with phenylethylamine. The combined organic layers were dried over MgSO4, filtered, and evaporated to obtain intermediate 384 (73.2 mg, 85%) as an orange oily substance.

[0868] Intermediate 389: 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-fluoro-4-methylbenzamide.

[0869] [ka]

[0870] Step A: A solution of 2-fluoro-5-((2-hydroxyethyl)thio)-4-methylbenzoate methyl benzoate, 2-fluoro-5-iodo-4-methyl-methyl ester (CAS [1427195-21-8], 0.5 g, 1.7 mmol), 2-mercaptoethanol (CAS [60-24-2], 119 μL, 1.7 mmol, 1 equivalent), and DIPEA (891 μL, 5.101 mmol, 3 equivalents) in 1,4-dioxane (8.5 mL) was degassed by bubbling nitrogen. Xantphos (CAS[161265-03-8], 98 mg, 0.17 mmol, 0.1 equivalent) and Pd(dba)2 (CAS[32005-36-0], 49 mg, 0.085 mmol, 0.05 equivalent) were added at room temperature. The reaction mixture was stirred at 110°C for 16 hours. After cooling, the reaction mixture was diluted with water and extracted with RINKAN (x3). The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash chromatography column (12 g silica, RINKAN / heptane, 0 / 100~25 / 75) to obtain the title compound (380 mg, yield: 90%).

[0871] Step B: 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)-2-fluoro-4-methylbenzoate. Tert-butyldimethylsilyl chloride (CAS[18162-48-6], 457 mg, 3.029 mmol, 2 equivalents) was added all at once at room temperature to a stirred mixture of methyl 2-fluoro-5-((2-hydroxyethyl)thio)-4-methylbenzoate (370 mg, 1.515 mmol) and imidazole (237 mg, 3.484 mmol, 2.3 equivalents) in THF (0.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with Et2O (x3). The combined organic layer was dried in (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash chromatography column (12g silica, Â1 / heptane, 0 / 100~99 / 1) to obtain the title compound (503mg, yield: 93%) as a yellow solid.

[0872] Step C: 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2-fluoro-4-methylbenzoate. 3-chloroperbenzoic acid (CAS[937-14-4], 629 mg, 2.808 mmol, 2 equivalents) in DCM (6 mL) was added dropwise over 20 minutes to a solution of methyl 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)-2-fluoro-4-methylbenzoate (500 mg, 1.395 mmol) in DCM (8.5 mL) cooled to 0°C. After addition, the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated NaHCO3 aqueous solution (2 x 50 mL). The layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (12g silica column, Â1 / heptane, 0 / 100~99 / 1) to obtain the title compound (470 mg, yield: 82%).

[0873] Step D: 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2-fluoro-4-methylbenzoate lithium salt. Lithium iodide (434 mg, 3.245 mmol, 3.5 equivalents) was added to a solution of methyl 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2-fluoro-4-methylbenzoate (360 mg, 0.922 mmol) in ethyl phosphate (5 mL). The reaction mixture was stirred at 80°C for 72 hours. After cooling, the reaction mixture was concentrated under vacuum to obtain the title compound (347 mg, yield: 98%) as a dark brown solid, which was dried under vacuum and used without further purification.

[0874] Step E: 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-fluoro-4-methylbenzamide. Starting from intermediate 11 and 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2-fluoro-4-methylbenzoate lithium salt, the title compound was prepared according to Method C (in DMF).

[0875] Intermediate 396: (3α,4β,5α))-1-(6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-4-fluoropyridine-2-yl)-3,5-dimethylpiperidine-4-ol.

[0876] [ka]

[0877] Step A: (3R,4r,5S)-1-benzyl-3,5-dimethylpiperidine-4-ylbenzoate. Benzoyl chloride (0.9 mL, 7.6 mmol, 1.5 equivalents), Et3N (3.5 mL, 25 mmol, 5 equivalents), and 4-(dimethylamino)pyridine (CAS[1122-58-3], 110 mg, 0.9 mmol, 0.2 equivalents) were added to a solution of (3α,4β,5α)-3,5-dimethyl-1-(phenylmethyl)-4-piperidinol (CAS[374067-77-3], 1.11 g, 5.1 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (80 g silica, acetone / heptane 0 / 100~20 / 80) to obtain the title compound (1.706 g, yield: 99%) as a white solid.

[0878] Step B: (3R,4r,5S)-3,5-dimethylpiperidine-4-ylbenzoate. Palladium hydroxide (36 mg, 0.052 mmol, 0.04 equivalents) was added to a stirred solution of (3R,4r,5S)-1-benzyl-3,5-dimethylpiperidine-4-ylbenzoate (550 mg, 1.360 mmol) in MeOH (8 mL) under a nitrogen atmosphere. The mixture was purged using vacuum and nitrogen, followed by hydrogen, and stirred at room temperature for 24 hours. The reaction mixture was filtered through a short pad of Celite®, and the solvent was removed under vacuum to obtain the title compound as a white solid (383 mg, quantitative), which was used without further purification.

[0879] Step C: (3R,4r,5S)-1-(6-bromo-4-nitropyridine-2-yl)-3,5-dimethylpiperidine-4-ylbenzoate. Nitrogen was purged into a solution of 2,6-dibromo-4-nitropyridine (CAS[175422-04-5], 1.788 g, 6.344 mmol) in 1,4-dioxane (54 mL). Cesium carbonate (4.547 g, 13.956 mmol, 2.2 equivalents), (3R,4r,5S)-3,5-dimethylpiperidine-4-ylbenzoate (1.628 g, 6.978 mmol), DavePhos (CAS[213697-53-1], 250 mg, 0.636 mmol, 0.1 equivalent), and Pd2dba3 (CAS[51364-51-3], 289 mg, 0.316 mmol, 0.05 equivalents) were added to a stirred solution at room temperature while bubbling through the solution with nitrogen. The reaction mixture was stirred at 90°C for 3 hours. Water and siRNA were added to the reaction mixture, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (80 g, acetone / heptane gradient 0 / 100 to 40 / 60) to obtain the title compound (1.5 g, yield: 50%) as an orange solid.

[0880] Step D: (3R,4r,5S)-1-(6-bromo-4-fluoropyridine-2-yl)-3,5-dimethylpiperidine-4-ylbenzoate. Tetramethylammonium fluoride (CAS[373-68-2], 495 mg, 5.318 mmol, 1.5 equivalents) was added to a solution of (3R,4r,5S)-1-(6-bromo-4-nitropyridine-2-yl)-3,5-dimethylpiperidine-4-ylbenzoate (1.54 g, 3.541 mmol) in DMF (15 mL). The reaction mixture was stirred at 65 °C for 3 hours. After cooling, the reaction mixture was diluted with ELISA (75 mL) and water (20 mL). The organic layer was washed with brine (30 mL), dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (25 g, alkyl / heptane 0 / 100~30 / 70) to obtain the title compound (970 mg, yield: 67%) as a yellow solid.

[0881] Step E: (3S,4r,5R)-1-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)-4-fluoropyridine-2-yl)-3,5-dimethylpiperidine-4-ylbenzoate. Intermediate 94 (1.418 g, 3.462 mmol), (3R,4r,5S)-1-(6-bromo-4-fluoropyridine-2-yl)-3,5-dimethylpiperidine-4-ylbenzoate (1.410 mg, 3.462 mmol, 1 equivalent), and K2CO3 (0.718 mg, 5.193 mmol, 1.5 equivalents) were dissolved in 1,4-dioxane (25 mL) in a sealed tube under a nitrogen stream. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 86 mg, 0.348 mmol, 0.1 equivalent) and Pd(OAc)2 (40 mg, 0.175 mmol, 0.05 equivalent) were added, and the reaction mixture was stirred at 120°C for 14 hours. After cooling, the reaction mixture was diluted with 1 M Na2CO3 aqueous solution and extracted with ethyl acetate (x3). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (80 g silica, ethyl acetate / heptane 0 / 100~60 / 40) to obtain the title compound (806 mg, yield: 39%) as a yellow solid.

[0882] Step F: (3S,4r,5R)-1-(6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-4-fluoropyridine-2-yl)-3,5-dimethylpiperidine-4-yl benzoate. A solution of (3S,4r,5R)-1-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)-4-fluoropyridine-2-yl)-3,5-dimethylpiperidine-4-yl benzoate (806 mg, 1.376 mmol) in a mixture of aqueous NaOH solution (2 M, 10.3 mL, 20.643 mmol, 15 equivalents) and 1,4-dioxane (28 mL) was stirred at 72°C for 48 hours. ELISA and water were added, and the layers were separated. The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated under vacuum to obtain the title compound (630 mg, yield: 93%) as a solid, which was used without further purification.

[0883] Step G: (3α,4β,5α))-1-(6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-4-fluoropyridine-2-yl)-3,5-dimethylpiperidine-4-ol. (3S,4r,5R)-1-(6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-4-fluoropyridine-2-yl)-3,5-dimethylpiperidine-4-ylbenzoate (500 mg, 1.1 mmol) was dissolved in a solution of HCl in dioxane (4N, 3.9 mL, 15.6 mmol, 15 equivalents) and DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum. The solid was ground in ACN (20 mL) for 1 hour, filtered, and washed with ACN (3 × 1 mL) and Et2O (2 × 3 mL) to obtain intermediate 396 (HCl salt, 460 mg, quantitative) as a red solid, which was used without further purification.

[0884] Intermediate 399: tert-butyl 7-(4-fluoro-5-iodopyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

[0885] [ka]

[0886] Step A: tert-butyl 7-(4-nitropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. A suspension of 2-chloro-4-nitropyridine (CAS[23056-36-2], 1.0 g, 6.31 mmol), 4-Boc-4,7-diazaspiro[2.5]octane (CAS[674792-08-6], 2.0 g, 9.42 mmol, 1.5 equivalents), and cesium carbonate (3.1 g, 9.52 mmol, 1.5 equivalents) in 1,4-dioxane (18 mL) was degassed with nitrogen for 15 minutes. The vial was closed and the reaction mixture was stirred at 110°C for 16 hours. After cooling, the reaction mixture was diluted with saturated NaHCO3 aqueous solution and siRNA. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (80 g silica, siRNA / heptane 0 / 100~20 / 80) to obtain the title compound (1.36 g, yield: 62%) as an orange oily substance.

[0887] Step B: tert-butyl 7-(4-fluoropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. Tetramethylammonium fluoride (CAS[373-68-2], 570 mg, 6.12 mmol, 1.5 equivalents) was added to a solution of tert-butyl 7-(4-nitropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (1.36 g, 4.07 mmol) in dry DMF (20 mL) in a sealed tube. The reaction mixture was stirred at 65°C for 3 hours. To complete the reaction, tetramethylammonium fluoride (570 mg, 6.12 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred again at 65°C for 18 hours. Ether and water were added. The organic layer was separated, washed again with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (25 g, acetone / heptane 0 / 100~20 / 80) to obtain the title compound (840 mg, yield: 64%) as a yellow oil.

[0888] Step C: tert-butyl 7-(4-fluoro-5-iodopyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. In a sealed tube, N-iodosuccinimide (CAS[516-12-1], 511 mg, 2.27 mmol, 1 equivalent) was added at 0°C to a solution of tert-butyl 7-(4-fluoropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (690 mg, 2.24 mmol) in hexafluoroisopropanol (CAS[920-66-1], 22 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The organic layer was dried over (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (25 g silica, acetone / heptane 0 / 100~10 / 90) to obtain intermediate 399 (937 mg, yield: 95%) as a yellow oil.

[0889] Intermediate 401: 4-methyl-3-(methylsulfonyl)-N-((2-(piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide.

[0890] [ka]

[0891] Step A: tert-butyl 4-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)piperazine-1-carboxylate. BOP (CAS[56602-33-6], 2.576 g, 5.82 mmol, 1.1 equivalents) was added at room temperature to a suspension of intermediate 346 (1950 mg, 5.25 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (CAS[6674-22-2], 4 mL, 26.25 mmol, 5 equivalents) in ACN (52 mL). After 15 minutes, 1-Boc-piperazine (CAS[57260-71-6], 1.467 g, 7.88 mmol, 1.5 equivalents) was added. The reaction mixture was stirred overnight at room temperature, then stirred at 60°C for 2 days. The reaction mixture was concentrated to dryness, and the residue was purified by column chromatography (120 g silica, 9:1 siRNA:MeOH / heptane 0 / 100~100 / 0). The resulting product was dissolved in DCM, and this solution was washed with water (3×) and then brine. The organic layer was dried over Na₂SO₄ and concentrated to obtain the title compound as a solid (4.06 g, still impure, quantitative), which was used without further purification.

[0892] Step B: 4-methyl-3-(methylsulfonyl)-N-((2-(piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide. 4-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)piperazine-1-carboxylate tert-butyl (2833 mg, 5.25 mmol) was dissolved in DCM (26 mL), and TFA (8.03 mL, 104.99 mmol, 20 equivalents) was added. The reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under vacuum. The resulting oily substance was dissolved in DCM and MeOH, and crystallized in Et2O to obtain intermediate 401 (1882 mg, yield: 82%).

[0893] Intermediate 402: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(5-pivalamidopyridine-3-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide.

[0894] [ka]

[0895] In a microwave vial, N-(5-bromo-3-pyridinyl)-2,2-dimethylpropanamide (CAS[873302-39-7], 150 mg, 0.58 mmol), intermediate 401 (308 mg, 0.7 mmol, 1.2 equivalents), Cs2CO3 (380 mg, 1.17 mmol, 1.17 mmol), and rac-BINAP Pd G4 (CAS[1599466-90-6], 117 mg, 0.12 mmol, 0.2 equivalents) were dissolved in 1,4-dioxane (6 mL). The vial was sealed, evacuated, and refilled with argon (3×). The reaction mixture was stirred at 100°C for 2 days. The reaction mixture was filtered through Celite®, and the filter pad was rinsed with DCM, MeOH, and siRNA. The solvent in the filtrate was evaporated, and the residue was purified by reverse-phase column chromatography (C18 30×100 mm column, 20-50% ACN (0.1% TFA):: water (0.1% TFA)) to obtain intermediate 402 (101 mg, yield: 28%) as a yellow solid.

[0896] Intermediate 403: tert-butyl 7-(6-chloro-3-fluoropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

[0897] [ka]

[0898] DIPEA (2.08 mL, 12.05 mmol, 4 equivalents) was added at room temperature to a solution of 2,6-dichloro-3-fluoropyridine (CAS[52208-50-1], 500 mg, 3.012 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (CAS[674792-08-6], 671 mg, 3.163 mmol, 1.05 equivalents) in DMSO (5 mL). The reaction mixture was stirred at 120 °C for 18 hours. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate, the organic layer was washed with brine (3 ×), dried, filtered, and concentrated. The residue was purified by column chromatography (40 g silica, ethyl acetate / heptane 0 / 100~100 / 0) to obtain intermediate 403 (830 mg, yield: 81%) as an oil.

[0899] Intermediate 405: (2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0900] [ka]

[0901] Step A: A vial containing tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)-3-fluoropyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. Intermediate 403 (500 mg, 1.463 mmol, 1.5 equivalents), hexamethylditine (CAS[661-69-8], 479 mg, 1.448 mmol, 1.5 equivalents), and tetrakis(triphenylphosphine)palladium(0) (CAS[14221-01-3], 676 mg, 0.573 mmol, 0.6 equivalents) was evacuated three times and refilled with argon. 1,4-Dioxane (12.5 mL) was added, and argon was blown into the suspension for 10 minutes. The reaction mixture was then stirred at 110°C for 3 hours. Tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2) (286 mg, 0.975 mmol) and tetrakis(triphenylphosphine)palladium (0) (230 mg, 0.195 mmol, 0.2 equivalents) were added, and the reaction mixture was stirred at 110°C for 18 hours. The reaction mixture was directly purified by column chromatography (40 g silica, ethyl / heptane 0 / 100~100 / 0) to obtain the labeled compound (390 mg, yield: 71%).

[0902] Step B: (2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthiridine-7-yl)methaneamine. TFA (0.529 mL, 6.907 mmol, 10 equivalents) was added dropwise to a solution of tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthiridine-2-yl)-3-fluoropyridine-2-yl)-4,7-diazaspiro[2.5]octan-4-carboxylate (390 mg, 0.691 mmol) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated to obtain intermediate 405 (TFA salt), which was used without further purification.

[0903] Intermediate 408: 2,6-dibromo-3-methyl-4-nitropyridine.

[0904] [ka]

[0905] Step A: 2,6-Dibromo-3-methylpyridine 1-oxide. To a stirred solution of 2,6-dibromo-3-methylpyridine (CAS[887571-15-5], 11.5 g, 45.83 mmol) in TFA (115.0 mL, 1.548 mol), H2O2 (30 wt%, 23.4 mL, 229.08 mmol) was added dropwise at 0°C. The resulting solution was stirred at 80°C for 12 hours, and then diluted with ice / water. The mixture was extracted with DCM. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (120 g silica, DCM:MeOH 9:1 in DCM, 0%~20%) to obtain the title compound (10 g, yield: 60%) as a pale yellow solid.

[0906] Step B: 2,6-Dibromo-3-methyl-4-nitropyridine 1-oxide. 2,6-Dibromo-3-methylpyridine 1-oxide (10 g, 37.46 mmol) was gradually added to sulfuric acid (140 mL, 2.61 mol), and the mixture was stirred at 0°C. Nitric acid (30 mL, 463.19 mmol) was added dropwise while maintaining the temperature below 0°C, and the reaction mixture was stirred at 60°C for 4 hours. The reaction product was quenched with ice / water, and the mixture was extracted by DCM. The organic layer was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (80 g silica, siRNA / heptane 0 / 100~20 / 80) to obtain the title compound (2.2 g, yield: 18%) as a pale yellow solid.

[0907] Step C: 2,6-dibromo-3-methyl-4-nitropyridine. To a solution of 2,6-dibromo-3-methyl-4-nitropyridine 1-oxide (2.2 g, 6.91 mmol) in CHCl3 (60 mL), PBr3 (CAS[7789-60-8], 5.9 mL, 62.77 mmol) was added at room temperature. The reaction mixture was stirred at 65°C for 24 hours, and the reaction product was quenched with H2O at 0°C. The mixture was extracted by DCM. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (80 g silica gel, siRNA / hexane 1 / 5) to obtain intermediate 408 (2.02 g, yield: 91%) as a white solid.

[0908] Intermediate 410: (3S,4r,5R)-1-(6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-4-fluoro-5-methylpyridine-2-yl)-3,5-dimethylpiperidine-4-ol.

[0909] [ka]

[0910] Step A: tert-butyl((2-(4-fluoro-6-((3S,4r,5R)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. The title compound was prepared according to the reaction sequence for the synthesis of intermediate 396, steps C to F, using intermediate 408 instead of 2,6-dibromo-4-nitropyridine in step C.

[0911] Step B: (3S,4r,5R)-1-(6-(7-(aminomethyl)-1,6-naphthyridine-2-yl)-4-fluoro-5-methylpyridine-2-yl)-3,5-dimethylpiperidine-4-ol. Trifluoroacetic acid (CAS[76-05-1], 0.2 mL, 2.61 mmol) was added at 0°C to a stirred solution of tert-butyl((2-(4-fluoro-6-((3S,4r,5R)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate (65 mg, 0.13 mmol) in DCM (0.4 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, and saturated Na2CO3 aqueous solution was added to bring the pH to 8. DCM was added, and the aqueous phase was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain intermediate 410 (50 mg, 95% yield) as a yellow solid.

[0912] Intermediate 411: tert-butyl 7-(4-chloropyrimidine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid and intermediate 412: 7-(2-chloropyrimidine-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid.

[0913] [ka]

[0914] A solution of 2,4-dichloropyrimidine (450 mg, 3.0 mmol) and DIPEA (0.8 mL, 4.64 mmol) in DCM (5 mL) was treated with tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (CAS[674792-08-6], 670 mg, 3.17 mmol) at room temperature and stirred for 30 minutes. The mixture was then concentrated to dryness, redissolved in the minimum amount of DCM, and purified by silica chromatography (40 g SiO2, 0 / 100~100 / 0 siRNA / heptane) to obtain intermediate 411 (110 mg, yield: 12%) and intermediate 412 (760 mg, yield: 78%).

[0915] Intermediate 417: (2-(6-((cis)-2,6-dimethylmorpholino)-4,5-dimethylpyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0916] [ka]

[0917] Step A: (cis)-4-(3-bromo-4-methylpyridine-2-yl)-2,6-dimethylmorpholine. A solution of 3-bromo-2-chloro-4-methylpyridine (CAS[55404-31-4], 1.0 g, 4.84 mmol) in cis-2,6-dimethylmorpholine (CAS[6485-55-8], 4.4 mL, 37.45 mmol, 7.7 equivalents) was stirred in a sealed tube at 140°C for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (12 g SiO2; siRNA / heptane 0 / 100~50 / 50) to obtain the title compound (1.381 g, yield: 99%) as a brown solid.

[0918] Step B: (cis)-4-(3,4-dimethylpyridine-2-yl)-2,6-dimethylmorpholine. Trimethylboroxine (CAS[823-96-1], 74 μL, 0.526 mmol, 1.5 equivalents), Cs2CO3 (229 mg, 0.701 mmol, 2 equivalents), and Pd(dppf)Cl2·DCM (CAS[95464-05-4], 29 mg, 0.035 mmol, 0.1 equivalents) were added to a solution of (2R,6S)-4-(3-bromo-4-methylpyridine-2-yl)-2,6-dimethylmorpholine (100 mg, 0.351 mmol) in 1,4-dioxane (1.5 mL) in a sealed tube while bubbling nitrogen into the solution. The reaction mixture was stirred at 80°C for 5 hours. Depositphotos and saturated NaHCO3 aqueous solution were added, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (12 g, Depositphotos / heptane 0 / 100~10 / 90) to obtain the title compound (64 mg, yield: 77%).

[0919] Step C: (cis)-4-(5-iodo-3,4-dimethylpyridine-2-yl)-2,6-dimethylmorpholine. N-iodosuccinimide (CAS[516-12-1], 1250 mg, 5.556 mmol, 1.2 equivalents) was added at 0°C to a mixture of (cis)-4-(3,4-dimethylpyridine-2-yl)-2,6-dimethylmorpholine (1020 mg, 4.63 mmol) in hexafluoroisopropanol (CAS[920-66-1], 15 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography (12 g silica, acetone / heptane 0 / 100~10 / 90) to obtain the title compound (1.46 g, yield: 86%).

[0920] Step D: tert-butyl((2-(6-((cis)-2,6-dimethylmorpholino)-4,5-dimethylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate. Tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate (intermediate 2) (71 mg, 0.241 mmol) was added at room temperature to a stirred solution of (cis)-4-(5-iodo-3,4-dimethylpyridine-2-yl)-2,6-dimethylmorpholine (100 mg, 0.289 mmol) in DME (3 mL) that had been pre-degassed with nitrogen. Next, 2-norbornene (CAS[498-66-8], 45 mg, 0.481 mmol, 2 equivalents), K3PO4 (CAS[7778-53-2], 179 mg, 0.842 mmol, 3.5 equivalents), exo-norborneol (CAS[497-37-0], 54 mg, 0.481 mmol, 2 equivalents), (2-butenyl)chloropalladium dimer (CAS[12081-22-0], 5 mg, 0.013 mmol, 0.05 equivalents), and triphenylphosphine (CAS[603-35-0], 13 mg, 0.048 mmol, 0.2 equivalents) were added to the reaction mixture. The reaction mixture was stirred at 100°C for 16 hours. Then, it was cooled to room temperature. (2-butenyl)chloropalladium dimer (CAS[12081-22-0], 5 mg, 0.013 mmol, 0.05 equivalents) was added again, and the mixture was stirred at 100°C for 21 hours. After cooling, the mixture was washed with saturated NaHCO3 aqueous solution and extracted with siRNA. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (12 g SiO2, siRNA / heptane, 100 / 0~30 / 70), followed by reversed-phase column chromatography (Phenomenex Gemini C18 30×100 mm 5 μm; gradient from 32% [25 mM NH4HCO3]-68% [ACN:MeOH (1:1)] to 4% [25 mM NH4HCO3]-96% [ACN:MeOH (1:1)]) to obtain the title compound (41 mg, yield: 35%) as a pale yellow solid.

[0921] Step E: (2-(6-((cis)-2,6-dimethylmorpholino)-4,5-dimethylpyridine-2-yl)-1,6-naphthiridine-7-yl)methaneamine. Hydrochloric acid (4M in 1,4-dioxane, 0.63 mL, 2.513 mmol, 20 equivalents) was added to a stirred solution of tert-butyl((2-(6-((cis)-2,6-dimethylmorpholino)-4,5-dimethylpyridine-2-yl)-1,6-naphthiridine-7-yl)methyl)carbamate (60 mg, 0.126 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum to obtain the marked compound (55 mg, yield: 100%) as an orange solid, which was used without further purification.

[0922] Intermediate 419: tert-butyl 3-(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)-2-methylphenyl)-3-hydroxypiperidine-1-carboxylate.

[0923] [ka]

[0924] Step A: 3-(1-(tert-butoxycarbonyl)-3-hydroxypiperidine-3-yl)-4-methylbenzoic acid. Under a nitrogen atmosphere, 3-bromo-4-methylbenzoic acid (CAS[7697-26-9], 3.0 g, 13.951 mmol) was dissolved in dry THF (45 mL), and the reaction mixture was cooled to -78°C and stirred for 10 minutes. 2.5 M n-butyllithium hexane (CAS[109-72-8], 11.2 mL, 28 mmol, 2 equivalents) was added dropwise, and the reaction mixture was stirred at -78°C for 20 minutes. Then, a solution of 1-Boc-3-piperidone (CAS[98977-36-7], 5.6 g, 28.11 mmol, 2 equivalents) in dry THF (5 mL) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated NH4Cl aqueous solution, and KHSO4 (1M in water) was added dropwise within 10 minutes while vigorously stirring. The pH reached a value of 2-3. DCM and water were added, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (80 g silica, DCM:MeOH (9:1) 0 / 100~40 / 60 in DCM) to obtain the title compound (850 mg, yield: 18%) as a yellow solid.

[0925] Step B: tert-butyl 3-(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)-2-methylphenyl)-3-hydroxypiperidine-1-carboxylate. 3-(1-(tert-butoxycarbonyl)-3-hydroxypiperidine-3-yl)-4-methylbenzoic acid (385 mg, 1.15 mmol) and DIPEA (660 mL, 3.79 mmol) were added to a solution of intermediate 11 (400 mg, 0.95 mmol) in DMF (10 mL). After stirring for 1 minute, HATU (CAS[148893-10-1], 450 mg, 1.18 mmol, 1.25 equivalents) was added, and the reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM (3x). The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (25g SiO2, DCM:MeOH (9:1) 0 / 100~80 / 20 in DCM) to obtain intermediate 419 (360mg, yield: 55%) as a yellow solid.

[0926] Intermediate 424: tert-butyl(4-(2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-4-yl)butyl)carbamate.

[0927] [ka]

[0928] Step A: tert-butyl(4-(2-fluoropyridine-4-yl)buto-3-in-1-yl)carbamate. 4-bromo-2-fluoropyridine (CAS[128071-98-7], 300 μl, 2.92 mmol) and tert-butylbuta-3-in-1-ylcarbamate (CAS[149990-27-2], 900 mg, 5.32 mmol, 1.8 equivalents) in DMF (10 mL) were placed in a resealable reaction vial, and the mixture was degassed by bubbling nitrogen for 10 minutes. PdCl2(PPh3)2 (CAS[13965-03-2], 100 mg, 0.142 mmol, 0.05 equivalents), copper iodide (CAS[7681-65-4], 12 mg, 0.063 mmol, 0.2 equivalents), and triethylamine (CAS[121-44-8], 1.5 mL, 10.7 mmol, 3.7 equivalents) were added. The resulting mixture was stirred at 80°C for 16 hours. After cooling, water (50 mL) and HCl (30 mL) were added to the mixture. The organic layer was separated, and the aqueous layer was extracted again with HCl (25 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was purified by chromatography on silica gel (25 g SiO2, acetone / heptane 0 / 100~35 / 65) to obtain the title compound (850 mg, yield: 100%) as a clear oil.

[0929] Step B: tert-butyl(4-(2-fluoropyridine-4-yl)butyl)carbamate. tert-butyl(4-(2-fluoropyridine-4-yl)buta-3-in-1-yl)carbamate (850 mg, 3.21 mmol) was dissolved in MeOH (20 mL), and the mixture was cooled to 0°C under a nitrogen atmosphere. Pd / C (CAS[7440-05-3], 10%, 250 mg) was added, and the reaction flask was connected to a hydrogen-filled balloon. The reaction vessel was evacuated and placed under a hydrogen atmosphere (3 times). Finally, the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. The catalyst was filtered through a Celite® pad and further rinsed with MeOH (3 × 10 mL). The filtrate was concentrated under vacuum to obtain the title compound (828 mg, yield: 95%) as a clear oil.

[0930] Step C: tert-butyl(4-(2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-yl)butyl)carbamate. Under the protection of nitrogen gas, tert-butyl(4-(2-fluoropyridine-4-yl)butyl)carbamate (300 mg, 1.12 mmol), bis(pinacorato)diboron (CAS[73183-34-3], 350 mg, 1.38 mmol, 1.2 eq), [Ir(COD)OMe]2 (CAS[12148-71-9], 12 mg, 18 μmol, 0.016 eq), and dtbpy (CAS[72914-19-3], 9 mg, 33 μmol, 0.03 eq) were dissolved in dry THF (4 mL). The reaction vessel was closed, and the reaction mixture was stirred at 80°C for 5 hours. After cooling, the solvent was evaporated under vacuum to obtain the title compound (700 mg, crude oil, used without further purification).

[0931] Step D: tert-butyl(4-(2-fluoro-6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-4-yl)butyl) carbamate. Intermediate 45 (190 mg, 0.487 mmol) and tert-butyl(4-(2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-yl)butyl) carbamate (700 mg, crude, 1.118 mmol) were dissolved in 1,4-dioxane (5 mL), and the solution was degassed by bubbling nitrogen. Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 38 mg, 0.047 mmol, 0.1 equivalent), potassium carbonate (250 mg, 1.81 mmol, 3.7 equivalents), and copper chloride (CAS[7758-89-6], 50 mg, 0.505 mmol, 1 equivalent) were added. The reaction mixture was then stirred at 90°C for 1 hour. To complete the reaction, water (2 mL) was added along with the newly added Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 38 mg, 0.047 mmol, 0.01 equivalent). The reaction mixture was stirred at 90°C for 45 minutes. After cooling, the mixture was diluted with water (10 mL) and extracted with siRNA (2 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel (25 g, MeOH / DCM 0 / 100~5 / 95) to obtain the title compound (204 mg, yield: 67%) as a sticky solid.

[0932] Step E: tert-butyl(4-(2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyrizin-2-yl)pyridin-4-yl)butyl)carbamate. A solution of tert-butyl(4-(2-fluoro-6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyrizin-2-yl)pyridin-4-yl)butyl)carbamate (200 mg, 0.322 mmol) and cis-2,6-dimethylmorpholine (CAS[6485-55-8], 500 mg, 4.34 mmol, 13.5 equivalents) in DMSO (1 mL) was stirred at 120 °C for 48 hours. After cooling, the mixture was diluted with ELISA (20 mL). Water (80 mL) and saturated NaHCO3 aqueous solution (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted again with ELISA (20 mL). The combined organic layers were washed with brine (10 mL), dried on MgSO4, filtered, and concentrated under vacuum. The crude residue was purified by chromatography on silica gel (25 g, MeOH / DCM 0 / 100~10 / 90) to obtain intermediate 424 (209 mg, yield: 80%) as a yellow solid.

[0933] Intermediate 426: 3-(methylsulfonyl)-5-(trifluoromethoxy)benzoic acid.

[0934] [ka]

[0935] Step A: Methyl 3-(methylsulfonyl)-5-(trifluoromethoxy)benzoate. Copper(I) iodide (CAS [7681-65-4], 211 mg, 1.104 mmol, 1.1 equivalents) was added at room temperature to a solution of methyl 3-bromo-5-(trifluoromethoxy)benzoate (CAS [1306763-53-0], 300 mg, 1.003 mmol) and sodium methanesulfinate (CAS [20277-69-4], 410 mg, 4.013 mmol, 4 equivalents) in DMSO (4 mL). The mixture was stirred at 100 °C for 18 hours. A second addition of sodium methanesulfinate (205 mg, 2.006 mmol, 2 equivalents) and copper(I) iodide (106 mg, 0.552 mmol, 0.55 equivalents) was performed. The reaction mixture was stirred at 100°C for 18 hours. After cooling, the reaction mixture was diluted with dimethyl alcohol and washed with water and NH3 aqueous solution (1 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The crude product wa...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, 【Chemistry 1】 During the ceremony, R １ However, the phenyl is optionally substituted, selected from the following: (a) 2-chlorophenyl, 2-methyl-5-(1H-tetrazole-1-yl)phenyl, 5-(tert-butyl)-2-methoxyphenyl, 3-fluoro-2-(1H-1,2,3-triazole-1-yl)phenyl, 2-fluoro-5-(1-hydroxyethyl)-4-methylphenyl, 【Chemistry 2】 And, During the ceremony, R ａ is selected independently from H, halo, C １～４ alkyl, OH, cyclopropyl, CN, and CH ２ CO ２ C １－４ alkyl substituted with one or two selected independently from each of the above, C １－４ alkyl, C １－４ haloalkyl, C substituted with one or two OH groups １－４ haloalkyl, CN, OC １－４ alkyl, OC １－４ haloalkyl, (P=O)(CH ３ ) ２ and, CO ２ C １－４ alkyl, NH(SO ２ -C ２－３ alkenyl), and NH(C=O)C ２－３ alkynyl, and is selected from, R ｂ However, Cl, F, Br, C １－４ Alkyl, OC １－４ Selected from alkyl, cyclopropyl, and 4-methyl-1H-imidazole-1-yl, R ｃ However, Cl, Br, I, C １－４ Alkyl, C １－４ Haloalkyl, OC １－４ Alkyl, O-CH ２ CH ２ OH,C(OH)(CH ３ ) ２ (C=O)CF ３ , CN, C(CH ３ ) ２ CN, N(CH ３ ) (CH ２ CH ２ OH), N (SO ２ CH ３ ) (CH ２ CH ２ OH), CH(OH)(CH ３ ), CH(OH)(OCH ３ ) and Halo, OH, CH ３ ,CH ２ CH ２ OH, OC １－４ Alkyl and CO ２ C １－４ A heterocycloalkyl group optionally substituted with one or two alkyl groups independently selected from each alkyl group, and selected from: R ｄ However, Cl or CH ３ And, R ｅ However, C substituted with one or two OH groups １－４ Selected from alkyl and 1H-tetrazole, R ｆ However, I, B (OH) ２ ,CH ２ NH ２ ,CH ２ N(CH ２ CH ３ ) ２ , and 【Transformation 3】 Selected from, (b) 【Chemistry 4】 And, R ｇ However, one OH group is optionally substituted for C １－４ It is alkyl, R ｈ However, C １－４ Alkyl, or C １－４ It is a haloalkyl, R ｊ However, the following: OH, CN, OC １－４ Alkyl, CN, NH ２ , N(C １－４ Alkyl) ２ , O-tetrahydropyranyl, C(OH)(CH ３ ) ２ Piperidine substituted with, and NH(CO ２ C ｌ－４ Alkyl) and NH(C １－４ Alkyl) and N(C) １－４ Alkyl) ２ And, NH(CH ２ CH ２ OH), tetrahydropyranyl, and C １－４ Haloalkyl and C ２－４ C is independently substituted with one, two, or three atoms selected from alkenyls, azetidines optionally substituted with OH groups, and (cis)-2,6-dimethylmorpholinyl. １－４ Selected from alkyl groups, Each R ｋ But, hello, C １－４ Alkyl, OC １－４ Alkyl, NH ２ , OC １－４ Haloalkyl, CN, CH ２ OH, C ３－６ Cycloalkyl, and C ２－４ Selected independently from Alkenil, R ｍ is C １－４ haloalkyl, CH ２ CH ２ OH, and CH ２ CN, selected from n is 0, 1, 2, or 3, X is O, NH, or N-CH ３ And, R ３ is one selected from H, OH, NH ２ , N(CH ３ ), ２ , NH(C=O)CH ３ , and morpholine, and is optionally substituted C １－４ alkyl, and is selected from, and R ５ However, the group consisting of the following i), ii), iii), iv), v), and vi): i) C ５－７ Cycloalkyl or C ５－７ A five-membered or six-membered heteroaryl obtained by optional condensation with a heterocycloalkyl group, the following: (cis)-2,6-dimethyl-4-(5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)morpholine, 7-((cis)-2,6-dimethylmorpholino)-2,3-dihydrofl[2,3-c]pyridine, 4-((cis)-2,6-dimethylmorpholino)-1,3-dihydrofl[3,4-c]pyridine, (cis)-2,6-dimethyl-4-(5,6,7 ,8-tetrahydroisoquinoline-1-yl)morpholine, 3-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-6-yl, (cis)-2,6-dimethyl-4-(pyrimidine-4-yl)morpholine, (cis)-2,6-dimethyl-4-(1H-pyrazole-3-yl)morpholine, (1H-pyrazole-1-yl), 【Transformation 5】 Selected from, In the formula, R ｎ However, the following: 【Transformation 6】 Selected from the group consisting of, R ｐ However, the following group is selected from (a), (b), (c), (d), and (e): (a) An 8- to 10-membered nitrogen-bonded spirocyclic heterocycloalkyl ring system, wherein each ring optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, and S, and includes OH, C １－４ Alkyl, C １－４ Haloalkyl, oxo, CO ２ C １－４ Alkyl, NH ２ , N(H)(C １－４ Alkyl), N (C １－４ Alkyl) ２ , N(H)(CO ２ C １－４ Alkyl), and OC １－４ An 8-10 member nitrogen-bonded spirocyclic heterocycloalkyl ring system, optionally substituted with one, two, or three alkyl groups independently selected from each alkyl group. (b) 【Transformation 7】 (c) CH ３ NH ２ , and NH(CO ２ C １－４ A nitrogen-bonded azetidine that is optionally substituted with one or two alkyl groups, each independently selected from the group, Hello, C １－４ Alkyl, CH ２ OH, CH ２ OCH ３ , C １－４ Haloalkyl, OH, NH ２ , oxo, NH(CO ２ C １－４ Alkyl), morpholinyl, and CH ２ - Nitrogen-bonded pyrrolidines, each independently selected from morpholinyl, are optionally substituted with one, two, three, or four atoms, and deuterium, halo, C １－４ Alkyl, CH ２ OH, CH ２ CH ２ OH, OH, NH ２ NH(C １－４ Alkyl), and OC １－４ A nitrogen-bonded piperidine that is optionally substituted with one, two, three, or four atoms independently selected from the alkyl group, Hello, C １－４ Alkyl, CH ２ OH, CH ２ CH ２ OH, CH ２ OCH ３ ,CH ２ CH ２ OCH ３ ,CH ２ CN, (C=O)NH ２ ,CH ２ (C=O)NH ２ CO ２ C １－４ Alkyl, CH ２ SO ２ CH ３ , C １－４ Haloalkyl, OH, oxo, C ３－６ Cycloalkyl, and CH ２ -C ３－６ A nitrogen-bonded piperazine, optionally substituted with one, two, three, or four atoms independently selected from cycloalkyl groups, and C １－４ Alkyl, C １－４ Haloalkyl, CO ２ OH, oxo, (CH ２ ) ４－６ -NH ２ , (CH ２ ) ４－６ -NH(C=O)CH ３ , and (CH ２ ) ４－６ -NH(CO) ２ C １－４ Nitrogen-bonded morpholine, which is optionally substituted with one, two, three, or four atoms independently selected from alkyl groups, One or two C １－４ A nitrogen-bonded diazepane that is optionally substituted with an alkyl group, One or two C １－４ A nitrogen-bonded oxazepane optionally substituted with an alkyl group, and a nitrogen-bonded thiomorpholine 1,1-dioxide, and (d) A 5-membered to 10-membered condensed or crosslinked ring, wherein each ring optionally contains 1, 2, or 3 heteroatoms independently selected from N, S, or O, and a halo, C １－４ Alkyl, OH, NH ２ NH(C １－４ Alkyl), N (C １－４ Alkyl) ２ NH(CO ２ C １－４ Alkyl), CO ２ C １－４ A 5-membered to 10-membered condensed or crosslinked ring, optionally substituted with one, two, or three atoms independently selected from alkyl and oxo, (e) 【Transformation 8】 Each R ｑ However, H, Haro, C １－４ Alkyl, C １－４ Haloalkyl, CN, CO ２ C １－４ Alkyl, CO ２ H, (C=O)NH ２ ,CH ２ OH, CH(OH)(CH ３ ), 【Chemistry 9】 Selected independently from, R ｓ However, it is H or halo, and R ｔ However, C １－４ Alkyl, oxetan-3-yl, and (CO ２ Selected from carbon-bonded azetidines optionally substituted with -tBu), tetrahydropyran, 1,3-oxazinan-2-one, 2,2,6,6-tetramethylpiperidine-4-yl, and 2,2,6,6-tetramethyltetrahydro-2H-pyran, ii) 【Chemistry 10】 And, R ｕ However, it is H, pyridine-3-yl, or pyridine-4-yl, R ｖ However, it is (cis)-2,6-dimethylmorpholinyl, pyridine-3-yl, or pyridine-4-yl, R ｗ However, H, F, or OCH ３ And, iii) 【Chemistry 11】 And, R ｘ However, it is pyridine-3-yl or pyridine-4-yl, R ｙ but, 【Chemistry 12】 Selected from pyridine-3-yl and pyridine-4-yl, R ｚ but, 【Chemistry 13】 iv) 【Chemistry 14】 v) 【Chemistry 15】 vi) C １－４ Haloalkyl or -CH ２ -R ａａ Selected from, here, R ａａ However, CH(CH ３ ) ２ ,CH ２ CH ２ OCH ３ Cyclopentyl 【Chemistry 16】 Phenyl, 【Chemistry 17】 A compound, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, selected from the above.

2. (i) R １ but, [Chemistry 18] is, or (ii) R １ but, 【Chemistry 19】 【Chemistry 20】 is, or (iii) R １ but, 【Chemistry 21】 The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof.

3. (i) R １ but, 【Chemistry 22】 is, or (ii) R １ but, 【Chemistry 23】 【Chemistry 24】 is, or (iii) R １ but, 【Chemistry 25】 is, or (iv)R １ but, 【Chemistry 26】 The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof.

4. R ３ but, H、CH ３ 、 【Chemistry 27】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof.

5. (i) R ５ but, 【Chemistry 28】 is, or (ii) R ５ but, 【Chemistry 29】 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof.

6. R ５ but, 【Transformation 30】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof.

7. (i) R ５ but, 【Chemistry 31】 is, or (ii) R ５ but, 【Chemistry 32】 is, or (iii) R ５ but, 【Transformation 33】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof.

8. R ５ but, 【Transformation 34】 and (i) R ｐ but, 【Chemistry 35】 is, or (ii) R ｐ but, 【Transformation 36】 is, or (iii) R ｐ but, 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 is, or (iv)R ｐ but, 【Chemistry 40】 is, or (v) R ｐ but, 【Chemistry 41】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof.

9. R ｑ が、H、Cl、F、I、CH ３ 、CN、CH ２ OH、CH(OH)(CH ３ )、CO ２ H、(C=O)NH ２ 、CHF ２ 、CF ３ 、CO ２ CH ３ 、 【Chemistry 42】 The compound according to claim 8, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof.

10. (i) R ５ but, 【Chemistry 43】 is, or (ii) R ５ but, 【Chemistry 44】 is, or (iii) R ５ but, 【Chemistry 45】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof.

11. N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((trifluoromethyl)sulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-fluoro-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-fluoro-4-methyl-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1-hydroxyethyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide, 3-Cyano-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-(1,1-difluoroethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)(methyl)amino)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(N-(2-hydroxyethyl)methylsulfonamide)-4-methylbenzamide 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((3-methoxypropyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-1-hydroxyethyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-1-hydroxyethyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-((tetrahydro-2H-pyran-4-yl)sulfonyl)benzamide, 4-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 3-(1,1-difluoroethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-fluorobenzamide, 3-(1,1-difluoroethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-ethoxybenzamide, 3-(cyclopropyl(hydroxy)methyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(isopropylsulfonyl)-4,5-dimethylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(N,N-dimethylsulfamoyl)-4,5-dimethylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(N-(2-hydroxyethyl)-N-methylsulfamoyl)-4,5-dimethylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-iodo-4,5-dimethylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(2-hydroxyethoxy)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethyl-5-(morpholinosulfonyl)benzamide, Methyl 2-(3-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)phenyl)acetate, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(2,2,2-trifluoroacetyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-ethoxyethyl)sulfonyl)-4,5-dimethylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-fluoro-5-(1-hydroxyethyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-fluoro-5-(( ＊ R)-1-hydroxyethyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-fluoro-5-(( ＊ S)-1-hydroxyethyl)-4-methylbenzamide, 4-Cyclopropyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1-hydroxyethyl)benzamide, 4-Cyclopropyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-1-hydroxyethyl)benzamide, 4-Cyclopropyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-1-hydroxyethyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-methoxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-iodo-4-methylbenzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(2-hydroxypropan-2-yl)benzamide, N-((2-(6-(4-(2-hydroxyethyl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2,2-dioxide-2-thia-6-azaspiro[3,3]heptan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(1,4-oxazepan-4-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2-oxa-6-azaspiro[3,3]heptan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(1-oxa-7-azaspiro[3.5]nonan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((1R,5S,8r)-8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((1R,5S,8s)-8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(4-hydroxy-4-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(1,1-dioxidethiomorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(4-(2-hydroxyethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(1,1-dioxide-1-thia-6-azaspiro[3,3]heptan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(1-oxa-6-azaspiro[3,3]heptan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-(trifluoromethyl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(6-oxa-1-azaspiro[3,3]heptan-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(2,2,6,6-tetramethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.1]heptan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(5-oxa-8-azaspiro[3.5]nonan-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-morpholinopyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(2,2-dimethyl-1,4-oxazepan-4-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(7,7-dimethyl-1,4-oxazepan-4-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-((cis)-2,6-dimethylmorpholino)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-ethyl-3-(methylsulfonyl)benzamide, N-((2-(6-(4-hydroxy-3-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((3 ＊ R,4 ＊ S)-4-hydroxy-3-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((3 ＊ S, 4 ＊ R)-4-hydroxy-3-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-Cyclopropyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethyl-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-iodopyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-(trifluoromethyl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((3-hydroxypropyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-methoxyethyl)sulfonyl)benzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-5-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1-hydroxyethyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(hydroxymethyl)-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-Cyclopropyl-3-(methylsulfonyl)-N-((2-(6-(2,2,6,6-tetramethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-cyclopropyl-3-(methylsulfonyl)benzamide, N-((2-(7-((cis)-2,6-dimethylmorpholino)-2,3-dihydrofluoro[2,3-c]pyridine-5-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzamide, N-((2-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethyl-5-(methylsulfonyl)benzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(1-hydroxyethyl)benzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ R)-1-hydroxyethyl)benzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ S)-1-hydroxyethyl)benzamide, N-((2-(6-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-cyclopropyl-3-(methylsulfonyl)benzamide, 4-Cyclopropyl-N-((2-(6-((1R,5S)-7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(2-hydroxypropan-2-yl)-4-methylbenzamide, N-((2-(6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethyl-5-(methylsulfonyl)benzamide, 4-Cyclopropyl-N-((2-(6-((3 ＊ S, 4 ＊ R)-4-hydroxy-3-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-Cyclopropyl-N-((2-(6-((3 ＊ R,4 ＊ S)-4-hydroxy-3-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-((3 ＊ S, 4 ＊ R)-4-hydroxy-3-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2,3-dimethyl-5-(methylsulfonyl)benzamide, N-((2-(6-((3 ＊ R,4 ＊ S)-4-hydroxy-3-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2,3-dimethyl-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide, N-((2-(1-((cis)-2,6-dimethylmorpholino)-5,6,7,8-tetrahydroisoquinoline-3-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-((cis)-2,6-dimethylmorpholino)-1,3-dihydrofluoro[3,4-c]pyridine-6-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 2-Fluoro-4-methyl-5-(methylsulfonyl)-N-((2-(6-(2,2,6,6-tetramethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-cyclopropyl-3-(methylsulfonyl)benzamide, 2-Fluoro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide, 3-Chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1-hydroxyethyl)benzamide, Methyl 3-(((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)benzoate, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, 3-(( ＊ S)-Cyclopropyl(hydroxy)methyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(( ＊ R)-Cyclopropyl(hydroxy)methyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide, 4-Chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-1-hydroxyethyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-1-hydroxyethyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4,5-dimethylbenzamide, (5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)-2,3-dimethylphenyl)boric acid, 3-Chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, 3-Chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, tert-butyl(1R,5S)-9-(6-(7-((3,4-dimethyl-5-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((methylsulfonyl)methyl)benzamide, N-((2-(3,5-dichloro-6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(3-cyano-6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-Cyclopropyl-3-(N,N-dimethylsulfamoyl)-N-((2-(6-(2,2,6,6-tetramethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-1-methoxyethyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-1-methoxyethyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1-methoxyethyl)-4-methylbenzamide, N-((2-(6-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethyl-5-(methylsulfonyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-methoxy-4-(4-methyl-1H-imidazole-1-yl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-methyl-5-(1H-tetrazole-1-yl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-methyl-5-(1H-tetrazole-1-yl)benzamide, 3-Fluoro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-(1H-1,2,3-triazole-1-yl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-methoxy-2-methyl-4-(methylsulfonyl)benzamide, 3-Cyano-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-methoxybenzamide, 3-Chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 2-Chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-isopropylbenzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(2-hydroxyethyl)benzamide, 3-Chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, 3-(difluoromethyl)-4-fluoro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3,4-Dichloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 5-(tert-butyl)-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-methoxybenzamide, 4-bromo-3-cyano-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-bromo-4-chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-iodo-4-(trifluoromethyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethoxybenzamide, N-((2-(6-((3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-1-hydroxyethyl)-4-methylbenzamide, N-((2-(6-((3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-1-hydroxyethyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoro-4-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-3,4-dimethylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((3α,4β,5α)-4-methoxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(3-hydroxyazetidine-3-yl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(4-hydroxypiperidine-4-yl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-1-hydroxyethyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-1-hydroxyethyl)benzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ R)-1-hydroxyethyl)benzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ S)-1-hydroxyethyl)benzamide, 4-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(3-hydroxyazetidine-3-yl)benzamide, N-((2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(5-chloro-6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-(2-cyanopropan-2-yl)-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-(( ＊ R)-1-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)ethyl)-4-methyl-3-(methylsulfonyl)benzamide, N-(( ＊ S)-1-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)ethyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-((diethylamino)methyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4,5-dimethylbenzamide, tert-butyl(4-((2 ＊ S, 6 ＊ R)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)morpholin-2-yl)butyl)carbamate, tert-butyl(4-((2 ＊ R, 6 ＊ S)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)morpholin-2-yl)butyl)carbamate, Methyl 2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl) isonicotinate, N-((2-(6-((2 ＊ S, 6 ＊ R)-2-(4-aminobutyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2 ＊ R, 6 ＊ S)-2-(4-aminobutyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)isonicotinic acid, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-(hydroxymethyl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(3-hydroxypyrrolidine-1-yl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((( ＊ R)-2-hydroxypropyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((( ＊ S)-2-hydroxypropyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((2 ＊ S, 6 ＊ R)-2-(4-acetamidobutyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2 ＊ R, 6 ＊ S)-2-(4-acetamidobutyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-(aminomethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4,5-dimethylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(( ＊ S)-morpholine-2-yl)benzamide, N-((2-(6-((cis)-3,5-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-3-hydroxypiperidine-3-yl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-(1-hydroxyethyl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)isonicotinamide, (R)-N-((2-(6-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, (S)-N-((2-(6-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-5-(methylsulfonyl)-2-vinylbenzamide, 3-Chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(2-hydroxyethyl)-3-(methylsulfonyl)benzamide, N-((2-(4-cyano-6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(3-((cis)-2,6-dimethylmorpholino)-2-fluorophenyl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(3-((cis)-2,6-dimethylmorpholino)-2,4-difluorophenyl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-morpholinobenzuamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(tetrahydrofuran-2-yl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3,4-dimethyl-5-((4-methylpiperazine-1-yl)methyl)benzamide, N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyrazine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-1-hydroxyethyl)-4-methylbenzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-1-hydroxyethyl)-4-methylbenzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-3-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(4-fluoro-3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(2-fluoro-3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(7-(pyridine-4-yl)-2,3-dihydrobenzofuran-5-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(2-methoxy-5-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(3-fluoro-5-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((3S,4s,5R)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(5,6-dihydro-2H-pyran-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(1'-(cyclopropanecarbonyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridine-4-yl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(3-((cis)-2,6-dimethylmorpholino)-6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-3-yl)pyrrolidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridine-4-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridine-3-yl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridine-3-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(9-oxa-2-azaspiro[5.5]undecane-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-4-yl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(3-(4-(2-hydroxypropan-2-yl)phenyl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-4-yl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(1'-(4-fluorobutanoyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridine-3-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(1-(pyridine-3-yl)piperidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ S)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-3-yl)pyrrolidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-3-yl)pyrrolidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-4-yl)pyrrolidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ S)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-4-yl)pyrrolidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(tetrahydro-2H-pyran-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ R)-4-methyl-3-(methylsulfonyl)-N-((2-(2-(pyridine-4-yl)morpholino)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ S)-4-methyl-3-(methylsulfonyl)-N-((2-(2-(pyridine-4-yl)morpholino)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(1-hydroxyethyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-nicotinoylpiperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(4-acetylpiperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(2-oxopiperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridazin-3-yl)piperazin-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(4-Isonicotinoylpiperazine-1-yl)-1,6-Naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-(6-methoxypyridine-3-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-(6-oxo-1,6-dihydropyridine-3-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyrazine-2-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-3-yl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(4-(6-aminopyridine-3-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-3-yl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ S)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridine-3-yl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(4-(2-hydroxy-2-methylpropanoyl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(4-(1-methyl-1H-pyrazole-4-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, ( ＊ R)-4-methyl-3-(methylsulfonyl)-N-((2-(1-(pyridine-3-yl)piperidine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ S)-4-methyl-3-(methylsulfonyl)-N-((2-(1-(pyridine-3-yl)piperidine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(3-((cis)-2,6-dimethylmorpholine-4-carbonyl)cyclohexa-1-en-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, Ethyl 1-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)piperidine-3-carboxylate, ( ＊ R)-N-((2-(3-(4-(2-hydroxypropan-2-yl)phenyl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(3-(4-(2-hydroxypropan-2-yl)phenyl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(1H-pyrazole-1-yl)-1,6-naphthyrizine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(3-((cis)-2,6-dimethylmorpholino)-1H-pyrazole-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(4-methyl-3-(pyridine-4-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 1-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)piperidine-3-carboxylic acid, N-((2-(6-(((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2-hydroxyethoxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-4-methyl-3-(methylsulfonyl)-N-((2-(1-(pyridine-4-yl)piperidine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(3,3-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide, (R)-N-((2-(6-(2-(methoxymethyl)pyrroridine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-(difluoromethyl)-6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(3-(6-aminopyridine-3-yl)piperidine-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridine-4-yl)azepan-1-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-fluoro-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, (S)-N-((2-(6-(2-(methoxymethyl)pyrroridine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-5-methylbenzamide, tert-butyl7-(4-fluoro-6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate, N-((2-(4-((cis)-2,6-dimethylmorpholino)pyrimidine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(5,8-diazaspiro[2,6]nonan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(4-hydroxy-3,3-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(tetrahydrofuran-2-yl)benzamide, N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(2-hydroxypropan-2-yl)-4-methylbenzamide, 3-Chloro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide, N-((2-(4-(5-aminopyridine-3-yl)piperazine-1-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, 4-methyl-N-((2-(6-(6-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-(6-ethyl-4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3-(hydroxymethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, (R)-N-((2-(6-(2-(hydroxymethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3-isopropylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, (R)-4-methyl-N-((2-(6-(2-methylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-(2-ethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3-(methoxymethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2R,5S)-5-ethyl-2-methylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, Methyl 4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)piperazine-2-carboxylate, N-((2-(6-((2S,5R)-5-ethyl-2-methylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, (S)-4-methyl-N-((2-(6-(2-methylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)piperazine-2-carboxamide, N-((2-(6-((cis)-2,6-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2S,5R)-2,5-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, (S)-N-((2-(6-(3-(cyanomethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, (S)-N-((2-(6-(3-(hydroxymethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, (R)-N-((2-(6-(3-(hydroxymethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4,5-dimethylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(5-Fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 4-Chloro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(5-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-(3-(2,2-difluoroethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3-(difluoromethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(1,4-diazepan-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2,5-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((4aR,7aS)-hexahydrofloxacin[3,4-b]pyrazine-1(2H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3-cyclopropyl-3-methylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2-cyclopropylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, (S)-4-methyl-N-((2-(6-(3-methylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-(2-(methoxymethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2-(2,2-difluoroethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(2-(cyclopropylmethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(5,8-diazaspiro[3.5]nonan-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((2R,3R)-3-methyl-2-(trifluoromethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-(2-(2-methoxyethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-(3-(2-(methylamino)-2-oxoethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-((4aS,7aR)-octahydro-1H-cyclopenta[b]pyrazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(2,5,5-trimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, (R)-4-methyl-N-((2-(6-(3-methylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-(2-isopropylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3,3-dimethyl-1,4-diazepan-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2,3-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2S,3R)-2,3-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((4aR,7aS)-6,6-dioxidehexahydrothieno[3,4-b]pyrazine-1(2H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(3-((methylsulfonyl)methyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, Ethyl 3-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)cyclobutan-1-carboxylate, 3-Chloro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, N-((2-(6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(5,8-diazaspiro[3.6]decane-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-3-hydroxypiperidine-3-yl)-4-methylbenzamide, 3-(N,N-dimethylsulfamoyl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(pyrroridine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, tert-butyl 3-((7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)methyl)pyrrolidine-1-carboxylate, 4-methyl-3-(methylsulfonyl)-N-((2-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-((tetrahydro-2H-pyran-4-yl)methyl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-((1-(pyrimidine-2-yl)piperidine-4-yl)methyl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(cyclopentylmethyl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(2-(methylsulfonyl)benzyl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(3-methoxypropyl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(3-methylbenzyl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(3,3,3-trifluoropropyl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methoxy-3-(methylsulfonyl)benzamide, N-((2-(4-(4-acetamidobutyl)-6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-(4-aminobutyl)-6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-((3α,4β,5α))-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)-5-(trifluoromethoxy)benzamide, N-((2-(3-chloro-4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-(difluoromethoxy)-N-((2-(4-fluoro-6-((3S,4r,5R)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(tetrahydrofuran-2-yl)benzamide, ( ＊ S)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(tetrahydrofuran-2-yl)benzamide, N-((2-(6-(3-hydroxy-3-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((3-hydroxyazetidine-1-yl)sulfonyl)-4-methylbenzamide, 3-Chloro-N-((2-(4-Fluoro-6-((3a,4b,5a))-4-Hydroxy-3,5-Dimethylpiperidine-1-yl)-3-Methylpyridine-2-yl)-1,6-Naphthyridine-7-yl)methyl)-5-(Methylsulfonyl)benzamide, N-((2-(6-(7-amino-5-azaspiro[2,4]heptan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, tert-butyl(3-methyl-1-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)azetidine-3-yl)carbamate, tert-butyl2-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)-9-oxa-2,6-diazaspiro[4.5]decane-6-carboxylate, N-((2-(6-(9-oxa-2,6-diazaspiro[4.5]decane-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methoxy-3-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(4-Fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide, 3-Fluoro-N-((2-(4-Fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(4-Fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(4-fluoro-3-methyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(2-cyanopropane-2-yl)-4-fluorobenzamide, N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-chloro-3-(2-cyanopropan-2-yl)benzamide, 4-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-(3-methyl-5-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(5-oxo-4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Fluoro-N-((2-(4-Fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide, ( ＊ R)-N-((2-(6-(3-hydroxy-3-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(3-hydroxy-3-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(4-Fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-chloro-3-methyl-5-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(3-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ R)-N-((2-(6-(9-oxa-2,6-diazaspiro[4.5]decane-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(9-oxa-2,6-diazaspiro[4.5]decane-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, tert-butyl((1R)-3-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)carbamate, 4-methyl-N-((2-(6-(3-methyl-3-morpholinopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((3 ＊ R,4 ＊ R)-3-methyl-4-morpholinopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((3 ＊ S, 4 ＊ S)-3-methyl-4-morpholinopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(6-(7-amino-5-azaspiro[2.4]heptan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(7-amino-5-azaspiro[2,4]heptan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-Chloro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-methyl-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-methyl-5-(methylsulfonyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-methyl-5-(methylsulfonyl)benzamide, N-((2-(6-(3-amino-3-(trifluoromethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((3 ＊ S, 4 ＊ R)-3-methyl-4-morpholinopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((3 ＊ R,4 ＊ S)-3-methyl-4-morpholinopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, tert-butyl 2-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)-8-oxa-2,5-diazaspiro[3.5]nonane-5-carboxylate, N-((2-(6-(3-amino-3-methylazetidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3-cyclopropylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2-cyclobutylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2-(difluoromethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, (S)-N-((2-(6-(3-isopropylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(3-(2,2,2-trifluoroethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-N-((2-(6-(3-methyl-4-morpholinopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, tert-butyl2-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate, N-((2-(6-(6-oxa-2,9-diazaspiro[4.5]decane-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(1-((cis)-2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((1R)-1-(methylamino)-3-azabicyclo[3.1.0]hexane-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(8-amino-5-azaspiro[2.5]octan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, tert-butyl 2-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)-5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate, N-((2-(6-(8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(4-amino-3,3-difluoropiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, tert-butyl(5-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)-5-azaspiro[2.5]octan-8-yl)carbamate, N-((2-(6-(8-(dimethylamino)-5-azaspiro[2.5]octan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(6-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3,4-dimethyl-N-((2-(6-((1R,5S)-7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-(2-methyl-3-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-(2-methyl-5-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-(3-ethyl-3-hydroxypyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2,5,8-triazaspiro[3.5]nonan-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-chloro-3-(methylsulfonyl)benzamide, N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide, N-((2-(6-(1-oxa-6-azaspiro[3,4]octan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(4-hydroxy-3,3-dimethylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(6-oxa-2,9-diazaspiro[4.5]decane-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(6-(6-oxa-2,9-diazaspiro[4.5]decane-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(6-(4-amino-3,3-difluoropiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(4-amino-3,3-difluoropiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(6,9-dioxa-2-azaspiro[4.5]decane-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(1-oxa-6-azaspiro[3.4]octan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(6-(1-oxa-6-azaspiro[3.4]octan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-(dimethylphosphoryl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(6-(3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(3,3-difluoro-4-hydroxypyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(6-(4-hydroxy-3,3-dimethylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(4-hydroxy-3,3-dimethylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(2-(1-fluorocyclopropyl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-(1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)-5-hydroxypentyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-((tetrahydrofuran-2-yl)methoxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((2,6-dimethylpiperidine-4-yl)oxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((4,4-difluoropyrroridine-3-yl)oxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((1-hydroxypropane-2-yl)oxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide and N-((2-(6-(2-hydroxypropoxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2-hydroxypropoxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(2-hydroxy-2-methylpropoxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-((2,2,2-trifluoroethyl)amino)ethoxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((4-azaspiro[2.5]octan-7-yl)oxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((1-(methylamino)cyclopropyl)methoxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-((3,3-difluoropiperidine-4-yl)oxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-((2-(trifluoromethyl)piperidine-4-yl)oxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((3R,4s,5S)-4-(hydroxymethyl)-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(4-(2-hydroxyethyl)-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(1-oxa-7-azaspiro[4,4]nonan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, tert-butyl(3-(((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamoyl)-5-(methylsulfonyl)benzyl)carbamate, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide, ( ＊ R)-N-((2-(6-(3,3-difluoro-4-hydroxypyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(3,3-difluoro-4-hydroxypyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2 ＊ R,4 ＊ S)-4-hydroxy-1-methylpyrrolidine-2-yl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2 ＊ S, 4 ＊ R)-4-hydroxy-1-methylpyrrolidine-2-yl)-4-methylbenzamide, 3-((3,3-difluoropropyl)sulfonyl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, ( ＊ R)-N-((2-(6-(8-amino-5-azaspiro[2.5]octan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(8-amino-5-azaspiro[2.5]octan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-(aminomethyl)-N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-(( ＊ R)-4,4-difluoropyrrolinidine-2-yl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide 4-methyl-3-(methylsulfonyl)-N-((2-(6-(1-oxo-2,7-diazaspiro[4.4]nonan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(5-oxo-2,6-diazaspiro[3.4]octan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(5-oxo-1,6-diazaspiro[3.4]octan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-methyl-N-((2-(4-methyl-1-(4-azaspiro[2.5]octan-7-yl)-1H-pyrazole-3-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, tert-butyl(4,4-difluoro-1-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)pyrrolidine-3-yl)carbamate, 3-(( ＊ S)-4,4-difluoropyrrolinidine-2-yl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, 3-Chloro-5-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Chloro-5-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(6-(8-hydroxy-5-azaspiro[2.5]octan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(6-((cis)-3-hydroxy-3,4-dimethylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, N-((2-(6-(4-amino-3,3-difluoropyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, tert-butyl(6-((2 ＊ R, 6 ＊ S)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)morpholin-2-yl)hexyl)carbamate, tert-butyl(6-((2 ＊ S, 6 ＊ R)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)morpholin-2-yl)hexyl)carbamate, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-( ＊ R-methylsulfonimidoyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-( ＊ S-methylsulfonimidoyl)benzamide, number N-((2-(6-(2-(2-hydroxyethoxy)ethoxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2 ＊ R, 6 ＊ S)-2-(6-aminohexyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2 ＊ S, 6 ＊ R)-2-(6-aminohexyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-(( ＊ R)-1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)-3-hydroxypropyl)-4-methyl-3-(methylsulfonyl)benzamide, N-(( ＊ S)-1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)-3-hydroxypropyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(1-hydroxy-3-azabicyclo[3.1.0]hexane-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2 ＊ R, 6 ＊ S)-2-(5-aminopentyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2 ＊ S, 6 ＊ R)-2-(5-aminopentyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, tet-butyl(5-((2 ＊ R, 6 ＊ S)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)morpholin-2-yl)pentyl)carbamate, tet-butyl(5-((2 ＊ S, 6 ＊ R)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)morpholin-2-yl)pentyl)carbamate, 3-(dimethylphosphoryl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((2 ＊ R, 6 ＊ S)-2-(5-acetamidopentyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2 ＊ S, 6 ＊ R)-2-(5-acetamidopentyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((1R)-1-amino-3-azabicyclo[3.1.0]hexane-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(6-(trans)-3-hydroxy-4-methyl-3-(trifluoromethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(6-(3-methoxy-3-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(6-(7-methoxy-5-azaspiro[2.4]heptan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-Cyano-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, N-((2-(6-(3,3-difluoro-4-(methylamino)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2 ＊ R, 6 ＊ S)-2-(6-acetamidehexyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2 ＊ S, 6 ＊ R)-2-(6-acetamidehexyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-3-hydroxycyclobutoxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((trans)-3-hydroxycyclobutoxy)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(6-(6,9-dioxa-2-azaspiro[4.5]decane-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(6,9-dioxa-2-azaspiro[4.5]decane-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfinyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-(morpholinomethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, N-(( ＊ R)-5-amino-1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide, N-(( ＊ S)-5-amino-1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide, N-(( ＊ R)-5-acetamido-1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide, N-(( ＊ S)-5-acetamide-1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-((6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)amino)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide,- 3-Fluoro-N-((2-(6-((2S,4S)-4-hydroxy-2-(hydroxymethyl)-4-(trifluoromethyl)pyrroridine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, N-((2-(6-(6-oxa-2-azaspiro[3,4]octan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide, N-((2-(6-(5,8-dioxa-2-azaspiro[3.5]nonan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide, N-((2-(6-((3 ＊ S, 4 ＊ r, 5 ＊ S)-4-(2-hydroxyethyl)-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((3 ＊ S, 4 ＊ s, 5 ＊ R)-4-(2-hydroxyethyl)-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((3 ＊ S, 4 ＊ r, 5 ＊ R)-4-(2-hydroxyethyl)-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(6-(4-amino-3,3-difluoropyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(4-amino-3,3-difluoropyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((3 ＊ R, ＊ s, 5 ＊ R)-4-(2-hydroxyethyl)-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-4-fluoro-3-(methylsulfonyl)benzamide, ( ＊ R)-3-fluoro-N-((2-(6-(8-hydroxy-5-azaspiro[2.5]octan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, ( ＊ S)-3-fluoro-N-((2-(6-(8-hydroxy-5-azaspiro[2.5]octan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, N-((2-(6-((1R)-1-(dimethylamino)-3-azabicyclo[3.1.0]hexane-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(6-(3,3-difluoro-4-(methylamino)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(3,3-difluoro-4-(methylamino)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ R)-4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-(morpholinomethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ S)-4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-(morpholinomethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((2-chloroethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, N-((2-(6-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)-N-((2-(6-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(6-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-((2-(dimethylamino)ethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, N-((2-(6-(((3α,4β,5α))-4-hydroxy-3,5-dimethylpiperidine-1-yl)methyl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(((cis)-2,6-dimethylmorpholino)methyl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-phenyl-1,6-naphthyridine-7-yl)methyl)benzamide, tert-butyl 5-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-carboxylate, ( ＊ R)-4-methyl-N-((2-(6-(8-(methylamino)-5-azaspiro[2.5]octan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, ( ＊ S)-4-methyl-N-((2-(6-(8-(methylamino)-5-azaspiro[2.5]octan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, (R)-3-fluoro-N-((2-(6-(2-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(6-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, N-((2-(6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(6-((2s,4r)-2-hydroxy-6-azaspiro[3.4]octan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(6-((2r,4s)-2-hydroxy-6-azaspiro[3.4]octan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, N-((2-(6-((1 ＊ R, 5 ＊ S)-1-hydroxy-3-azabicyclo[3.1.0]hexane-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((1 ＊ S, 5 ＊ R)-1-hydroxy-3-azabicyclo[3.1.0]hexane-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-fluoro-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(vinylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(vinylsulfonyl)benzamide, N-(( ＊ R)-3-(dimethylamino)-1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)propyl)-4-methyl-3-(methylsulfonyl)benzamide, N-(( ＊ S)-3-(dimethylamino)-1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)propyl)-4-methyl-3-(methylsulfonyl)benzamide, N-(( ＊ R)-1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)-3-morpholinopropyl)-4-methyl-3-(methylsulfonyl)benzamide, N-(( ＊ S)-1-(2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)-3-morpholinopropyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-4-(difluoromethyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((2 ＊ R, 6 ＊ R)-2-methyl-6-(trifluoromethyl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((2 ＊ R, 6 ＊ S)-2-methyl-6-(trifluoromethyl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((2 ＊ S, 6 ＊ R)-2-methyl-6-(trifluoromethyl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((2-(6-((2 ＊ S, 6 ＊ S)-2-methyl-6-(trifluoromethyl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide, ( ＊ R)-N-((2-(6-(1-oxa-7-azaspiro[4.4]nonan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, ( ＊ S)-N-((2-(6-(1-oxa-7-azaspiro[4.4]nonan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-morpholinopyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, 3-Fluoro-N-((2-(6-((3α,4β,5α))-4-(hydroxymethyl)-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)morpholine-2-carboxylic acid, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-fluoro-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, 3-((2-hydroxyethyl)sulfonyl)-4-methyl-N-((2-phenyl-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Fluoro-5-(methylsulfonyl)-N-((2-phenyl-1,6-naphthyridine-7-yl)methyl)benzamide, 4-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(S-methylsulfonimidoyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(prop-1-in-1-ylsulfonamide)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1,4-dioxan-2-yl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl-4-d)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((3α,4α,5α))-4-hydroxy-3,5-dimethylpiperidine-1-yl-4-d)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(morpholino-d8)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(vinylsulfonamide)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(vinylsulfonyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(( ＊ R)-methylsulfinyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(( ＊ S)-methylsulfinyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-(2-hydroxyethyl)sulfinyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-(2-hydroxyethyl)sulfinyl)-4-methylbenzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((3α,4β,5α))-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(6,6-dimethyl-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-1,4-dioxan-2-yl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-1,4-dioxan-2-yl)-4-methylbenzamide, N-((2-(4-fluoro-6-(morpholino-d8)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-(4-amino-3,3-difluoropiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfinyl)-4-(trifluoromethyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(2-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(2-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(2-(6-oxa-2,9-diazaspiro[4.5]decane-2-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((2-(6-(5-oxo-4,6-diazaspiro[2.4]heptan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-phenyl-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-fluoro-3-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(N,S-dimethylsulfonimidoyl)-4-methylbenzamide, N-((2-(6-(2,6-dimethylmorpholino-2,3,3,5,5,6-d6)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((4,7-diazaspiro[2.5]octan-7-yl)methyl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2S,5S)-2,5-dimethyl-3-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((2R,5R)-2,5-dimethyl-3-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-methoxypyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-isopropoxypyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-methyl-5-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(2-(3,4,4-trimethyl-2-oxoimidazolidine-1-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(3,3-dimethyl-5-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(2-(4-amino-3,3-difluoropiperidine-1-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(2-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(2,6-dimethylmorpholino-2,3,3,5,5,6-d6)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-(methyl-d3)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-(methyl-d3)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(5-fluoro-6-methoxypyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(6,8-dioxo-2,5,7-triazaspiro[3,4]octan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(3-amino-3-methyl-2-oxopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(5,5-dimethyl-2-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-(5,8-diazaspiro[3.5]nonan-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-oxo-5,8-diazaspiro[3.5]nonanane-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1,1,2,2-tetrafluoroethoxy)benzamide, N-((2-(6-(2,6-dimethylmorpholino-2,3,3,5,5,6-d6)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl-2,2-d2)sulfonyl)-4-(methyl-d3)benzamide, ( ＊ R)-3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-methyl-5-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ S)-3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-methyl-5-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-((2,2-difluoroethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-(((difluoromethyl)sulfonyl)methyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((fluoromethyl)sulfonyl)benzamide, 3-(difluoromethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(3-amino-4,4-dimethyl-2-oxopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-3-(N-methylsulfamoyl)benzamide, N-((2-(2-(4-amino-3,3-difluoropiperidine-1-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, tert-butyl 3-((5-(7-((3-((difluoromethyl)sulfonyl)benzamide)methyl)-1,6-naphthyridine-2-yl)pyridine-2-yl)oxy)azetidine-1-carboxylate, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl-2,2-d2)sulfonyl)-4-methylbenzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-3,5-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 4-amino-N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(2-((cis)-2,6-dimethylmorpholino)-6-oxo-1,6-dihydropyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ S)-3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-(trifluoromethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ R)-3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-(trifluoromethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-fluorobenzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((2,2,6,6-tetramethylpiperidine-4-yl)oxy)pyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-3,5-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((3R,5S)-3,5-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-((methylsulfonyl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((methylsulfonyl)methyl)benzamide, 3-Chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ R)-N-((2-(6-(3,3-difluoro-4-hydroxypiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide, ( ＊ S)-N-((2-(6-(3,3-difluoro-4-hydroxypiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide, ( ＊ S)-4-methyl-N-((2-(6-(3-methyl-3-morpholinopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, ( ＊ R)-4-methyl-N-((2-(6-(3-methyl-3-morpholinopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(methylsulfonyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((2-oxo-1,3-oxadinan-5-yl)oxy)pyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(oxetan-3-yloxy)pyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Chloro-N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 4-((cyanomethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-((2,2,2-trifluoroethyl)sulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-(azetidine-3-yloxy)-5-fluoropyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide, 3-(2,2-difluoroethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((1R,5S,6r)-6-hydroxy-3-azabicyclo[3.1.1]heptan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(2-(4,4-dimethyl-2-oxoimidazolidine-1-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2,2,2-trifluoroethyl)sulfonyl)benzamide, 3-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((S)-3-methyl-5-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((S)-3-methyl-5-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(3-(dimethylamino)-2-oxopyridine-1(2H)-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(difluoromethoxy)-5-((difluoromethyl)sulfonyl)-N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, ( ＊ S)-N-((2-(2-(4-amino-3,3-difluoropiperidine-1-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide, ( ＊ R)-N-((2-(2-(4-amino-3,3-difluoropiperidine-1-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide, 3-(( ＊ R)-Azetidine-1-Sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, 3-(( ＊ S)-Azetidine-1-Sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, 3-((cyanomethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(3-(2-hydroxyethyl)oxetane-3-yl)-4-methylbenzamide, 3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Fluoro-N-((2-(6-(2-hydroxy-2-methyl-7-azaspiro[3.5]nonan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-hydroxy-6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(2-hydroxy-2-methyl-7-azaspiro[3.5]nonan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(2-(2-hydroxy-2-methyl-7-azaspiro[3.5]nonane-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(2-(6-hydroxy-6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(3-(difluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)-1,6-naphthyridine-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide, 3-(difluoromethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)benzamide, ( ＊ S)-4-methyl-3-(methylsulfonyl)-N-((2-(1-(pyridine-4-yl)piperidine-3-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-iodopyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(3-(difluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)-1,6-naphthyridine-7-yl)methyl)-3-(S-(difluoromethyl)sulfonimidoyl)benzamide, 3-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-(6-(difluoromethyl)-6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide, 3-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Chloro-5-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Chloro-5-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, and 3-((difluoromethyl)sulfonyl)-N-((2-(6-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide A compound according to claim 1, selected from the group consisting of the above, and pharmaceutically acceptable salts, stereoisomers, and isotopic variants thereof.

12. N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide, N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide, N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(2-hydroxyethyl)-3-(methylsulfonyl)benzamide, N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-5-methylbenzamide, N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 3-Fluoro-N-((2-(4-Fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide, 3-Chloro-5-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Chloro-5-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((2R,6S)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ S)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(( ＊ R)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, 3-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-methylbenzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-fluorobenzamide, 3-Chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, 3-Chloro-5-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide, and 3-Chloro-5-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide A compound according to claim 1, selected from the group consisting of the above, and pharmaceutically acceptable salts, isotopic variants, and stereoisomers thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 12 and at least one pharmaceutically acceptable excipient.

14. A compound according to any one of claims 1 to 12 for use in therapeutic purposes.

15. A compound according to any one of claims 1 to 12, for use in the treatment of SMARCA4-deficient cancer.

16. The compound for use according to claim 15, wherein the SMARCA4-deficient cancer is SMARCA4-deficient non-small cell lung cancer (NSCLC).

17. A compound according to any one of claims 1 to 12, for use in the treatment of a pathological condition or state mediated by the SMARCA2 protein.

18. The compound for use according to claim 17, wherein the pathological condition or state mediated by the SMARCA2 protein is cancer or non-small cell lung cancer (NSCLC).

19. Use of a compound according to any one of claims 1 to 12 for manufacturing a pharmacopoeia for the treatment of cancer or NSCLC.

20. An in vitro method for modulating SMARCA2 activity, comprising contacting the SMARCA2 protein, or a portion thereof, with a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

21. A method for the treatment of SMARCA4-deficient cancer, comprising administering a compound according to any one of claims 1 to 12 to a subject in need thereof.

22. The method according to claim 21, wherein the SMARCA4-deficient cancer is a SMARCA4-deficient NSCLC.

23. A method for treating a pathological condition or state mediated by the SMARCA2 protein, comprising administering the compound according to any one of claims 1 to 12 to a subject in need thereof.

24. The method according to claim 23, wherein the disease or condition is selected from cancer or NSCLC.

25. The method according to any one of claims 21 to 24, wherein the subject is a mammal.

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