1,6-naphthridine compounds as smarca2 inhibitors useful for the treatment of smarca4 deficient cancers

Abstract

The invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds as inhibitors of the SMARCA2 protein and to their use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC).

Description

1 ,6-NAPHTHRIDINE COMPOUNDS AS SMARCA2 INHIBITORS USEFULFOR THE TREATMENT OF SMARCA4 DEFICIENT CANCERSFIELD OF THE INVENTION

[0001] The invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds as inhibitors of the SMARCA2 protein and to their use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC).BACKGROUND OF THE INVENTION

[0002] The Switch / Sucrose Non-Fermentable (SWI / SNF), also known as BAF complex, is a multi-subunit complex that modulates chromatic structure through the activity of two mutually exclusive helicase / ATPase catalytic subunits: SWI / SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2, BRAHMA or BRM) and SWI / SNF-Related, Matrix- Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 4 (SMARCA4 or BRG1). The core and the regulatory subunits couple ATP hydrolysis to the perturbation of histone-DNA contacts, thereby providing access points to transcription factors and cognate DNA elements that facilitate gene activation and repression.

[0003] Mutations in the genes encoding the twenty canonical SWI / SNF subunits are observed in nearly 20% of all cancers with the highest frequency of mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical and endometrial), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and renal clear cell carcinoma. Despite having a high degree of homology, and their presumed overlapping functions, SMARCA2 and SMARCA4 have been reported as having different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is infrequent in tumor development. In fact, numerous types of cancer have been shown to be SMARCA4-related (e.g., cancers having a SMARCA4-mutation or a SMARCA4-deficiency, such as lack of expression), including, e.g., lung cancer (such as non- small cell lung cancer or NSCLC).

[0004] SMARCA2 has been demonstrated as one of the top essential genes in SMARCA4- related or -mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells depend exclusively on SMARCA2 activity - i.e., there is a greater incorporation ofSMARCA2 into the complex to compensate for the SMARCA4 deficiency. Thus, SMARCA2 may be targeted in SMARCA4-related / deficient cancers. The co-occurrence of the deficiency of the expression of two (or more) genes that leads to cell death is known as synthetic lethality. Accordingly, synthetic lethality can be leveraged in the treatment of certain SMARCA2 / SMARCA4-related cancers.

[0005] There is an ongoing need for effective treatment for diseases that are treatable by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, non-specific effects, and the inability to selectively target and modulate SMARCA2 remains an obstacle to the development of effective treatments. As such, small-molecule therapeutic agents that target SMARCA2 would be very useful.

[0006] An objective of the present invention is to provide compounds that are selective on SMARCA2 over SMARCA 4.

[0007] An objective of the present invention is to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient cancers.

[0008] An objective of the present invention is to provide compounds SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient NSCLC.SUMMARY OF THE INVENTION

[0009] Embodiments of the present invention relate to certain uses and methods of use of 1,6- naphthyridine chemical entities having SMARCA2 modulating properties, and pharmaceutical compositions comprising these chemical entities, to the use of said chemical entities as inhibitors of the SMARCA2 protein, and to methods of treatment or use in the treatment of SMARCA4 deficient cancers, as described in the claims.

[0010] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

[0011] Embodiments of this invention are uses and methods of treatment using compounds of Formula (I),WhereinR1is an optionally substituted phenyl selected from:(a) 2-chlorophenyl, 2-methyl-5-(lH-tetrazol-l-yl)phenyl, 5-(tert-butyl)-2- methoxyphenyl, 3-fluoro-2-(lH-l,2,3-triazol-l-yl)phenyl, 2-fluoro-5-(l- hydroxyethyl)-4-methylphenyl,whereinRais selected from: H; halo; C1-4alkyl; C1-4alkyl substituted with one or two members each independently selected from OH, cyclopropyl, CN, and CH2CO2C1-4alkyl; C1-4haloalkyl; C1-4haloalkyl substituted with one or two OH members; CN; OC1-4alkyl; OC1-4haloalkyl; (P=O)(CH3)2; CO2C1-4alkyl; NH(SO2-C2-3alkenyl), and NH(C=O)C2-3alkynyl;Rbis selected from: Cl, F, Br, C1-4alkyl, OC1-4alkyl, cyclopropyl, and 4-methyl-lH- imidazol-l-yl;Rcis selected from: Cl, Br, I, C1-4alkyl, C1-4haloalkyl, OC1-4alkyl, 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), heterocycloalkyl optionally substituted with one or two members each independently selected from halo, OH, CH3, CH2CH2OH, OC1-4alkyl, and CO2C1-4alkyl;Rdis Cl or CH3;Reis selected from: C1-4alkyl substituted with one or two OH members, and IH-tetrazole;whereinRgis C1-4alkyl optionally substituted with one OH member;Rhis C1-4alkyl, or C1-4haloalkyl;R1is selected from: C1-4alkyl optionally independently substituted with one, two or three members selected from: OH, CN, OC1-4alkyl, CN, NH2, N(C1-4alkyl)2, O-tetrahydropyranyl, piperidine substituted with C(OH)(CH3)2, and NH(CO2C1-4alkyl); NH(C1-4alkyl); N(C1-4alkyl)2; NH(CH2CH2OH); tetrahydropyranyl; C1-4haloalkyl; C2-4alkenyl; azetidine optionally substituted with OH; and (cis)-2,6-dimethylmorpholinyl; each Rkis independently selected from: halo, C1-4akyl, OC1-4alkyl, NH2, OC1-4haloalkyl, CN, CH2OH, C3-6cyclalkyl, and C2-4alkenyl;Rmis selected from: C1-4haloalkyl, CH2CH2OH, and CH2CN; n is 0, 1, 2, or 3;X is O, NH, or N-CH3;R3is selected from: H, and C1-4alkyl optionally substituted with one member selected from: OH, NH2, N(CH3)2, NH(C=O)CH3, and morpholine; andR5is selected from the group consisting of: i) a 5- or 6-membered heteroaryl, optionally fused with a C5-7cycloalkyl or Cs-vheterocycloalkyl, selected from:(cis)-2,6-dimethyl-4-(5,6,7,8-tetrahydro-2,6-naphthyridin-l-yl)morpholine; 7- ((cis)-2,6-dimethylmorpholino)-2,3-dihydrofuro[2,3-c]pyridine; 4-((cis)-2,6- dimethylmorpholino)-l,3-dihydrofuro[3,4-c]pyridine; (cis)-2,6-dimethyl-4- (5,6,7,8-tetrahydroisoquinolin-l-yl)morpholine; 3-((2,2,6,6-tetramethyltetrahydro- 2H-pyran-4-yl)oxy)pyridazin-6-yl; (cis)-2,6-dimethyl-4-(pyrimidin-4- yl)morpholine; (cis)-2,6-dimethyl-4-(lH-pyrazol-3-yl)morpholine; (IH-pyrazol-l- yi);wherein Rnis selected from the group consisting of:Rpis selected from the group consisting of:(a) an eight to ten membered nitrogen linked spirocyclic heterocycloalkyl ring system, wherein each ring optionally contains one, two or three heteroatoms each independently selected from N, O, and S, optionally substituted with one, two or three members each independently selected from: OH, C1-4alkyl, Ci- 4haloalkyl, oxo, CO2C1-4alkyl, NH2, N(H)(C1-4alkyl), N(C1-4alkyl)2, N(H)(CO2C1-4alkyl), and OC1-4alkyl;(c) Nitrogen linked azetidine optionally substituted with a one or two members each independently selected from: CH3, NH2, and NH(CO2C1-4alkyl);Nitrogen linked pyrrolidine optionally substituted with one, two, three or four members each independently selected from: halo, C1-4alkyl, CH2OH, CH2OCH3, C1-4haloalkyl, OH, NH2, oxo, NH(CO2C1-4alkyl), morpholinyl, and CH2- morpholinyl; Nitrogen linked piperidine optionally substituted with one, two, three or four members each independently selected from: deuterium, halo, Ci- 4alkyl, CH2OH, CH2CH2OH, OH, NH2, NH(C1-4alkyl), and OC1-4alkyl;Nitrogen linked piperazine optionally substituted with one, two, three or four members each independently selected from: halo, C1-4alkyl, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, CH2CN, (C=0)NH2, CH2(C=O)NH2, CO2C1-4alkyl, CH2SO2CH3, C1-4haloalkyl, OH, oxo, Cs-ecycloalkyl, and CH2-C3- ecycloalkyl; Nitrogen linked morpholine optionally substituted with one, two, three or four members each independently selected from: Cwalkyl, Ci-4haloalkyl, CO2OH, oxo, (CH2)4-6-NH2, (CH2)4-6-NH(C=O)CH3, and (CH2)4-6- NH(CO2CI-4 alkyl);Nitrogen linked diazepane optionally substituted with one or two C1-4alkyl members;Nitrogen linked oxazepane optionally substituted with one or two C1-4alkyl members; and Nitrogen linked thiomorpholine 1,1-dioxide;(d) 5-10 membered fused or bridged ring, wherein each ring optionally contains one, two or three heteroatoms each independently selected from N, S, or O, optionally substituted with one, two or three members each independently selected from: halo, C1-4alkyl, OH, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NH(CO2C1-4alkyl), CO2C1-4alkyl, and oxo; andwherein each Rqis independently selected from: H, halo, Cwalkyl, Cwhaloalkyl, CN,Rsis H or halo;Rlis selected from: C1-4alkyl; oxetan-3-yl; carbon linked azetidine optionally substituted with (CO2-tBu); tetrahydropyran; l,3-oxazinan-2-one; 2, 2,6,6- tetramethylpiperidin-4-yl; and 2,2,6,6-tetramethyltetrahydro-2H-pyran;whereinRuis H, pyridin-3-yl, or pyridin-4-yl;Rvis (cis)-2,6-dimethylmorpholinyl, pyridin-3-yl, or pyridin-4-yl; and Rwis H, F, or OCH3;whereinRxis pyridin-3-yl, or pyridin-4-yl;Ryis selected from:, pyridin-3-yl, and pyridin-4-yl; andRzis selected from:vi) a C1-4haloalkyl; or -CH2-Raa, wherein Raais selected from: CH(CH3)2, CH2CH2OCH3,and pharmaceutically acceptable salts, isotopes, and stereoisomers thereof.In one embodiment of the present invention, the compound is not 3-chloro-5- ((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)- 1 ,6-naphthyridin-7-yl)methyl)benzamide, or 3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6- ((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide.INCORPORATION BY REFERENCE

[0012] All publications, patents, patent applications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, patent application, or published nucleotide and amino acid sequence, was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. Where reference is made to a URL or other such identifier or address, it is understood that suchidentifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0014] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0015] In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise.

[0016] When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. As used herein, “about X” (where X is a numerical value) preferably refers to ±10% of the recited value, inclusive. For example, the phrase “about 8” refers to a value of 7.2 to 8.8, inclusive; as another example, the phrase “about 8%” refers to a value of 7.2% to 8.8%, inclusive. Where present, all ranges are inclusive and combinable. For example, when a range of “1 to 5” is recited, the recited range should be construed as including ranges “1 to 4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3 & 5”, and the like. In addition, when a list of alternatives is positively provided, such a listing can also include embodiments where any of the alternatives may be excluded. For example, when a range of “1 to 5” is described, such a description can support situations whereby any of 1, 2, 3, 4, or 5 are excluded; thus, a recitation of “1 to 5” may support “1 and 3-5, but not 2”, or simply “wherein 2 is not included.”

[0017] Some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions and acceptable error margins, for such given value.

[0018] As used herein, the expression “one or more” refers to at least one, for example one, two, three, four, five or more, whenever possible and depending on the context.

[0019] Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0020] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0021] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4thEd.” Vols. A (2000) and B (2001), Plenum Press, New York.

[0022] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0023] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0024] Hereinbefore and hereinafter, the term “compound of Formula (I)” is meant to include the addition salts, and the stereoisomers thereof.

[0025] As used herein, “Cx-y” (where x and y are integers) refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents). Thus, a Ci-ealkyl group contains from 1 to 6 carbon atoms, a Cs-ecycloalkyl group contains from 3 to 6 carbon atoms, and so on.

[0026] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.

[0027] The “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also coversthe occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “Ci-ealkyl” or similar designations.

[0028] By way of example, the term “C1-4alkyl”, or “Ci-ealkyl” as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 1 to 4 or 1 to 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, and the like.

[0029] The term “haloalkyl” refers to an alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with one or more halogens. The term “haloalkyl” includes “C1-4haloalkyl”, “Ci-ehaloalkyl”, monohaloC1-4alkyl, monohaloCi-ealkyl, polyhaloC1-4alkyl, and polyhaloCi-ealkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the C1-4haloalkyl or Ci-ehaloalkyl may have one, two, three or more halogens. Examples of “haloalkyl” groups include trifluoromethyl (CFs), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

[0030] The term “alkenyl” refers to a type of alkyl group 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 an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2 and - C(CH3)=CHCH3. The alkenyl moiety may be branched or a straight chain. Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e. , an alkenylene group). Examples of “alkenyl” include also “C2-4alkenyl” or “C2-6alkenyl”.

[0031] The term “alkynyl” refers to a type of alkyl group in which at least two atoms of the alkyl group form a triple bond. Non-limiting examples of an alkynyl group include -C=CH, - C=CCH3, -C=CCH2CH3 and -C=CCH2CH2CH3. The alkynyl moiety may be branched or a straight chain. An alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group). Examples of “alkynyl” include also “C2-4alkynyl” or “C2-6alkynyl”

[0032] “Amino” refers to a -NH2 group.

[0033] The term “alkylamine” or “alkylamino” refers to the -N(alkyl)xHygroup, where alkyl is as defined herein and x and y are selected from the group x=l, y=l and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system. “Dialkylamino” refers to a -N(alkyl)2group, where alkyl is as defined herein.

[0034] The terms “carboxy” or “carboxyl” refer to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to,

[0035] The term “aromatic” refers to a planar ring having a delocalized 7i-electron system containing 4n+2 n electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthal enyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0036] The term “non-aromatic group” embraces, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and fully saturated heterocycloalkyl ring systems.

[0037] The terms “unsaturated” and “partially saturated” refer to rings wherein the ring structure(s) contains atoms sharing more than one valence bond i.e. the ring contains at least one multiple bond e.g. a C=C, C=C or N=C bond.

[0038] The term “fully saturated” refers to rings where there are no multiple bonds between ring atoms. Saturated heterocycloalkyl groups include piperidine, morpholine, thiomorpholine, piperazine. Partially saturated heterocycloalkyl groups include pyrazolines, for example 2-pyrazoline and 3-pyrazoline.

[0039] The term “aryl” refers to a monocyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having 6 atoms per ring (Carbon atoms in the aryl groups are sp2 hybridized.)

[0040] The term “phenyl” represents the following moiety:

[0041] The term “cycloalkyl” or “cycloalkenyl” refers to a monocyclic or polycyclic non- aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. “Cycloalkyl” or “cycloalkenyl” may be saturated, or partially unsaturated. An example of a “cycloalkyl” is “Cs-ecycloalkyl”. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl or cycloalkenyl

[0042] groups include, but are not limited to, the following moi eties:, and the like.

[0043] The term “heterocyclyl” or “heterocycloalkyl”, is as defined herein, contains at least one heteroatom typically selected from nitrogen, oxygen or sulphur, in particular containing up to 5, up to 4, up to 3, up to 2, or a single heteroatom. Where reference is made herein to a heterocyclyl or heterocycloalkyl ring system, the heterocyclyl or heterocycloalkyl ring can, unless the context indicates otherwise, be optionally substituted (i.e. unsubstituted or substituted) by one or more substituents as discussed herein. The radicals may be fused with an aryl or heteroaryl. It is understood that a heterocyclyl or heterocycloalkyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocycloalkyl ring. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include:

[0044] The heterocyclyl or heterocycloalkyl ring systems can be heteroaryl ring systems having from 5 to 12 ring members, more usually from 5 to 10 ring members.

[0045] The heterocyclyl or heterocycloalkyl rings also include spiro, fused, and bridged ring systems. For example, bridged cycloalkanes, such as for example norbomane (1,4-endo- methylene-cyclohexane), adamantane, oxa-adamantane; bridged morpholine rings such as for example 8-oxa-3 -azabicyclo [3.2.1] octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8- azabicyclo [3.2.1] octane; bridged piperazine rings such as for example 3,6-diazabicyclo[3.1.1]heptane; bridged piperidine rings such as for example 1,4- ethylenepiperidine. For an explanation of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992.

[0046] The term “heteroaryl” is used herein to denote a heterocyclyl ring system having aromatic character. The term “heteroaryl” embraces polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system may be attached to the remainder of the compound by an aromatic ring or by a non-aromatic ring.

[0047] Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings, or two fused five membered rings. The heteroaryl ring system may contain up to about five heteroatoms typically selected from nitrogen, oxygen, and sulphur. Typically, the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. It is understood that a heteroaryl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heteroaryl ring. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include:and the like.

[0048] A nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. Each ring may, in addition, contain up to about four other heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, for example 1, 2 or 3, more usually up to 2 nitrogens, for example a single nitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0049] Examples of non-aromatic heterocyclyl groups are groups having from 3 to 12 ring members, more usually 5 to 10 ring members. Such groups can be monocyclic or bicyclic, for example, and typically have from 1 to 5 heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ring members), usually selected from nitrogen, oxygen and sulphur. The heterocyclyl groups can contain, for example, cyclic ether moieties (e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. as in pyrrolidine), and combinations thereof (e.g. thiomorpholine).

[0050] The heterocyclyl and cycloalkyl rings also include bridged ring systems such as for example bridged cycloalkanes, such as for example norbomane (1,4-endo-methylene- cyclohexane), adamantane, oxa-adamantane; bridged morpholine rings such as for example 8- oxa-3-azabicyclo[3.2. l]octane, 2-oxa-5-azabicyclo[2.2. l]heptane, 3-oxa-8- azabicyclo [3.2.1] octane; bridged piperazine rings such as for example 3,6-diazabicyclo[3.1.1]heptane; bridged piperidine rings such as for example 1,4- ethylenepiperidine. For an explanation of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992.

[0051] Lines drawn into ring systems indicate that the bond may be attached to any of the suitable and available ring atoms. The term “variable point of attachment” means that a group is allowed to be attached at more than one alternative position in a structure. The attachment will always replace a hydrogen atom on one of the ring atoms. In other words, all permutations of bonding are represented by the single diagram, as shown in the illustration below.

[0052] Those skilled in the art will recognize that that if more than one such substituent is present for a given ring, the bonding of each substituent is independent of all of the others. The groups listed or illustrated above are not exhaustive.

[0053] The term “optional” or “optionally” means the event described subsequent thereto may or may not happen. This term encompasses the cases that the event may or may not happen.

[0054] In the compounds of the present disclosure the carbon atom indicated with a “*” in the drawn formula, is a chiral center. When the carbon atom is indicated with “(R*)”, it means that it is a pure enantiomer but that it is unknown whether is it an R or S enantiomer.Similarly, when the carbon atom is indicated with “(S*)”, it means that it is a pure enantiomer but that it is unknown whether is it an R or S enantiomer.

[0055] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.

[0056] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0057] The term a “therapeutically effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that, when administered to a mammal in need, is effective to at least partially ameliorate or to at least partially prevent diseases, disorders or conditions described herein.

[0058] As used herein, the term “composition” is intended to encompass a product comprising specified ingredients in specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[0059] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0060] The term “antagonist” as used herein, refers to a small-molecule agent that binds to a receptor and subsequently decreases the agonist induced transcriptional activity of the receptor.

[0061] The term “agonist” as used herein, refers to a small-molecule agent that binds to a receptor and subsequently increases receptor transcriptional activity in the absence of a known agonist.

[0062] The term “inverse agonist” as used herein, refers to a small-molecule agent that binds to a receptor and subsequently decreases the basal level of receptor transcriptional activity that is present in the absence of a known agonist.

[0063] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0064] The term “subject” or “patient” encompasses 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 ascattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

[0065] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0066] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells. A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0067] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignantneoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.

[0068] As used herein, the term “cancer” refers to a malignant neoplasm.

[0069] The term “angiogenesis” refers to the formation and the growth of new blood vessels. Normal angiogenesis occurs in the healthy body of a subject for healing wounds and for restoring blood flow to tissues after injury. The healthy body controls angiogenesis through a number of means, e.g., angiogenesis-stimulating growth factors and angiogenesis inhibitors. Many disease states, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e. , increased or excessive) angiogenesis. Abnormal angiogenesis refers to angiogenesis greater than that in a normal body, especially angiogenesis in an adult not related to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels that feed diseased tissues and / or destroy normal tissues, and in the case of cancer, the new vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).

[0070] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. Biological samples also include those biological samples that are transgenic, such as transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus.Isomers, salts, N-oxides, isotopically labeled derivatives

[0071] Hereinbefore and hereinafter, the term “compound of Formula (I)”, “compounds of the present disclosure or invention”, “compounds presented herein”, or similar terms, is meant to include the addition salts, and the stereoisomers thereof.

[0072] In certain embodiments, the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns. In some embodiments, a compound of the present disclosure is used as a single enantiomer. In some embodiments, a compound of the present disclosure is used as a racemic mixture. In some embodiments, a compound of the present disclosure possesses hindered rotation about a single bond resulting in atropisomers.

[0073] In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0074] For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced. Examples of tautomeric forms include, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / enediamines, nitroso / oxime, thioketone / enethiol, and nitro / aci -nitro.

[0075] Such forms in so far as they may exist, are intended to be included within the scope of the compounds presented herein. It follows that a single compound may exist in both stereoisomeric and tautomeric form.

[0076] Where compounds described herein contain one or more chiral centers and can exist in the form of two or more optical isomers, references to the compounds described herein include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) of two or more optical isomers, unless the context requires otherwise. When a compound has more than one chiral centre, and one chiral centre is indicated as having an absolute stereoconfiguration, the other chiral centre(s) include all optical isomeric forms, either as individual optical isomers,or mixtures (e.g. racemic mixtures) of two or more optical isomers, thereof, unless the context requires otherwise. The optical isomers may be characterized and identified by their optical activity (i.e. as + and - isomers depending on the direction in which they rotate plane polarized light, or d and I isomers) or they may be characterized in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4thEdition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.

[0077] Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)- pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)- camphorsulphonic, separating the diastereoisomers by preferential crystallization, and then dissociating the salts to give the individual enantiomer of the free base.

[0078] Where compounds exist as two or more isomeric forms, one isomeric form, e.g. one enantiomer in a pair of enantiomers, may exhibit advantages over the other isomeric form, e.g. over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers.

[0079] When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound described herein is for instance specified as (S), this means that the compound is substantially free of the (R) isomer.

[0080] When a compound described herein is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound described herein is for instance specified as cis, this means that the compound is substantially free of the trans isomer.

[0081] As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise not indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.

[0082] The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

[0083] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0084] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

[0085] 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 for instance specified as “cis”, this means that the two groups point in the same direction relative to the plane of the ring. In the “trans” isomer, they point in the opposite direction. Exemplified below are “cis” and “trans” isomers of 2,6-dimethyl-morpholine. There are two possible relative configurations based on the relative positions of the two substituents and whether they are on the same side or opposite faces of the cyclic structure.Relative Configuration(cis)-2,6-dimethyl-morpholino (trans)-2,6-dimethyl-morpholino

[0086] For example:N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1 ,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide

[0087] In the present invention, trisubstituted piperidine moieties with stereocenters are defined as (3a, 4a, 5a) or (3a, 4|3, 5a).(3a,4a,5a)-3,5-dimethyl-4-piperidinol (3a,4p,5a)-3,5-dimethyl-4-piperidinol(3a,4a,5a)-3,5-dimethyl-4-piperidinol (3a,4b,5a)-3,5-dimethyl-4-piperidinol(3p,4p,5P)-3,5-dimethyl-4-piperidinol (3p,4a,5p)-3,5-dimethyl-4-piperidinol(3b,4b,5b)-3,5-dimethyl-4-piperidinol (3b,4a,5b)-3,5-dimethyl-4-piperidinol

[0088] Therefore, the present disclosure includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

[0089] The meaning of all those terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

[0090] The methods and formulations described herein include the use of N-oxides (if appropriate), pharmaceutically acceptable salts, and combinations thereof, of compounds having the structures presented herein and having the same type of activity.

[0091] The salt forms of the compounds presented herein are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977) “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non- pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0092] The pharmaceutically acceptable salts include pharmaceutically acceptable acid and base addition salts and are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds described herein are able to form.

[0093] The salts of the present disclosure can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in “Pharmaceutical Salts: Properties, Selection, and Use”, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of thesecompounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The compounds of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed.

[0094] The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like) or organic acids such (as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid and the like) in an anion form.

[0095] Appropriate anions comprise, for example, acetate, 2,2-dichloroacetate, adipate, alginate, ascorbate (e.g. L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4- acetamidobenzoate, butanoate, bicarbonate, bitartrate, bromide, (+) camphorate, camphor- sulphonate, (+)-(! 5')-camphor- l()-sulphonate. calcium edetate, camsylate, caprate, caproate, caprylate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecylsulphate, edetate, estolate, esylate, ethane- 1,2-disulphonate, ethanesulphonate, formate, fumarate, galactarate, gentisate, glucoheptonate, gluceptate, gluconate, D-gluconate, glucuronate (e.g. D-glucuronate), glutamate (e.g. L-glutamate), a-oxoglutarate, glycolate, glycollylarsanilate, hexylresorcinate, hippurate, hydrabamine, hydrobromide, hydrochloride, hydriodate, 2-hydroxyethane-sulphonate, hydroxy naphthoate, iodide, isethionate, lactate (e.g. (+)-L-lactate, (±)-DL-lactate), lactobionate, malate, (-)-L-malate, maleate, malonate, mandelate, (±)-DL-mandelate, mesylate, methansulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthalene-sulphonate (e.g.naphthalene-2-sulphonate), naphthalene- 1,5-disulphonate, 1 -hydroxy -2 -naphthoate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate (embonate), pantothenate, phosphate / diphosphate, propionate, polygalacturonate, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylate, sebacate, stearate, subacetate, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, teoclate, thiocyanate, toluenesulphonate (e.g. p-toluenesulphonate), tosylate, triethiodide, undecylenate, valeric acids, as well as acylated amino acids and cation exchange resins. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

[0096] The compounds of the present disclosure containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases in a cation form. Appropriate basic salts comprise 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, tromethamine, and the like; those formed with ammonium ion (i.e., NH4+), quaternary ammonium ion NfCHsh'. and substituted ammonium ions (e.g., NHsR1. NH2R2+ NHRs1. NR.4+); and those formed with metallic cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. Where the compounds described herein contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of the compounds presented herein.

[0097] Conversely said salt forms can be converted by treatment with an appropriate acid into the free form.

[0098] In some embodiments, sites on the compounds disclosed herein are susceptible to various metabolic reactions. Therefore, incorporation of appropriate substituents at the places of metabolic reactions will reduce, minimize or eliminate the metabolic pathways. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium or an alkyl group.

[0099] The compounds of the present disclosure include compounds that are isotopically labeled, i.e., with one or more isotopic substitutions. These compounds are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. A reference to a particular element includes within its scope all isotopes of the element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. In another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may also be useful in a diagnostic context. Radiolabeled compounds described herein may comprise a radioactive isotope selected from the group of2H,3H, "C.18F,122I,123I,125I,131I,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of2H,3H,nC and18F. More preferably, the radioactive isotope is2H. In particular, deuterated compounds are intended to be included within the scope of the present invention. In some embodiments, metabolic sites on the compounds described herein are deuterated.

[0100] Throughout the specification, groups and substituents thereof can be chosen to provide stable moi eties and compounds.

[0101] Embodiments of the 1,6-naphthyridine compounds for use as described herein are compounds of Formula (I):WhereinR1is an optionally substituted phenyl selected from:(a) 2-chlorophenyl, 2-methyl-5-(lH-tetrazol-l-yl)phenyl, 5-(tert-butyl)-2- methoxyphenyl, 3-fluoro-2-(lH-l,2,3-triazol-l-yl)phenyl, 2-fluoro-5-(l- hydroxyethyl)-4-methylphenyl,whereinRais selected from: H; halo; C1-4alkyl; C1-4alkyl substituted with one or two members each independently selected from OH, cyclopropyl, CN, and CH2CO2C1-4alkyl; C1-4haloalkyl; C1-4haloalkyl substituted with one or two OH members; CN; OC1-4alkyl; OC1-4haloalkyl; (P=O)(CH3)2; CO2C1-4alkyl; NH(SO2-C2-3alkenyl), and NH(C=O)C2-3alkynyl;Rbis selected from: Cl, F, Br, C1-4alkyl, OC1-4alkyl, cyclopropyl, and 4-methyl-lH- imidazol-l-yl;Rcis selected from: Cl, Br, I, C1-4alkyl, C1-4haloalkyl, OC1-4alkyl, 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), heterocycloalkyloptionally substituted with one or two members each independently selected from halo, OH, CH3, CH2CH2OH, OC1-4alkyl, and CO2C1-4alkyl;Rdis Cl or CH3;Reis selected from: C1-4alkyl substituted with one or two OH members, andIH-tetrazole;whereinRgis C1-4alkyl optionally substituted with one OH member;Rhis C1-4alkyl, or C1-4haloalkyl;R1is selected from: C1-4alkyl optionally independently substituted with one, two or three members selected from: OH, CN, OC1-4alkyl, CN, NH2, N(C1-4alkyl)2, O-tetrahydropyranyl, piperidine substituted with C(OH)(CH3)2, and NH(CO2C1-4alkyl); NH(C1-4alkyl); N(C1-4alkyl)2; NH(CH2CH2OH); tetrahydropyranyl; C1-4haloalkyl; C2-4alkenyl; azetidine optionally substituted with OH; and (cis)-2,6-dimethylmorpholinyl; each Rkis independently selected from: halo, C1-4akyl, OC1-4alkyl, NH2, OC1-4haloalkyl, CN, CH2OH, C3-ecyclalkyl, and C2-4alkenyl;Rmis selected from: C1-4haloalkyl, CH2CH2OH, and CH2CN; n is 0, 1, 2, or 3;X is O, NH, orN-CH3;R3is selected from: H, and C1-4alkyl optionally substituted with one member selected from: OH, NH2, N(CH3)2, NH(C=O)CH3, and morpholine; andR5is selected from the group consisting of: i) a 5- or 6-membered heteroaryl, optionally fused with a Cs-vcycloalkyl or Cs-vheterocycloalkyl, selected from:(cis)-2,6-dimethyl-4-(5,6,7,8-tetrahydro-2,6-naphthyridin-l-yl)morpholine; 7-((cis)-2,6-dimethylmorpholino)-2,3-dihydrofuro[2,3-c]pyridine; 4-((cis)-2,6- dimethylmorpholino)-l,3-dihydrofuro[3,4-c]pyridine; (cis)-2,6-dimethyl-4-(5,6,7,8-tetrahydroisoquinolin-l-yl)morpholine; 3-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-6-yl; (cis)-2,6-dimethyl-4-(pyrimidin-4- yl)morpholine; (cis)-2,6-dimethyl-4-(lH-pyrazol-3-yl)morpholine; (IH-pyrazol-l- yi);Rpis selected from the group consisting of:(a) an eight to ten membered nitrogen linked spirocyclic heterocycloalkyl ring system, wherein each ring optionally contains one, two or three heteroatoms each independently selected from N, O, and S, optionally substituted with one, two or three members each independently selected from: OH, C1-4alkyl, Ci- dialoalkyl, oxo, CO2C1-4alkyl, NH2, N(H)(C1-4alkyl), N(C1-4alkyl)2, N(H)(CO2C1-4alkyl), and OC1-4alkyl;(c) Nitrogen linked azetidine optionally substituted with a one or two members each independently selected from: CH3, NH2, and NH(CO2C1-4alkyl);Nitrogen linked pyrrolidine optionally substituted with one, two, three or four members each independently selected from: halo, C1-4alkyl, CH2OH, CH2OCH3, C1-4haloalkyl, OH, NH2, oxo, NH(CO2C1-4alkyl), morpholinyl, and CH2- morpholinyl; Nitrogen linked piperidine optionally substituted with one, two, three or four members each independently selected from: deuterium, halo, Ci- 4alkyl, CH2OH, CH2CH2OH, OH, NH2, NH(C1-4alkyl), and OC1-4alkyl;Nitrogen linked piperazine optionally substituted with one, two, three or four members each independently selected from: halo, C1-4alkyl, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, CH2CN, (C=O)NH2, CH2(C=O)NH2, CO2C1-4alkyl, CH2SO2CH3, C1-4haloalkyl, OH, oxo, Cs-ecycloalkyl, and CH2-C3- ecycloalkyl; Nitrogen linked morpholine optionally substituted with one, two, three or four members each independently selected from: Cwalkyl, Ci- 4haloalkyl, CO2OH, oxo, (CH2)4-6-NH2, (CH2)4-6-NH(C=O)CH3, and (CH2)4-6- NH(CO2CI-4 alkyl);Nitrogen linked diazepane optionally substituted with one or two C1-4alkyl members;Nitrogen linked oxazepane optionally substituted with one or two C1-4alkyl members; and Nitrogen linked thiomorpholine 1,1-dioxide;(d) 5-10 membered fused or bridged ring, wherein each ring optionally contains one, two or three heteroatoms each independently selected from N, S, or O, optionally substituted with one, two or three members each independently selected from: halo, C1-4alkyl, OH, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NH(CO2C1-4alkyl), CO2C1-4alkyl, and oxo; andwherein each Rqis independently selected from: H, halo, Cwalkyl, Cwhaloalkyl, CN,Rsis H or halo;Rlis selected from: Cmalkyl; oxetan-3-yl; carbon linked azetidine optionally substituted with (CO2-tBu); tetrahydropyran; l,3-oxazinan-2-one; 2, 2,6,6- tetramethylpiperidin-4-yl; and 2,2,6,6-tetramethyltetrahydro-2H-pyran;whereinRuis H, pyridin-3-yl, or pyridin-4-yl;Rvis (cis)-2,6-dimethylmorpholinyl, pyridin-3-yl, or pyridin-4-yl; andRwis H, F, or OCHs;whereinRxis pyridin-3-yl, or pyridin-4-yl;Ryis selected from:, pyridin-3-yl, and pyridin-4-yl; andRzis selected from:vi)and pharmaceutically acceptable salts, isotopes, and stereoisomers thereof.

[0102] In one embodiment of the present invention, the compound is not 3-chloro-5- ((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)- 1 ,6-naphthyridin-7-yl)methyl)benzamide, or 3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide.

[0103] In some embodiments, R1is

[0106] In some embodiments, R1is

[0113] In some embodiments, (i) R5is

[0114] In some embodiments,wherein:(i) Rpis(iv) Rpis

[0116] In some embodiments, R5is:

[0117] In some embodiments, the compound of Formula (I) is a compound as shown below in Table 1.0118] and pharmaceutically acceptable salts, isotopic variants, and stereoisomers thereof.

[0119] In some embodiments, the 1,6-naphthyridine compound is selected from the group consisting of:N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3- ((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3- ((2-hydroxyethyl)sulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(4-fluoro-6-(4,7 -di azaspiro [2.5] octan-7-yl)pyridin-2-yl)- 1 ,6-naphthyridin-7- yl)methyl)-4-(2-hydroxyethyl)-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-5-methylbenzamide;N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;3-fluoro-N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide;3-chloro-5-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)-4-fluoropyri din-2 -yl)- 1 ,6-naphthyri din- 7 -yl)methyl)benzamide;3-chloro-5-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((2R,6S)-2,6- dimethylmorpholino)-4-fluoropyri din-2 -yl)- 1 ,6-naphthyri din- 7 -yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-3-((*S)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-3-((*R)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide;3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropy ridin-2-y 1)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropy ridin-2-y 1)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methylbenzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-fluorobenzamide;3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2- yl)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;3-chloro-5-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide; and3-chloro-5-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide; and pharmaceutically acceptable salts, isotopic variants, and stereoisomers thereof.

[0120] An additional embodiment of the invention is a method of treating cancer or non- small-cell lung carcinoma (NSCLC) in a subject comprising administering an effective amount of a pharmaceutical composition, or use of a pharmaceutical composition for treating cancer or non-small-cell lung carcinoma (NSCLC), or a pharmaceutical composition for such use, comprising: at least one compound selected from compounds of Formula (I); and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of compounds of Formula (I); and (B) at least one pharmaceutically acceptable excipient.

[0121] In some embodiments, such pharmaceutical compositions comprise a therapeutically effective amount of at least one compound in Table 1, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, or a pharmaceutically acceptable prodrug of at least one compound of Table 1, or at least one pharmaceutically active metabolite of Table 1; and at least one pharmaceutically acceptable excipient.Synthesis of Compounds

[0122] In this section, as in all other sections of this application unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein.

[0123] The synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures, and other reaction conditions presented herein may vary. Techniques and materials recognized in the field are described, for example, in 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 Suppiementals (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 4thEd., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4thEd., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rdEd., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagentsand conditions, for the introduction of the various moieties found in the formulae as provided herein.

[0124] The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

[0125] In the reactions described herein, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0126] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyl dimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

[0127] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxy carbonyl (Fmoc).. Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively -removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.

[0128] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd°-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.

[0129] Typically blocking / protecting groups may be selected from:

[0130] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007, which is incorporated herein by reference for such disclosure.General synthetic pathwaysSCHEME 1

[0131] A suitably substituted ester compound of formula (II) is commercially available or synthetically accessible. An aryl iodide compound of formula (II), such as methyl 3-chloro-5- iodo-4-methylbenzoate, is reacted in a palladium-catalyzed sulfination using triphenylphosphine; 1,10-phenanthroline; in the presence of K2S2O5 and sodium formate; tert- butyl ammonium bromide; a palladium catalyst such as palladium acetate, and the like; followed by in situ alkylation with 2-(2-bromoethoxy)tetrahydro-27 / -pyran; in a suitable solvent such as DMSO, ACN, and the like; at temperatures ranging from room temperature to 100 °C; affords methyl 3-chloro-4-methyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonyl)benzoate. Deprotection of the pyran is achieved under acidic conditions known to one skilled in the art such as HCl / MeOH, to provide methyl 3-chloro-5- ((2-hydroxyethyl)sulfonyl)-4-methylbenzoate.

[0132] An ester compound of formula (II), wherein ring B has a halide such as I, for example, 3-chloro-5-iodobenzoic acid methyl ester; is further functionalized by reaction with i- PrMgCl; and acetone; in a suitable solvent such as THF, and the like; at temperatures ranging from -78 °C to room temperature; affords a compound of formula (II), where the I is now replaced by C(OH)(CH3)2.

[0133] A commercially available or synthetically accessible ester compound of formula (II), where ring B is a suitably substituted phenyl can be reacted under basic conditions such as NaOH, LiOH, KOH, and the like; in a suitable solvent such as methanol (MeOH), ethanol (EtOH), THF, ACN, H2O, or a mixture thereof; at a temperature of 60 °C to 80 °C; for a period of 1-6 h; to afford an acid compound of formula (III).

[0134] An acid compound of formula (III), wherein ring B has a halide such as Br (bromide); can be further functionalized by reaction with a suitable boronic acid or boronate derivative such as, for example, potassium cyclopropyltrifluoroborate (CAS [1065010-87-8]); in the presence of a suitable base such as, for example, Na2CO3, in the presence of a suitable catalyst such as, for example, Pd(dppl)C12.DCM (CAS [95464-05-4]), and the like; in a suitable solvent such as a mixture of 1,4-di oxane and water, at a suitable temperature such as 80 °C. An acid compound 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 reaction with BuLi, in a suitable solvent such as THF, and the like; and acetaldehyde; at temperatures of about -78 °C; for a period of 1 h; to provide a compound of formula (III), where the Br is now replaced by CH(OH)CH3.SCHEME 2 c BorylationR5— Hal(IV)

[0135] According to SCHEME 2, a compound of formula (IV), where Hal is Br or Cl and R5is a suitably substituted heteroaryl, can be borylated employing conditions known to one skilled in the art such as Miyaura borylation conditions. For example, a compound of formula (IV), where Hal is Br or Cl, can be treated with a transition metal catalyst such as 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(XIX) (Pd(dppl)C12), and the like; in asuitable solvent such as dimethylsulfoxide (DMSO) or 1,4-di oxane, and the like; and a base such as potassium acetate, and the like; and a boron source such as bis(pinacolato)diboron, pinacol borane, and the like; at a temperature ranging from 80 °C to 100 °C; for a period of 2- 8 h; to provide a compound of formula (V).

[0136] According to SCHEME 3, A compound of formula (XXIII), where R3is H, can be prepared in a metal mediated coupling reaction of a commercially available or synthetically accessible compound of formula (VII), where Hal is a suitable halogen such as Br (bromine); with a boronic acid or boronic ester such as potassium trifluoro(vinyl)borate; in the presence of a catalyst such as bis(triphenylphosphine)palladium(XIX) chloride, and the like; a base such as CS2CO3, and the like; in a suitable solvent such as THF, 1,4-di oxane, toluene, water, or a mixture thereof; at temperatures ranging from 70 °C to 100 °C; for a period of 12-18 h. Halogenation of a compound of formula (VI), employing a chlorinating agent such as POCh, and the like, in a suitable solvent such as 1,2-di chloroethane, chloroform, and the like, at temperatures ranging from 70-90 °C, can afford a compound of formula (VIII). A compound of formula (VIII) can be oxidized by treatment with osmium tetroxide and NalOr. in a suitable solvent such as 1,4-di oxane, THF, water, or a mixture thereof, to provide a compound of formula (XXI). Reduction of a compound of formula (IX) can be achieved employing a suitable reducing agent such as NaBH4, and the like; in a suitable solvent, such as MeOH, EtOH, and the like; to provide a compound of formula (X). Subsequent mesylation of the hydroxy compound of formula (X) can be achieved employing methanesulfonyl chloride (mesyl chloride), a suitable base such as triethylamine (TEA), in a suitable solvent such as DCM, and the like, to provide a compound of formula (XI). An azide compound of formula(XII) can be prepared from a compound of formula (XI) employing azidation conditions known to one skilled in the art. In a preferred method, a compound of formula (XI), can be reacted with sodium azide, in a suitable solvent such as DMF, and the like, at room temperature, for a period of 18 h, to provide a compound of formula (XII). A compound of formula (XIII) can be prepared by reacting an compound of formula (XII) with a suitable reductant such as, for example, triphenylphosphine, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, room temperature. A compound of formula (XIII) can be protected with a Boc protecting group, employing conditions known to one skilled in the art, for example, by reacting a compound of formula (XIII) with Boc- anhydride, in the presence of a suitable base such as, for example, EtsN; at room temperature; for a period of about 4-7 h, to provide a compound of formula (XIV), where P1is Boc.SCHEME 4(VII) (XV) (XVI) (XIV)

[0137] According to SCHEME 4, a compound of formula (VII), where Hal is Cl, can undergo a palladium-catalyzed cyanation employing conditions known to one skilled in the art. For example, a compound of formula (VII), can be reacted with a palladium catalyst such as Pd(dppf)C12.CH2C12, and the like; and zinc cyanide as the nucleophile; in a suitable solvent such as DMA, V,7V-dimethylformamide (DMF), and the like; at a temperature of about 100 °C; for a period of 2-6 h; to provide a cyano compound of formula (XV). Halogenation of a compound of formula (XV) can be achieved employing methods previously described, such as using POCh, to afford a compound of formula (XVI). A compound of formula (XVI) can be reduced using a suitable reducing agent such as DIBAL-H; in a suitable solvent such as DCM, toluene, and the like; at a temperature of -78 °C to room temperature; subsequent reaction with a suitable protecting group precursor such as, for example, Boc anhydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, room temperature can afford a compound of formula (XIV).SCHEME 5

[0138] According to SCHEME 5, a compound of formula (XIV), where P1is Boc, R3is H, and Hal is Cl, can be reacted in a metal mediated cross coupling reaction with a commercially available or synthetically accessible boronic acid of formula R5-B(OH)2 or boronate derivative of formula (XLIa), where R5is an optionally substituted heteroaryl, employing methods known to the art. For example, a compound of formula (XVIII) can be reacted with 6-fluoropyridine-2-boronic acid; a suitable base such as CS2CO3, K2CO3, K3PO4, K2HPO4, KHCO3, Na2CO3,NaHCO3, and the like; a palladium catalyst such as bis(triphenylphosphine)palladium(XIX) chloride, and the like; in a suitable solvent such as 1,4-di oxane, DMF, acetonitrile (ACN), ethanol, water, or a mixture thereof; at a temperature ranging from 50 to 100 °C; for a period of about 16 to 24 h; to provide a compound of formula (XVII), where R3is H and R5is 6-fluoropyridyl.

[0139] A compound of formula (XVII), where R5is a suitable heteroaryl such as, for example, 2-pyridyl substituted with a suitable halogen leaving group such as, for example, F (fluorine), can be reacted with an optionally substituted heterocycloalkyl (including but not limited to a 4-8 membered heterocycloalkyl, fused, spiro, and bridged 8-10 membered heterocycloalkyl, each optionally one or two heteroatoms independently selected from N, S, and O) such as c7.s-2.6-dmrethyl morpholine; a base such as DIPEA, and the like, in a suitable solvent such as DMSO, ACN, and the like, at temperatures ranging from 50-130 °C, for a period of 12-24 h, to provide a compound of formula (XVIII), wherein R5is a suitable heteroaryl substituted with a nitrogen linked heterocycloalkyl.

[0140] Deprotection of a compound of formula (XVIII), where P1is Boc, can be achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999, pgs 518-525. For example, deprotection under acidic conditions such as trifluoroacetic acid (TFA) / CH2Ch, HCl / Dioxane,and the like, at room temperature for a period of 2 h, to provide a compound of formula (XIX).SCHEME 6

[0141] According to SCHEME 6, a compound of formula (XIX), wherein R3is H (hydrogen), can be reacted with a suitable ketone such as, for example, benzophenone; in the presence of a suitable catalyst such as, for example, pTsOH; in a suitable solvent such as, for example, toluene, and the like; at a suitable temperature such as, for example, reflux of the solvent; to provide an imine derivative compound of formula (XX). A compound of formula (XX) can be reacted with a suitable alkylating agent R3Hal, wherein R3is as defined in the claims and Hal is a suitable halogen leaving group, such as, for example, iodide; in the presence of a suitable base such as, for example, potassium tert-butoxide, and the like; in a suitable solvent such as, for example, THF, DMF, and the like; at a suitable temperature such as, for example, room temperature; to provide a compound of formula (XXI), where R3is as defined in the claims. Deprotection of the imine compound of formula (XXI) can be achieved employing acidic conditions known to one skilled in the art such as HCl / Dioxane, and the like, at room temperature for a period of 30 min - 2 h, to provide a compound of formula (XIX).SCHEME 7

[0142] According to SCHEME 7, a compound of formula (XIV), where R3is H, Hal is Cl, and P1is Boc, can be reacted with a suitable sulfinate such as, for example, sodium 1-methyl 3-sulfinopropanoate (CAS [90030-48-1]); in the presence of a suitable catalyst such as, for example, Cui; in a suitable solvent such as, for example, DMSO, and the like; at a suitable temperature such as, for example, 110 °C; to provide a compound of formula (XXII). Acompound of formula (XXII) can be reacted with a commercially available or synthetically accessible suitably substituted 2-halogeno-R5, such as, for example, (cis)-4-(6-bromo-4- fluoropyridin-2-yl)-2,6-dimethylmorpholine; in the presence of a suitable phosphonium salt such as di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3]); in the presence of a suitable base such as, for example, K2CO3, and the like; in the presence of a suitable catalyst such as, for example, Pd(OAc)2, and the like; in a suitable solvent such as, for example, 1,4-di oxane; at a suitable temperature such as, for example, 150 °C; to provide a compound of formula (XVIII). Deprotection of the Boc protecting group on a compound of formula (XVIII) can be achieved employing acidic conditions known to one skilled in the art or as previously described to provide a compound of formula (XIX).SCHEME 8

[0143] According to SCHEME 8, a compound of formula (XVII), where R3is H, P1is Boc, and R5is a suitably substituted heteroaryl halide, can be deprotected employing methods known to one skilled in the art or as previously described, to provide a compound of formula (XXIII). A compound of formula (XXIII) can be reacted with a suitably substituted commercially available or synthetically accessible carboxylic acid; employing conventional amide bond forming techniques such as coupling reactions which are well known to those skilled in the art. For example, a compound of formula (XXIII) can be reacted with a carboxylic acid of formula (III), where ring B is a suitably substituted phenyl ring; in the presence of a suitable coupling agent such as, for example, HATU, HBTU, 1- propanephosphonic anhydride, and the like; in the presence of a suitable base such as TEA, DIPEA, and the like; in a suitable solvent such as, for example, DCM, DMF, and the like; at a suitable temperature such as, for example, room temperature; to provide a compound of formula (XXIV).

[0144] In an alternate method, a compound of formula (XXIV) can be prepared in two steps from a compound of formula (XIII). In a first step, a compound of formula (XIII) can be reacted in an amide bond forming reaction with a carboxylic acid of formula (III), where ring B is a suitably substituted phenyl ring; employing methods known to one skilled in the art or as previously described to provide a compound of formula (XXV). Alternatively, an acid chloride derived from the acid of formula (III) can be reacted with a compound of formula (XIII), in the presence of a base such as DIPEA, in a suitable solvent such as DCM, and the like; to provide a compound of formula (XXV). In a second step, a compound of formula (XXV) can be reacted in a coupling reaction with a suitable boronic acid such as R5-B(OH)2, for example, 6-fluoro-pyridine-2-boronic acid or a boronate derivative such as 2-fluoro-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine; in the presence of a suitable base such as, for example, Na2CO3 or NaHCO3; in the presence of suitable catalyst such as bis(triphenylphosphine)palladium(II)chloride (CAS [13965-03-2]) or Pd(dppf)C12.CH2C12 (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; to provide a compound of formula (XXIV).

[0145] A compound of formula (XXIV) or similarly a compound of Formula (I), wherein R1has a halide such as Br (bromide); can be further functionalized by reaction with a suitable boronic acid or boron derivative such as, for example, potassium cyclopropyltrifluoroborate (CAS [1065010-87-8]); in the presence of a suitable base such as, for example, Na2CO3, in the presence of a suitable catalyst such as, for example, Pd(dppf)Ch.DCM (CAS [95464-05- 4]), and the like; in a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature such as 80 °C.SCHEME 9

[0146] According to SCHEME 9, a compound of Formula (XXV), where R3is H, and Hal is Cl, and R1is a suitably substituted phenyl as 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, and the like; in a suitable solvent such as DMSO, and the like; at temperatures ranging from 90 to 110 °C; to provide a compound of formula (XXVI).

[0147] A compound of formula (XXVI), can be reacted with a suitably substituted heteroaryl halide of formula R5Hal, wherein Hal is Br or Cl, and R5is heteroaryl as defined in claim 1; in the presence of a suitable phosphonium salt such as, for example, di-tert- butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3]); in the presence of a suitable base such as K2CO3, and the like; in the presence of a suitable catalyst such as Pd(OAc)2, and the like; to provide a compound of Formula (I).SCHEME 10(XVI) (XXVII) (XVII)

[0148] According to SCHEME 10, a compound of formula (XVI) can be reacted with a suitable boronic acid or boronate derivative R5-B(OR)2, such as, for example, 2-fluoro-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine, in the presence of a suitable base such as, for example, NaHCO3, in the presence of a suitable catalyst such as, for example, Pd(dppl)C12.DCM, in a suitable solvent such as, for example, a mixture of 1,4-di oxane and water, at a suitable temperature such as, for example, 90 °C to provide a compound of formula (XXVII). A compound of formula (XXVII) can be reacted with a suitable reducing agent such as, for example, NaBH4, in the presence of a suitable catalyst such as, for example, NiCh, in the presence of a suitable protecting group precursor such as, for example, di-tert- butyl dicarbonate, in a suitable solvent such as, for example, MeOH, at a suitable temperature such as, for example, room temperature, to provide a compound of formula (XVII).SCHEME 11

[0149] According to SCHEME 11, a compound of formula (X), R3is H and Hal is Cl, can be reacted with a suitable boronic acid R5-B(OH)2 or a boronate derivative of formula (V), employing coupling methods known to one skilled in the art or as previously described. For example, a compound of formula (X), R3is H and Hal is Cl, can be reacted with R5-B(OH)2,where R5-B(OH)2 is 6-fluoro-pyridine-2-boronic acid; in the presence of a suitable base such as CS2CO3, K2CO3, K3PO4, K2HPO4, KHCO3, Na2CO3,NaHCO3, and the like; in the presence of a suitable catalyst such as, for example, 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 ranging from 80 to 100 °C; to provide a compound of formula (XXVIII), where R5is 6-fluoro-pyridyl. A compound of formula (XXVIII) can be reacted with phthalimide; in the presence of a suitable phosphine such as, for example, triphenylphosphine; a suitable azodicarboxylate such as DIAD, DEAD, and the like; in a suitable solvent such as THF, and the like; at a suitable temperature such as room temperature; to provide a compound of formula (XXIX).

[0150] In an alternate method, a compound of formula (XXIX) can be prepared in two steps from a compound of formula (X). In a first step, a compound of formula (X), where R3is H and Hal is Cl, can be reacted with phthalimide; in the presence of a suitable phosphine such as, for example, triphenylphosphine, and the like; a suitable azodicarboxylate such as, for example, DIAD, DEAD, and the like; in a suitable solvent such as, for example, THF, toluene, or a mixture thereof; at a suitable temperature such as room temperature; to provide a compound of formula (XXXII). In a second step, a compound of formula (XXXII) can be reacted under coupling conditions known to one skilled in the art, or as previously described to provide a compound of formula (XXIX).

[0151] A compound of formula (XXIX), can be reacted with a suitable deprotection reagent such as, for example, hydrazine hydrate, in a suitable solvent such as, for example, EtOH, at a suitable temperature such as, for example, 65 °C, to provide a compound of formula (X).SCHEME 12

[0152] According to SCHEME 12, a compound of formula (XIV), where Hal is Cl, P1is a suitable nitrogen protecting group such as Boc, and R3is H, can be reacted with a suitable hydrolyzing reagent such as, for example, 37 % aqueous HC1, in a suitable solvent such as, for example, 1,4-di oxane, at a suitable temperature such as, for example, 60 °C to provide a compound of formula (XXXI). A compound of formula (XXXI) can be reacted with a commercially available or synthetically accessible suitably substituted acid of formula (III), in the presence of a suitable coupling agent, such as, for example, HATU, in the presence of a suitable base such as, for example, DIPEA, in a suitable solvent such as, for example, ACN, at a suitable temperature such as, for example, room temperature to provide a compound of formula (XXXII). A compound of formula (XXXII) can be reacted with a suitable amine or heteroaryl R5H, in the presence of a suitable activating agent such as, for example, BOP (CAS [56602-33-6]), in the presence of a suitable base such as, for example, DBU, in a suitable solvent such as, for example, ACN, at a suitable temperature such as, for example, 80 °C, to provide a compound of Formula (I).SCHEME 13

[0153] According to SCHEME 13, a compound of formula (XXV), where Hal is Cl, can be reacted with a commercially available or synthetically accessible suitably substituted heterocycle such as, for example, 2-piperidone, using standard Buchwald coupling conditions, in the presence of a suitable base such as, for example, cesium carbonate, and the like; in the presence of a suitable catalyst such as, for example, XantPhos Pd G4 (CAS [1621274-19-8]), and the like; in a suitable solvent such as, for example, 1,4-di oxane; at a suitable temperature such as, for example, 100 °C; to provide a compound of Formula (I), wherein R5is defined as an N-linked heteroaryl group or an N-linked heterocycloalkyl group, as defined in the general scope.

[0154] A compound of formula (XXV) can be reacted with a commercially available or synthetically accessible suitably substituted boronic acid or boronate derivative, such as (cis)- 4-(3-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2,6- dimethylmorpholine, for example, using standard Suzuki coupling conditions, in the presence of a suitable base such as, for example, sodium carbonate, in the presence of a suitablecatalyst such as, for example, [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (CAS [72287-26-4]), in a suitable solvent such as, for example, a mixture of water and 1,4- di oxane, at a suitable temperature such as, for example, 100 °C, to provide a compound of Formula (I), wherein R5is defined as a C-linked heteroaryl, aryl, or heterocycloalkyl group. According to SCHEME 13, a compound of formula (XXV), can be reacted with a suitable stannane derivative such as [4-(6-trimethylstannyl)-4-pyrimidinyl]-2,6-dimethylmorpholine; in the presence of a suitable source of Pd such as tetrakis(triphenylphosphine)palladium(0), and the like; in a suitable solvent such as 1,4-di oxane, and the like; at a temperature of 110 °C; to provide a compound of Formula (I), wherein R5is defined as a C-linked heteroaryl.SCHEME 14

[0155] According to SCHEME 14, a compound of formula (XIX) can be reacted with a suitable commercially available or synthetically accessible carboxylic acid, employing conventional amide bond forming techniques such as coupling reactions which are well known to those skilled in the art. For example, a compound of formula (XIX), where R3and R5are as described in claim 1, can be reacted with a suitable carboxylic acid, in the presence of a suitable coupling agent such as, for example, HATU (l-[bis(dimethylamino)methylene]- 17 / -l,2,3-triazolo[4,5-6]pyridinium 3-oxide hexafluorophosphate), HBTU, or 1- propanephosphonic anhydride; in the presence of a suitable base such as, for example, N- ethyldiisopropylamine (DIPEA), triethylamine (TEA), and the like; in a suitable solvent such as, for example, DCM, THF, DMF, and the like; at a suitable temperature such as, for example, ranging from 0 °C to room temperature, to provide a compound of Formula (I). Alternatively, Compounds of Formula (I) can be prepared by reacting a compound of formula (XIX) with a suitable activated form of a carboxylic acid, such as, for example, an acyl chloride, or its corresponding anhydride, in the presence of a suitable base such as, forexample, DIPEA or EtsN, in a suitable solvent such as, for example, DCM or DMF, at a suitable temperature such as, for example, 0 °C or room temperature.

[0156] A compound of formula (XXIV), wherein R5is a suitable heteroaryl, such as, for example, 2-pyridyl, and Hal is a suitable halogen leaving group such as, for example, F (fluorine), can react with a suitable amine HNR9aR9b, in the presence of a suitable base such as, for example, DIPEA, in a suitable solvent such as, for example, DMSO, at a suitable temperature such as, for example, 90 °C or up to 150 °C, to provide a compound of Formula (I).

[0157] Alternatively, compounds of Formula (I), wherein R5is defined as a C-linked heteroalkyl group, as defined in the general scope, can be prepared according to Scheme 14: a compound of formula (XXIV) can be reacted with a suitable heteroalkyl organozinc derivative R5-Zn-Hal, wherein Hal is a suitable halide such as, for example, iodide, in the presence of a suitable catalyst such as, for example, Palladium (II) acetate (CAS [3375-31-3]), in the presence of a suitable ligand such as, for example, RuPhos (CAS [787618-22-8]), in a suitable solvent such as, for example, THF or a mixture of THF and DMF, at a suitable temperature such as, for example, 100 °C.

[0158] Wherein a compound of Formula (I) has a protecting group such as, for example, Boc, the protecting group can be removed employing conditions known to one skilled in the art. For example, reaction with a reagent such as, for example, pTsOH (p-toluenesulfonic acid), TFA, or HC1, in a suitable solvent such as, for example, DCM, or 1,4-di oxane, at a suitable temperature such as, for example, room temperature or 40 °C.

[0159] Wherein when a compound of Formula (I) has a protecting group such as, for example, TBDMS, the protecting group can be removed by reaction with a suitable deprotection agent such as, for example, TBAF, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, room temperature or 50 °C.

[0160] Wherein a compound of Formula (I) has a protecting group on the R1group such as, for example, Boc or THP, the protecting group can be removed by reaction with a suitable reagent such as, for example, HC1, pTsOH, or pyridinium p-toluenesulfonate, in a suitable solvent such as, for example, 1,4-di oxane, or EtOH, at a suitable temperature such as, for example, room temperature. Wherein when the protecting group is an ester, a compound of Formula (I) can be reacted with a suitable hydrolyzing agent such as, for example, LiOH or NaOH, in a suitable solvent such as, for example, THF, MeOH, water, or a mixture thereof, at a suitable temperature such as, for example, room temperature.

[0161] The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of Formula (I).

[0162] The skilled person will realize that intermediates and final compounds shown in the schemes below may be further functionalized according to methods well-known by the person skilled in the art.

[0163] The compounds of Formula (I) may also be converted into each other via art-known reactions or functional group transformations. For instance, substituents like -C(=O)-O-Ci- ealkyl can be converted into a carboxylic acid in the presence of lithium hydroxide, and in the presence of a suitable solvent, such as for example tetrahydrofuran or an alcohol, e.g. methanol.

[0164] The skilled person will realize that in the reactions described in the Schemes, in certain cases it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N2-gas atmosphere.

[0165] It will be apparent for the skilled person that it may be necessary to cool the reaction mixture before reaction work-up, meaning those series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, or extraction.

[0166] The skilled person will realize that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.

[0167] The compounds of the invention as prepared in the processes described herein may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures. Racemic compounds of Formula (I) containing a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I), and the pharmaceutically acceptable addition salts thereof, involves liquid chromatography using a chiral stationary phase e.g. by supercritical fluid chromatography. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereo specifically. Preferably if a specific stereoisomer is desired, said compound would besynthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

[0168] In all these preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration, and chromatography. The purity of the reaction products may be determined according to methodologies generally known in the art such as for example LC-MS, TLC, HPLC.Methods of Treatment and Medical Uses, Pharmaceutical compositions, and combinations

[0169] The present invention also provides methods for the treatment or prevention of a proliferative disease (e.g., cancer, benign neoplasm, angiogenesis) in a subject. Such methods comprise the step of administering to the subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.

[0170] The subject being treated is a mammal. The subject may be a human. The subject may be a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. The subject may be a companion animal such as a dog or cat. The subject may be a livestock animal such as a cow, pig, horse, sheep, or goat. The subject may be a zoo animal. The subject may be a research animal such as a rodent, dog, or non-human primate. The subject may be a non- human transgenic animal such as a transgenic mouse or transgenic pig.

[0171] The proliferative disease to be treated or prevented using the compounds of Formula (I) will typically be associated with aberrant activity of SMARCA2. Aberrant activity of SMARCA2 may be an elevated and / or an inappropriate (e.g., abnormal) activity of SMARCA2. In certain embodiments, SMARCA2 is not overexpressed, and the activity of SMARCA2 is elevated and / or inappropriate. In certain other embodiments, SMARCA2 is overexpressed, and the activity of SMARCA2 is elevated and / or inappropriate. The compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, may inhibit the activity of SMARCA2 and be useful in treating and / or preventing proliferative diseases.

[0172] A proliferative disease may also be associated with inhibition of apoptosis of a cell in a biological sample or subject. All types of biological samples described herein or known in the art are contemplated as being within the scope of the invention. Inhibition of the activityof SMARCA2 is expected to cause cytotoxicity via induction of apoptosis. The compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, may induce apoptosis, and therefore, be useful in treating and / or preventing proliferative diseases.

[0173] In certain embodiments, the proliferative disease to be treated or prevented using the compounds of the present disclosure is cancer.

[0174] The cell described herein may be an abnormal cell. The cell may be in vitro or in vivo. The cell may be a proliferative cell.

[0175] In another aspect, the present invention provides methods of downregulating the expression of SMARCA2 in a biological sample or subject.

[0176] In yet another aspect, the present invention provides the compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, for use in the treatment of a proliferative disease in a subject. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inhibiting cell growth. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inducing apoptosis in a cell. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inhibiting transcription.

[0177] One skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is the amount sufficient to have therapeutic activity and that this amount varies inter alias, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, the amount of a compound of the present invention to be administered as a therapeutic agent for treating the disorders referred to herein will be determined on a case by case by an attending physician.

[0178] Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount may be from about 0.005 mg / kg to 50 mg / kg body weight. The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect may vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakesper day. In these methods of treatment, the compounds according to the invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.

[0179] While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

[0180] The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington’s Pharmaceutical Sciences (18thed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, or a nose spray. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises apenetration enhancing agent and / or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and / or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.

[0181] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions, or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

[0182] The exact dosage and frequency of administration depends on the particular compound used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the instant invention.

[0183] The methods described herein may also comprise the additional step of administering one or more additional pharmaceutical agents in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof. Thus, the combination of the inventive compounds or compositions and the additional pharmaceutical agent(s) may be useful in treating proliferative diseases resistant to a treatment using the additional pharmaceutical agent(s) without the inventive compounds or compositions.

[0184] Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound according to the present invention and one or more additional therapeutic agents, as well as administration of the compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, a compound according to the present invention and atherapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

[0185] Therefore, an embodiment of the present invention relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more anticancer agent, as a combined preparation for simultaneous, separate, or sequential use in the treatment of patients suffering from cancer.

[0186] The one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated, and the particular host being treated. The optimum method and order of administration and the dosage amounts, and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.

[0187] The weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of Formula (I) and another anticancer agent may range from 1 / 10 to 10 / 1, more in particular from 1 / 5 to 5 / 1, even more in particular from 1 / 3 to 3 / 1.EXAMPLES

[0188] The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. All literature citations in these examples and throughout this specification are incorporated herein by references for all legal purposes to be served thereby. The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0189] When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained.

[0190] For intermediates that may be used in a next reaction step as a crude or as a partially purified intermediate, theoretical mol amounts may be indicated in the reaction protocols described below.

[0191] Hereinafter, “DCM” and “CH2C12”means dichloromethane; “r.t.” means room temperature; “Boc” means / c / V-butoxy carbonyl; “CH3CN”and “ACN” means acetonitrile; “MeOH” means methanol; “EtOH” means ethanol; “iPrOH” means isopropanol; “DMF” means dimethylformamide; “iPrNHi” means isopropylamine; “SOCh” means thionylchloride; “EtsN” means triethylamine; “NH4OAC” means ammonium acetate; “NH4OH” means ammonium hydroxide; “NH4CI” means ammonium chloride;“NaBH(OAc)3” means sodium triacetoxyborohydride; “POCh” means phosphorus oxychloride; “RuPhos Pd G3” means (2-Dicyclohexylphosphino-2',6'-diisopropoxy-l,r- biphenyl)(2-(2’ -amino- l,r-biphenyl))palladium(II) methanesulfonate; “Na2CC>3” means sodium carbonate; “KHSO4” means potassium hydrogenasulfate, “HBTU” means 2-(lH- Benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate; “EA” means ethylamine; “NH4HCO3” means ammonium bicarbonate; “TFA” means trifluoroacetic acid; “THF” means tetrahydrofuran; “h” means hours; “RM” means reaction mixture; “SFC” means Supercritical fluid chromatography; “Bredereck’s reagent” means / c / V-Butoxy bis(dimethylamino)methane; ’’AcOEt” means ethyl acetate; “K2CO3” means potassium carbonate; “MgSCE” means magnesium sulfate; “BOC2O” means di -tert-butyl decarbonate.

[0192] Example A: Preparation of the Intermediates and the final Compounds, and characterization thereof

[0193] Several methods for preparing the Compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods.Table 1: Abbreviations.

[0194] As understood by a person skilled in the art, Compounds synthesized using the protocols as indicated may contain residual solvent or minor impurities.

[0195] A skilled person will realize that, even where not mentioned explicitly in the experimental protocols below, typically after a column chromatography purification, the desired fractions were collected and the solvent was evaporated.

[0196] In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context.EXAMPLES

[0197] In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0198] Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were “dried,” they were generally dried over a drying agent such as Na2SC>4 or MgSC>4. Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure.

[0199] The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time... ) in order to obtain ionsallowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+(protonated molecule) and / or [M-H]' (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]', etc). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

[0200] Some NMR experiments were carried out using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe head with z gradients and operating at 500 MHz for the proton and 125 MHz for carbon. Some NMR experiments were carried out using a Bruker Avance III 400 spectrometer, using internal deuterium lock and equipped with reverse double-resonance (' H.13C, SEI) probe head with z gradients and operating at 400 MHz for the proton. Experiments were performed at ambient temperature (298.6 K), unless otherwise mentioned. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. Definitions for 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 = double of quartets, dp = doublet of pentets, td = triplet of doublets, tt = triplet of triplets, ddd = doublet of doublet of doublets, m = multiplet, br = broad. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution.Preparation of intermediates

[0201] For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below.

[0202] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem Vl.4.0.4 (Open Eye).

[0203] Compounds designated as *R or *S are enantiopure compounds where the absolute configuration was not determined.Intermediate 1: (2-chloro-l,6-naphthyridin-7-yl)methanamine.

[0204] Step A: 7-vinyl-l,6-naphthyridin-2(lH)-one. 7-Bromo-l,6-naphthyridin-2(lH)-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 eq.), bis(triphenylphosphine)palladium(II) chloride (CAS [13965-03-2], 434 mg, 0.619 mmol, 0.06 eq.), and CS2CO3 (10.077 g, 30.928 mmol, 3 eq.) were dissolved in THF (40 mL) and water (10 mL) under nitrogen atmosphere. The mixture was stirred at 80 °C for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and water was added. The layers were separated, and the organic layer was dried on MgSO4. filtered, and evaporated. The residue was purified by flash column chromatography (80 g; SiCh; EtOAc / heptane 10 / 90 to 100 / 0) to yield the title compound (1150 mg, yield: 64 %) as a white solid.

[0205] Step B: 2-chloro-7-vinyl-l,6-naphthyridine. POCh (1.86 mL, 20.037 mmol, 3 eq.) was added to a suspension of 7-vinyl-l,6-naphthyridin-2(lH)-one (1.15 g, 6.679 mmol) in 1,2- di chloroethane (34 mL). The mixture was stirred at 80 °C for 16 h. The mixture was diluted with aqueous Na2CO3 and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 x). The combined organic layer was dried (MgSO4), filtered, and evaporated to yield the title compound (1.16 g, yield: 90 %) as an orange solid, used without further purification.

[0206] Step C: 2-chloro-l,6-naphthyridine-7-carbaldehyde. 2-chloro-7-vinyl-l,6- naphthyridine (1.16 g, 6.064 mmol) and 2,6-lutidine (1.41 mL, 12.128 mmol, 2 eq.) were dissolved in water (6 mL) and 1,4-dioxane (23 mL). NaIO4 (5.19 g, 24.257 mmol, 4 eq.) and OsO4 (38 mg, 0.152 mmol, 0.025 eq.) were added at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCCh and extracted with DCM several times. The combined organic layer was dried over MgSO4. filtered, and evaporated to yield the title compound (820 mg, yield: 63 %) as a dark brown solid used without further purification.

[0207] Step D: (2-chloro-l,6-naphthyridin-7-yl)methanol. A solution of 2-chloro-l,6- naphthyridine-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 eq.) was added. The reaction mixture was stirred at room temperature for 20 min. The mixture was diluted with water and extracted with EtOAc.The organic layer was dried (Na2SC>4), filtered, and evaporated. The residue was purified by flash column chromatography (80 g SiCh; DCM:MeOH (9:1) in DCM 0 / 100 to 20 / 80) to yield the title compound (387 mg, yield: 51 %) as a white solid.

[0208] Step E: (2-chloro-l,6-naphthyridin-7-yl)methyl methanesulfonate. EtsN (114 pL, 0.832 mmol, 1.2 eq.) was added to a solution of (2-chloro-l,6-naphthyridin-7-yl)methanol (135 mg, 0.694 mmol) in DCM (5 mL) at room temperature. Then, MsCl (59μL, 0.763 mmol, 1.1 eq.) was added portion-wise at 0 °C and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo to yield the title compound (190 mg, yield: 95 %) as a brown oil, used without further purification.

[0209] Step F: 7-(azidomethyl)-2-chloro-l,6-naphthyridine. Sodium azide (59 mg, 0.906 mmol, 1.3 eq.) was added to a solution of (2-chloro-l,6-naphthyridin-7-yl)methyl methanesulfonate (190 mg, 0.697 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were dried over MgSOi and concentrated in vacuo to yield the title compound as a brown oil. The product was used as such in next step.

[0210] Step G: (2-chloro-l,6-naphthyridin-7-yl)methanamine. Triphenylphosphine (252 mg, 0.963 mmol, 1.4 eq.) was added to a solution of 7-(azidomethyl)-2-chloro-l,6-naphthyridine (151 mg, 0.688 mmol) in dry THF (5 mL). The mixture was stirred at room temperature for 1 h. Additional triphenylphosphine (90 mg, 0.343 mmol, 0.5 eq.) was added and the mixture was stirred at room temperature for 1.5 h. Water (2 mL) was added and the mixture was stirred at room temperature for 16 h. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (12 g silica; gradient of DCM / MeOH / NHs (9 / 1 / 0.25) in DCM from 0 to 60 %) to yield the title compound (50 mg, yield: 38 %) as a brown oil.Intermediate 2: tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate.Method 1:

[0211] Boc anhydride (7.486 g, 34.301 mmol, 1.1 eq.) followed by EtsN (13 mL, 93.548 mmol, 3 eq.) were added portion wise to a suspension of (2-chloro-l,6-naphthyridin-7- yl)methanamine (Intermediate 1, HC1 salt, 7.175 g, 31.183 mmol) in dry DCM (200 mL) atroom temperature under nitrogen atmosphere. The resulting solution was stirred at room temperature for 2.5 h. 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 layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 20:80) to give the title compound (6.1 g, yield: 67 %) as a white solid.Method 2:

[0212] Step A: 2-oxo-l,2-dihydro-l,6-naphthyridine-7-carbonitrile. Into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DMA (2.24 L), Pd(dppf)C12.CH2C12 (CAS [95464-05-4], 22.4 g, 0.1 eq.), 7-chloro-177-l,6- naphthyridin-2-one (CAS [1345091-18-0], 224 g, 1240.37 mmol), zinc (16.22 g, 248.07 mmol, 0.2 eq.), and zinc cyanide (145.65 g, 1240.37 mmol, 1 eq.). The resulting solution was stirred for 4 h at 100 °C. The reaction mixture was cooled to room temperature. The solids were filtered out and washed with 2 x 100 mL of DMA. The reaction was then quenched by the addition of 5 L of water / ice. The solids were collected by filtration to afford the title compound (147 g, yield: 69 %) as a brown solid.

[0213] Step B: 2-chloro-l,6-naphthyridine-7-carbonitrile. Into a 2-L 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed phosphorus oxychloride (1.47 L) and 2-oxo-l,2-dihydro-l,6-naphthyridine-7-carbonitrile (147.00 g, 858.85 mmol). The resulting solution was stirred for 3 h at 80 °C. The reaction mixture was concentrated. The resulting solution was diluted with 2 L of DCM. The reaction was then quenched by the addition of 4 L of water / ice. The resulting solution was extracted with 3 x 3 L of DCM, the organic layer was dried over Na2SC>4, and concentrated to afford the title compound (58 g, yield: 36 %) as a yellow solid.

[0214] Step C: tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate. Into a 5-L 4- necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DCM (1.74 L), 2-chloro-l,6-naphthyridine-7-carbonitrile (58 g, 305.90 mmol). This was followed by the dropwise addition over 30 min of DIBAL-H (1 N, 765 mL, 2.5 eq.) while stirring at -78 °C. The resulting solution was stirred for 2 h at -78 °C. To this was added potassium sodium tartrate (Rochelle Salt) (257 g, 1224 mmol, 4 eq.) at -78 °C. The resulting solution was stirred for 1 h at room temperature. This was followed by the addition of di-tert- butyl dicarbonate (73.3 g, 336.50 mmol, 1.1 eq.). The resulting solution was stirred overnight at room temperature. The solids were filtered out and washed with 3 x 300 mL of DCM. Thefiltrate was concentrated. The residue was purified by column chromatography on silica gel (EtOAc / petroleum ether 1 / 3 to 1 / 2) to afford the title compound (60.9 g, yield: 68 %) as a yellow solid.Intermediate 9: tert-butyl ((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate.

[0215] A suspension of tert-butyl ((2-chloro-l,6-naphthyridin-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 eq.), and sodium carbonate (10716 mg, 101.105 mmol, 3 eq.), in 1,4-di oxane (90 mL) and water (30 mL) was degassed by bubbling nitrogen through for 5 min. Bis(triphenylphosphine)palladium(II) chloride (CAS [13965-03-2], 1183 mg, 1.685 mmol, 0.05 eq.) was added and the mixture was further degassed with nitrogen for 5 min. The reaction mixture was stirred at 90 °C overnight under nitrogen atmosphere. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The solid residue was triturated in Et20 and filtered. The white solid was washed with a small amount of Et20 to give Intermediate 9 (7.47 g, yield: 58 %) as a white solid.Intermediate 10: tert-butyl ((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)carbamate.

[0216] A suspension of Intermediate 9 (5208 mg, 11.169 mmol), cA-2,6-dimethylmorpholine (CAS [6485-55-8], 5.7 mL, 44.676 mmol, 4 eq.), and DIPEA (5.8 mL, 33.507 mmol, 3 eq.) in dry DMSO (20 mL) was distributed in two thick wall vials. The vials were sealed and the reaction mixture was stirred at 130 °C overnight. The reaction mixture was diluted with waterand EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4. filtered, and evaporated. The residue was triturated in DCM / Et2O 1 / 1. The solid was filtered and washed with a small amount of Et20. This solid was combined with the filtrate and was purified by column chromatography (Biotage Sfar 200 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 20:80) to give Intermediate 10 (5.1 g, quantitative).Intermediate 11 : (2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methanamine.

[0217] HC1 (37 % in H2O, 40 mL, 484.24 mmol, 20 eq.) was added dropwise (1 drop / sec, slightly exothermic) to ayellow suspension of Intermediate 10 (10.85 g, 24.135 mmol) in 1,4- di oxane (100 mL) at room temperature. The reaction mixture turned red then yellow again and was stirred at room temperature for 16 h. The yellow suspension was evaporated to dryness and the residue was co-evaporated several times with toluene to give Intermediate 11 (HC1 salt, 12 g, quantitative) as an orange solid, dried under vacuum at 50 °C.Intermediate 15: 4-methyl-3-((3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)sulfonyl)benzoic acid.

[0218] Step A: methyl 4-methyl-3-((3-((tetrahydro-2H-pyran-2- yl)oxy)propyl)sulfonyl)benzoate. 1,10-Phenanthroline (CAS [66-71-7], 55 mg, 0.308 mmol, 0.17 eq.), PPhs (81 mg, 0.29 mmol, 0.16 eq.), K2S2O5 (906 mg, 4.075 mmol, 2.25 eq.), sodium formate (308 mg, 4.528 mmol, 2.5 eq.), and tetrabutylammonium bromide (730 mg, 2.264 mmol, 1.25 eq.) 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 through for 20 min. Pd(OAc)2 (23 mg, 0.101 mmol, 0.06 eq.) was addedand the reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, 2- (3-bromopropoxy)tetrahydro-2H-pyran (394μL, 2.21 mmol, 1.2 eq.) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. 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 SiCh; EtOAc / heptane 0 / 100 to 50 / 50) to afford the title compound (1.359 g, yield: 43 %) as an orange oil.

[0219] Step B: 4-methyl-3-((3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)sulfonyl)benzoic acid. NaOH (1 M in water, 1.35 mL, 1.347 mmol, 2 eq.) was added to solution of methyl 4-methyl- 3-((3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)sulfonyl)benzoate (240 mg, 0.673 mmol) in EtOH (4 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (20 mL). KHSO4 (1 M in water, 2.1 mL) was added dropwise over 10 min. with vigorous stirring. The pH reached 2-3. EtOAc was added and the mixture was stirred for 2 min. The layers were separated and the organic layer was dried on MgSO4, filtered, and concentrated in vacuo to afford Intermediate 15 (125 mg, yield: 54 %), as a white oil, used without further purification.Intermediate 19: 3-chloro-4-methyl-5-(methylsulfonyl)benzoic acid.

[0220] Step A: methyl 3-chloro-4-methyl-5-(methylsulfonyl)benzoate. 1,10-Phenanthroline (CAS [66-71-7], 197 mg, 1.095 mmol, 0.17 eq.), PPh3(287 mg, 1.031 mmol, 0.16 eq.), K2S2O5 (3222 mg, 14.492 mmol, 2.25 eq.), sodium formate (1095 mg, 16.102 mmol, 2.5 eq.), and tetrabutyl ammonium bromide (2595 mg, 8.051 mmol, 1.25 eq.) 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 through for 20 min. Pd(OAc)2 (81 mg, 0.361 mmol, 0.06 eq.) was added and the reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, methyl iodide (489μL, 7.858 mmol, 1.2 eq.) was added. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water, dried on MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (25 gSiCh; EtOAc / heptanes 0 / 100 to 50 / 50 ) to afford the title compound (638 mg, yield: 38 %) as a white solid.

[0221] Step B: 3-chloro-4-methyl-5-(methylsulfonyl)benzoic acid. NaOH (1 M in water, 3.8 mL, 3.808 mmol, 1.6 eq.) was added to solution of methyl 3-chloro-4-methyl-5- (methylsulfonyl)benzoate (638 mg, 2.38 mmol) in MeOH (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water and KHSO4 (1 M in water) was added, reaching a pH ~2-3. The mixture was extracted with EtOAc. The organic layer was dried on MgSO4. filtered, and concentrated in vacuo to give the title compound (546 mg, yield: 83 %) as a white solid, used without further purification.Intermediate 28: 3-(l,l-difluoroethyl)-4-fluorobenzoic acid.

[0222] NaOH (5 M in water, 0.61 mL, 3.049 mmol, 5.6 eq.) was added to a stirred solution of 3-(l,l-difluoroethyl)-4-fluorobenzonitrile (CAS [1253792-43-6], 100 mg, 0.54 mmol) in EtOH (2 mL) at room temperature. The mixture was stirred at reflux for 17 h. Na2CO3 (1 M in water) was added and the mixture was extracted with DCM. The aqueous layer was acidified until pH = 2-3 with HC1 (37 % in water) and extracted with DCM. The organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo to yield the 1:1 mixture of 3- (l,l-difluoroethyl)-4-fluorobenzoic acid (Intermediate 28) and 3-(l,l-difluoroethyl)-4- ethoxybenzoic acid (Intermediate 29) (112 mg) as an oil, used without further purification.Intermediate 29: 3-(l,l-difluoroethyl)-4-ethoxybenzoic acid.

[0223] The title compound was isolated from the reaction mixture from Intermediate 28, (112 mg) as an oil, used without further purification.Intermediate 37: 4-cyclopropyl-3-(l-hydroxyethyl)benzoic acid.

[0224] Under nitrogen atmosphere, 3-bromo-4-cyclopropylbenzoic acid (350 mg, 1.452 mmol) was dissolved in dry THF (9 mL) and the reaction mixture was cooled to -78 °C. After 10 min, n-BuLi (2.5 M in hexanes, 1.16 mL, 2.904 mmol, 2 eq.) was added dropwise and the reaction mixture was stirred at -78 °C for 20 min. A solution of acetaldehyde (163μL, 2.904 mmol, 2 eq.) in dry THF (1 mL) was then added dropwise and the reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous NH4CI and the mixture was diluted with DCM and water. The layers were separated and the organic layer was concentrated in vacuo. The residue was purified by flash column chromatography (silica; DCM:MeOH (9:1) in DCM, 0 / 100 to 20 / 80) to yield Intermediate 37 (179 mg, yield: 57 %) as a white solid.Intermediate 41 : (2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methanamine.

[0225] HC1 (37 % in H2O, 47 mL, 588.7 mmol, 20 eq.) was added dropwise (1 drop / sec, slightly exothermic) to a light brown solution of Intermediate 9 (10 g, 27.94 mmol) in 1,4- dioxane (300 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The precipitate that appeared during the reaction was filtered and the solid was washed with dioxane to give Intermediate 41 (HC1 salt, 8.3 g, quantitative) as a grey solid, dried under vacuum at 50 °C and used without further purification.Intermediate 43: 3-chloro-5-(2-hydroxypropan-2-yl)benzoic acid.

[0226] Step A: methyl 3-chloro-5-(2-hydroxypropan-2-yl)benzoate. Under nitrogen atmosphere, 3-chloro-5-iodobenzoic acid methyl ester (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 andstirred for 10 min. i-PrMgCl (2 M in THF, 1.212 mL, 2.425 mmol, 1.44 eq.) was added dropwise and the reaction mixture was stirred at -50 °C for 2 h. After cooling to -78 °C, a solution of acetone (250μL, 3.373 mmol, 2 eq.) in dry THF (1 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for 1 h. The solvent was removed under vacuum, DCM was added, and the reaction mixture was washed with saturated aqueous NaHCO3. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography (silica; EtOAc in heptane 0 / 100 to 30 / 70) to yield impure title compound (350 mg, 25 % pure, yield: 23 %) as a colorless oil, used without further purification.

[0227] Step B: 3-chloro-5-(2-hydroxypropan-2-yl)benzoic acid. NaOH (1 M in water, 765 pL, 0.765 mmol, 2 eq.) was added to solution of methyl 3-chloro-5-(2-hydroxypropan-2- yl)benzoate (25 % pure, 350 mg, 0.383 mmol) in MeOH (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and aqueous KHSO4 (1 M) was added dropwise over 10 min with vigorous stirring. The pH reached 2-3. EtOAc was added and the mixture was stirred for 2 min. The layers were separated and the organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g SiO2, DCM:Methanol (9:1) in DCM, 0 / 100 to 40 / 60) to yield Intermediate 43 (80 mg, yield: 96 %) as a white solid.Intermediate 44: 3-chloro-N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-(2- hydroxypropan-2-yl)benzamideMethod AA

[0228] Intermediate 43 (126 mg, 0.588 mmol, 1.15 eq.) and DIPEA (267μL, 1.534 mmol, 3 eq.) were added to a solution of Intermediate 41 (130 mg, 0.511 mmol) in DMF (5 mL). The reaction mixture was stirred for 1 min before addition of HATU (243 mg, 0.639 mmol, 1.25 eq.). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and was extracted with DCM (3 x). The combinedorganic layer was dried on MgSO4. filtered, and concentrated in vacuo. The residue was recrystallized in ACN, filtered, washed with Et2O, and dried in vacuo to yield Intermediate 44 (184 mg, yield: 79 %) as a white solid.

[0229] The compounds in Table 3 were prepared from Intermediate 41 and the corresponding acid, following procedures similar to the methods shown in Table 3. *reaction mixture work- up conditions may vary.Table 3

[0230] The Intermediates in Table 4 were prepared from Intermediate 11 and the corresponding acid, following procedures similar to the methods shown in Table 4. *reaction mixture work-up conditions may vary. Table 4Intermediate 45: N-((2-chloro-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide.

[0231] A solution of 4-methyl-3-(methylsulfonyl)benzoyl chloride (CAS [1146702-14-8], 4477 mg, 19.24 mmol, 1 eq.) in dry DCM (50 mL) was added to a solution of (2-chloro-l,6- naphthyridin-7-yl)methanamine (Intermediate 1) (5129 mg, 19.24 mmol, 1 eq.) in dry DCM (200 mL) at 0 °C under nitrogen atmosphere. After 5 min, DIPEA (11.730 mL, 67.34 mmol, 3.5 eq.) was added dropwise at 0 °C, under nitrogen atmosphere. The dark brown reaction mixture was stirred at room temperature for 1 h. 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 layer was dried on MgSO4. filtered, and evaporated. The residue was triturated in warm DCM. After cooling, the solid was filtered and washed with cold DCM to give Intermediate 45 (4485 mg, yield: 60 %) as an off-white solid, dried under vacuum at 50Intermediate 46: N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide.

[0232] Intermediate 45 (1.1 g, 2.596 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (CAS [842136-58-7], 0.81 g, 3.634 mmol, 1.4 eq.) and Na2CO3 (825 mg, 7.787 mmol, 3 eq.) were dissolved in 1,4-dioxane (10 mL) and water (5 mL) atroom temperature in a thick wall vial. The mixture was degassed by bubbling with nitrogen for 10 min. Then, bis(triphenylphosphine)palladium(II)chloride (CAS [13965-03-2], 91 mg, 0.13 mmol, 0.05 eq.) was added and the mixture was stirred at 85 °C overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried, and concentrated in vacuo to give Intermediate 46 (810 mg, 68 % pure, yield: 47 %), used without further purification.Intermediate 49: 3-chloro-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzoic acid.

[0233] Step A: methyl 3-chloro-4-methyl-5-((2-((tetrahydro-2H-pyran-2- yl)oxy)ethyl)sulfonyl)benzoate. 1,10-Phenanthroline (CAS [66-71-7], 392 mg, 2.175 mmol, 0.17 eq.), triphenylphosphine (570 mg, 2.047 mmol, 0.16 eq.), potassium metabisulfite (6.4 g, 28.78 mmol, 2.25 eq.), sodium formate (2.175 g, 31.98 mmol, 2.5 eq.) and tert-butyl ammonium bromide (5.15 g, 15.99 mmol, 1.25 eq.) were added to a solution of methyl 3- chl oro-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 through the solution for 20 min. Palladium (II) acetate (161 mg, 0.716 mmol, 0.06 eq.) was added, the reaction mixture was heated at 100 °C for 3 h. After cooling to room temperature, 2-(2- bromoethoxy)tetrahydro-27 / -pyran. CAS [17739-45-6], 2.36 mL, 1.22 eq.) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. 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 SiCh; EtOAc in heptanes 0 / 100 to 60 / 40) to afford the title compound (1.92 g, yield: 39 %) as an oil.

[0234] Step B: methyl 3-chloro-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzoate. HC1 (37 % in water, 0.4 mL, 5.1 mmol, 1 eq.) was added to 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 min. Aqueous 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 layer was dried overMgS04, filtered, and concentrated to afford the title compound (1.49 g, yield: 93 %) as a solid, used without further purification.

[0235] Step C: 3-chloro-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzoic acid.LiOH»H2O (278 mg, 6.625 mmol, 10 eq.) was added to a solution of Intermediate 48 (198 mg, 0.66 mmol) in THF (2 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. IM aq. HC1 was added to adjust the pH to <2, then the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford the title compound (120 mg, yield: 65 %), which was used without further purification.Intermediate 50: 3-chloro-5-((2-hydroxyethyl)sulfonyl)benzoic acid.

[0236] The title compound was prepared in a manner analogous to Intermediate 49, using methyl 3-chloro-5-iodo-benzoate (CAS [289039-85-6]) instead of methyl 3-chloro-5-iodo-4- methylbenzoate in Step A.Intermediate 61 : N-((2-(6-((cis)-4-((tert-butyldimethylsilyl)oxy)-3-methylpiperi din-1- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.Relative configuration-CTS', mixture of 2 stereoisomers

[0237] Intermediate 61 was prepared in a manner analogous to Compound 45, Method J, starting from Intermediate 46 and re / -(3R,4S)-4-[[(l,l-dimethylethyl)dimethylsilyl]oxy]-3- methylpiperidine (CAS [1610033-91-4]).Intermediate 65: 4-cyclopropyl-N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3- (methylsulfonyl)benzamide.

[0238] A mixture of Intermediate 53 (140 mg, 0.272 mmol), potassium cyclopropyltrifluoroborate (CAS [1065010-87-8], 121 mg, 0.815 mmol, 3 eq.), and Na2CO3 (115 mg, 1.087 mmol, 4 eq.) in 1,4-dioxane (6 mL) and water (1.5 mL). The mixture was degassed by bubbling nitrogen for 15 min. Pd(dppf)Ch.DCM (CAS [95464-05-4], 24 mg, 0.027 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80 °C for 16 h under a nitrogen stream. More potassium cyclopropyltrifluoroborate (60 mg, 0.407 mmol, 1.5 eq) and Na2CO3 (57 mg, 0.543 mmol, 2 eq.) were added to the reaction mixture. The mixture was again degassed with nitrogen for 10 min, and Pd(dppf)Ch.DCM (24 mg, 0.027 mmol, 0.1 eq.) was added. The reaction mixture was stirred at 80 °C for 16 h. After cooling, the reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO4. filtered, and the solvents were evaporated in vacuo. The residue was purified by flash column chromatography (silica 12 g, DCM:MeOH (9:1) in DCM 0 % to 30 %) to yield Intermediate 65 (47 mg, yield: 36 %) as a yellow solid.Intermediate 67 : N-((2-chloro-l,6-naphthyridin-7-yl)methyl)-3,4-dimethyl-5- (methylsulfonyl)benzamide.

[0239] Intermediate 67 was prepared in a manner analogous to Intermediate 44, starting from (2-chloro-l,6-naphthyridin-7-yl)methanamine (Intermediate 1) and 3-methanesulfonyl-4,5- dimethylbenzoic acid (CAS [15110466-4]).Intermediate 68: N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3,4-dimethyl-5- (methylsulfonyl)benzamide.

[0240] 2-Fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (CAS [842136-58- 7], 503 mg, 2.255 mmol, 1.8 eq.) and Na2CO3 (1 M in water, 3.8 mL, 3.8 mol, 3 eq.) were added to a solution of Intermediate 67 (506 mg, 1.253 mmol) in 1,4-dioxane (50 mL) previously degassed by bubbling nitrogen, at room temperature. Pd(dppl)C12.CH2C12 (CAS [95464-05-4], 51 mg, 0.063 mmol, 0.1 eq.) was added, and the mixture was stirred at 90 °C under nitrogen stream for 16 h. After cooling, water was added and the mixture was extracted with EtOAc, dried over MgSO4 f,iltered, and concentrated to dryness. The residue was purified by flash column chromatography (25 g silica column, EtOAc in heptane from 0 / 100 to 100 / 0) to yield Intermediate 68 (263 mg, yield: 45 %) as a brown solid.Intermediate 69: 2-((2-chloro-l,6-naphthyridin-7-yl)methyl)isoindoline-l, 3-dione.

[0241] A solution of (2-chloro-l,6-naphthyridin-7-yl)methanol (Intermediate 1, product from Step D, 1.14 g, 5.858 mmol), phthalimide (948 mg, 6.443 mmol, 1.1 eq.), and triphenylphosphine (1.844 g, 7.029 mmol, 1.2 eq.) in dry THF (45 mL) was degassed by bubbling with nitrogen. DIAD (1.384 mL, 7.029 mmol, 1.2 eq.) dissolved in toluene (2 mL) was added dropwise to the reaction mixture. Stirring was continued for 2 h at room temperature. The mixture was diluted with water and EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was triturated in ACN and the solid was filtered, washed with Et20, and dried in vacuo to yield Intermediate 69 (1.46 g, yield: 73 %) as a white solid.Intermediate 70: 2-(((2-(6-fluoro-4-methylpyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)carbamoyl)benzoic acid.

[0242] 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 eq.), and Na2CO3(128 mg, 1.205 mmol, 3 eq.) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) at room temperature. The mixture was degassed by bubbling nitrogen for 10 min.Bis(triphenylphosphine)palladium(II)chloride (CAS [13965-03-2], 14 mg, 0.020 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 85 °C for 3 h. The mixture was diluted with water and extracted twice with EtOAc. The aqueous layer was acidified with HC1 1 N until pH 4-5. A beige solid precipitated and was filtered, washed with DCM and Et2O, and dried in vacuo to yield Intermediate 70 (104 mg, yield: 58 %) as a beige solid.Intermediate 71 : (2-(6-fluoro-4-methylpyridin-2-yl)-l,6-naphthyridin-7-yl)methanamine.

[0243] Hydrazine hydrate (182μL, 3.746 mmol, 15 eq.) was added to a solution of Intermediate 70 (104 mg, 0.25 mmol) in EtOH (2 mL).The reaction mixture was stirred at 65 °C for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (x 3). The combined organic layer was dried (MgSCE), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g SiO2; DCM / MeOH / NHs (9 / 1 / 0.25) in DCM, from 0 % to 40 %) to yield Intermediate 71 (27 mg, yield: 36 %) as a white solid.Intermediate 72: N-((2-(6-fluoro-4-methylpyridin-2-yl)-l ,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

[0244] Intermediate 72 was according to Intermediate 44, starting from Intermediate 71 and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]).Intermediate 90: 2-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridine.

[0245] A mixture of 6-bromo-2-fluoro-3-methylpyridine (CAS [1211536-81-0], 800 mg, 4.21 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 1283 mg, 5.052 mmol, 1.2 eq.), Pd(dppf)C12.CH2Cl2(CAS [95464-05-4], 86 mg, 0.105 mmol, 0.02 eq.), and KOAc (1.24 g, 12.631 mmol, 3 eq.) in 1,4-dioxane (12 mL) was degassed by bubbling nitrogen for 15 min and then stirred under nitrogen at 90 °C for 6 h. After cooling, the mixture was filtered through a pad of Celite® and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (330 g silica column; gradient of EtOAc in heptane from 0 / 100 to 60 / 40) to yield Intermediate 90 (1.2 g, 80 % pure, yield: 86 %) as a yellow oil.Intermediate 91 : N-((2-(6-fluoro-5-methylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

[0246] Intermediate 45 (90 mg, 0.231 mmol), Intermediate 90 (105 mg, 0.332 mmol, 1.44 eq.), and Na2CO3 (73 mg, 0.693 mmol, 3 eq.) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) at room temperature in a pressure flask. The mixture was degassed by bubbling with nitrogen for 10 min. Pd(dppl)C12.CH2C12 (CAS [95464-05-4], 9 mg, 0.011 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 85 °C for 3 h. The mixture was diluted with water and extracted twice with EtOAc. The aqueous phase was acidified with aqueous HC1 (1 N) until pH 4-5. The beige solid that precipitated was filtered, washed with DCM and Et20, and dried in vacuo to yield Intermediate 91 (87 mg, yield: 77 %) as a beige solid.Intermediate 93 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l ,6-naphthyridin-7- yl)methyl)-4-methyl-3-((3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)sulfonyl)benzamide.

[0247] The title compound was prepared in a manner analogous to Intermediate 44, starting from Intermediate 11 and Intermediate 15.Intermediate 94: methyl 3-((7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)sulfonyl)propanoate.

[0248] tert-Butyl ((2-chloro-l,6-naphthyridin-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 eq.) and copper iodide (1.34 g, 7.013 mmol, 2 eq.) in DMSO (10 mL). The reaction mixture was stirred under nitrogen atmosphere at 110 °C for 1 h. After cooling, the reaction mixture was diluted with EtOAc and washed with water containing aqueous NFL (1 mL). The organic layer was separated, dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g column, gradient of EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 94 (801 mg, yield: 53 %) as an orange solid.Intermediate 96: (cis)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6-dimethylmorpholine.CIS

[0249] Step A: (cis)-4-(6-bromo-4-nitropyridin-2-yl)-2,6-dimethylmorpholine. 2,6-Dibromo- 4-nitropyridine (CAS [175422-04-5], 5 g, 17.737 mmol) and c7.s-2.6-dmiethyl morpholine (CAS [6485-55-8], 2.42 mL, 19.511 mmol, 1.1 eq.) were dissolved in toluene (140 mL) and the solution was degassed by bubbling with nitrogen for 15 min. CS2CO3 (8.67 g, 26.606 mmol, 1.5 eq.), rac-BINAP (CAS [98327-87-8], 1.10 g, 1.774 mmol, 0.1 eq.), and Pd(OAc)2(CAS [3375-31-3], 398 mg, 1.774 mmol, 0.1 eq.) were then added and the resulting mixture was stirred at reflux under nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 250 ml). The combined organic layer was washed with brine, dried over MgSCL. filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (120 g column, gradient of EtO Ac / heptane from 0 / 100 to 40 / 60) to give the title compound (3.2 g, yield: 56 %) as an orange solid.

[0250] Step B: (cis)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6-dimethylmorpholine. Tetramethylammonium fluoride (CAS [373-68-2], 663 mg, 7.117 mmol, 1.5 eq.) was added to a solution of (cis)-4-(6-bromo-4-nitropyridin-2-yl)-2,6-dimethylmorpholine (1500 mg, 4.745 mmol) in DMF (40 mL) in a sealed tube. The mixture was stirred for 3 h at 65 °C. The reaction was quenched by addition of water and the mixture was extracted with EtO Ac. The organic layer was washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (80 g column, gradient of EtO Ac / heptane from 0 / 100 to 30 / 70) to give Intermediate 96 (1139 mg, yield: 81 %) as an orange solid.Intermediate 97: tert-butyl ((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamate.CIS

[0251] Intermediate 94 (950 mg, 2.32 mmol), Intermediate 96 (1006 mg, 3.48 mmol, 1.5 eq.), and K2CO3 (481 mg, 3.48 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (24 mL) in a sealed tube under a nitrogen stream. Di- / c / 7-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 58 mg, 0.232 mmol, 0.1 eq.) and Pd(OAc)2(CAS [3375-31-3], 26 mg, 0.116 mmol, 0.05 eq.) were added and the reaction mixture was stirred at 150 °C for 4 h. Themixture was cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g column, gradient of EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 97 (428 mg, yield: 39 %) as a yellow solid.Intermediate 98: (2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthy ridin-7-yl)methanamine.

[0252] Intermediate 97 (428 mg, 0.906 mmol) was dissolved in a solution of HC1 (4 M in 1,4- dioxane, 2.27 mL, 9.063 mmol, 10 eq.) and 1,4-dioxane (40 mL) and the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue was triturated in Et20 to yield Intermediate 98 (HC1 salt, 406 mg, quantitative) as an orange solid.Intermediate 102: 3-chloro-5-((2-hydroxyethyl)sulfonyl)benzoic acid.

[0253] Intermediate 102 was prepared in a similar manner as Intermediate 49, starting from methyl 3-chloro-5-iodo-benzoate (CAS [289039-85-6]) instead of methyl 3-chloro-5-iodo-4- methylbenzoate.Intermediate 103: 3-((2-hydroxyethyl)sulfonyl)-5-methylbenzoic acid.

[0254] Intermediate 103 was prepared in a similar manner as Intermediate 49, starting from methyl 3-iodo-5-methylbenzoate (CAS [597563-45-6]) instead of methyl 3-chloro-5-iodo-4- methylbenzoate.Intermediate 104: 3-(hydroxymethyl)-5-(methylsulfonyl)benzoic acid.

[0255] LiOH(150 mg, 3.58 mmol) was added 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) at room temperature. The reaction mixture was stirred at room temperature for 16 h. IM aq. KHSO4 was added to adjust the pH to 3, then the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over MgSCL, filtered, and concentrated to afford Intermediate 104 (98 mg, yield: 55 %), which was used without further purification. Intermediate 105: 3-chloro-5-(l-hydroxyethyl)benzoic acid.

[0256] Intermediate 105 was prepared in a similar manner as Intermediate 15, starting from benzoic acid, 3-chloro-5-(l -hydroxyethyl)-, methyl ester (CAS [2438162-92-4]) instead of the product of Intermediate 15, Step A. Intermediate 121: tert-butyl ((2-(6-fluoro-3-methylpyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)carbamate.

[0257] Intermediate 121 was prepared in a similar manner as Intermediate 97, starting from 2- bromo-6-fluoro-3 -methylpyridine (CAS [1211536-01-4]) instead of Intermediate 96.Intermediate 123: (2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridin-2-yl)-l,6- naphthy ridin-7-yl)methanamine.CIS

[0258] Step A: tert-butyl ((2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamate. The title compound was prepared according to Method I, starting from Intermediate 121 and cA-2,6-dimethylmorpholine (CAS [6485-55-8]).

[0259] Step B: (2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridin-2-yl)-l,6-naphthyridin- 7-yl)methanamine. TFA (604μL, 7.895 mmol, 30 eq.) was added to a solution of tert-butyl ((2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)carbamate (122 mg, 0.263 mmol) in DCM (1.2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated to yield Intermediate 123 (TFA salt, 126 mg, assumed quantitative) as a brown oil, used as such without further purification.Intermediate 124: methyl 3-((7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyri din-2 -yl)sulfonyl)propanoate.

[0260] Intermediate 124 was prepared in a similar manner as Intermediate 94, starting from Intermediate 45 instead of tert-Butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2).Intermediate 127 : 5-chloro-7-((cis)-2,6-dimethylmorphohno)-2,3-dihydrofuro[2,3-c]pyridine.CIS

[0261] Step A: 7-chloro-2,3-dihydrofuro[2,3-c]pyridine 6-oxide. m-CPBA (946 mg, 4.111 mmol, 1.3 eq.) was added portion-wise over 15 min to a solution of 7-chloro-2,3- dihydrofuro[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 h. The reaction mixture was diluted with DCM (50 mL) and washed with 1 M aqueous Na2CO3 (50 mL). The aqueous layer was extracted again with DCM (50 mL). The combined organic layer was dried over MgSOi. filtered, and concentrated. The residue was purified by column chromatography over silica gel (25 g column, MeOH / DCM from 0 / 100 to 6 / 94) to afford the title compound (334 mg, yield: 59 %) as a white solid.

[0262] Step B: 5,7-dichloro-2,3-dihydrofuro[2,3-c]pyridine. Phosphorus oxychloride (1.8 mL, 19.466 mmol, 10 eq.) was added to Intermediate 125 (334 mg, 1.947 mmol) at room temperature. The reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was cooled to room temperature and was poured onto ice. Solid Na2CO3 was added until pH = 7. The mixture was extracted with DCM, dried (MgSO4). filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, 25g; EtOAc / heptane from 0 / 100 to 80 / 20) to yield the title compound (260 mg, 90 % pure, yield: 63 %) as a white solid.

[0263] Step C: 5-chloro-7-((cis)-2,6-dimethylmorpholino)-2,3-dihydrofuro[2,3-c]pyridine. ( 7.s-2.6-dimethylmorpholine (CAS [6485-55-8], 3.4 mL, 27.365 mmol, 20 eq.) was added to a stirred solution of 5,7-dichloro-2,3-dihydrofuro[2,3-c]pyridine (260 mg, 1.368 mmol) in DMSO (4 mL) at room temperature. The reaction mixture was stirred at 120 °C for 3 h. The mixture was cooled to room temperature, diluted with aqueous Na2CO3 (1 M) and extracted with EtOAc. The organic layer was dried (MgSO4). filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (80 g silica, EtOAc / heptane from 0 / 100 to 100 / 0) to yield Intermediate 127 (81 mg, yield: 22 %) as ayellow solid.Intermediate 129: (2-(6-(2,2,6,6-tetramethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methanamine.

[0264] Step A: tert-butyl ((2-(6-(2,2,6,6-tetramethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamate. The title compound was prepared according to Method J, starting from Intermediate 9 and 2,2,6,6-tetramethylmorpholine (CAS [19151-69-0]).

[0265] Step B: (2-(6-(2,2,6,6-tetramethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methanamine. HC1 (4 M in 1,4-dioxane, 4.3 mL, 17.127 mmol, 10 eq.) was added to a stirred solution of tert-butyl ((2-(6-(2,2,6,6-tetramethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-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 h. To push the reaction to completion, more HC1 (4 M in 1,4-dioxane, 4.3 mL, 17.127 mmol, 10 eq.) was added and the mixture was stirred at 50 °C for 16 h. The solvent was evaporated in vacuo to yield Intermediate 129 (HC1 salt, 448 mg, 86 % pure, quantitative) as an orange solid.

[0266] The compounds in Table 5 were prepared in a manner analogous to Intermediate 129, using Intermediate 9 and the corresponding amine, following procedures analogous to the methods shown in the table:Table 5Intermediate 135: 4-cyclopropyl-3-(methylsulfonyl)benzoic acid.

[0267] A solution of 4-bromo-3-(methylsulfonyl)benzoic acid (CAS [158608-01-6], 2.8 g, 10.032 mmol), potassium cyclopropyltrifluoroborate (CAS [1065010-87-8], 4.453 g, 30.096 mmol, 3 eq.), and NazCOs (6.38 g, 60.192 mmol, 6 eq.) in 1,4-dioxane (40 mL) and water (10 mL). The mixture was degassed by bubbling nitrogen for 15 min. Pd(dppf)Ch.DCM (CAS [95464-05-4], 904 mg, 1.003 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. To push the reaction to completion, more potassium cyclopropyltrifluoroborate (2.226 g, 15.048 mmol, 1.5 eq.) and NazCOs (2.13 g, 20.064 mmol, 2 eq.) were added to the reaction mixture and the mixture was degassed with nitrogen for 10 min. Pd(dppf)C12.DCM (904 mg, 1.003 mmol, 0.1 eq.) was then added and the mixture was stirred at 80 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated and the aqueous layer was acidified with HC1 (1 N in water) until pH 4-5, then extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvents evaporated in vacuo to yield Intermediate 135 (3.2 g, 75 % pure, quantitative) as a brown solid.Intermediate 138: 3-((2-hydroxyethyl)(methyl)amino)-4-methylbenzoic acid.

[0268] Step A: methyl 3-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-4-methylbenzoate. A solution of methyl 3-amino-4-methylbenzoate(CAS [18595-18-1], 100 mg, 0.605 mmol), (tert-butyldimethylsilyloxy)acetaldehyde (CAS [102191-92-4], 154μL, 0.726 mmol, 1.2 eq.) in DCM (2 mL) and AcOH (38μL, 0.666 mmol, 1.1 eq.) was stirred at room temperature for 30 min. NaBH(OAc)3 (257 mg, 1.211 mmol, 2 eq.) was then added and the reaction mixture was stirred at room temperature for 72 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over MgSO4 f,iltered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 12 g, EtOAc / heptane from 0 / 100 to 8 / 92) to yield the title compound (95 mg, yield: 46 %) as a colorless oil.

[0269] 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, 208μL, 2.79 mmol, 10 eq.), and AcOH (18μL, 0.307 mmol, 1.1 eq.) in DCM (1.5 mL) was stirred at room temperature for 30 min. NaBHsCN (53 mg, 0.837 mmol, 3 eq.) was then added and the mixture was stirred at room temperature for 16 h. To push the reaction to completion, more formaldehyde (37 % in water, 104μL, 1.395 mmol, 5 eq.) was added and the mixture was stirred at room temperature for 30 min. NaBHsCN (35 mg, 0.558 mmol, 2 eq.) was added and the mixture was stirred at room temperature for 4 h. Again, another batch of formaldehyde (37 % in water, 104μL, 1.395 mmol, 5 eq.) was added and the mixture was stirred at room temperature for 30 min. Finally, NaBHsCN (35 mg, 0.558 mmol, 2 eq.) was added and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over MgSO4 f,iltered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g; EtOAc / heptane from 0 / 100 to 10 / 90) to yield the title compound (57 mg, yield: 57 %) as a colourless oil.

[0270] Step C: 3-((2-hydroxyethyl)(methyl)amino)-4-methylbenzoic acid. NaOH (276 mg, 6.899 mmol, 12 eq.) 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 h. The reaction mixture was diluted with water and extracted with EtOAc. The aqueouslayer was neutralized with HC1 (1 M in water). This aqueous solution was then washed with EtOAc (x 3). The aqueous layer was evaporated and the residue was washed with DCM:MeOH (9:1). The washing solution was evaporated to yield Intermediate 138 (100 mg, 89 % pure, yield: 74 %) as a yellow solid, used without further purification.Intermediate 140: 3-(N-(2-hydroxyethyl)methylsulfonamido)-4-methylbenzoic acid.

[0271] Step A: methyl 3-(N-(2-hydroxyethyl)methylsulfonamido)-4-methylbenzoate. NaH (60 % in mineral oil, 154 mg, 3.847 mmol, 4 eq.) was added portion wise 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 nitrogen atmosphere. The reaction mixture was stirred at 5 °C for 30 min. Then, 2-bromoethoxy- / c / 7-butyl dimethylsilane (CAS [86864-60- 0], 1.24 mL, 5.771 mmol, 6 eq.) was added at 5 °C under nitrogen flow and the reaction mixture was stirred at room temperature for 16 h. More NaH (60 % in mineral oil, 77 mg, 1.924 mmol, 2 eq.) was added to the mixture at 0 °C and it was stirred at 0 °C for 30 min. Then, 2-bromoethoxy- / c77-butyl dimethylsilane (619μL, 2.886 mmol, 3 eq.) was added at 5 °C under nitrogen flow and the reaction mixture was stirred at 60 °C for 21 h. The mixture was and the residue was dissolved in HC1 (4 M in 1,4-dioxane, 4.8 mL, 19.24 mmol, 20 eq.) and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (silica 25 g; MeOH in DCM from 0 / 100 to 1 / 99) to yield the title compound (226 mg, 81 % pure, yield: 66 %) as a yellow oil.

[0272] Step B: 3-(N-(2-hydroxyethyl)methylsulfonamido)-4-methylbenzoic acid. NaOH (428 mg, 10.691 mmol, 12 eq.) was added to a stirred solution of methyl 3-(N-(2- hydroxyethyl)methylsulfonamido)-4-methylbenzoate (256 mg, 0.891 mmol) in MeOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with water and the pH was adjusted to 2-3 with HC1 (1 M in water). The mixture was evaporated in vacuo and the residue was washed with DCM:MeOH (9:1). The washing solution was evaporated in vacuo to yield Intermediate 140 (154 mg, 92 % pure, yield: 58 %), used without further purification.Intermediate 141 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-iodo-4-(trifluoromethyl)benzamide.CIS

[0273] HATU ([148893-10-1], 56 mg, 0.148 mmol, 1.3 eq.) was added 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 eq.) in dry DMF (1 mL) at room temperature. DIPEA (69μL, 0.398 mmol, 3.5 eq.) was then added dropwise to the suspension at room temperature. The reaction mixture became clear yellow and was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3, and evaporated to give Intermediate 141 (70 mg, 52 % pure, yield: 49 %) as a black solid, used without further purification.Intermediate 142: (cis)-4-(3-chloro-5,6,7,8-tetrahydroisoquinolin-l-yl)-2,6- dimethylmorpholine and Intermediate 143: (cis)-4-(l-chloro-5,6,7,8-tetrahydroisoquinolin-3- yl)-2,6-dimethylmorpholine.

[0274] ( 7.s-2.6-dimethylmorpholine (CAS [6485-55-8], 12 mL, 96.688 mmol, 23 eq.) was added to a solution of l,3-dichloro-5,6,7,8-tetrahydroisoquinoline (CAS [38969-63-0], 848 mg, 4.196 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 72 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g silica column, EtOAc / heptane from 0 / 100 to15 / 85) to yield Intermediate 142 (128 mg, yield: 11 %) and Intermediate 143 (236 mg, yield: 20 %), both as solids.Intermediate 144: 6-chloro-4-((cis)-2,6-dimethylmorpholino)-l,3-dihydrofuro[3,4-c]pyridine and Intermediate 145: 4-chloro-6-((cis)-2,6-dimethylmorpholino)-l,3-dihydrofuro[3,4- c] pyridine.

[0275] Intermediate 144 and Intermediate 145 were prepared in a similar manner as Intermediate 142 and Intermediate 143, respectively, starting from 4,6-dichloro-l,3- dihydrofuro[3,4-c]pyridine (CAS [754992-21-7]) instead of l,3-dichloro-5, 6,7,8- tetrahydroisoquinoline.Intermediate 152: 3,4-dimethyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonyl)benzoic acid.

[0276] Step A: methyl 3,4-dimethyl-5-((2-((tetrahydro-2H-pyran-2- yl)oxy)ethyl)sulfonyl)benzoate. The title compound was prepared in a similar manner as Intermediate 49 (step A), starting from methyl 3-iodo-4,5-dimethylbenzoate (CAS [1529736- 58-0]) instead of methyl 3-chloro-5-iodo-4-methylbenzoate.

[0277] Step B: 3,4-dimethyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonyl)benzoic acid. NaOH (1 M in water, 614μL, 0.614 mmol, 1 eq.) was added 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) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (20 mL). KHSO4 (1 M in water, 0.7 mL) was added dropwise over 10 min, with vigorous stirring (pH 2-3). The reaction mixture was extracted with EtOAc. The organic layer was dried with MgSO4. filtered, and concentrated to yield Intermediate 152 (132 mg, 70 % pure, yield: 44 %) as a white solid.Intermediate 153: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3,4-dimethyl-5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonyl)benzamide.CIS

[0278] Intermediate 153 was prepared according to Intermediate 44, starting fromIntermediate 11 and Intermediate 152.Intermediate 154: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3,4-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide.CIS

[0279] A solution of N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-3-iodo-4,5-dimethylbenzamide (Compound 27) (117 mg, 0.193 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 147 mg, 0.578 mmol, 3 eq.), and KOAc (57 mg, 0.578 mmol, 3 eq.) in dry DMF (3 mL) was degassed for 5 min. 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (CAS [95464-05-4,] 31 mg, 0.038 mmol, 0.2 eq.) was added and the solution was degassed for a further 5 min. The vial was sealed and was stirred at 100 °C for 2 h in a microwave oven. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried by filtration on ExtrelutNT3, and evaporated. The residue was purified by columnchromatography (Biotage Sfar 10 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 20:80) to give Intermediate 154 (108 mg, yield: 87 %) as ayellow solid.Intermediate 158: tert-butyl ((2-(3,6-difluoropyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)carbamate.

[0280] Intermediate 158 was prepared in a similar manner as Intermediate 97, using 2-bromo- 3,6-difluoropyridine (CAS [1382786-22-2]) instead of Intermediate 96.Intermediate 159: tert-butyl ((2-(6-((cis)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamate.CIS

[0281] To a solution of cis-2,6-dimethylmorpholine [CAS RN 6485-55-8] (37μL, O.mmol ) and DIPEA [7087-68-5] (0.7 mmol) in DMSO (1 mL) was added Intermediate 158 (94mg, 0.25mmol), the reaction mixture was stirred 16 h at 130 °C. The reaction mixture was diluted with saturated NaHCO3 aq. solution and was extracted with DCM (3x). The combined organic layers were dried with MgSO4. filtered, and concentrated in vacuo. Purification (flash column chromatography, 12g column, gradient of B (DCM / Methanol 9:1) in A (DCM)) [from 0% to 35% of B])). The desired fractions were collected and concentrated in vacuo, the impure product (250 mg) was purified by reverse phase chromatography using as column: Brand Phenomenex; Type Gemini; Product number OOD-4435-EO-AX; I.D. (mm) 100 x 30; Particle size 5um (C18) 110A; Installed Gilson 1. Method: MMP4BIC From 81:19 to 45:55 [25mM NH4HCO3] / [ACN:MeOH (1:1)]. The fractions were combined and evaporated in vacuo to yield the title compound and tert-butyl ((2-(3-((cis)-2,6-dimethylmorpholino)-6- fluoropyri din-2 -yl)- 1 ,6-naphthyri din-7 -yl)methyl)carbamate.Intermediate 160: (2-(6-((cis)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)-l,6- naphthy ridin-7-yl)methanamine.CIS

[0282] Intermediate 160 (TFA salt) was prepared in a similar manner as Intermediate 123, starting from Intermediate 159 instead of the product of Intermediate 123, step A.Intermediate 165: 4-cyclopropyl-3-(N,N-dimethylsulfamoyl)benzoic acid.

[0283] Step A: 3-(chlorosulfonyl)-4-cyclopropylbenzoic acid. 4-Cyclopropylbenzoic acid (CAS [1798-82-9], 150 mg, 0.925 mmol) was added portion wise to chlorosulfonic acid (385 pL, 5.79 mmol, 6.3 eq.) at 0 °C. The reaction mixture was stirred for 10 min at 0 °C, then at 100 °C for 1 h. The mixture was poured onto ice. The precipitate was filtered, washed with water, and dried to yield the title compound (113 mg, yield: 46 %) as a brown solid, used without further purification.

[0284] Step B: 4-cyclopropyl-3-(N,N-dimethylsulfamoyl)benzoic acid. Dimethylamine (2 M in THF, 13.16 mL, 26.314 mmol, 7 eq.) was added to a solution of 3-(chlorosulfonyl)-4- cyclopropylbenzoic acid (980 mg, 3.759 mmol) in THF (25 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo. The pH of the resulting crude mixture was brought to 2 with HC1 (1 M in water). The mixture was extracted with EtOAc (x 3). The organic layer was concentrated in vacuo to yield Intermediate 165 (650 mg, 90 % pure, yield: 58 %), used without further purification.Intermediate 167: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(l -hydroxy ethyl)-4-methylbenzamide.CIS

[0285] Intermediate 167 was prepared in a manner analogous to Compound 45, Method J, starting from Intermediate 166 and cA-2,6-dimethylmorpholine(CAS [6485-55-8]).Intermediate 171: (*R)-N-((2-(6-fluoropyridin-2-yl)- 1 ,6-naphthy ri din-7 -yl)methy l)-3 -( 1 - hydroxyethyl)-4-methylbenzamide and Intermediate 172: (*S)-N-((2-(6-fluoropyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-3-(l-hydroxyethyl)-4-methylbenzamide.Intermediate 171, pure stereoisomer but absolute stereochemistry undeterminedIntermediate 172, pure stereoisomer but absolute stereochemistry undetermined

[0286] Intermediate 166 was separated into its stereoisomers by preparative SFC (i-cellulose- c column; isocratic mode method: 60 % [EtOH + 0.1 % DEA] - 40 % [CO2]) to yield Intermediate 171, pure stereoisomer but absolute stereochemistry undetermined ((*R)-N-((2- (6-fluoropyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-3-(l -hydroxy ethyl)-4- methylbenzamide) and Intermediate 172, pure stereoisomer but absolute stereochemistry undetermined ((*S)-N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3-(l- hydroxyethyl)-4-methylbenzamide), both as yellow solids.Intermediate 174: (cis)-4-(6-chloro-3-fluoro-4-methylpyridin-2-yl)-2,6-dimethylmorpholine.CIS

[0287] Step A: 6-chloro-2-((cis)-2,6-dimethylmorpholino)-4-methylpyridin-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 eq.) were placed in a stainless steel pressure reactor and the reaction mixture was stirred at 170 °C for 48 h. After cooling, the reaction mixture was diluted with EtOAc (100 mL). The solution was washed twice with water (2 x 100 mL) and once with brine (30 mL). The organic layer was dried over MgSOi. filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (80 g, EtOAc / heptane from 0 / 100 to 75 / 25) followed by preparative reverse phase chromatography (Column Gemini 5 pm C18 (100 x 30 mm); gradient of a mixture MeOH / ACN (1 / 1, v / v) in 0.1 % aqueous formic acid from 19 to 64 %) to give the title compound (1183 mg, yield: 81 %) as an oil that crystallized upon standing.

[0288] Step B: (cis)-4-(6-chloro-3-fluoro-4-methylpyridin-2-yl)-2,6-dimethylmorpholine. 6- chloro-2-((cis)-2,6-dimethylmorpholino)-4-methylpyri din-3 -amine (750 mg, 2.933 mmol) dissolved in DCM (7 mL) was added to a suspension of nitrosyl tetrafluoroborate (CAS [14635-75-7], 377 mg, 3.226 mmol, 1.1 eq.) in DCM (8 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was allowed to reach room temperature, was diluted with xylene, and was stirred at 130 °C for 1 h. After cooling, the suspension was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g silica; EtOAc / heptane from 0 / 100 to 10 / 90) to afford Intermediate 174 (580 mg, yield: 76 %) as ayellow oil.Intermediate 175: (cis)-4-(6-chloro-4,5-dimethylpyridin-2-yl)-2,6-dimethylmorpholine.CIS

[0289] ( 7.s-2.6-dimethylmorpholine (CAS [6485-55-8], 16.24 mL, 130.883 mmol, 23 eq.) was added to 2,6-dichloro-3,4-dimethylpyridine (CAS [72605-55-1], 1 g, 5.68 mmol) in a closed tube at room temperature. The mixture was stirred at 100 °C for 48 h. After cooling, the mixture was diluted with water and was extracted with EtOAc. The organic layer was dried (MgSCL), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g silica, EtOAc / heptane from 0 / 100 to 15 / 85), followed by preparative SFC (Lux Amylose-1 250 x 30 mm 5 um column; isocratic mode method: 50 % [iPrOH + 0.1 % DEA] - 50 % [CO2]) to yield Intermediate 175 (400 mg, yield: 27 %) as a white solid.Intermediate 183: (3a,4p,5a)-4-methoxy-3,5-dimethylpiperidine.(3a,4p,5a)

[0290] Step A: tert-butyl (3a,4a,5a)-4-hydroxy-3,5-dimethylpiperidine-l-carboxylate and tert-butyl (3a, 4p,5a)-4-hydroxy-3,5-dimethylpiperidine-l -carboxylate. EtsN (84 mL, 604 mmol, 5 eq.) was added dropwise to a suspension of 3,5-dimethylpiperidin-4-ol (HC1 salt, CAS [1822604-07-8], 20.02 g, 120.848 mmol) and di- / e / 7-butyl dicarbonate (32.97 g, 151.06 mmol, 1.25 eq;) in dry DCM (500 mL) at 0 °C under nitrogen atmosphere. After the addition, the thick white slurry was stirred at room temperature for 3 h. The reaction mixture was diluted with water and the layers were separated. The organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography (silica, 330 g, EtOAc / heptane 0 / 100 to 35 / 65, in two batches) to give tert-butyl (3a,4a,5a)-4- hydroxy-3, 5 -dimethylpiperi dine- 1 -carboxy late (11.61 g, yield: 42 %) and (3a,4p,5a)-4- hydroxy-3, 5 -dimethylpiperi dine- 1 -carboxy late (10.29 g, yield: 37 %), both as white solids.

[0291] Step B: tert-butyl (3a,4p,5a)-4-methoxy-3,5-dimethylpiperidine-l-carboxylate. Sodium hydride (60 % in mineral oil, 418 mg, 10.9 mmol, 5 eq.) was added to an ice-cold solution of (3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidine-l-carboxylate (500 mg, 2.18 mmol) in THF (20 mL). The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for an additional 30 min. The reaction mixture was cooled to 0 °C and methyl iodide (163μL, 2.62 mmol, 1.2 eq.) was added. The reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with EtOAc (100 mL), water (20 mL), and brine (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to give the title compound (676 mg, 78 % pure, yield: 99 %), used without further purification.

[0292] Step C: (3a,4p,5a)-4-methoxy-3,5-dimethylpiperidine. HC1 (4 M in 1,4-dioxane, 5.42 mL, 21.67 mmol, 10 eq.) was added to a solution of tert-butyl (3a,4p,5a)-4-methoxy-3,5- dimethylpiperidine-1 -carboxylate (676 mg, 2.167 mmol) in 1,4-dioxane (5 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dried to yield Intermediate 183 (HC1 salt, 657 mg, quantitative).Intermediate 184: tert-butyl 3-hydroxy-3-(5-(methoxycarbonyl)-2-methylphenyl)azetidine-l- carboxylate.

[0293] Under nitrogen atmosphere, methyl 3-iodo-4-methylbenzoate [90347-66-3] (0.5 g, 1.81 mmol) was dissolved in THF dry (5 mL). The reaction mixture was cooled to -50 °C and stirred for 10 minutes. Isopropylmagnesium chloride solution (2M in THF) [1068-55-9] (1.3 mL, 2.6 mmol) was added dropwise and the reaction mixture was stirred at -50 °C for 2h. The reaction mixture was cooled to -78 °C and a solution of A-Boc-3 -oxoazetidine [398489-26-4] (0.62 g, 3.62 mmol) in THF dry (1 mL) was added dropwise. The reaction mixture was stirred at -78 °C for Ih, then warmed to room temperature and stirred for 1 h. The solvent was removed under vacuum, DCM was added and the reaction mixture was washed with sat. aq. NaHCCL solution. The combined organic layers were concentrated to dryness and purified by flash column chromatography (25g; silica; DCM / MeOH(9:l) in DCM [from 0% to 100%]). The desired fractions were collected and concentrated to yield Intermediate 184 (249 mg, yield: 42%) as a colorless oil.Intermediate 188: 3-(l-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)-4-methylbenzoic acid.

[0294] Intermediate 188 was prepared in a similar manner as Intermediate 506 (step E), using Intermediate 184 instead of methyl 3-((3,3-difluoropropyl)sulfonyl)-4-methylbenzoate. Intermediate 189: tert-butyl 3-(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)carbamoyl)-2-methylphenyl)-3-hy droxy azetidine- 1 -carboxylate.

[0295] Intermediate 189 was prepared following the same procedure as Intermediate 44, starting from Intermediate 11 and Intermediate 188.Intermediate 190: tert-butyl 4-hydroxy-4-(5-(methoxycarbonyl)-2-methylphenyl)piperidine-l- carboxylate.

[0296] Intermediate 190 was prepared in a similar manner as Intermediate 184, using JV-Boc- 4-piperidone (CAS[79099-07-3]) instead of JV-Boc-3 -oxoazetidine.Intermediate 191: 3-(l-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)-4-methylbenzoic acid.

[0297] Intermediate 191 was prepared in a similar manner as Intermediate 187, using Intermediate 190 instead of Intermediate 186.Intermediate 193: tert-butyl 4-(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)carbamoyl)-2-methylphenyl)-4-hy droxypiperidine- 1 -carboxylate.CIS

[0298] Intermediate 193 was prepared according to Method L, starting from Intermediate 192 and c7.s-2.6-dmrethyl morpholine (CAS [6485-55-8]).Intermediate 194: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- y l)methyl)- 1 , 1 -diphenylmethanimine.CIS

[0299] A solution of Intermediate 11 (free base, 282 mg, 0.71 mmol), benzophenone (131 mg, 0.71 mmol, 1 eq.), and para-toluenesulfonic acid monohydrate (CAS [6192-52-5], 7 mg, 0.0355 mmol, 0.05 eq.) in toluene (60 mL), was refluxed overnight in a flask equipped with aDean-Stark trap. The solvent was evaporated to give Intermediate 194 (350 mg, 49 % pure, yield: 47 %) as a brown solid, used directly in the next step.Intermediate 195: N-(l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7 -y 1) ethy 1)- 1 , 1 -diphenylmethanimine.CIS

[0300] Potassium tert-butoxide (59 mg, 0.501 mmol, 1.5 eq.) was added in one portion to a solution of Intermediate 194 (350 mg, 0.334 mmol) in dry DMF (5 mL) under nitrogen atmosphere at room temperature. The reaction mixture instantly turned deep black. After 2 min, iodomethane (31μL, 0.501 mmol, 1.5 eq.) was added dropwise and the brown reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted again with EtOAc. The combined organic layer was washed with brine, dried on MgSCL, filtered, and the solvent was evaporated to give Intermediate 195 (354 mg, 63 % pure, assumed quantitative) as a brown solid, used directly in the next step.Intermediate 196: l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)ethan-l -amine.CIS

[0301] HC1 (37 % in water, 0.7 mL, 8.453 mmol, 20 eq.) was added dropwise (1 drop / sec) to a solution of Intermediate 195 (354 mg, 63 % pure, 0.423 mmol) in 1,4-dioxane (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The brown suspension was evaporated to dryness and the residue was co-evaporated several times with toluene to give Intermediate 196 (HC1 salt, 383 mg, 22 % pure) as a brown solid, dried under vacuum at 50 °C and used without further purification.Intermediate 201: 4-((trans)-4-benzyl-6-methylmorpholin-2-yl)butan-l-ol and Intermediate 202: 4-((cis)-4-benzyl-6-methylmorpholin-2-yl)butan-l-ol and Intermediate 203: 4- ((2*S,6*R)-4-benzyl-6-methylmorpholin-2-yl)butan-l-ol and Intermediate 204: 4-((2*R,6*S)- 4-benzyl-6-methylmorpholin-2-yl)butan-l-ol.Intermediate 201 Intermediate 202 Intermediate 203 Intermediate 204 (trans) (cis) pure but absolute pure but absolute stereochemistry stereochemistry undetermined undetermined

[0302] Step A: l-(benzylamino)-6-((tert-butyldimethylsilyl)oxy)hexan-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 eq.) were combined in iPrOH (10 mL) and the mixture was stirred at reflux for 16 h. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (120 g, EtOAc / heptane from 0 / 100 to 100 / 0) to afford the title compound (3.41 g, yield: 76 %).

[0303] Step B: N-benzyl-N-(6-((tert-butyldimethylsilyl)oxy)-2-hydroxyhexyl)-2- chloropropanamide. l-(benzylamino)-6-((tert-butyldimethylsilyl)oxy)hexan-2-ol (3.4 g, 10.072 mmol) and EtsN (2.81 mL, 20.144 mmol, 2 eq.) were dissolved in DCM (20 mL) and the solution was cooled in an ice-water bath. A solution of 2-chloropropionyl chloride (1.07 mL, 11.079 mmol, 1.1 eq.) in DCM (10 mL) was then added dropwise over 5-10 min. The reaction mixture was stirred at 0 °C for 1 h and then allowed to reach room temperature over 1 h. The reaction was quenched by addition of 1 M aqueous Na2CO3 (50 mL). The mixture was extracted with DCM (2 x 50 mL), dried over MgSO4. filtered, and concentrated in vacuo. The residue was purified by column chromatography over silica gel (80 g column, gradient EtOAc / heptane from 0 / 100 to 40 / 60) to give the title compound (3.83 g, yield: 88 %) as a clear oil (mixture of diastereoisomers).

[0304] Step C: 4-benzyl-6-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-methylmorpholin-3-one. NaH (60 % in mineral oil, 422 mg, 10.54 mmol, 1.2 eq.) 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 nitrogen atmosphere. The mixture was stirred for 16 h allowing the temperature to raise slowly to room temperature. The reaction was quenched by addition of saturated aqueous NaHCO3 (20 mL). Water (20 mL) was added and the mixture was extracted with EtOAc (2 x 25 mL). The combined organic layer was dried over MgSO4. filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (80 g column, EtOAc / heptane from 0 / 100 to 35 / 65) to afford the title compound (3.13 g, yield: 90 %) as a colorless oil (mixture of diastereoisomers).

[0305] Step D: 4-benzyl-6-(4-hydroxybutyl)-2-methylmorpholin-3-one. HC1 (35 % in water, 1.4 mL, 16.985 mmol, 2 eq.) was added to a solution of 4-benzyl-6-(4-((tert- butyldimethylsilyl)oxy)butyl)-2-methylmorpholin-3-one (3.13 g, 7.992 mmol) in MeOH (20 mL) at room temperature. The reaction mixture was stirred for 2 h. The mixture was diluted with DCM (200 mL) and saturated aqueous NaHCO3 (100 mL) was added. The layers were separated, and the aqueous layer was extracted again with DCM (100 mL). The combined organic layer was dried over MgSO4. filtered, and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (80 g column, MeOH / DCM from 0 / 100 to 10 / 90) to give the title compound (2.27 g, quantitative) as a clear oil (mixture of diastereoisomers).

[0306] Step E: A solution of 4-benzyl-6-(4-hydroxybutyl)-2-methylmorpholin-3-one (2.27 g, 8.184 mmol) in THF (30 mL) was added dropwise to a suspension of LiAlFh (373 mg, 9.821 mmol, 1.2 eq.) in THF (20 mL), at room temperature. The reaction mixture was then stirred at 60 °C for 2 h. After cooling, the reaction was quenched by addition of acetone (5 mL) and water (20 mL). NaOH (1 M in water, 20 mL) and DCM (100 mL) were then added. The mixture was filtered through a pad of Celite® that was further rinsed with DCM (2 x 50 mL). The layers were separated and the aqueous layer was extracted once more with DCM (50 mL). The combined organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by column chromatography over silica gel (80 g column, EtOAc / heptane from 0 / 100 to 100 / 0) to afford Intermediate 201 (975 mg, yield: 45 %) and Intermediate 202 (930 mg, yield: 43 %), both as colorless oils. Intermediate 202 was separated into its stereoisomers by preparative SFC (Column: Amylose-1; Method: Isocratic 7 % MeOH + 0.1 % DEA) to afford Intermediate 203 (380 mg, yield: 17 %) and Intermediate 204 (376 mg, yield: 17 %), both as oils.Intermediate 208: tert-butyl (4-((2*S,6*R)-6-methylmorpholin-2-yl)butyl)carbamate.

[0307] Step A: 2-(4-((2*S,6*R)-4-benzyl-6-methylmorpholin-2-yl)butyl)isoindoline- 1,3- dione. 4-((2*S,6*R)-4-benzyl-6-methylmorpholin-2-yl)butan-l-ol (Intermediate 203, 378 mg, 1.435 mmol), phthalimide (253 mg, 1.722 mmol, 1.2 eq.), and PPhi (565 mg, 2.153 mmol, 1.5 eq.) were dissolved in dry THF (10 mL) under nitrogen atmosphere. A solution of DIAD (CAS [2446-83-5], 424μL, 2.153 mmol, 1.5 eq.) in dry THF (5 mL) was then added dropwise over 5 min at room temperature. The reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (80 g column, EtOAc / heptane from 0 / 100 to 40 / 60) to give the title compound (958 mg, 50 % pure, yield: 85 %) as an oil that solidified upon standing.

[0308] Step B: 4-((2*S,6*R)-4-benzyl-6-methylmorpholin-2-yl)butan-l-amine. Hydrazine monohydrate (321μL, 3.631 mmol, 3 eq.) was added to a solution of 2-(4-((2*S,6*R)-4- benzyl-6-methylmorpholin-2-yl)butyl)isoindoline- 1,3-dione (950 mg, 50 % pure, 1.21 mmol) in EtOH (10 mL) at room temperature. The reaction was stirred at 70 °C for 3 h. After cooling, the white precipitate was filtered off and washed with EtOH (3 x 10 mL). The filtrate was concentrated under vacuum and the residue was purified by column chromatography over silica gel (25 g column, gradient of DCM / MeOH / NHiOH. 90 / 9 / 1, v / v / v in DCM from 0 to 100 %) to afford the title compound (313 mg, yield: 99 %) as a colorless oil.

[0309] Step C: tert-butyl (4-((2*S,6*R)-4-benzyl-6-methylmorpholin-2-yl)butyl)carbamate. Boc anhydride (310 mg, 1.422 mmol, 1.2 eq.) was added to a solution of 4-((2*S,6*R)-4- benzyl-6-methylmorpholin-2-yl)butan-l -amine (311 mg, 1.185 mmol) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (12 g column, EtOAc / heptane from 0 / 100 to 50 / 50) to afford the title compound (421 mg, yield: 97 %) as a clear oil.

[0310] Step D: tert-butyl (4-((2*S,6*R)-6-methylmorpholin-2-yl)butyl)carbamate. Pd / C 10 % (100 mg, 0.094 mmol, 0.08 eq.) was added to a solution of tert-butyl (4-((2*S,6*R)-4-benzyl- 6-methylmorpholin-2-yl)butyl)carbamate (408 mg, 1.125 mmol) in MeOH (15 mL) and the suspension was placed under atmosphere of hydrogen (1 atm). The reaction mixture was stirred at room temperature for 16 h. The catalyst was filtered off through a pad of Celite® thatwas further rinsed with MeOH (3 x 10 mL). The filtrate was concentrated to give Intermediate208 (292 mg, yield: 95 %) as a colorless oil, used without further purification.Intermediate 209: tert-butyl (4-((2*R,6*S)-6-methylmorpholin-2-yl)butyl)carbamate.(2-*R, 6-*S) pure stereoisomer but absolute stereochemistry undetermined

[0311] The title compound was prepared in a similar manner as Intermediate 208, starting from Intermediate 204 instead of Intermediate 203.Intermediate 210: methyl 2-fluoro-6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)- l,6-naphthyridin-2-yl)isoni cotinate.

[0312] Methyl 2-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4- pyridinecarboxylate (CAS [1622217-30-4], 1.139 g, 4.051 mmol, 3 eq.) and NaHCO3 (1 M in water, 2.70 mL, 2.701 mmol, 2 eq.) were added to a solution of Intermediate 45 (0.65 g, 1.35 mmol) at room temperature in 1.4-dioxane (10 mL) previously degassed by bubbling nitrogen through. Then, l,T-bis(diphenylphosphino)ferrocene-palladium(II) di chloride dichloromethane complex (CAS [95464-05-4], 110 mg, 0.135 mmol, 0.1 eq.) was added, and the mixture was stirred at 90 °C under nitrogen atmosphere for 5 h. After cooling, water was added and the mixture was extracted with EtOAc. 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) in DCM from 0 / 100 to 20 / 80) to give Intermediate 210 (250 mg, yield: 33 %) as a pale brown solid.Intermediate 215: tert-butyl ((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate.

[0313] Intermediate 215 was prepared according to Method I, using Intermediate 9 and (3a,4p,5a)-3,5-dimethyl-4-piperidinol (CAS [374067-78-4]).Intermediate 217: 3-(4-(tert-butoxycarbonyl)morpholin-2-yl)-4-methylbenzoic acid.

[0314] Step A: methyl 3-(l-hydroxy-2-((2-hydroxyethyl)amino)ethyl)-4-methylbenzoate. Ethanolamine (CAS [141-43-5], 139μL, 2.295 mmol, 3 eq.) was added to a solution of 4- methyl-3-(2-oxiranyl)-benzoic acid methyl ester (CAS [2344806-63-7], 147 mg, 0.765 mmol) in EtOH (6 mL). The reaction mixture was stirred at 45 °C for 14 h. The solvent was removed in vacuo and the residue was diluted in EtOAc and washed with water. The aqueous layer was extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 24 g; EtOAc / heptane from 0 / 100 to 80 / 20) to yield the title compound (323 mg, 60 % pure, quantitative) as a yellow oil.

[0315] Step B: methyl 3-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)-l -hydroxy ethyl)- 4-methylbenzoate. Di-tert-butyl dicarbonate (CAS [24424-99-5], 176μL, 0.765 mmol, 1 eq.) was added to a solution of methyl 3-(l-hydroxy-2-((2 -hydroxy ethyl)amino)ethyl)-4- methylbenzoate (194 mg, 0.765 mmol) and EtsN (107μL, 0.765 mmol, 1 eq.) in DCM (1 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (80 g silica; EtOAc / heptane from 0 / 100 to 50 / 50) to yield the title compound (300 mg, 90 % pure, quantitative) as a colorless oil.

[0316] Step C: tert-butyl 2-(5-(methoxycarbonyl)-2-methylphenyl)morpholine-4-carboxylate. A solution of DIAD (CAS [2446-83-5], 226μL, 1.148 mmol, 1.5 eq.) in toluene (4 mL) was added dropwise to a solution of methyl 3-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)-l-hydroxyethyl)-4-methylbenzoate (270 mg, 0.765 mmol), EtsN (320μL, 2.295 mmol, 3 eq.), and triphenylphospine (301 mg, 1.148 mmol, 1.5 eq.) in toluene (20 mL) at 45 °C, under nitrogen atmosphere. After the addition, stirring was continued for 1 h at 45 °C. The mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with EtOAc. The organic layer was dried (MgSOr). filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica 80 g; EtOAc / heptane 0 / 100 to 90 / 10) to yield the title compound (98 mg, 81 % pure, yield: 31 %) as a colorless solid, and remaining starting material (100 mg, 80 % pure, yield: 29 %).

[0317] Step D: 3-(4-(tert-butoxycarbonyl)morpholin-2-yl)-4-methylbenzoic acid. NaOH (4 N in water, 178μL, 0.711 mmol, 3 eq.) was added to solution of tert-butyl 2-(5- (methoxycarbonyl)-2-methylphenyl)morpholine-4-carboxylate (79 mg, 0.237 mmol) in EtOH (2 mL) at room temperature. The mixture was stirred at room temperature for 12 h, followed by 4 h at 60 °C. The reaction mixture was diluted with water (20 mL) and KHSO4 (1 M in water, 3 mL) was added dropwise over 10 min with vigorous stirring, reaching pH 2-3. EtOAc was added and the mixture was stirred for 2 min. The layers were separated and the organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g; MeOH / DCM from 0 / 100 to 10 / 90) to yield Intermediate 217 (67 mg, 89 % pure, yield: 78 %) as a brown oil.Intermediate 220: 3-(3-hydroxypyrrolidin-l-yl)-4-methylbenzoic acid.

[0318] Step A: methyl 3-(3-hydroxypyrrolidin-l-yl)-4-methylbenzoate. Pds(dba)2 (CAS [51364-51-3], 29 mg, 0.031 mmol, 0.05 eq.) and Xphos (CAS [564483-18-7], 30 mg, 0.063 mmol, 0.1 eq.) were added to a solution of 3-pyrrolidinol (CAS [40499-83-0], 55μL, 0.688 mmol, 1.1 eq.), methyl 3-bromo-4-methylbenzoate (CAS [104901-43-01], 100μL, 0.626 mmol), and CS2CO3 (611 mg, 1.877 mmol, 3 eq.) in 1,4-dioxane (15 mL) at room temperature under nitrogen atmosphere. The mixture was stirred at 90 °C for 16 h. The mixture was diluted with EtOAc and water and extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g; EtOAc / heptane from 0 / 100 to 75 / 25) to yield the title compound (22 mg, yield: 14 %) as a white solid.

[0319] Step B: 3-(3-hydroxypyrrolidin-l-yl)-4-methylbenzoic acid. Intermediate 220 was prepared in a similar manner as Intermediate 43, starting from methyl 3-(3-hydroxypyrrolidin-1-yl)-4-methylbenzoate instead of Intermediate 42.Intermediate 223 : (3a,4p,5a)- 1 -(6-(7 -(aminomethyl)- 1 ,6-naphthyridin-2-yl)-5-methylpyridin-2-yl)-3,5-dimethylpiperidin-4-ol.(3a,4p,5a)

[0320] Step A: tert-butyl ((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- iodopyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. / V-iodosuccinimide (199 mg, 0.884 mmol, 1 eq.) was added to a solution of tert-butyl ((2-(6-((3a,4p,5a)-4-hydroxy-3,5- dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 215, 410 mg, 0.884 mmol) in hexafluoroisopropanol (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4). filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica; EtOAc / heptane 0 / 100 to 50 / 50) to yield the title compound (450 mg, 66 % pure, yield: 57 %) as a yellow oil.

[0321] Step B: tert-butyl ((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. A solution of tert-butyl ((2-(6- ((3a, 4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3-iodopyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)carbamate (450 mg, 66 % pure, 0.504 mmol), trimethylboroxine (CAS [823-96-1], 423μL, 3.023 mmol, 6 eq.), and K2CO3 (418 mg, 3.023 mmol, 6 eq.) in 1,4-dioxane (0.5 mL) and water (0.3 mL) was degassed with nitrogen for 5 min. XantPhos Pd G3 (CAS [1445085- 97-1], 48 mg, 0.050 mmol, 0.1 eq.) was added to the solution at room temperature and the mixture was stirred at 80 °C for 12 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g; EtOAc / heptane from 0 / 100 to 100 / 0) followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm Column; from 81 % [0.1 % HCOOH] - 19 % ACN to 45 %[0.1 % HCOOH] - 55 % ACN) to yield the title compound (77 mg, yield: 32 %) as a yellow solid.

[0322] Step C: (3a,4p,5a)-l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-5-methylpyridin-2- yl)-3,5-dimethylpiperidin-4-ol. HC1 (4 M in 1,4-dioxane, 419μL, 1.675 mmol, 20 eq.) was added to a solution of tert-butyl ((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (40 mg, 0.084 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated to yield Intermediate 223 (HC1 salt, 42 mg, 90 % pure, quantitative) as an orange solid.Intermediate 225: tert-butyl (5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamoyl)-2,3-dimethylbenzyl)carbamate.CIS

[0323] Tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 27 mg, 0.023 mmol, 0.1 eq.) was added to a suspension of Compound 27 (140 mg, 0.230 mmol), potassium (((tert- butoxycarbonyl)amino)methyl)trifluoroborate (CAS [1314538-55-0], 82 mg, 0.346 mmol, 1.5 eq.), and Na2CO3 in water (1.15 mL, 1 M, 1.152 mmol, 5 eq.) in 1,4-dioxane (3 mL) while degassing with nitrogen. After further degassing with nitrogen for 2 min, the vial was sealed and the reaction mixture was stirred in a micro wave oven for 3 h at 110 °C. More potassium ((( / c / 7-butoxycarbonyl)amino)methyl)trifluoroborate (164 mg, 0.691 mmol, 3 eq.) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.023 mmol, 0.1 eq.) were added and the reaction mixture was degassed with nitrogen for 5 min. After sealing the vial, the reaction mixture was stirred in a microwave oven for 2 h at 120 °C. Again, more potassium (((tert- butoxy carbonyl)amino)methyl)trifluoroborate (164 mg, 0.691 mmol, 3 eq.) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.023 mmol, 0.1 eq.) were added and the reaction mixture was degassed with nitrogen for 5 min. After sealing the vial, the reaction mixture was stirred at 120 °C overnight. After cooling, the reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSCE. filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent:heptane:EtOAc / EtOH 3 / 1 100:0 to 0:100) to give Intermediate 225 (45 mg, 66 % pure, yield: 21 %), as a yellow solid, used without further purification.Intermediate 231: 6-methyl-7-(methylsulfonyl)isochroman-l-one.

[0324] Chlorosulfonic acid (2.25 mL, 1.75 g / mL, 33.665 mmol, 10 eq.) was added to 3,4- dihydro-6-methyl-17 / -2-benzopyran-l-one (CAS [74786-78-0], 546 mg, 3.366 mmol) at room temperature. The reaction mixture was then stirred at 100 °C overnight. The reaction mixture was poured carefully onto ice. The resulting mixture was extracted with DCM. The organic layer was dried over MgSCE, filtered, and concentrated. A solution of this solid in THF (12 mL) was added dropwise over 15 min to a solution of sodium sulfite (513 mg, 4.073 mmol, 1.2 eq.) and NaHCO3 (1225 mg, 14.577 mmol, 4.3 eq.) in water (12 mL) at 70 °C. The reaction mixture was stirred at 70 °C for 1 h. After cooling to room temperature, methyl iodide (0.91 mL, 14.577 mmol, 4.3 eq.) was added and the reaction mixture was stirred at 50 °C overnight. More Mel (0.91 mL, 14.577 mmol, 4.3 eq.) was added and the mixture was further stirred at 60 °C overnight. Water was added, followed by aqueous HC1 (1 N). The solid that appeared was filtered and dried to give Intermediate 231 (349 mg, yield: 43 %).Intermediate 232: 2-(2-chloroethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide

[0325] SOCI2(1.66 mL, 22.89 mmol, 50 eq.) and DMF (5μL, 0.071 mmol, 0.15 eq.) were added to 6-methyl-7-(methylsulfonyl)isochroman-l-one (Intermediate 231, 110 mg, 0.458 mmol) and the mixture was stirred at 80 °C overnight. The excess SOCI2was evaporated and the residue was dissolved in DCM (7 mL). DIPEA (0.79 mL, 4.58 mmol, 10 eq.) and Intermediate 11 (193 mg, 0.405 mmol, 0.88 eq.) were added and the mixture was stirred at room temperature for 2 h. Water was added to the mixture and it was extracted with DCM. The organic layer was dried (MgSO4), filtered, and evaporated to give Intermediate 232 (253 mg, yield: 91 %), used without further purification.Intermediate 235: tert-butyl 7-(6-chloro-3-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate.

[0326] DIPEA (2.1 mL, 12.05 mmol, 4 eq.) was added to a solution of 2,6-dichloro-3- fluoropyridine (CAS [52208-50-1], 500 mg, 3.012 mmol), tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate (CAS [674792-08-6], 671 mg, 3.163 mmol, 1.05 eq.), and DMSO (5 mL) at room temperature. The reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was diluted with water and EtOAc and the layers were separated. The organic layer was washed with brine (3 x), dried (MgSO4). and concentrated. The residue was purified by silica gel column chromatograph (40 g silica, EtOAc / heptane 0 / 100 to 100 / 0) to give Intermediate 235 (830 mg, yield: 81 %) as an oil.Intermediate 237: (cis)-4-(2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,6-dimethylmorpholine.

[0327] 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 eq.), and CS2CO3 (1195 mg, 3.669 mmol, 2 eq.) in 1,4-dioxane (6 mL) was degassed by bubbling nitrogen through for 15 min. Palladium (II) acetate (CAS [3375-31-3], 41 mg, 0.183 mmol, 0.1 eq.) and Xantphos (CAS [161265-03-8], 106 mg, 1.183 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 100 °C for 4 h. After cooling the mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25g SiCh; EtOAc / heptane from 0 / 100 to 50 / 50) to afford the title compound (196 mg, yield: 37 %) as a yellow solid.

[0328] Step B: (cis)-4-(2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,6- dimethylmorpholine. (cis)-4-(3-bromo-2-fluorophenyl)-2,6-dimethylmorpholine (196 mg, 0.68 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 224 mg, 0.884 mmol, 1.3 eq.), and KO Ac (200 mg, 2.041 mmol, 3 eq.) were suspended in 1,4-di oxane (5 mL). The mixture was degassed by bubbling nitrogen for 15 min. Pd(dppf)C12.CH2C12 (CAS [95464-05-4], 33 mg, 0.041 mmol, 0.06 eq.) was added and the reaction mixture was stirred at 90 °C overnight. A degassed solution of bis(pinacolato)diboron (172 mg, 0.680 mmol, 1 eq.) and Pd(dppf)C12.CH2C12 (16 mg, 0.020 mmol, 0.03 eq.) in 1,4-dioxane (2 mL) was added to the reaction mixture and it was stirred at 90 °C for 5 h. After cooling, the reaction mixture was partitioned between aqueous Na2CO3 (1 M) and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4. filtered, and evaporated in vacuo. The residue was purified by flash column chromatography (25 g SiCh; EtOAc / heptane from 0 / 100 to 40 / 60) to afford Intermediate 237 (107 mg, yield: 47 %) as a yellow oil.Intermediate 238: (cis)-4-(3-bromo-2,6-difluorophenyl)-2,6-dimethylmorpholineCIS

[0329] Intermediate 238 was prepared in a similar manner as Intermediate 237, Step A, starting from l-bromo-2,4-difluoro-3-iodo-benzene (CAS [1208075-99-3]), instead of 1- bromo-2-fluoro-3 -iodobenzene.Intermediate 262: tert-butyl 7-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

[0330] 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]).Intermediate 263 : (cis)-4-(6-bromopyrazin-2-yl)-2,6-dimethylmorpholine.CIS

[0331] DIPEA (1.48 mL, 8.476 mmol, 3 eq.) was added to a solution of 2-bromo-6- fluoropyrazine (CAS [1209458-12-7], 500 mg, 2.825 mmol) and cA-2,6-dimethylmorpholine (CAS [6485-55-8], 348 μL, 2.825 mmol, 1 eq.) in DMSO (3 mL) and the reaction mixture was stirred at 50 °C for 1 h. 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 x 50 mL). The combined organic layer was dried over MgSCL, filtered, and concentrated. The residue was purified by flash column chromatography (silica, 40 g, EtOAc / heptane 0 / 100 to 100 / 0) to yield Intermediate 263 (693 mg, 92 % pure, yield: 83 %).Intermediate 273: 3-(l-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)-4-chlorobenzoic acid

[0332] Under 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 hexanes, 3.4 mL, 8.5 mmol, 2 eq.) was added dropwise and the reaction mixture was stirred at -78 °C for 20 min. A solution of l-Boc-3-azetidinone (CAS [398489-26-4], 1.5 g, 8.762 mmol, 2.06 eq.) in dry THF (5 mL) was then added dropwise. The reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for 1 h. The reaction was quenched by addition of saturated aqueous NH4CI, and 1 M aqueous KHSO4 was added dropwise over 10 min with vigorous stirring, to reach a pH of 2-3. DCM and water were added and the layers were separated. The organic layer wasconcentrated in vacuo to afford Intermediate 273 (520 mg, 80 % pure, yield: 30 %) as a yellow oil, used without further purification.Intermediate 275: 3-(l-(tert-butoxycarbonyl)-3-hydroxypiperidin-3-yl)-4-methylbenzoic acid.

[0333] 3-Bromo-4-methylbenzoic acid (CAS [7697-26-9], 2 g, 9.3 mmol) was dissolved in dry THF (5 mL) and the reaction mixture was cooled to -78 °C under nitrogen atmosphere, n- BuLi (2.5 M in hexanes, 7.44 mL, 18.601 mmol, 2 eq.) was added dropwise and the reaction mixture was stirred at -78 °C for 20 min. A solution of l-Boc-3-piperidone (CAS [98977-36- 7], 3.7 g, 18.601 mmol, 2 eq.) in dry THF (1 mL) was then added drop wise. The reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for 1 h. The reaction was quenched by addition of saturated aqueous NH4CI, followed by dropwise addition of 1 M aqueous KHSO4 over 10 min, with vigorous stirring, to reach a pH of 2-3. DCM and water were added and the layers were separated. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography (silica 80 g; DCM / MeOH (9 / 1) in DCM, 0 / 100 to 40 / 60) to yield Intermediate 275 (377 mg, yield 12 %) as a yellow solid.Intermediate 283: (2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)-l,6- naphthy ridin-7-yl)methanamine.

[0334] Step A: (cis)-4-(6-bromo-3-nitropyridin-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 eq.) and K2CO3 (1.05 g, 7.627 mmol, 1 eq.) in toluene (25 mL) was stirred at 50 °C for 3 h. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (12 gSiCh; EtOAc / heptane from 0 / 100 to 10 / 90) to yield the title compound (1.81 g, yield: 74 %) as a yellow solid.

[0335] Step B: 6-bromo-2-((cis)-2,6-dimethylmorpholino)pyridin-3-amine. Iron powder (2.65 g, 47.484 mmol, 10 eq.) was added to a solution of (cis)-4-(6-bromo-3-nitropyridin-2-yl)-2,6- dimethylmorpholine (1.5 g, 4.748 mmol), NH4CI (1.27 g, 23.742 mmol, 5 eq.), in water (13 mL) and EtOH (48 mL). The reaction mixture was stirred at 70 °C for E5 h. After cooling, the mixture was filtered through Celite® and the filter was washed with EtOH and EtOAc. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the solution was washed with saturated aqueous NaHCCL. The organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo to yield the title compound (860 mg, yield: 63 %) as a yellow solid, used without further purification.

[0336] Step C: (cis)-4-(6-bromo-3-fluoropyridin-2-yl)-2,6-dimethylmorpholine. 6-bromo-2- ((cis)-2,6-dimethylmorpholino)pyridin-3-amine (784 mg, 2.74 mmol) dissolved in DCM (4 mL) was added to a slurry of nitrosyl tetrafluoroborate (CAS [14635-75-7], 352 mg, 3.014 mmol, 1.1 eq.) in DCM (4mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was allowed to reach room temperature, was diluted with xylene (12 mL) and stirred at 130 °C for 1.5 h. After cooling, the mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g silica; gradient EtOAc / heptane from 0 / 100 to 10 / 90) to yield the title compound (710 mg, yield: 85 %) as a colorless oil.

[0337] Step D: tert-butyl ((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamate. The title compound was prepared in a similar manner as Intermediate 97, starting from (cis)-4-(6-bromo-3-fluoropyridin-2-yl)-2,6- dimethylmorpholine instead of Intermediate 96.

[0338] Step E: (2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)-l,6-naphthyridin- 7-yl)methanamine. TFA (565 μL, 7.379 mmol, 30 eq.) was added to a solution of tert-butyl ((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)carbamate (115 mg, 0.246 mmol) in DCM (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (x 3). The combined organic layer was dried (MgSCL), filtered, and the solvents evaporated in vacuo to yield Intermediate 283 (TFA salt, 86 mg, yield: 72 %), used without further purification.Intermediate 291: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-formylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.CIS

[0339] Dess-Martin periodinane (CAS [87413-09-0], 172 mg, 0.393 mmol, 1.5 eq.) 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 h. Aqueous 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 (SiO225 g, MeOH:DCM (9:1) in DCM 0 / 100 to 50 / 50) to yield Intermediate 291 (105 mg, 86 % pure, yield: 60 %) as a yellow solid.Intermediate 300: (2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthy ridin-7-yl)methanamine.

[0340] Step A: tert-butyl 7-(6-bromo-4-nitropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. Nitrogen was purged through 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 eq.), DavePhos (CAS [213697-53-1], 279 mg; 0.709 mmol, 0.1 eq.), and Pd2dba3 (CAS [51364-51-3], 325 mg; 0.355 mmol, 0.05 eq.) were added to the reaction mixture at room temperature while nitrogen was bubbled through. 4-Boc-4,7-diazaspiro[2.5]octane (CAS [674792-08-6], 1.732 g, 8.159 mmol, 1.15 eq.) was added and the vial was sealed. The reaction mixture was stirred at 90 °C for 3 h. The reaction was quenched by addition of saturated aqueous NaHCCL (1 M). The mixture was extracted with EtOAc (3 x 20 mL). The organic layer was dried with MgSO4. filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (silica 12 g, EtOAc / heptane from 0 / 100 to 25 / 75) to yield the title compound (2.4 g, yield: 74 %) as an orange solid.

[0341] Step B: tert-butyl 7-(6-bromo-4-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. Tetramethylammonium fluoride (CAS [373-68-2], 584 mg; 6.275 mmol, 1.2 eq.) was added to a solution of tert-butyl 7-(6-bromo-4-nitropyridin-2-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (2161 mg; 5.229 mmol) in dry DMF (15 mL) in a sealed tube. The reaction mixture was stirred at 65 °C for 3 h. After cooling, the reaction mixture was diluted with EtOAc (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 MgSCL, filtered, and concentrated. The residue was purified by flash chromatography (silica 80 g; EtOAc / heptane 0 / 100 to 20 / 80) to yield the title compound (1.23 g, yield: 59 %) as an orange solid.

[0342] Step C: tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)-4-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. Intermediate 94 (459 mg; 1.121 mmol), tert-butyl 7-(6-bromo-4-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (650 mg; 1.682 mmol, 1.5 eq.), and K2CO3 (232 mg, 1.682 mmol, 1.5 eq.) was dissolved in 1,4-di oxane (3 mL). The reaction mixture was degassed by bubbling nitrogen through for 10 min. Then, Pd(OAc)2 (CAS [3375-31-3], 13 mg, 0.056 mmol, 0.05 eq.) and di- / c / 7-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 28 mg; 0.112 mmol, 0.1 eq.) were added and the mixture was stirred at 150 °C for 4 h. The mixture was diluted with water, extracted with EtOAc, and washed twice with brine. The organic layer was separated, filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica 24 g, EtOAc / heptane from 0 / 100 to 100 / 0) to yield the title compound (232 mg, yield: 36 %) as a yellow solid.

[0343] Step D: (2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methanamine. HC1 (4 M in 1,4-dioxane, 1.08 mL, 4.34 mmol, 10 eq.) was added to a solution of tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)-4- fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (245 mg, 0.434 mmol) in 1,4- dioxane (1.1 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was filtered and the solid was washed with 1,4-dioxane (20 mL) to yield Intermediate 300 (HC1 salt, 159 mg, yield: 83 %) as a red solid. The filtrate was diluted with water (10 mL) and extracted with EtOAc (20 mL). The pH of the aqueous layer was brought to pH 10 with Na2CO3 (1 M in water, 2 mL) and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica 24 g,MeOH / DCM 0 / 100 to 20 / 80) to yield another batch of the title compound (free base, 11 mg, yield: 7 %) as a green solid.Intermediate 304: 4-methyl-3-(tetrahydrofuran-2-yl)benzoic acid.

[0344] Step A: methyl 4-methyl-3-(tetrahydrofuran-2-yl)benzoate. A solution of tetrahydro-2 - furoic acid (CAS [16874-33-2], 472 μL 4,.911 mmol, 1.2 eq.), 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 eq.), 4.4'-di- / e / 7- butyl-2,2'-dipyridyl (CAS [72914-19-3], 165 mg, 0.614 mmol, 0.15 eq.), (Ir[dF(CF3)ppy]2(dtbpy))PFe (CAS [870987-63-6], 46 mg, 0.041 mmol, 0.01 eq.), and CS2CO3 (4 g, 12.277 mmol, 3 eq.) in DMF (50 mL) was degassed by bubbling nitrogen for 15 min. The reaction mixture was stirred and irradiated with blue LED (internal temperature = 55 - 60 °C) for 6 h. The reaction mixture was diluted with EtOAc. The solution was washed twice with water, dried over MgSO4 f.iltered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g, EtOAc / heptane from 0 / 100 to 70 / 30) to yield the title compound (70 mg, yield: 8 %) as a yellow oil.

[0345] Step B: 4-methyl-3-(tetrahydrofuran-2-yl)benzoic acid. Sodium hydroxide (1 M in water, 1 mL, 1 mmol, 3 eq.) was added to a solution of methyl 4-methyl-3-(tetrahydrofuran-2- yl)benzoate (76 mg, 0.345 mmol) in MeOH (5 mL) at room temperature. The mixture was stirred at room temperature for 72 h. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with HC1 (1 M in water) to pH = 1 and then extracted twice with EtOAc. This organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 304 (56 mg, yield: 78 %) as a white powder.Intermediate 323: 3-methyl-5-(lH-tetrazol-l-yl)benzoic acid.

[0346] Step A: methyl 3-methyl-5-(lH-tetrazol-l-yl)benzoate. A mixture of methyl 3-amino- 5-methyl-benzoate (1.5 g, 9.1 mmol) and triethyl orthoformate (6 mL, 36 mmol, 4 eq.) inAcOH (8 mL) was stirred at room temperature for 2 h. The solvent was then evaporated. AcOH (8 mL) followed by NaNs (2.3 g, 35 mmol, 3.8 eq.) were added. The mixture was stirred at 70 °C for 1 h. Additional AcOH (4 mL) was added and the mixture was further stirred at 70 °C for 1 h. After cooling, water was added and the mixture was stirred for 30 min. The precipitate was filtered, washed with water, and dried to yield the title compound (1.82 g, yield: 91 %).

[0347] Step B: 3-methyl-5-(lH-tetrazol-l-yl)benzoic acid. A mixture of methyl 3-methyl-5- (IH-tetrazol-l-yl)benzoate (1.82 g, 8.3 mmol) and NaOH (1 N in water, 8.34 mL, 8.3 mmol, 1 eq.) in MeOH (150 mL) was stirred at room temperature for 48 h, then evaporated. The residue was taken up in water. The solution was washed with DCM, made acidic with aqueous HC1, and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and evaporated to yield Intermediate 323 (1.6 g, yield: 94 %).Intermediate 327: 2-(((2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7- yl)methyl)carbamoyl)benzoic acid.

[0348] Intermediate 69 (175 mg, 0.541 mmol, 1 eq.), 4-[3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]pyridine (CAS [1009033-83-3], 243 mg, 0.778 mmol, 1.44 eq.) and Na2CO3 (172 mg, 1.62 mmol, 3 eq.) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) in a pressure flask. Nitrogen was bubbled through the reaction mixture for 10 min then Pd(dppf)C12.CH2C12 (CAS [95464-05-4], 22 mg, 0.027 mmol, 0.05 eq.) was added. The reaction vessel was sealed and the reaction mixture was stirred at 85 °C for 3 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The aqueous layer was acidified with aqueous HC1 (1 N) until reaching a pH of 4-5. The precipitate was filtered and washed with DCM and Et20 then dried in vacuo to afford Intermediate 327 (251 mg, yield: 70 %) as a beige solid.Intermediate 328: (2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methanamine.

[0349] Intermediate 327 (175 mg, 0.38 mmol, 1 eq.) was added to a solution of hydrazine hydrate (CAS [10217-52-4], 92 μL 1,.9 mmol, 5 eq.) in EtOH (6 mL) and the reaction mixture was stirred at 65 °C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 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, from 100 / 0 to 90 / 10) to afford Intermediate 328 (92 mg, yield: 77 %) as a white solid.Intermediate 329: 2-(((2-(3-(pyridin-3-yl)phenyl)-l,6-naphthyridin-7- yl)methyl)carbamoyl)benzoic acid.

[0350] Intermediate 329 was synthesized in a similar fashion as Intermediate 327 using 3-[3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyridine (CAS [939430-30-5]) instead of 4-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyridine (CAS [1009033-83-3]).Intermediate 330: (2-(3-(pyridin-3-yl)phenyl)-l,6-naphthyridin-7-yl)methanamine.

[0351] Intermediate 330 was synthesized in a similar fashion as Intermediate 328 using Intermediate 329 instead of Intermediate 327.Intermediate 332: (2-(4-fluoro-3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methanamine.

[0352] Step A: 2-(((2-(4-fluoro-3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7- yl)methyl)carbamoyl)benzoic acid. The title compound was prepared in a manner analogous to Intermediate 327 using 3-[2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl] pyridine (CAS [425378-79-6]) instead of 4-[3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]pyridine (CAS [1009033-83-3]).

[0353] Step B: (2-(4-fluoro-3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methanamine. The title compound was synthesized in a similar fashion as Intermediate 328 using 2-(((2-(4- fluoro-3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)carbamoyl)benzoic acid instead of Intermediate 327.Intermediate 333: 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran- 7-yl)pyridine.

[0354] 4-(5-Bromo-2,3-dihydro-7-benzofuranyl)pyridine (CAS [923297-52-3], 301 mg, 1.09 mmol, 1 eq.), bis(pinacolato)diboron (CAS [73183-34-3], 360 mg, 1.417 mmol, 1.3 eq.), Pd(dppf)C12.CH2C12 (CAS [95464-05-4], 27 mg, 0.033 mmol, 0.03 eq.), and KOAc (321 mg, 3.27 mmol, 3 eq.) were dissolved in 1,4-dioxane (10 mL), and a flow of nitrogen was bubbled through the reaction for 15 min. The reaction mixture was stirred at 90 °C for 2 h. The mixture was diluted with 1 M aqueous Na2CO3 and DCM and the layers were separated. The organic layer was washed with brine, dried over MgSO f4il.tered, and evaporated. The residue was purified by flash column chromatography on silica gel (heptane / EtOAc from 100 / 0 to 50 / 50) to afford Intermediate 333 (298 mg, 83 %) as a white oil.Intermediate 334: 4-(4-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyridine.

[0355] Intermediate 334 was prepared similarly to 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]).Intermediate 335: 4-(3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyridine.

[0356] Intermediate 335 was prepared similarly to 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]).Intermediate 339: tert-butyl ((2-(6-(5,6-dihydro-2H-pyran-3-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamate.

[0357] Step A: 2-bromo-6-(5,6-dihydro-2H-pyran-3-yl)pyridine. 3,6-Dihydropyran-5-boronic ester (CAS [212127-81-6], 265 mg, 1.26 mmol, 1 eq.), 2,6-dibromopyridine (CAS [626-05- 1], 1.20 g, 5.05 mmol, 4 eq.), and K2CO3 (349 mg, 2.52 mmol, 2 eq.) were suspended in 1,4- dioxane (4 mL) and water (1 mL) and the mixture was bubbled through with a flow of nitrogen for 1 min. Then, Pd(PPh3)4 (CAS [14221-01-3], 73 mg, 0.063 mmol, 0.05 eq.) was added and the mixture was slowly heated to 80 °C and maintained at this temperature for 16h. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSCti, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (25 g; heptane / EtOAc, 100 / 0 to 90 / 10) to afford the title compound (223 mg, yield: 73 %) as a colorless oil.

[0358] Step B: tert-butyl ((2-(6-(5,6-dihydro-2H-pyran-3-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. The title compound was prepared similarly to Intermediate 97 using 2- bromo-6-(5,6-dihydro-2H-pyran-3-yl)pyridine instead of Intermediate 96.Intermediate 340: (2-(6-(5,6-dihydro-2H-pyran-3-yl)pyridin-2-yl)-l ,6-naphthyridin-7- yl)methanamine.

[0359] Intermediate 339 was dissolved in TFA (274 pL) and DCM (1 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The TFA salt of Intermediate 340 was obtained by evaporation (purity 87 %, quantitative) and was used without further purification.Intermediate 343: (6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-3',6'-dihydro-[2,4'-bipyridin]- l'(2'H)-yl)(cyclopropyl)methanone.

[0360] Step A: (6-bromo-3',6'-dihydro-[2,4'-bipyridin]-l'(2'H)-yl)(cyclopropyl)methanone. DIPEA (948 μL, 5.443 mmol, 5 eq.) was added to a suspension of 6-bromo-T,2',3',6'- tetrahydro-2,4'-bipyridine (CAS [478366-38-0], 300 mg, 1.089 mmol, 1 eq.) and cyclopropanecarbonyl chloride (CAS [4023-34-1], 198 μL 2,.177 mmol, 2 eq.) in DCM (4 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (x 3). The combined organic layer was dried over MgSCL, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (12 g, heptane / EtOAc from 100 / 0 to 60 / 40) to afford the title compound (200 mg, yield: 58 %) as a yellow oil.

[0361] Step B: tert-butyl ((2-(T-(cyclopropanecarbonyl)-r,2',3',6'-tetrahydro-[2,4'-bipyridin]- 6-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. The title compound was prepared similarly to Intermediate 97, using (6-bromo-3',6'-dihydro-[2,4'-bipyridin]-l'(2'H)- yl)(cyclopropyl)methanone instead of Intermediate 96.

[0362] Step C: (6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-3',6'-dihydro-[2,4'-bipyridin]- l'(2'H)-yl)(cyclopropyl)methanone. The title compound (TFA salt) was prepared similarly to Intermediate 340 using tert-butyl ((2-(T-(cyclopropanecarbonyl)-T,2',3',6'-tetrahydro-[2,4'- bipyridin]-6-yl)-l,6-naphthyridin-7-yl)methyl)carbamate instead of Intermediate 339.Intermediate 346: 4-methyl-3-(methylsulfonyl)-N-((2-oxo-l,2-dihydro-l,6-naphthyridin-7- yl)methyl)benzamide.

[0363] Step A: 7-(aminomethyl)-l,6-naphthyridin-2(lH)-one. HC1 (37 % in H2O, 3.41 mL, 40.85 mmol, 6 eq.) was added at room temperature to a solution of tert-butyl ((2-chloro-l,6- naphthyridin-7-yl)methyl)carbamate (Intermediate 2) (2 g, 6.81 mmol, 1 eq.) in 1,4-di oxane (34 mL) and the mixture was heated at 60 °C for 30 min. The reaction was cooled to room temperature and ACN (10 mL) was added. The solid was isolated by filtration and dried under vacuum to afford the title compound (HC1 salt, 1.44 g, 85 %) as a light brown solid.

[0364] Step B: 4-methyl-3-(methylsulfonyl)-N-((2-oxo-l,2-dihydro-l,6-naphthyridin-7- yl)methyl)benzamide. A suspension of 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6], 115 mg, 0.537 mmol, 1.3 eq.) in ACN (5 mL) was treated with DIPEA (0.4 mL, 2.32 mmol, 5.6 eq.). HATU (200 mg, 0.526 mmol, 1.27 eq.) was added and the reaction mixture was stirred for 10 min at room temperature. 7-(aminomethyl)-l,6-naphthyridin- 2(lH)-one (103 mg, 0.415 mmol, 1 eq.) was added and the reaction mixture was stirred for 10 more min. The product was isolated by filtration, washed with ACN, and dried under vacuum to afford Intermediate 346 (136 mg, yield: 88 %) as a beige solid.Intermediate 350: (2-(3-(pyridin-3-yl)pyrrolidin-l-yl)-l,6-naphthyridin-7-yl)methanamine.

[0365] Step A: tert-butyl ((2-(3-(pyridin-3-yl)pyrrolidin-l-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2) (150 mg, 0.511 mmol, 1 eq.) was dissolved in THF (2.5 mL), then DIPEA (0.176 mL, 1.021 mmol, 2 eq.) and 3-(3-pyrrolidinyl)pyridine (CAS [150281-46-2], 151 mg, 1.021 mmol. 2 eq.) were added and the reaction mixture was stirred at 100 °C for 3 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (40 g, DCM / MeOH from 100 / 0 to 95 / 5) to afford the title compound (180 mg, yield: 87 %).

[0366] Step B: (2-(3-(pyridin-3-yl)pyrrolidin-l-yl)-l,6-naphthyridin-7-yl)methanamine. The title compound was prepared similarly to Intermediate 340 using tert-butyl ((2-(3-(pyridin-3- yl)pyrrolidin-l-yl)-l,6-naphthyridin-7-yl)methyl)carbamate instead of Intermediate 339. The crude product was purified by reverse phase chromatography (Kinetex 5 umEVO cl8 100; 0.1 % TFA in water and ACN, 10 % ACN to 100 % ACN) to afford Intermediate 350 as a solid.Intermediate 352: (2-(4-(pyridin-4-yl)piperazin-l-yl)-l,6-naphthyridin-7-yl)methanamine.

[0367] The title compound was prepared similarly to Intermediate 350 using l-(4- pyridyl)piperazine (CAS [1008-91-9]) instead of 3-(3-pyrrolidinyl)pyridine in Step A. The crude product was purified by reverse phase chromatography (Kinetex 5 um EVO cl 8 100; 0.1 % TFA in water and ACN, 10 % ACN to 100 % ACN).Intermediate 354: (2-(4-(pyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7-yl)methanamine.

[0368] The title compound was prepared similarly to Intermediate 350 using l-(3- pyridinyl)piperazine (CAS [67980-77-2]) instead of 3-(3-pyrrolidinyl)pyridine in Step A.Intermediate 357: l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-3',6'-dihydro-[2,4'- bipy ridin] - l'(2'H)-yl)-4-fluorobutan- 1 -one.

[0369] Step A: l-(6-bromo-3',6'-dihydro-[2,4'-bipyridin]-l'(2'H)-yl)-4-fluorobutan-l-one.DIPEA (1.39, 7.983 mmol, 5 eq.) was added to a suspension of 6-bromo-T,2',3',6'-tetrahydro- 2,4'-bipyridine (CAS [478366-38-0], 440 mg, 1.597 mmol, 1 eq.), 4-fluorobutanoic acid (CAS [462-23-7], 186 mg, 1.756 mmol, 1.1 eq.), and HATU (759 mg, 2.00 mmol, 1.25 eq.) in DCM (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (x 3). The combined organic layer was dried over MgSO f4i.ltered, and evaporated. The residue was purified by flash column chromatography on silica gel (25 g, DCM / MeOH 100 / 0 to 90 / 10) to afford the title compound (350 mg, yield: 64 %) as a yellow oil.

[0370] Step B: tert-butyl ((2-(l'-(4-fluorobutanoyl)-r,2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)- l,6-naphthyridin-7-yl)methyl)carbamate. The title compound was prepared similarly to Intermediate 97, using l-(6-bromo-3',6'-dihydro-[2,4'-bipyridin]-T(2'H)-yl)-4-fluorobutan-l- one instead of Intermediate 96.

[0371] Step C: l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-3',6'-dihydro-[2,4'-bipyridin]- l'(2'H)-yl)-4-fluorobutan-l-one. The title compound (TFA salt) was prepared similarly to Intermediate 340 using tert-butyl ((2-(T-(4-fluorobutanoyl)-T,2',3',6'-tetrahydro-[2,4'- bipyridin]-6-yl)-l,6-naphthyridin-7-yl)methyl)carbamate instead of Intermediate 339.Intermediate 359: (2-(4-(pyridin-3-yl)phenyl)-l,6-naphthyridin-7-yl)methanamine.

[0372] Step A: tert-butyl ((2-(4-(pyridin-3-yl)phenyl)-l,6-naphthyridin-7- yl)methyl)carbamate. The title compound was prepared similarly to Intermediate 9, using (4- (pyridin-3-yl)phenyl)boronic acid (CAS [170230-28-1]) instead of 6-fluoropyridine-2-boronic acid, but was purified by flash column chromatography on silica gel (heptane / EtOAc from 100 / 0 to 0 / 100) instead of precipitation.

[0373] Step B: (2-(4-(pyridin-3-yl)phenyl)-l,6-naphthyridin-7-yl)methanamine. The title compound (TFA salt) was prepared similarly to Intermediate 340 using tert-butyl ((2-(4- (pyridin-3-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)carbamate instead of Intermediate 339.Intermediate 361: (2-(l-(pyridin-3-yl)piperidin-4-yl)-l,6-naphthyridin-7-yl)methanamine.

[0374] Step A: methyl 4-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)-l- (pyridin-3-yl)piperidine-4-carboxylate. tert-butyl ((2-chl oro-1, 6-naphthyri din-7- yl)methyl)carbamate (Intermediate 2) (100 mg, 0.34 mmol, 1 eq.), 4-piperidinecarboxylic acid, l-(3-pyridinyl)-, methyl ester (CAS [1823499-87-1], 90 mg, 0.409 mmol, 1.2 eq.), P(t- Bu)s palladacycle gen. 4, (CAS [1621274-11-0], 14 mg, 0.0238 mmol, 0.1 eq.), and toluene (2.5 mL) were combined in a vial and the mixture was evacuated and backfilled with nitrogen three times. LiHMDS (1.06 M in THF, CAS [4039-32-1], 0.963 mL, 1.021 mmol, 3 eq.) was added dropwise. The reaction mixture was stirred at room temperature for 18 h, concentrated, and purified by flash column chromatography on silica gel (24 g, DCM / MeOH from 100 / 0 to 90 / 10) to afford the title compound (80 mg, yield: 49 %).

[0375] Step B: (2-(l-(pyridin-3-yl)piperidin-4-yl)-l,6-naphthyridin-7-yl)methanamine. methyl 4-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)-l-(pyridin-3- yl)piperidine-4-carboxylate (80 mg, 0.168 mmol, 1 eq.) was dissolved in THF (277 pL) and MeOH (553 pL). NaOH (50 % in water, 35 μL 0,.67 mmol, 5 eq.) was added and the reactionmixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure and DCM (1 mL) was added. TFA (0.128 mL, 1.675 mmol, 10 eq.) was added dropwise and the mixture was stirred for 2 h at room temperature then evaporated to afford Intermediate 361 which was used without further purification.Intermediate 362: (2-(4-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methanamine.

[0376] The title compound was prepared similarly to Intermediate 359 using (4-(pyridin-4- yl)phenyl)boronic acid (CAS [1045332-30-6]) in Step A.Intermediate 366: 4-methyl-3-(methylsulfonyl)-N-((2-(piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)benzamide.

[0377] Step A: benzyl 4-(7-(((tert-butoxy carbonyl)amino)methyl)-l,6-naphthyri din-2 - yl)piperazine- 1 -carboxylate, tert-butyl ((2-chloro- 1 ,6-naphthyridin-7 -yl)methyl)carbamate (Intermediate 2) (1500 mg, 4.7 mmol, 1 eq.) and 1 -cbz-piperazine (CAS [31166-44-6], 1.09 mL, 5.64 mmol, 1.2 eq.), and CS2CO3 (3061 mg, 9.4 mmol, 2 eq.) were dissolved in ACN (31 mL). The reaction mixture was stirred at 80 °C for 4 h, then 1 -cbz-piperazine (CAS [31166- 44-6], 45 μL, 0.5 eq.) and CS2CO3 (1.53 g, 4.7 mmol, 1 eq.) were added and stirring was continued overnight. The reaction mixture was diluted with water and the organics were extracted with EtOAc (x 3). The combined organic layer was washed with aqueous HC1 (1 M) and brine, dried over MgSO4. filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (24 g, heptane / EtOAc from 100 / 0 to 0 / 100) to afford the title compound (1742 mg, yield: 78 %) as a light yellow solid.

[0378] Step B: benzyl 4-(7-(aminomethyl)-l,6-naphthyridin-2-yl)piperazine-l -carboxylate. The title compound (TFA salt) was prepared similarly to Intermediate 340 using benzyl 4-(7- (((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)piperazine-l -carboxylate instead of Intermediate 339.

[0379] Step C: benzyl 4-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthy ri din-2 -yl)piperazine-l -carboxylate. The title compound was prepared similarly to Compound 233, starting from benzyl 4-(7-(aminomethyl)-l,6-naphthyri din-2 -yl)piperazine-l- carboxylate instead of Intermediate 359.

[0380] Step D: 4-methyl-3-(methylsulfonyl)-N-((2-(piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)benzamide. benzyl 4-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l ,6- naphthy ri din-2 -yl)piperazine-l -carboxylate (56 mg, 0.098 mmol, 1 eq.) was dissolved in EtOAc (1.95 mL) and Pd / C (10 %, 56 mg, 0.46 mmol, 1 eq.) was added. The vial was fitted with a hydrogen balloon, sparged for 5 min, and the mixture was stirred at room temperature under hydrogen atmosphere for 3 h. The reaction mixture was filtered over a short pad of Celite®, washing with EtOAc, and the filtrate was evaporated to afford Intermediate 366, used without further purification.Intermediate 367 : (2-(4-(pyridazin-3-yl)piperazin- 1 -yl)-l ,6-naphthyri din-7 -yl)methanamine.

[0381] tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2) (400 mg, 1.362 mmol, 1 eq.) and 1 -(6-pyridazinyl)piperazine (CAS [51047-56-4], 447 mg, 2.723 mmol, 2 eq.) were dissolved in THF (7 mL) and DIPEA (469 μ 2L.7,23 mmol, 2 eq.) was added. The reaction mixture was stirred at 100 °C for 18 h. The reaction mixture was adsorbed on silica and purified by flash column chromatography on silica gel (DCM / MeOH from 100 / 0 to 90 / 10). The resulting product was dissolved in DCM (1 mL) and treated with TFA (1 mL, 13.617 mmol, 10 eq.) at room temperature for 2 h. The reaction mixture was evaporated to afford Intermediate 367 (TFA salt, 424 mg, yield: 35 %), used without further purification.Intermediate 368: (2-(4-(6-methoxypyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7- yl)methanamine.

[0382] Intermediate 368 (TFA salt) was prepared similarly to Intermediate 367 using l-(6- methoxypyridin-3-yl)piperazine (CAS [158399-76-9]) instead of 1 -(6-pyridazinyl)piperazine (CAS [51047-56-4]).Intermediate 369: (2-(4-(pyrazin-2-yl)piperazin- 1 -yl)- 1 ,6-naphthyri din-7 -yl)methanamine.

[0383] Intermediate 369 (TFA salt) was prepared similarly to Intermediate 367 using 2- (piperazin-l-yl)pyrazine (CAS [34803-68-4]) instead of l-(6-pyridazinyl)piperazine (CAS [51047-56-4]).Intermediate 372: (2-(l-(pyridin-3-yl)piperidin-3-yl)-l,6-naphthyridin-7-yl)methanamine.

[0384] Step A: tert-butyl ((2-(3-butyryl-l-(pyridin-3-yl)piperidin-3-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. tert-butyl ((2-chloro- 1 ,6-naphthyri din-7 -yl)methyl)carbamate (Intermediate 2) (148 mg, 0.504 mmol, 1 eq.), ethyl 1 -(3 -pyridinyl)-3 -piperidinecarboxylate (CAS [1369241-44-0], 177 mg, 0.755 mmol, 1.5 eq.), P(t-Bu)3palladacycle gen. 4 (CAS [1621274-11-0], 30 mg, 0.050 mmol, 0.1 eq.), and toluene (2 mL) were combined in a vial and the mixture was sparged with nitrogen for 10 min. LiHMDS (1.06 M in THF, CAS [4039-32-1], 1.51 mL, 1.51 mmol, 3 eq.) was added dropwise. The reaction mixture was stirred at room temperature overnight, then DCM (0.5 mL) and MeOH (0.5 mL) were added, and the reaction mixture was stirred for 5 min. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SC>4,filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (24 g, heptane / MeOH (10 % in EtOAc) from 100 / 0 to 30 / 70) to afford the title compound (98 mg, yield: 40 %) as a yellow solid.

[0385] Step B: (2-(l-(pyridin-3-yl)piperidin-3-yl)-l,6-naphthyridin-7-yl)methanamine. tert- butyl ((2-(3-butyryl-l-(pyridin-3-yl)piperidin-3-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (98.4 mg, 0.2 mmol, 1 eq.) 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 min. The reaction mixture was evaporated and dried under vacuum. The residue was dissolved in DCM (1 mL) and TFA (1 mL) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was evaporated, and the residue was diluted with DCM and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM, then twice with 10 % trifluoroethanol / DCM. The combined organic layer was dried with Na2SC>4, filtered, and evaporated to give Intermediate 372 (63 mg, yield 99 %).Intermediate 376: 3-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2- yl)cyclohex-2-ene-l -carboxylic acid.

[0386] Step A: ethyl 3-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)cyclohex-2-ene-l -carboxylate. A vial containing tert-butyl ((2-chloro-l,6-naphthyridin-7- yl)methyl)carbamate (Intermediate 2) (400 mg, 1.362 mmol, 1 eq.), 2-cyclohexene-l- carboxylic acid, 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-, ethyl ester (CAS [1536395- 80-8], 496 mg, 1.77 mmol, 1.3 eq.), PdCh(dppf) (CAS [72287-26-4], 50 mg, 0.0681 mmol, 0.05 eq.), and K2CO3 (565 mg, 4.085 mmol, 3 eq.) was evacuated and backfilled with nitrogen 3 times. Then 1,4-di oxane (5 mL) and water (2 mL) were added and the reaction mixture was sparged with nitrogen for 10 min. The reaction mixture was stirred at 100 °C for 18 h. After evaporation of the solvent, the crude mixture was directly purified by flash column chromatography on silica gel (40 g, DCM / EtOAc from 100:0 to 0: 100) to afford the title compound (525 mg, yield: 94 %).

[0387] Step B: ethyl 3-(7-(aminomethyl)-l,6-naphthyridin-2-yl)cyclohex-2-ene-l- carboxylate. The title compound (TFA salt) was prepared similarly to Intermediate 340 usingethyl 3-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)cyclohex-2-ene-l- carboxylate instead of Intermediate 339.

[0388] Step C: ethyl 3-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin- 2-yl)cyclohex-2-ene-l -carboxylate. The title compound was prepared similarly to Compound 224 starting from ethyl 3-(7-(aminomethyl)-l,6-naphthyridin-2-yl)cyclohex-2-ene-l- carboxylate instead of Intermediate 350.

[0389] Step D: 3-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2- yl)cyclohex-2-ene-l -carboxylic acid. Ethyl 3-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)- 1 ,6-naphthyri din-2 -yl)cy cl ohex-2-ene- 1 -carboxylate (20 mg, 0.0394 mmol, 1 eq.) was dissolved in MeOH (133 pL) and THF (133 pL), then NaOH (50 % in H2O, 32 μL, 0.394 mmol, 10 eq.) was added and the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated and the residue was purified by reverse phase chromatography (Kinetex 5 um EVO cl8 100; 0.1 % TFA in water and ACN, 10 % ACN to 100 % ACN) to afford Intermediate 376 (TFA salt, 34 mg, quantitative).Intermediate 378: ethyl l-(7-(aminomethyl)-l,6-naphthyridin-2-yl)piperidine-3-carboxylate.

[0390] Step A: ethyl l-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyri din-2 - yl)piperidine-3-carboxylate. tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2) (800 mg, 2.723 mmol, 1 eq.) was added to a 50 mL vial, evacuated, and backfilled with nitrogen, followed by anhydrous ACN (12 mL). Ethyl nipecotate (CAS [25137-01-3], 0.50 mL, 3.132 mmol, 1.15 eq.) was added and the vial was evacuated and backfilled with nitrogen twice, then DIPEA (1.08 mL, 6.264 mmol, 2.3 eq.) was added. The reaction mixture was stirred at 70 °C for 5 h. Ethyl nipecotate (CAS [25137-01-3], 0.5 mL) was added and stirring was continued overnight. The reaction mixture was diluted with EtOAc, and water / brine 1 / 1. The organic layer was separated, washed with brine then water, dried over Na2SC>4, filtered, and evaporated. The residue was purified by flash column chromatography (40 g, heptane / MeOH (10 % in EtOAc) from 80 / 20 to 30 / 70) to afford the title compound as a sticky off-white solid (780 mg, yield: 69 %).

[0391] Step B: ethyl l-(7-(aminomethyl)-l,6-naphthyridin-2-yl)piperidine-3-carboxylate. The title compound (TFA salt) was prepared similarly to Intermediate 340 using ethyl l-(7-(((tert-butoxy carbonyl)amino)methyl)-l,6-naphthyridin-2-yl)piperidine-3-carboxylate instead of Intermediate 339.Intermediate 379: methyl 4-(l-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)piperidin-3-yl)benzoate.

[0392] Intermediate 379 was prepared similarly to Intermediate 378, Step A, using methyl 4- (piperi din-3 -yl)benzoate hydrochloride (CAS [1187173-13-2]) instead of ethyl nipecotate, and Intermediate 45 instead of tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2).Intermediate 380: N-((2-(3-bromo-lH-pyrazol-l-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl- 3-(methylsulfonyl)benzamide.

[0393] Intermediate 346 (163 mg, 0.439 mmol, 1 eq.), 3-bromopyrazole (CAS [14521-80-3], 101 mg, DBU (CAS [6674-22-2], 0.25 mL, 1.64 mmol, 3.7 eq.) and BOP (CAS [56602-33-6], 221 mg, 0.5 mmol, 1.14 eq.) were dissolved in ACN (5 mL) and the reaction mixture was stirred at 80 °C for 16 h. The product was isolated by filtration, washed with ACN, and dried under vacuum to afford Intermediate 380 (164 mg, yield: 75 %) as a light brown solid.Intermediate 381: Methyl 3-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)- l-(pyridin-4-yl)piperidine-3-carboxylate.

[0394] Intermediate 381 was prepared similarly to Intermediate 372 (Step A), using methyl 1- (4-pyridinyl)-3-piperidinecarboxylate (CAS [1550628-47-1]) instead of ethyl l-(3-pyridinyl)- 3 -piperidinecarboxylate.Intermediate 382: (2-(l-(Pyridin-4-yl)piperidin-3-yl)-l,6-naphthyridin-7-yl)methanamine.

[0395] Intermediate 382 was prepared similarly to Intermediate 372 starting from Intermediate 381 instead of Intermediate 371.Intermediate 384: (2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthy ridin-7-yl)methanamine.

[0396] Step A: tert-butyl ((2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)carbamate. N-chlorosuccinimide (CAS [128-09-6], 73 mg, 0.55 mmol, 1.5 eq.) was added to a solution of Intermediate 97 (170 mg, 0.36 mmol, 1 eq.) in l,l,l,3,3,3-hexafluoro-2-propanol (11 mL) at 0 °C and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc (x 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 / EtOAc from 100 / 0 tol0 / 90) to afford the title compound (107 mg; 46 %) as a brown solid.

[0397] Step B: (2-(3-chloro-6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methanamine. Hydrochloric acid (4 M in 1,4-dioxane, 0.53 mL, 2.13 mmol, 10 eq.) was added to a solution of tert-butyl ((2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)- 4-fluoropyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)carbamate (107 mg, 0.21 mmol, 1 eq.) in 1,4-dioxane (3 mL) and the mixture was stirred at room temperature for 12 h. Hydrochloric acid (4 M in 1,4-dioxane, 0.027 mL, 1.07 mmol, 5 eq.) was added and stirring was continued for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was basified to pH 10 with Na2CO3 (1 M in water) and the product was extracted twice with EtOAc. The combined organic layer was dried over MgSO4, filtered, and evaporated to afford Intermediate 384 (73.2 mg; 85 %) as an orange oil.Intermediate 389: 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-2-fluoro-4- methylbenzamide.

[0398] Step A: methyl 2-fluoro-5-((2-hydroxyethyl)thio)-4-methylbenzoate. A solution of benzoic acid, 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 eq.), and DIPEA (891 pL, 5.101 mmol, 3 eq.) in 1,4-dioxane (8.5 mL) was degassed by bubbling nitrogen through. Xantphos (CAS [161265-03-8], 98 mg, 0.17 mmol, 0.1 eq.) and Pd(dba)2(CAS [32005-36-0], 49 mg, 0.085 mmol, 0.05 eq.) were added at room temperature. The reaction mixture was stirred at 110 °C for 16 h. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (x 3). The combined organic layer was dried (MgSO4). filtered, and the solvents evaporated in vacuo. The residue was purified by flash chromatography column (12 g silica, EtOAc / heptane, from 0 / 100 to 25 / 75) to yield the title compound (380 mg, yield: 90 %)•

[0399] Step B: methyl 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)-2-fluoro-4- methylbenzoate. Tert-butyldimethylsilyl chloride (CAS [18162-48-6], 457 mg, 3.029 mmol, 2 eq.) was added in one portion 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 eq.) in THF (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with Et2O (x 3). The combined organic layer was dried (MgSO4). filtered, and the solvents evaporated in vacuo. The residue was purified by flash chromatography column (12 g silica, EtOAc / heptane, from 0 / 100 to 99 / 1) to afford the title compound (503 mg, yield: 93 %) as a yellow solid.

[0400] Step C: methyl 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2-fluoro-4- methylbenzoate. 3-Chloroperbenzoic acid (CAS [937-14-4], 629 mg, 2.808 mmol, 2 eq.) in DCM (6 mL) was added dropwise over 20 min 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 at 0 °C. After the addition, the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NaHCCL (2 x 50 mL). The layers were separated. The organic layer was dried over Na2SC>4, filtered, and concentrated. The residue was purified by flash column chromatography (12 g silica column, EtOAc / heptane, from 0 / 100 to 99 / 1) to afford the title compound (470 mg, yield: 82 %).

[0401] Step D: 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2-fluoro-4-methylbenzoate lithium salt. Lithium Iodide (434 mg, 3.245 mmol, 3.5 eq.) was added to a solution of methyl 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2-fluoro-4-methylbenzoate (360 mg, 0.922 mmol) in EtOAc (5 mL). The reaction mixture was stirred at 80 °C for 72 h. After cooling, the reaction mixture was concentrated under vacuum to afford the title compound (347 mg, yield: 98 %) as a dark brown solid, dried under vacuum and used without further purification.

[0402] Step E: 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-2-fluoro-4- methylbenzamide. The title compound was prepared according to Method C (in DMF), starting from Intermediate 11 and 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2-fluoro- 4-methylbenzoate lithium salt.Intermediate 396: (3a , 4|3 , 5a))- 1 -(6-(7 -(aminomethyl)- 1 ,6-naphthyridin-2-yl)-4- fluoropyridin-2-yl)-3,5-dimethylpiperidin-4-ol.(3a,4|3,5a)

[0403] Step A: (3R,4r,5S)-l-benzyl-3,5-dimethylpiperidin-4-yl benzoate. Benzoyl chloride (0.9 mL, 7.6 mmol, 1.5 eq.), EtsN (3.5 mL, 25 mmol, 5 eq.), and 4-(dimethylamino)pyridine (CAS [1122-58-3], 110 mg, 0.9 mmol, 0.2 eq.) were added to a solution of (3a,4[3,5a)-3,5- dimethyl-l-(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 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCCL. The organic layer was dried on MgSCL. filtered, and concentrated. The residue was purified by flash columnchromatography over silica gel (80 g, EtOAc / heptane from 0 / 100 to 20 / 80) to yield the title compound (1.706 g, yield: 99 %) as a white solid.

[0404] Step B: (3R,4r,5S)-3,5-dimethylpiperidin-4-yl benzoate. Palladium hydroxide (36 mg, 0.052 mmol, 0.04 eq.) was added to a stirred solution of (3R,4r,5S)-l-benzyl-3,5- dimethylpiperidin-4-yl benzoate (550 mg, 1.360 mmol) in MeOH (8 mL) under nitrogen atmosphere. The mixture was purged using vacuum and nitrogen, followed by hydrogen and stirred for 24 h at room temperature. The reaction mixture was filtered through a short pad of Celite® and the solvent was removed in vacuo to yield the title compound (383 mg, quantitative) as a white solid, used without further purification.

[0405] Step C: (3R,4r,5S)-l-(6-bromo-4-nitropyridin-2-yl)-3,5-dimethylpiperidin-4-yl benzoate. Nitrogen was purged through 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 eq.), (3R,4r,5S)-3,5-dimethylpiperidin-4-yl benzoate (1.628 g, 6.978 mmol), DavePhos (CAS [213697-53-1], 250 mg, 0.636 mmol, 0.1 eq.), and Pd2dbas (CAS [51364-51-3], 289 mg, 0.316 mmol, 0.05 eq.) were added to the stirred solution at room temperature while nitrogen was bubbled through the solution. The vial was closed and the reaction mixture was stirred at 90 °C for 3 h. Water and EtOAc were added to the reaction mixture and the layers were separated. The organic layer was dried on MgSO4. filtered, and concentrated under vacuo. The residue was purified by silica gel column chromatography (80 g, EtOAc / heptane from 0 / 100 to 40 / 60) to yield the title compound (1.5 g, yield 50 %) as an orange solid.

[0406] Step D: (3R,4r,5S)-l-(6-bromo-4-fluoropyridin-2-yl)-3,5-dimethylpiperidin-4-yl benzoate. Tetramethylammonium fluoride (CAS [373-68-2], 495 mg, 5.318 mmol, 1.5 eq.) was added to a solution of (3R,4r,5S)-l-(6-bromo-4-nitropyridin-2-yl)-3,5-dimethylpiperidin- 4-yl benzoate (1.54 g, 3.541 mmol) in DMF (15 mL). The reaction mixture was stirred at 65 °C for 3 h. After cooling, the reaction mixture was diluted with EtOAc (75 mL) and water (20 mL). The organic layer was washed with brine (30 mL), dried over MgSO4, filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (25 g, EtOAc / heptane from 0 / 100 to 30 / 70) to yield the title compound (970 mg, yield: 67 %) as a yellow solid.

[0407] Step E: (3S,4r,5R)-l-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)-4-fluoropyridin-2-yl)-3,5-dimethylpiperidin-4-yl benzoate. Intermediate 94 (1.418 g, 3.462 mmol), (3R,4r,5 S)- 1 -(6-bromo-4-fluoropyridin-2-y l)-3 ,5 -dimethy lpiperidin-4-y 1benzoate (1.410 mg, 3.462 mmol, 1 eq.), and K2CO3 (0.718 mg, 5.193 mmol, 1.5 eq.) were dissolved in 1,4-di oxane (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 eq.) and Pd(OAc)2 (40 mg, 0.175 mmol, 0.05 eq.) were added and the reaction mixture was stirred at 120 °C for 14 h. After cooling, the reaction mixture was diluted with aqueous 1 M Na2CO3 and extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography (80 g silica, EtOAc / heptane from 0 / 100 to 60 / 40) to yield the title compound (806 mg, yield: 39 %) as a yellow solid.

[0408] Step F: (3S,4r,5R)-l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-4-fluoropyridin-2- yl)-3,5-dimethylpiperidin-4-yl benzoate. A solution of (3S,4r,5R)-l-(6-(7-(((tert- butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)-4-fluoropyridin-2-yl)-3,5- dimethylpiperidin-4-yl benzoate (806 mg, 1.376 mmol) in a mixture of aqueous NaOH (2 M, 10.3 mL, 20.643 mmol, 15 eq.) and 1,4-dioxane (28 mL) was stirred at 72 °C for 48 h. EtOAc and water were added and the layers were separated. The organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo to yield the title compound (630 mg yield 93 %) as a solid, used without further purification.

[0409] Step G: (3a,4|3,5a))-l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-4-fluoropyridin-2- yl)-3,5-dimethylpiperidin-4-ol. (3S,4r,5R)-l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-4- fluoropyridin-2-yl)-3,5-dimethylpiperidin-4-yl benzoate (500 mg, 1.1 mmol) was dissolved in a solution of HC1 in dioxane (4 N, 3.9 mL, 15.6 mmol, 15 eq.) and DCM (3 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo. The solid was triturated in ACN (20 mL) for 1 h, filtered, and washed with ACN (3 x 1 mL) and Et20 (2 x 3 mL) to yield Intermediate 396 (HC1 salt, 460 mg, quantitative) as a red solid, used without further purification.Intermediate 399: tert-butyl 7-(4-fluoro-5-iodopyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate.

[0410] Step A: tert-butyl 7-(4-nitropyridin-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 eq.), and cesium carbonate (3.1 g, 9.52 mmol, 1.5 eq.) in 1,4-dioxane (18 mL) was degassed with nitrogen for 15 min. The vial was closed and the reaction mixture was stirred at 110 °C for 16 h. After cooling, the reaction mixture was diluted with saturated aqueous NaHCO3 and EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (80 g silica, EtOAc / heptane from 0 / 100 to 20 / 80) to yield the title compound (1.36 g, yield: 62 %) as an orange oil.

[0411] Step B: tert-butyl 7-(4-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. Tetramethylammonium fluoride (CAS [373-68-2], 570 mg, 6.12 mmol, 1.5 eq.) was added to a solution of tert-butyl 7-(4-nitropyridin-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 h. To push the reaction to completion, more tetramethylammonium fluoride (570 mg, 6.12 mmol, 1.5 eq.) was added and the reaction mixture was stirred again at 65 °C for 18 h. EtOAc and water were added. The organic layer was separated, washed once more with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g, EtOAc / heptane from 0 / 100 to 20 / 80) to give the title compound (840 mg, yield: 64 %) as a yellow oil.

[0412] Step C: tert-butyl 7-(4-fluoro-5-iodopyridin-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 eq.) was added to a solution of tert-butyl 7-(4-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane- 4-carboxylate (690 mg, 2.24 mmol) in hexafluoroisopropanol (CAS [920-66-1], 22 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica 25 g; EtOAc / heptane 0 / 100 to 10 / 90) to yield Intermediate 399 (937 mg , yield: 95 %) as a yellow oil.Intermediate 401 : 4-methyl-3-(methylsulfonyl)-N-((2-(piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)benzamide.

[0413] Step A: tert-butyl 4-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthy ri din-2 -yl)piperazine-l -carboxylate. BOP (CAS [56602-33-6], 2.576 g, 5.82 mmol, 1.1 eq.) was added to a suspension of Intermediate 346 (1950 mg, 5.25 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (CAS [6674-22-2], 4 mL, 26.25 mmol, 5 eq.) in ACN (52 mL) at room temperature. After 15 min, 1 -Boc-piperazine (CAS [57260-71-6], 1.467 g, 7.88 mmol, 1.5eq.) was added. The reaction mixture was stirred at room temperature overnight, then 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 EtOAc:MeOH / heptane 0 / 100 to 100 / 0). The obtained product was taken up in DCM and this solution was washed with water (3 x) then brine. The organic layer was dried over Na2SC>4 and concentrated to give the title compound (4.06 g, still impure, quantitative) as a solid, used without further purification.

[0414] Step B: 4-methyl-3-(methylsulfonyl)-N-((2-(piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)benzamide. tert-butyl 4-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthy ri din-2 -yl)piperazine-l -carboxylate (2833 mg, 5.25 mmol) was dissolved in DCM (26 mL), and TFA (8.03 mL, 104.99 mmol, 20 eq.) was added. The reaction mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated under vacuum. The resulting oil was dissolved in DCM and MeOH and crystallized with Et20 to give Intermediate 401 (1882 mg, yield: 82 %).Intermediate 402: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(5-pivalamidopyridin-3-yl)piperazin- 1 -yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide.

[0415] In a microwave vial were dissolved 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 eq.), 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 eq.) in 1,4-dioxane (6 mL). The vial was sealed, evacuated, and purged with argon (3 x). The reaction mixture was stirred at 100 °C for 2 days The reaction mixture was filtered over Celite® and the filter pad was rinsed with DCM, MeOH, and EtOAc. The solvents of the filtrate were evaporated and the residue was purified by reverse phase column chromatography (C18 30 x 100 mm column, 20-50 % ACN (0.1 % TFA):water (0.1 % TFA)) to afford Intermediate 402 (101 mg, yield: 28 %) as a yellow solid.Intermediate 403: tert-butyl 7-(6-chloro-3-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate.

[0416] DIPEA (2.08 mL, 12.05 mmol, 4 eq.) was added to a solution of 2,6-dichloro-3- fluoropyridine (CAS [52208-50-1], 500 mg, 3.012 mmol), tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate (CAS [674792-08-6], 671 mg, 3.163 mmol, 1.05 eq.) in DMSO (5 mL) at room temperature. The reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was poured into water. The mixture was extracted with EtOAc and the organic layer was washed with brine (3 x), dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography (40g silica, EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 403 (830 mg, yield: 81 %) as an oil.Intermediate 405: (2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthy ridin-7-yl)methanamine.

[0417] Step A: tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)-3-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. A vial containing Intermediate 403 (500 mg, 1.463 mmol, 1.5 eq.), hexamethylditin (CAS [661-69-8], 479 mg, 1.448 mmol, 1.5 eq.), tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 676 mg, 0.573 mmol, 0.6 eq.) was evacuated and back-filled with argon three times. 1,4-Dioxane (12.5 mL) was added and argon was bubbled through the suspension for 10 min before the reactionmixture was stirred at 110 °C for 3 h. tert-butyl ((2-chloro-l,6-naphthyridin-7- yl)methyl)carbamate (Intermediate 2) (286 mg, 0.975 mmol) and tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.195 mmol, 0.2 eq.) were added and the reaction mixture was stirred at 110 °C for 18 h. The reaction mixture was directly purified by column chromatography (40 g silica, EtOAc / heptane from 0 / 100 to 100 / 0) to afford the title compound (390 mg, yield: 71 %).

[0418] Step B: (2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methanamine. TFA (0.529 mL, 6.907 mmol, 10 eq.) was added dropwise to a solution of tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)-3- fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (390 mg, 0.691 mmol) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. Solvents were evaporated to give Intermediate 405 (TFA salt), used without further purification.Intermediate 408: 2,6-dibromo-3-methyl-4-nitropyridine.

[0419] 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) was added H2O2 (30 % wt, 23.4 mL, 229.08 mmol) dropwise at 0 °C. The resulting solution was stirred for 12 h at 80 °C, then was diluted with ice / water. The mixture was extracted with DCM. The combined organic layer was dried over anhydrous MgSO fil4t.ered, and concentrated in vacuo. The crude product was purified by flash column chromatography (120 g silica, DCM:MeOH 9: 1 in DCM from 0 % to 20 %) to yield the title compound (10 g, yield: 60 %) as a light yellow solid.

[0420] Step B: 2,6-dibromo-3-methyl-4-nitropyridine 1-oxide. 2,6-dibromo-3-methylpyridine 1-oxide (10 g, 37.46 mmol) was added in portions 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, keeping the temperature below 0 °C and the reaction mixture was stirred at 60 °C for 4 h. The reaction was quenched with ice / water and the mixture was extracted with DCM. The organic layer was dried (MgSO4). filtered, and concentrated. The crude product was purified by flash column chromatography (silica 80 g; EtOAc / heptane from 0 / 100 to 20 / 80) to yield the title compound (2.2 g, yield: 18 %) as a pale yellow solid.

[0421] 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 CHCh (60 mL) was added PBrs (CAS [7789-60-8], 5.9 mL, 62.77 mmol) at room temperature and the reaction mixture was stirred at 65 °C for 24 h, before quenching the reaction with H2O at 0 °C. The mixture was extracted with DCM. The organic layer was dried over MgSO f4i.ltered, and concentrated in vacuo. The residue was purified by flash column chromatography (80 g of silica gel, EtOAc / hexane 1 / 5) to afford Intermediate 408 (2.02 g, yield: 91 %) as a white solid.Intermediate 410: (3S,4r,5R)-l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-4-fluoro-5- methylpyridin-2-yl)-3,5-dimethylpiperidin-4-ol.

[0422] Step A: tert-butyl ((2-(4-fluoro-6-((3S,4r,5R)-4-hydroxy-3,5-dimethylpiperidin-l-yl)- 3-methylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. The title compound was prepared following the sequence of reactions for the synthesis of Intermediate 396, Steps C-F using Intermediate 408 instead of 2,6-dibromo-4-nitropyridine in Step C.

[0423] Step B: (3S,4r,5R)-l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-4-fluoro-5- methylpyridin-2-yl)-3,5-dimethylpiperidin-4-ol. Trifluoroacetic acid (CAS [76-05-1], 0.2 mL, 2.61 mmol) was added to a stirred solution of tert-butyl ((2-(4-fluoro-6-((3S,4r,5R)-4- hydroxy-3,5-dimethylpiperidin-l-yl)-3-methylpyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)carbamate (65 mg, 0.13 mmol) in DCM (0.4 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2h. The reaction mixture was cooled to 0 °C, and a saturated Na2CO3 aqueous solution was added until pH 8. DCM was added and the aqueous phase was extracted with DCM. The combined organic layer was dried over MgS fOil4t.ered, and concentrated in vacuo to yield Intermediate 410 (50 mg, yield: 95 %) as a yellow solid.Intermediate 411: tert-butyl 7-(4-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate and Intermediate 412: tert-butyl 7-(2-chloropyrimidin-4-yl)-4,7- diazaspiro [2.5] octane-4-carboxylate.Intermediate 411 Intermediate 412

[0424] 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 min. The mixture was then concentrated to dryness, redissolved in a minimal amount of DCM, and purified via silica chromatography (40g SiCh, EtOAc / heptane from 0 / 100 to 100 / 0) to yield Intermediate 411 (110 mg, yield: 12 %) and Intermediate 412 (760 mg, yield: 78 %).Intermediate 417: (2-(6-((cis)-2,6-dimethylmorpholino)-4,5-dimethylpyridin-2-yl)-l ,6- naphthy ridin-7-yl)methanamine.

[0425] Step A: (cis)-4-(3-bromo-4-methylpyridin-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 eq.) was stirred at 140 °C for 16 h in a sealed tube. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (12 g SiCh; EtOAc / heptane from 0 / 100 to 50 / 50) to yield the title compound (1.381 g, yield: 99 %) as a brown solid.

[0426] Step B: (cis)-4-(3,4-dimethylpyridin-2-yl)-2,6-dimethylmorpholine.Trimethylboroxine (CAS [823-96-1], 74 μL 0,.526 mmol, 1.5 eq.), CS2CO3 (229 mg, 0.701 mmol, 2 eq.), and Pd(dppl)C12.DCM (CAS [95464-05-4], 29 mg, 0.035 mmol, 0.1 eq.) were added to a solution of (2R,6S)-4-(3-bromo-4-methylpyri din-2 -yl)-2,6-dimethylmorpholine (100 mg, 0.351 mmol) in 1,4-dioxane (1.5 mL) while nitrogen was bubbling in the solution, in a sealed tube. The reaction mixture was stirred at 80 °C for 5 h. EtOAc and saturated aqueousNaHCO3 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 over silica gel (12 g; EtOAc / heptane from 0 / 100 to 10 / 90) to yield the title compound (64 mg, yield: 77 %).

[0427] Step C: (cis)-4-(5-iodo-3,4-dimethylpyridin-2-yl)-2,6-dimethylmorpholine. N- lodosuccinimide (CAS [516-12-1], 1250 mg, 5.556 mmol, 1.2 eq.) was added to a mixture of (cis)-4-(3,4-dimethylpyri din-2 -yl)-2,6-dimethylmorpholine (1020 mg, 4.63 mmol) in hexafluoroisopropanol (CAS [920-66-1], 15 mL) at 0 °C. The mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSCL, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; EtOAc / heptane 0 / 100 to 10 / 90) to yield the title compound (1.46 g, 86 %).

[0428] Step D: tert-butyl ((2-(6-((cis)-2,6-dimethylmorpholino)-4,5-dimethylpyridin-2-yl)- 1 ,6-naphthyridin-7-yl)methyl)carbamate. tert-butyl ((2-chloro- 1 ,6-naphthyri din-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-dimethylpyridin-2-yl)-2,6-dimethylmorpholine (100 mg, 0.289 mmol) in DME (3 mL), previously degassed with nitrogen. Then, 2-norbomene (CAS [498-66-8], 45 mg, 0.481 mmol, 2 eq.), K3PO4 (CAS [7778-53-2], 179 mg, 0.842 mmol, 3.5 eq.), exo-norbomeol (CAS [497-37-0], 54 mg, 0.481 mmol, 2 eq.), (2- butenyl)chloropalladium dimer (CAS [12081-22-0], 5 mg, 0.013 mmol, 0.05 eq.), and triphenylphosphine (CAS [603-35-0], 13 mg, 0.048 mmol, 0.2 eq.) were added to the reaction mixture. The reaction mixture was stirred at 100 °C for 16 h. The mixture was allowed to cool to room temperature. (2-Butenyl)chloropalladium dimer (CAS [12081-22-0], 5 mg, 0.013 mmol, 0.05 eq.) was added again, and the mixture was stirred at 100 °C for 21 h. After cooling, the mixture was washed with saturated aqueous NaHCCL and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified by flash column chromatography (12 g SiO2, EtOAc / heptane, from 100 / 0 to 30 / 70), followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 32 % [25 mM NH4HCO3] - 68 % [ACN:MeOH (1:1)] to 4 % [25 mM NH4HCO3] - 96 % [ACN:MeOH (1:1)]) to yield the title compound (41 mg, yield: 35 %) as a light yellow solid.

[0429] Step E: (2-(6-((cis)-2,6-dimethylmorpholino)-4,5-dimethylpyridin-2-yl)-l,6- naphthyridin-7-yl)methanamine. Hydrochloric acid (4 M in 1,4-dioxane, 0.63 mL, 2.513mmol, 20 eq.) was added to a stirred solution of tert-butyl ((2-(6-((cis)-2,6- dimethylmorpholino)-4,5-dimethylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (60 mg, 0.126 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo to yield the title compound (55 mg, yield: 100 %) as an orange solid which was used without further purification.Intermediate 419: tert-butyl 3-(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)carbamoyl)-2-methylphenyl)-3-hy droxypiperidine- 1 -carboxylate.

[0430] Step A: 3-(l-(tert-butoxycarbonyl)-3-hydroxypiperidin-3-yl)-4-methylbenzoic acid. Under 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 min. n-Butyllithium 2.5 M hexanes (CAS [109-72-8], 11.2 mL, 28 mmol, 2 eq.) was added dropwise and the reaction mixture was stirred at -78 °C for 20 min. Then, a solution of l-Boc-3-piperidone (CAS [98977-36-7], 5.6 g, 28.11 mmol, 2 eq.) in dry THF (5 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous NH4CI and KHSO4 (1 M in water) was added dropwise within 10 min with vigorous stirring. The pH reached the value of 2-3. DCM and water were added and the layers were separated. The organic layer was dried over MgSCL, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 80 g; DCM:MeOH (9:1) in DCM from 0 / 100 to 40 / 60) to yield the title compound (850 mg, yield: 18 %) as a yellow solid.

[0431] Step B: tert-butyl 3-(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)carbamoyl)-2-methylphenyl)-3-hy droxypiperidine- 1 -carboxylate. To a solution of Intermediate 11 (400 mg, 0.95 mmol) in DMF (10 mL), 3-(l-(tert- butoxycarbonyl)-3-hydroxypiperidin-3-yl)-4-methylbenzoic acid (385 mg, 1.15 mmol) and DIPEA (660 mL, 3.79 mmol) were added. After 1 min of stirring, HATU (CAS [148893-10-1], 450 mg, 1.18 mmol, 1.25 eq.) was added and the reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and was extracted with DCM (3 x). The combined organic layer was dried with MgS fOilt4e.red, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO2, DCM:MeOH (9:1) in DCM from 0 / 100 to 80 / 20) to yield Intermediate 419 (360 mg, yield: 55 %) as a yellow solid.Intermediate 424: tert-butyl (4-(2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyridin-4-yl)butyl)carbamate.

[0432] Step A: tert-butyl (4-(2-fluoropyridin-4-yl)but-3-yn-l-yl)carbamate. A resealable reaction vial was charged with 4-bromo-2-fluoropyridine (CAS [128071-98-7], 300 pl, 2.92 mmol), tert-butyl but-3-yn-l-ylcarbamate (CAS [149990-27-2], 900 mg, 5.32 mmol, 1.8 eq.) in DMF (10 mL) and the mixture was degassed by bubbling nitrogen for 10 min. PdC12(PPh3)2 (CAS [13965-03-2], 100 mg, 0.142 mmol, 0.05 eq.), copper iodide (CAS [7681-65-4], 12 mg, 0.063 mmol, 0.2 eq.), and triethylamine (CAS [121-44-8], 1.5 mL, 10.7 mmol, 3.7 eq.) were added. The resulting mixture was then stirred at 80 °C for 16 h. After cooling, water (50 mL) and EtOAc (30 mL) were added to the mixture. The organic layer was separated and the aqueous layer extracted once more with EtOAc (25 mL). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by chromatography over silica gel (25 g SiO2, EtOAc / heptane from 0 / 100 to 35 / 65) to give the title compound (850 mg, yield: 100 %).

[0433] Step B: tert-butyl (4-(2-fluoropyridin-4-yl)butyl)carbamate. tert-butyl (4-(2- fluoropyridin-4-yl)but-3-yn-l-yl)carbamate (850 mg, 3.21 mmol) was dissolved in MeOH (20 mL) and the mixture was cooled to 0 °C under nitrogen atmosphere. Pd / C (CAS [7440-05-3], 10 %, 250 mg) was added and reaction flask was connected to a balloon filled with hydrogen. The reaction vessel was evacuated and placed under atmosphere of hydrogen (3 times).Finally, the reaction mixture was stirred at room temperature under hydrogen atmosphere for 18 h. The catalyst was filtered off through a pad of Celite® that was further rinsed with MeOH (3 x 10 mL). The filtrate was concentrated in vacuo to afford the title compound (828 mg, yield: 95 %) as a clear oil.

[0434] Step C: tert-butyl (4-(2-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 4-yl)butyl)carbamate. tert-butyl (4-(2-fluoropyridin-4-yl)butyl)carbamate (300 mg, 1.12 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 350 mg, 1.38 mmol, 1.2 eq), [Ir(COD)OMe]2(CAS [12148-71-9], 12 mg, 18μmol, 0.016 eq.), and dtbpy (CAS [72914- 19-3], 9 mg, 33μmol, 0.03 eq.) were dissolved in dry THF (4 mL) under nitrogen atmosphere. The reaction vessel was closed and the reaction mixture was stirred at 80 °C for 5 h. After cooling, the solvent was evaporated in vacuo to give the title compound (700 mg, crude oil, used without further purification).

[0435] Step D: tert-butyl (4-(2-fluoro-6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)- l,6-naphthyridin-2-yl)pyridin-4-yl)butyl)carbamate. Intermediate 45 (190 mg, 0.487 mmol) and tert-butyl (4-(2-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-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(dppl)C12.CH2C12 (CAS [95464-05-4], 38 mg, 0.047 mmol, 0.1 eq.), potassium carbonate (250 mg, 1.81 mmol, 3.7 eq.), and copper chloride (CAS [7758-89-6], 50 mg, 0.505 mmol, 1 eq.) were added. The reaction was then stirred at 90 °C for 1 h. To push the reaction to completion, water (2 mL) was added with a new charge of Pd(dppl)C12.CH2C12 (CAS [95464-05-4], 38 mg, 0.047 mmol, 0.01 eq.). The reaction mixture was stirred at 90 °C for 45 min. After cooling, the mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over MgSO4. filtered, and concentrated. The crude product was purified by chromatography over silica gel (25 g, MeOH / DCM from 0 / 100 to 5 / 95) to give the title compound (204 mg, yield: 67 %) as a sticky solid.

[0436] Step E: tert-butyl (4-(2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)- 1 ,6-naphthyri din-2 -yl)pyridin-4-yl)butyl)carbamate. A solution of tert-butyl (4-(2-fluoro-6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-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 eq.) in DMSO (1 mL) was stirred at 120 °C for 48 h. After cooling, the mixture was diluted with EtOAc (20 mL). Water (80 mL) and saturated aqueous NaHCOs (20 mL) were added. The organic layer wasseparated, and the aqueous layer was extracted once more with EtOAc (20 mL). The combined organic layer was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by chromatography over silica gel (25 g, MeOH / DCM from 0 / 100 to 10 / 90) to give Intermediate 424 (209 mg, yield: 80 %) as a yellow solid.Intermediate 426: 3-(methylsulfonyl)-5-(trifluoromethoxy)benzoic acid.

[0437] Step A: methyl 3-(methylsulfonyl)-5-(trifluoromethoxy)benzoate. Copper(I) iodide (CAS [7681-65-4], 211 mg, 1.104 mmol, 1.1 eq.) was added to a solution of methyl 3-bromo- 5-(trifluoromethoxy)benzoate (CAS [1306763-53-0] , 300 mg, 1.003 mmol) and methanesulfinic acid sodium salt (CAS [20277-69-4], 410 mg, 4.013 mmol, 4 eq.) in DMSO (4 mL) at room temperature. The mixture was stirred at 100 °C for 18 h. A second addition of methanesulfinic acid sodium salt (205 mg, 2.006 mmol, 2 eq.) and copper(I) iodide (106 mg, 0.552 mmol, 0.55 eq.) was done. The mixture was stirred at 100 °C for 18 h. After cooling, the mixture was diluted with EtOAc and washed with water and aqueous NHs (1 mL). The organic layer was separated, dried over MgSO f4i.ltered, and concentrated. The crude product was purified by flash column chromatography (silica 12 g; EtOAc / heptane from 0 / 100 to 30 / 70) to yield the title compound (130 mg, yield: 41 %) as a white solid.

[0438] Step B: 3-(methylsulfonyl)-5-(trifluoromethoxy)benzoic acid. In a round bottom flask, NaOH (0.44 mL, 0.88 mmol, 2 eq.) was added to a solution of methyl 3-(methylsulfonyl)-5- (trifluoromethoxy)benzoate (130 mg, 0.44 mmol) in MeOH (4 mL). The reaction mixture was stirred at room temperature for 18 h. HC1 (1 M in water) was added to reach pH 4. The solvent was evaporated to yield a solid. The solid was triturated in DCM:MeOH (9:1). The salts were filtered off and the filtrate was concentrated to afford the title compound (95 mg, yield: 73 %) as a white solid.Intermediate 428: (2-(3-chloro-4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthy ridin-7-yl)methanamine.

[0439] Step A: tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)-5-chloro-4-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. N- chlorosuccinimide (CAS [128-09-6], 41 mg, 0.31 mmol, 1.6 eq.) was added to a solution of tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)-4- fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (Intermediate 300, product from Step C, 124 mg, 0.2 mmol) in l,l,l,3,3,3-hexafluoro-2-propanol (5 mL) at 0 °C and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and saturated aqueous NaS20s, dried over MgSO4. filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; EtOAc / heptane from 0 / 100 to 50 / 50) to yield the title compound (113 mg, yield: 73 %) as a yellow foam.

[0440] Step B: (2-(3-chloro-4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methanamine. Hydrochloric acid (4 M in 1,4-dioxane, 1 mL, 4 mmol, 21 eq.) was added to a stirred solution of tert-butyl 7-(6-(7-(((tert- butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)-5-chloro-4-fluoropyridin-2-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (113 mg, 0.19 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo to yield Intermediate 428 (97 mg (crude), quantitative) as an orange solid, used without further purification.Intermediate 429: 4-methyl-3-(tetrahydrofuran-2-yl)benzoic acid.

[0441] Sodium hydroxide (CAS [1310-66-3], 1.6 mL, 1.64 mmol, 3 eq.) was added to a stirred solution of methyl 4-methyl-3-(tetrahydro-2-furanyl)benzoate (CAS [2252250-22-7], 185 mg, 0.55 mmol) in MeOH (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. Theaqueous layer was acidified with HC1 (1 M in water) to pH = 1 and then extracted with EtOAc (x 2). The organic layer was dried over MgSO4 f,iltered, and concentrated in vacuo to yield Intermediate 429 (89 mg, yield: 75 %) as a yellow solid.Intermediate 431 : 3-((3-((tert-butyldimethylsilyl)oxy)azeti din-1 -yl)sulfonyl)-N-((2-(4-fluoro- 6-(4,7 -di azaspiro [2.5] octan-7-yl)pyridin-2-yl)- 1 ,6-naphthy ri din-7 -yl)methy l)-4- methylbenzamide.

[0442] Step A: 3-((3-((tert-butyldimethylsilyl)oxy)azetidin-l-yl)sulfonyl)-4-methylbenzoic acid. 3-chlorosulfonyl-4-methyl-benzoic acid (CAS [2548-29-0], 158.23 mg, 0.67 mmol) was added to a stirred solution of azetidin-3-yloxy-tert-butyldimethylsilane (CAS [875340-81-1], 379 mg, 2.02 mmol, 3 eq.) in DCM (4 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with a saturated citric acid aqueous solution and extracted with DCM (x 3). The combined organic layer was dried over MgSO4 f,iltered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel (12 g; DCM:MeOH (9:1) in DCM from 0 to 10 %) to afford the title compound (113 mg; yield: 41 %) as a white solid.

[0443] Step B: 3-((3-((tert-butyldimethylsilyl)oxy)azetidin-l-yl)sulfonyl)-N-((2-(4-fluoro-6- (4,7-diazaspiro [2.5] octan-7 -y l)py ri din-2 -yl)- 1 ,6-naphthy ri din-7 -y l)methyl)-4- methylbenzamide. To a solution of 3-((3-((tert-butyldimethylsilyl)oxy)azetidin-l-yl)sulfonyl)- 4-methylbenzoic acid (40 mg, 0.10 mmol, 0.8 eq.) in DMF (3 mL), DIPEA (182 pl, 1.05 mmol, 8 eq.) and HATU (CAS [148893-10-1], 77 mg, 0.20 mmol, 1.2 eq.) were added. The reaction mixture was stirred and after 1 min was treated with Intermediate 300 (62 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and was extracted with DCM (x 3). The combined organic layer was dried with MgSO4. filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g SiCh, DCM:MeOH (9:1) in DCM from 0 % to 30 %) to yield Intermediate 431 (79 mg, yield: 81 %) as a yellow solid.Intermediate 437: 3-fluoro-5-((2-hydroxyethyl)sulfonyl)benzoic acid.

[0444] Step A: methyl 3-fluoro-5-((2-hydroxyethyl)sulfonyl)benzoate. 1,10-Phenanthroline (CAS [66-71-7], 79 mg, 0.438 mmol, 0.17 eq.), triphenylphosphine (CAS [603-35-0], 115 mg, 0.412 mmol, 0.16 eq.), potassium metabisulfite (CAS [16731-55-8], 1.288 g, 5.793 mmol, 2.25 eq.), formic acid sodium salt (CAS [141-53-7], 0.438 g, 6.437 mmol, 2.5 eq.), and TBAB (CAS [1643-19-2], 1.038 g, 3.218 mmol, 1.25 eq.) were added to a solution of methyl 3-bromo-5-fluorobenzoate (CAS [334792-52-8], 0.6 g, 2.575 mmol) in DMSO (15 mL). The mixture was bubbled with nitrogen for 20 min. Palladium (II) acetate (CAS [3375-31-3], 32 mg, 0.144 mmol, 0.056 eq.) was added and the reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, 2-(2-bromoethoxy)tetrahydro-2 / / -pyran (CAS [17739-45- 6], 0.476 mL, 3.141 mmol, 1.22 eq.) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layer was washed with water, dried over MgSO fil4t.ered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (25 g SiCh; EtOAc / heptane from 0 / 100 to 60 / 40) to afford the title compound (199 mg, yield: 28 %) as a pale-yellow oil.

[0445] Step B: 3-fluoro-5-((2-hydroxyethyl)sulfonyl)benzoic acid. Sodium hydroxide (4.566 mL, 1 M in water, 4.566 mmol, 6 eq.) was added to a stirred solution of methyl 3-fluoro-5- ((2-hydroxyethyl)sulfonyl)benzoate in MeOH (10 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc (x 2). The aqueous layer was acidified to pH 4 with HC1 (1 M in water) and extracted with EtOAc (x 2). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 437 (77 mg, yield: 40 %) as a white sticky solid.Intermediate 439: 5-amino-5-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)pentyl acetate.CIS

[0446] Step A: 5-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-5- ((diphenylmethylene)amino)pentyl acetate. Potassium tert-butoxide (601 μ 1L M, in THF, 0.601 mmol, 1.2 eq.) was added dropwise to a yellow suspension of Intermediate 194 (268 mg, 96 % pure, 0.501 mmol) in dry THF (5 mL) under nitrogen atmosphere at room temperature. The reaction mixture instantly turned deep violet / black. After 2 min, 4- bromobutyl acetate (CAS [4753-59-7], 94 μL 0,.651 mmol, 1.3 eq.) was added dropwise and the dark reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated to give the title compound (400 mg, yield: 27 % pure, yield: 34 %) as a brown oil, used without further purification.

[0447] Step B: 5-amino-5-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)pentyl acetate. HC1 (37 % in H2O, 287 μ 3L.4,41 mmol, 20 eq.) was added dropwise (1 drop / sec) to a light brown solution of 5-(2-(6-((2S,6R)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthy ri din-7 -y 1) -5 - ((diphenylmethylene)amino)pentyl acetate (400 mg, 27 % pure, 0.172 mmol) in 1,4-dioxane (5 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature for 15 min. Nitrogen was bubbled through the reaction mixture for 10 min. The solvent was evaporated, and the crude product was co-evaporated with toluene several times to yield Intermediate 439 (295 mg, 27 % pure, quantitative) as a black solid, dried under vacuum at 50 °C, and used without further purification.Intermediate 441: 3-amino-3-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)propan-l -ol.CIS

[0448] Step A: N-(3-((tert-butyldimethylsilyl)oxy)-l-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)propyl)- 1 , 1 -diphenylmethanimine. Potassium tert-butoxide (245 μL, 1 M in THF, 0.245 mmol, 1.2 eq.) was added dropwise to an orange solution of Intermediate 194 (118 mg, 89 % pure, 0.204 mmol) in dry THF (3 mL)under nitrogen atmosphere at room temperature. The reaction mixture instantly turned deep violet / black. After 2 min, (2 -bromoethoxy )-tert-butyldimethylsilane (CAS [86864-60-0], 56μL, 0.266 mmol, 1.2 eq.) was added dropwise and the dark reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated to give the title compound (165 mg, 65 % pure, yield: 78 %) as a thick brown oil, used without further purification.

[0449] Step B: 3-amino-3-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)propan-l-ol. A mixture of N-(3-((tert-butyldimethylsilyl)oxy)-l-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)propy 1)- 1 , 1 - diphenylmethanimine (165 mg, 0.16 mmol) in HC1 (4 M in 1,4-dioxane, 0.8 mL, 3.192 mmol, 20 eq.) was stirred at room temperature overnight. To push the reaction to completion, HC1 (36 % in water, 0.5 mL) was added, and the mixture was stirred at room temperature for 2 h. The brown mixture was evaporated to dryness to give Intermediate 441 (148 mg, 50 % pure, assumed quantitative) as a black solid, used without further purification.Intermediate 445: N-(l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-5-(l,3-dioxoisoindolin-2-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide.CIS

[0450] Step A: 2-(5-((diphenylmethylene)amino)-5-(2-(6-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)pentyl)isoindoline-l, 3-dione. Potassium tert-butoxide (3.73 mL, 1 M in THF, 3.728 mmol, 1.2 eq.) was added dropwise to a suspension of Intermediate 194 (1413 mg, 92 % pure, 3.106 mmol) in dry THF (30 mL) under nitrogen atmosphere at room temperature. The reaction mixture instantly turned deep violet / black. 5 min after the addition, a solution of N-(4-bromobutyl)phthalimide (CAS [5394-18-3], 1139 mg, 4.038 mmol, 1.3 eq.)in dry THF (5 mL) was added dropwise and the reaction mixture was stirred at room temperature for 3 h. More potassium tert-butoxide (0.7 mL, 1 M in THF, 0.700 mmol) was added dropwise to the reaction mixture and it was stirred at room temperature for 2 h. The reaction mixture was diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4. filtered, and the solvent was evaporated to give the title compound (1790 mg, 40 % pure, yield: 37 %) as an orange solid, used without further purification.

[0451] Step B: 2-(5-amino-5-(2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7- yl)pentyl)isoindoline- 1,3-dione. HC1 (37 % in H2O, 1.9 mL, 22.59 mmol, 20 eq.) was added dropwise to a solution of 2-(5-((diphenylmethylene)amino)-5-(2-(6-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)pentyl)isoindoline-l, 3-dione (1750 mg, 40 % pure, 1.13 mmol) in 1,4- dioxane (20 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated and the crude product was co- evaporated with toluene several times to yield the title compound (HC1 salt, 1570 mg, 38 % pure, assumed quantitative) as a black solid, used without further purification.

[0452] Step C: N-(5-(l,3-dioxoisoindolin-2-yl)-l-(2-(6-fluoropyridin-2-yl)-l,6-naphthyridin- 7-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide. 1-Propanephosphonic anhydride solution (CAS [68957-94-8], 874 μL 1,.468 mmol, 1.3 eq.) was added to a suspension of 4- methyl-3-(methylsulfonyl)benzoic acid (CAS [51522-22-6], 266 mg, 1.242 mmol, 1.1 eq.) and 2-(5-amino-5-(2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)pentyl)isoindoline-l,3- dione (38 % pure, 1570 mg, 1.129 mmol) in dry DCM (20 mL) at room temperature.Triethylamine (785 μL, 5.645 mmol, 5 eq.) was then added dropwise to the suspension. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM and water. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layer was dried on MgSCti, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g; eluent: EtOAc / EtOH 3 / l:heptanes from 0: 100 to 100:0) to give the title compound (167 mg, yield: 22 %) as a yellow solid.

[0453] Step D: N-(l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)-5-(l,3-dioxoisoindolin-2-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide A suspension of N-(5-(l,3-dioxoisoindolin-2-yl)-l-(2-(6-fluoropyri din-2 -yl)-l,6-naphthyri din-7-yl)pentyl)- 4-methyl-3-(methylsulfonyl)benzamide (167 mg, 0.246 mmol), cis-2,6-dimethylmorpholine (121μL, 0.984 mmol, 4 eq.), and DIPEA (127 μL 0,.738 mmol, 3 eq.) in dry DMSO (2 mL)was introduced into a thick glass vial. The vial was sealed, and the reaction mixture was stirred at 130 °C overnight. The reaction mixture was diluted with water and DCM. The layers were separated, and the aqueous layer was extracted again with DCM. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated to give Intermediate 445 (296 mg, 82 % pure, quantitative) as a thick brown oil, used without further purification.Intermediate 448: 3,5-dimethylpiperidin-4-d-4-ol.(3 a, 5 a)

[0454] Step A: tert-butyl 4-hydroxy-3,5-dimethylpiperidine-l-carboxylate-4-d. Sodium borodeuteride (CAS [15681-89-7], 246 mg, 5.279 mmol) was added in portions to a solution of rel- 1,1 -dimethylethyl (3R,5S)-3,5-dimethyl-4-oxo-l-piperidinecarboxylate (CAS [1221821-84-6], 600 mg, 2.64 mmol) in MeOH (20 mL) cooled to 0 °C. The reaction mixture was stirred at 0 °C for 20 min, then at room temperature for 3.5 h. Water (5 mL) was added dropwise and the reaction mixture was concentrated under reduced pressure. The residue was partitioned between water and EtOAc. The layers were separated, and the organic layer was dried on MgSO4. filtered, and evaporated to give Intermediate 447 (572 mg, 46 % pure, yield: 43 %) as a white solid, used without further purification.

[0455] Step B: 3,5-dimethylpiperidin-4-d-4-ol. HC1 (4 M in 1,4-dioxane, 2.8 mL, 4 M, 11.424 mmol, 10 eq.) was added to a solution of tert-butyl 4-hydroxy-3,5-dimethylpiperidine-l- carboxylate-4-d (572 mg, 1.142 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to give Intermediate 448 (HC1 salt, 190 mg, quantitative) as a white solid, used without further purification.Intermediate 450: tert-butyl ((2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)carbamate.

[0456] Step A: (2-chloropyrimidin-4-yl)zinc(II): Chloride: A mixture of 2-chloropyrimidine(CAS [1722-12-9], 229 mg, 2 mmol) in THF (30 mL) was cooled at -60 °C under nitrogenatmosphere. Then, 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (CAS [898838-07-8], 0.85 M in THF / toluene, 2.824 mL, 2.4 mmol) was added dropwise and the reaction mixture was stirred for 1.5 h at -60 °C under nitrogen atmosphere. Zinc chloride (CAS [7646-85-7], 1 M in Et20, 3 mL, 3 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was used as such for the next step.

[0457] Step B: tert-butyl ((2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. (2-chloropyrimidin-4-yl)zinc(II) chloride (0.18 M in THF / Et2O, 14.18 mL, 2.55 mmol, 3 eq.) was added to a solution of tert-butyl ((2-chloro-l,6-naphthyridin-7- yl)methyl)carbamate (Intermediate 2) (0.250 g , 0.851 mmol) and tetrakis(triphenylphosphine)palladium (CAS [14221-01-3], 49 mg, 0.043 mmol, 0.05 eq.) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried (MgSO4). filtered, and the solvent evaporated in vacuo. The residue was crystallized in ACN to yield Intermediate 450 (213 mg, yield: 65 %) as a solid.Intermediate 453: l-(4-(7-(aminomethyl)-l,6-naphthyridin-2-yl)pyrimidin-2-yl)-3,4,4- trimethylimidazolidin-2-one.

[0458] Step A: tert-butyl ((2-(2-((2-methyl-2-(methylamino)propyl)amino)pyrimidin-4-yl)- l,6-naphthyridin-7-yl)methyl)carbamate. A suspension of Intermediate 450 (176 mg, 0.173 mmol), (l-amino-2-methylpropan-2-yl)(methyl)amine (CAS [116577-09-4], 97 mg, 0.947 mmol, 2 eq.), and DIPEA (245 μL 1,.420 mmol, 3 eq.) in dry DMSO (2 mL) was introduced into a microwave vial. The vial was sealed, and the reaction m...

Claims

CLAIMS1. A compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof,whereinR1is an optionally substituted phenyl selected from:(a) 2-chlorophenyl, 2-methyl-5-(lH-tetrazol-l-yl)phenyl, 5-(tert-butyl)-2- methoxyphenyl, 3-fluoro-2-(lH-l,2,3-triazol-l-yl)phenyl, 2-fluoro-5-(l-whereinRais selected from: H; halo; C1-4alkyl; C1-4alkyl substituted with one or two members each independently selected from OH, cyclopropyl, CN, and CH2CO2C1-4alkyl; C1-4haloalkyk C1-4haloalkyl substituted with one or two OH members; CN; OC1-4alkyl; OC1-4haloalkyk (P=O)(CH3)2; CO2C1-4alkyl; NH(SO2-C2-3alkenyl), and NH(C=O)C2-3alkynyl;Rbis selected from: Cl, F, Br, C1-4alkyl, OC1-4alkyl, cyclopropyl, and 4-methyl-lH- imidazol-l-yl;Rcis selected from: Cl, Br, I, C1-4alkyl, C1-4haloalkyl, OC1-4alkyl, 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), heterocycloalkyl optionally substituted with one or two members each independently selected from halo, OH, CH3, CH2CH2OH, OC1-4alkyl, and CO2C1-4alkyl;Rdis Cl or CH3;Reis selected from: C1-4alkyl substituted with one or two OH members, and IH-tetrazole;Rgis C1-4alkyl optionally substituted with one OH member;Rhis C1-4alkyl, or C1-4haloalkyl;R1is selected from: C1-4alkyl optionally independently substituted with one, two or three members selected from: OH, CN, OC1-4alkyl, CN, NH2, N(C1-4alkyl)2, O-tetrahydropyranyl, piperidine substituted with C(OH)(CH3)2, and NH(CO2C1-4alkyl); NH(C1-4alkyl); N(C1-4alkyl)2; NH(CH2CH2OH); tetrahydropyranyl; C1-4haloalkyl; C2-4alkenyl; azetidine optionally substituted with OH; and (cis)-2,6-dimethylmorpholinyl; each Rkis independently selected from: halo, C1-4akyl, OC1-4alkyl, NH2, OC1-4haloalkyl, CN, CH2OH, Cs-ecyclalkyl, and C2-4alkenyl;Rmis selected from: C1-4haloalkyl, CH2CH2OH, and CH2CN; n is 0, 1, 2, or 3;X is O, NH, orN-CHs;R3is selected from: H, and C1-4alkyl optionally substituted with one member selected from: OH, NH2, N(CH3)2, NH(C=O)CH3, and morpholine; andR5is selected from the group consisting of: i) a 5- or 6-membered heteroaryl, optionally fused with a Cs-vcycloalkyl or Cs-vheterocycloalkyl, selected from:(cis)-2,6-dimethyl-4-(5,6,7,8-tetrahydro-2,6-naphthyridin-l-yl)morpholine; 7- ((cis)-2,6-dimethylmorpholino)-2,3-dihydrofuro[2,3-c]pyridine; 4-((cis)-2,6- dimethylmorpholino)-l,3-dihydrofuro[3,4-c]pyridine; (cis)-2,6-dimethyl-4- (5,6,7,8-tetrahydroisoquinolin-l-yl)morpholine; 3-((2,2,6,6-tetramethyltetrahydro- 2H-pyran-4-yl)oxy)pyridazin-6-yl; (cis)-2,6-dimethyl-4-(pyrimidin-4- yl)morpholine; (cis)-2,6-dimethyl-4-(lH-pyrazol-3-yl)morpholine; (IH-pyrazol-l- yi);Rpis selected from the group consisting of:(a) an eight to ten membered nitrogen linked spirocyclic heterocycloalkyl ring system, wherein each ring optionally contains one, two or three heteroatoms each independently selected from N, O, and S, optionally substituted with one, two or three members each independently selected from: OH, C1-4alkyl, Ci- dialoalkyl, oxo, CO2C1-4alkyl, NH2, N(H)(C1-4alkyl), N(C1-4alkyl)2, N(H)(CO2C1-4alkyl), and OC1-4alkyl;(c) Nitrogen linked azetidine optionally substituted with a one or two members each independently selected from: CH3, NH2, and NH(CO2C1-4alkyl);Nitrogen linked pyrrolidine optionally substituted with one, two, three or four members each independently selected from: halo, C1-4alkyl, CH2OH, CH2OCH3, C1-4haloalkyl, OH, NH2, oxo, NH(CO2C1-4alkyl), morpholinyl, and CH2- morpholinyl; Nitrogen linked piperidine optionally substituted with one, two, three or four members each independently selected from: deuterium, halo, Ci- 4alkyl, CH2OH, CH2CH2OH, OH, NH2, NH(C1-4alkyl), and OC1-4alkyl;Nitrogen linked piperazine optionally substituted with one, two, three or four members each independently selected from: halo, C1-4alkyl, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, CH2CN, (C=O)NH2, CH2(C=O)NH2, CChC1-4alkyl, CH2SO2CH3, C1-4haloalkyl. OH, oxo, Cs-ecycloalkyl, and CH2-C3- ecycloalkyl; Nitrogen linked morpholine optionally substituted with one, two, three or four members each independently selected from: Cwalkyl, Ci- 4haloalkyl, CO2OH, oxo, (CH2)4-6-NH2, (CH2)4-6-NH(C=O)CH3, and (CH2)4-6- NH(CO2CI-4 alkyl);Nitrogen linked diazepane optionally substituted with one or two members Ci- 4alkyl members;Nitrogen linked oxazepane optionally substituted with one or two C1-4alkyl members; and Nitrogen linked thiomorpholine 1,1-dioxide; and(d) 5-10 membered fused or bridged ring, wherein each ring optionally contains one, two or three heteroatoms each independently selected from N, S, or O, optionally substituted with one, two or three members each independently selected from: halo, C1-4alkyl, OH, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NH(CO2C1-4alkyl), CO2C1-4alkyl, and oxo;each Rqis independently selected from: H, halo, Cwalkyl, Cwhaloalkyl, CN,Rsis H or halo; andRlis selected from: C1-4alkyl; oxetan-3-yl; carbon linked azetidine optionally substituted with (CCh-tBu); tetrahydropyran; l,3-oxazinan-2-one; 2, 2,6,6- tetramethylpiperidin-4-yl; and 2,2,6,6-tetramethyltetrahydro-2H-pyran;Ruis H, pyridin-3-yl, or pyridin-4-yl;Rvis (cis)-2,6-dimethylmorpholinyl, pyridin-3-yl, or pyridin-4-yl;Rwis H, F, or OCHs;Rxis pyridin-3-yl, or pyridin-4-yl;Ryis selected from:, pyridin-3-yl, and pyridin-4-yl;Rzis selected from:vi) a C1-4haloalkyl; or -CH2-Raa, wherein Raais selected from: CH(CH3)2, CH2CH2OCH3,2. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, wherein:(i) R1is:(ii) R1is:(iii) R1is:

3. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or isotopic4. A compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer or isotopic variant thereof, wherein R3is:

5. A compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt, stereoisomer or isotopic variant thereof, wherein:

6. A compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, wherein R5is:

7. A compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, wherein:

8. A compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, whereinwherein:(i) RP is(iii) Rpis(iv) Rpis9. A compound of claim 8 or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, wherein Rqis: H, Cl, F, I, CHs, CN, CH2OH, CH(OH)(CH3), CO2H,10. A compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, wherein:

11. A compound of claim 1 selected from the group consisting of:N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((trifluoromethyl)sulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2-fluoro-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2-fluoro-4-methyl-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(l -hydroxy ethyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide;3-cyano-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-5-(methylsulfonyl)benzamide;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-5-(methylsulfonyl)benzamide;3-(l,l-difluoroethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-hydroxyethyl)(methyl)amino)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(N-(2-hydroxyethyl)methylsulfonamido)-4-methylbenzamide3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((3-methoxypropyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*R)-l-hydroxyethyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*S)-l-hydroxyethyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-((tetrahydro-2H-pyran-4-yl)sulfonyl)benzamide;4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-3-(methylsulfonyl)benzamide;3-(l,l-difluoroethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-fluorobenzamide;3-(l,l-difluoroethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-ethoxybenzamide;3-(cyclopropyl(hydroxy)methyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyridin-7 -yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(isopropylsulfonyl)-4,5-dimethylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(N,N-dimethylsulfamoyl)-4,5-dimethylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(N-(2 -hydroxy ethyl)-N-methylsulfamoyl)-4, 5- dimethylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3,4-dimethylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-iodo-4,5-dimethylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(2-hydroxyethoxy)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3,4-dimethyl-5-(morpholinosulfonyl)benzamide; methyl 2-(3-(((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)carbamoyl)phenyl)acetate;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(2,2,2-trifluoroacetyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-ethoxyethyl)sulfonyl)-4,5-dimethylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2-fluoro-5-(l-hydroxyethyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2-fluoro-5-((*R)-l -hydroxy ethyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2-fluoro-5-((*S)-l-hydroxyethyl)-4-methylbenzamide;4-cyclopropyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthy ridin-7-y l)methyl)-3 -( 1 -hydroxy ethyl)benzamide;4-cyclopropyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)-3-((*R)- 1 -hydroxy ethyl)benzami de;4-cyclopropyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((*S)-l -hy droxy ethyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-methoxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-iodo-4-methylbenzamide;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-5-(2-hydroxypropan-2-yl)benzamide;N-((2-(6-(4-(2-hy droxy ethyl)piperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2,2-dioxido-2-thia-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(l,4-oxazepan-4-yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(l-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((lR,5S,8r)-8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((lR,5S,8s )-8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(4-hydroxy-4-methylpiperi din-1 -yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(l,l-dioxidothiomorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(4-(2-hydroxyethyl)piperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(l,l-dioxido-l-thia-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-( 1 -oxa-6-azaspiro[3.3]heptan-6-y l)pyridin-2-yl)- 1 ,6-naphthy ridin-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-(trifluoromethyl)morpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-(6-oxa- 1 -azaspiro[3.3]heptan- 1 -y l)pyridin-2-yl)- 1 ,6-naphthy ridin-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide ;4-methyl-3-(methylsulfonyl)-N-((2-(6-(2,2,6,6-tetramethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((lR,5S,6s )-6-hydroxy-3-azabicyclo[3.

1. l]heptan-3-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(5-oxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-morpholinopyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(6-(2,2-dimethyl-l,4-oxazepan-4-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(7,7-dimethyl-l,4-oxazepan-4-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-((cis)-2,6-dimethylmorpholino)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3- (methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-ethyl-3-(methylsulfonyl)benzamide;N-((2-(6-(4-hydroxy-3-methylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide ;N-((2-(6-((3*R,4*S)-4-hydroxy-3-methylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((3*S,4*R)-4-hydroxy-3-methylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(methylsulfonyl)benzamide;4-cyclopropyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3,4-dimethyl-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-methylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-methylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-iodopyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((3-hydroxypropyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din- 7-yl)methyl)-3-((2-methoxyethyl)sulfonyl)benzamide;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-5-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din- 7-yl)methyl)-3-(l-hydroxyethyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-3-(hydroxymethyl)-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-cyclopropyl-3-(methylsulfonyl)-N-((2-(6-(2, 2,6,6- tetramethylmorpholino)py ridin-2-y 1)- 1 ,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-cyclopropyl-3-(methylsulfonyl)benzamide;N-((2-(7-((cis)-2,6-dimethylmorpholino)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-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)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3,4-dimethyl-5-(methylsulfonyl)benzamide;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-5-(l-hydroxyethyl)benzamide;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-5-((*R)-l -hydroxy ethyl)benzamide;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7 -yl)methyl)-5-((* S)- 1 -hydroxy ethyl)benzami de;N-((2-(6-((lR,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-cyclopropyl-3-(methylsulfonyl)benzamide;4-cyclopropyl-N-((2-(6-((lR,5S)-7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3- (methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(2-hydroxypropan-2-yl)-4-methylbenzamide;N-((2-(6-(6-oxa-3-azabicyclo[3. l.l]heptan-3-yl)pyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-3,4-dimethyl-5-(methylsulfonyl)benzamide;4-cyclopropyl-N-((2-(6-((3*S,4*R)-4-hydroxy-3-methylpiperidin-l-yl)pyri din-2- yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-cyclopropyl-N-((2-(6-((3*R,4*S)-4-hydroxy-3-methylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(6-((3*S,4*R)-4-hydroxy-3-methylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2,3-dimethyl-5-(methylsulfonyl)benzamide;N-((2-(6-((3*R,4*S)-4-hydroxy-3-methylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2,3-dimethyl-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide;N-((2-(l-((cis)-2,6-dimethylmorpholino)-5,6,7,8-tetrahydroisoquinolin-3-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-((cis)-2,6-dimethylmorpholino)-l,3-dihydrofuro[3,4-c]pyridin-6-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;2-fluoro-4-methyl-5-(methylsulfonyl)-N-((2-(6-(2, 2,6,6- tetramethylmorpholino)py ridin-2-y 1)- 1 ,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyri din-2 -yl)-l,6-naphthyri din- 7-yl)methyl)-4-cyclopropyl-3-(methylsulfonyl)benzamide;2-fluoro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide;3-chloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(l -hydroxy ethyl)benzamide; methyl 3-(((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)carbamoyl)benzoate;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;3-((*S)-cyclopropyl(hydroxy)methyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 , 6-naphthyri din- 7 -yl)methyl)benzamide;3-((*R)-cyclopropyl(hydroxy)methyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 , 6-naphthyri din- 7 -yl)methyl)benzamide;N-((2-(6-((3a,4a,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide;4-chloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l, 6-naphthyri din-7-yl)methyl)-3-(methylsulfonyl)benzami de;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din-7- yl)methyl)-3-((*R)-l -hydroxy ethyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din-7- yl)methyl)-3-((* S)- 1 -hydroxyethyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din-7- yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4,5-dimethylbenzamide;(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)carbamoyl)-2,3-dimethylphenyl)boronic acid;3-chloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l, 6-naphthyri din-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-4- methylbenzamide;3-chloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l, 6-naphthyri din-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-fluoropyri din-2 -yl)-l, 6-naphthyri din- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; tert-butyl (lR,5S)-9-(6-(7-((3,4-dimethyl-5-(methylsulfonyl)benzamido)methyl)- 1, 6-naphthyri din-2-yl)pyridin-2-yl)-3-oxa-7,9-diazabicyclo[3.

3. l]nonane-7- carboxylate;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((methylsulfonyl)methyl)benzamide;N-((2-(3,5-dichloro-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(3-cyano-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-cyclopropyl-3-(N,N-dimethylsulfamoyl)-N-((2-(6-(2, 2,6,6- tetramethylmorpholino)py ridin-2-y 1)- 1 ,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*R)-l -methoxy ethyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*S)-l -methoxy ethyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(l -methoxy ethyl)-4-methylbenzamide;N-((2-(6-((lR,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3,4-dimethyl-5-(methylsulfonyl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-methoxy-4-(4-methyl-lH-imidazol-l- yl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-methyl-5-(lH-tetrazol-l-yl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2-methyl-5-(lH-tetrazol-l-yl)benzamide;3-fluoro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- y 1)- 1 ,6-naphthy ri din-7 -y l)methyl)-2-( 1H- 1 ,2,3-triazol- 1 -yl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-methoxy-2-methyl-4- (methylsulfonyl)benzamide;3-cyano-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyri din-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-methoxy benzamide;3-chloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;2-chloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-isopropylbenzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(2-hydroxyethyl)benzamide;3-chloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-4-methylbenzamide;3-(difluoromethyl)-4-fluoro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5- dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;3,4-dichloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;5-(tert-butyl)-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-2-methoxybenzamide;4-bromo-3-cyano-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-bromo-4-chloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamideN-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-iodo-4-(trifluoromethyl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3,4-dimethoxybenzamide;N-((2-(6-((3a, 4a, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((*R)-l-hydroxyethyl)-4-methylbenzamide;N-((2-(6-((3a, 4a, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((*S)-l -hydroxy ethyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoro-4-methylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-3,4-dimethylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((3a,4p,5a)-4-methoxy-3,5-dimethylpiperi din-1 -yl)pyri din-2 -yl)-l, 6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(3-hydroxyazetidin-3-yl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(4-hydroxypiperidin-4-yl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyri din- 7-yl)methyl)-3-((*R)-l -hydroxy ethyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyri din- 7 -yl)methyl)-3-((* S)- 1 -hydroxy ethyl)benzami de;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)-5-((*R)- 1 -hydroxy ethyl)benzami de;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)-5-((* S)- 1 -hydroxy ethyl)benzami de;4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din- 7-yl)methyl)-3-(3-hy droxy azetidin-3-yl)benzamide;N-((2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(5-chloro-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-(2-cyanopropan-2-yl)-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-1 -y l)py ridin-2-y 1)- 1 , 6-naphthyri din- 7 -y l)methyl)benzamide;N-((*R)-l-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)ethyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((*S)-l-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)ethyl)-4-methyl-3-(methylsulfonyl)benzamide;3-((diethylamino)methyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4,5-dimethylbenzamide; tert-butyl (4-((2*S,6*R)-6-methyl-4-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyridin-2- yl)morpholin-2-yl)butyl)carbamate; tert-butyl (4-((2*R,6*S)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyridin-2- yl)morpholin-2-yl)butyl)carbamate; methyl 2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2-yl)isonicotinate;N-((2-(6-((2*S,6*R)-2-(4-aminobutyl)-6-methylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2*R,6*S)-2-(4-aminobutyl)-6-methylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)isonicotinic acid;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-(hydroxymethyl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(3-hydroxypyrrolidin-l-yl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(((*R)-2-hydroxypropyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(((*S)-2-hydroxypropyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((2*S,6*R)-2-(4-acetamidobutyl)-6-methylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2*R,6*S)-2-(4-acetamidobutyl)-6-methylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-(aminomethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4,5-dimethylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-((*S)-morpholin-2-yl)benzamide;N-((2-(6-((cis)-3,5-dimethylpiperazin-l-yl)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*S)-3-hydroxypiperidin-3-yl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-(l-hydroxyethyl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)isonicotinamide;(R)-N-((2-(6-(2-(hydroxymethyl)pyrrolidin-l-yl)pyri din-2 -yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(S)-N-((2-(6-(2-(hydroxymethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-5-(methylsulfonyl)-2-vinylbenzamide;3-chloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)benzamide;N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-(2-hydroxyethyl)-3-(methylsulfonyl)benzamide;N-((2-(4-cyano-6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(3-((cis)-2,6-dimethylmorpholino)-2-fluorophenyl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(3-((cis)-2,6-dimethylmorpholino)-2,4-difluorophenyl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-morpholinobenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(tetrahydrofuran-2-yl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3,4-dimethyl-5-((4-methylpiperazin-l-yl)methyl)benzamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyrazin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)-3-((*R)- 1 -hydroxy ethyl)-4-methylbenzami de;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((*S)-l -hydroxy ethyl)-4-methylbenzamide;4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7- yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)phenyl)-l,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(4-fluoro-3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(2-fluoro-3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(7-(pyridin-4-yl)-2,3-dihydrobenzofuran-5- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(2-methoxy-5-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;N-((2-(3-fluoro-5-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((3S,4s,5R)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(5,6-dihydro-2H-pyran-3-yl)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(l'-(cyclopropanecarbonyl)-r,2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-4-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(3-((cis)-2,6-dimethylmorpholino)-6-fluoropyri din-2 -yl)-l,6-naphthyri din- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)pyrrolidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-4-yl)piperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-3-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-3-yl)piperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(9-oxa-2-azaspiro[5.5]undecan-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;(*R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(3-(4-(2-hydroxypropan-2-yl)phenyl)piperidin-l-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(l'-(4-fluorobutanoyl)-r,2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-3-yl)phenyl)-l,6-naphthyridin-7- yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(l-(pyridin-3-yl)piperidin-4-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;(*S)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)pyrrolidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;(*R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)pyrrolidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7- yl)methyl)benzamide;(*R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)pyrrolidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;(*S)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)pyrrolidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(tetrahydro-2H-pyran-3-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)benzamide;(*R)-4-methyl-3-(methylsulfonyl)-N-((2-(2-(pyridin-4-yl)morpholino)-l,6- naphthyridin-7-yl)methyl)benzamide;(*S)-4-methyl-3-(methylsulfonyl)-N-((2-(2-(pyridin-4-yl)morpholino)-l,6- naphthyridin-7-yl)methyl)benzamide;3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)-5-(l -hy droxyethyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-nicotinoylpiperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(4-acetylpiperazin- 1 -yl)- 1 ,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(2-oxopiperidin- 1 -yl)- 1 ,6-naphthy ridin-7 - yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridazin-3-yl)piperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(4-isonicotinoylpiperazin-l-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide;N-((2-(4-(6-methoxypyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7-yl)methyl)- 4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-(6-oxo-l,6-dihydropyridin-3-yl)piperazin- l-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyrazin-2-yl)piperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(4-(6-aminopyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;(*R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;(*S)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(4-(2-hydroxy-2-methylpropanoyl)piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(4-(l-methyl-lH-pyrazol-4-yl)piperazin-l-yl)-l,6-naphthyridin- 7-yl)methyl)-3-(methylsulfonyl)benzamide;(*R)-4-methyl-3-(methylsulfonyl)-N-((2-(l-(pyridin-3-yl)piperidin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;(*S)-4-methyl-3-(methylsulfonyl)-N-((2-(l-(pyridin-3-yl)piperidin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(3 -((cis)-2,6-dimethy lmorpholine-4-carbonyl)cy clohex- 1 -en- 1 -yl)- 1,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; ethyl l-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2- yl)piperidine-3-carboxylate;(*R)-N-((2-(3-(4-(2-hydroxypropan-2-yl)phenyl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(3-(4-(2-hydroxypropan-2-yl)phenyl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(lH-pyrazol-l-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(3-((cis)-2,6-dimethylmorpholino)- IH-py razol- 1 -y 1)- 1 ,6-naphthy ri din-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(4-methyl-3 -(pyridin-4-yl)piperazin- 1 -yl)- 1 ,6-naphthy ri din-7 - yl)methyl)-3-(methylsulfonyl)benzamide;1 -(7 -((4-methyl-3 -(methylsulfonyl)benzamido)methyl)- 1 ,6-naphthyridin-2- yl)piperidine-3-carboxylic acid;N-((2-(6-(((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2-hydroxy ethoxy )pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;(*R)-4-methyl-3-(methylsulfonyl)-N-((2-(l-(pyridin-4-yl)piperidin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(6-(3,3-dimethylpiperazin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide;(R)-N-((2-(6-(2-(methoxymethyl)pyrrolidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-(difluoromethyl)-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(3-(6-aminopyridin-3-yl)piperidin-l-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-4-yl)azepan-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2-fluoro-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;(S)-N-((2-(6-(2-(methoxymethyl)pyrrolidin-l-yl)pyri din-2 -yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-5- methylbenzamide; tert-butyl 7-(4-fluoro-6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)- l,6-naphthyridin-2-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate;N-((2-(4-((cis)-2,6-dimethylmorpholino)pyrimidin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(5,8-diazaspiro[2.6]nonan-5-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(4-hydroxy-3,3-dimethylpiperi din-1 -yl)pyri din-2 -yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(tetrahydrofuran-2-yl)benzamide;N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 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)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide;N-((2-(4-(5-aminopyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;N-((2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;4-methy l-N-((2-(6-(6-methyl-4,7 -diazaspiro [2.5] octan-7-yl)py ri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(6-(6-ethyl-4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3-(hy droxymethyl)piperazin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyri din-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(R)-N-((2-(6-(2-(hydroxymethyl)piperazin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyri din- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3-isopropylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- 4-methyl-3-(methylsulfonyl)benzamide;(R)-4-methyl-N-((2-(6-(2-methylpiperazin- 1 -yl)pyri din-2 -yl)- 1 ,6-naphthyri din- 7-yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(6-(2-ethylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamideN-((2-(6-(3-(methoxymethyl)piperazin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2R,5S)-5-ethyl-2-methylpiperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; methyl 4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyri din-2 -yl)pyri din-2 -yl)piperazine-2-carboxylate;N-((2-(6-((2S,5R)-5-ethyl-2-methylpiperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide(S)-4-methyl-N-((2-(6-(2-methylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-3-(methylsulfonyl)benzamide;4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2- yl)pyridin-2-yl)piperazine-2-carboxamide;N-((2-(6-((cis)-2,6-dimethylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2S,5R)-2,5-dimethylpiperazin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(S)-N-((2-(6-(3-(cyanomethyl)piperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(S)-N-((2-(6-(3-(hydroxymethyl)piperazin-l-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(R)-N-((2-(6-(3-(hydroxymethyl)piperazin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4,5-dimethylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-fluoro-N-((2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;4-chloro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5] octan-7 -yl)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(5-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4- methylbenzamide;N-((2-(6-(3-(2,2-difluoroethyl)piperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3-(difluoromethyl)piperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(l,4-diazepan-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2,5-dimethylpiperazin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((4aR,7aS)-hexahydrofuro[3,4-b]pyrazin-l(2H)-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3-cyclopropyl-3-methylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2-cy clopropy Ipiperazin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthy ri din-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(S)-4-methyl-N-((2-(6-(3-methylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(6-(2-(methoxymethyl)piperazin-l-yl)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2-(2,2-difluoroethyl)piperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(piperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(6-(2-(cyclopropylmethyl)piperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(5,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((2R,3R)-3-methyl-2-(trifluoromethyl)piperazin-l-yl)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(6-(2-(2-methoxyethyl)piperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-(3-(2-(methylamino)-2-oxoethyl)piperazin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-((4aS,7aR)-octahydro-lH- cyclopenta[b]pyrazin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(2,5,5-trimethylpiperazin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;(R)-4-methyl-N-((2-(6-(3-methylpiperazin- 1 -yl)pyri din-2 -yl)- 1 ,6-naphthyridin- 7-yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(6-(2-isopropylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- 4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3,3-dimethyl-l,4-diazepan-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2,3-dimethylpiperazin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2S,3R)-2,3-dimethylpiperazin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((4aR,7aS)-6,6-dioxidohexahydrothieno[3,4-b]pyrazin-l(2H)- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(3-((methylsulfonyl)methyl)piperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide; ethyl 3-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2- yl)cyclobutane-l -carboxylate;3-chloro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5] octan-7 -yl)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;N-((2-(6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(5,8-diazaspiro[3.6]decan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*R)-3-hydroxypiperidin-3-yl)-4-methylbenzamide;3-(N,N-dimethylsulfamoyl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methylbenzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide; tert-butyl 3-((7 -((4-methyl-3-(methylsulfonyl)benzamido)methyl)- 1,6- naphthyridin-2-yl)methyl)pyrrolidine- 1 -carboxylate;4-methyl-3-(methylsulfonyl)-N-((2-(tetrahydro-2H-pyran-4-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-((tetrahydro-2H-pyran-4-yl)methyl)-l,6- naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-((l-(pyrimidin-2-yl)piperidin-4-yl)methyl)- l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(cyclopentylmethyl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide;N-((2-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l,6-naphthyridin-7-yl)methyl)- 4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(2-(methylsulfonyl)benzyl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(3-methoxypropyl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide;4-methyl-N-((2-(3-methylbenzyl)-l,6-naphthyridin-7-yl)methyl)-3- (methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(3,3,3-trifluoropropyl)-l,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-4-methoxy-3-(methylsulfonyl)benzamide ;N-((2-(4-(4-acetamidobutyl)-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-(4-aminobutyl)-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-((3a, 4p, 5a))-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)-5- (trifluoromethoxy)benzamide;N-((2-(3-chloro-4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-(difluoromethoxy)-N-((2-(4-fluoro-6-((3S,4r,5R)-4-hydroxy-3,5- dimethylpiperi din-1 -yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)benzamide;(*R)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(tetrahydrofuran-2-yl)benzamide;(*S)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(tetrahydrofuran-2-yl)benzamide;N-((2-(6-(3-hydroxy-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7 -y l)methyl)-3-((3 -hydroxy azeti din- 1 -yl)sulfonyl)-4-methy Ibenzamide;3-chloro-N-((2-(4-fluoro-6-((3a, 4p, 5a))-4-hydroxy-3,5-dimethylpiperidin-l- yl)-3-methylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)benzamide;N-((2-(6-(7-amino-5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; tert-butyl (3-methyl-l-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)- 1 ,6-naphthyridin-2-yl)pyridin-2-yl)azetidin-3-yl)carbamat e; tert-butyl 2-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyri din-2-yl)pyri din-2 -yl)-9-oxa-2,6-diazaspiro[4.5]decane-6- carboxylate;N-((2-(6-(9-oxa-2,6-diazaspiro[4.5]decan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyri din-2- yl)-l,6-naphthyridin-7-yl)methyl)-4-methoxy-3-(methylsulfonyl)benzamide;3-fluoro-N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-((2- hy droxy ethyl)sulfonyl)benzamide;3-fluoro-N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-5- (methylsulfonyl)benzamide ;3-fluoro-N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-((2-hy droxy ethyl)sulfonyl)- 4-methylbenzamide;N-((2-(4-fluoro-3-methyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(2-cyanopropan-2-yl)-4-fluorobenzamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-chloro-3-(2-cyanopropan-2-yl)benzamide;4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-(3-methyl-5-oxopiperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(5-oxo-4,7-diazaspiro[2.5]octan-7- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-fluoro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide;(*R)-N-((2-(6-(3-hydroxy-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(3-hydroxy-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-fluoro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-chloro-3-methyl-5-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(3-oxopiperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;(*R)-N-((2-(6-(9-oxa-2,6-diazaspiro[4.5]decan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(9-oxa-2,6-diazaspiro[4.5]decan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; tert-butyl ((lR)-3-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-l-yl)carbamate;4-methyl-N-((2-(6-(3-methyl-3-morpholinopyrrolidin- l-yl)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((3*R,4*R)-3-methyl-4-morpholinopyrrolidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((3*S,4*S)-3-methyl-4-morpholinopyrrolidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;(*R)-N-((2-(6-(7-amino-5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(7-amino-5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-chloro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5] octan-7 -yl)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-methyl-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-methyl-5-(methylsulfonyl)benzamide;N-((2-(6-((3a, 4p, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-methyl-5-(methylsulfonyl)benzamide;N-((2-(6-(3-amino-3-(trifluoromethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((3*S,4*R)-3-methyl-4-morpholinopyrrolidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((3*R,4*S)-3-methyl-4-morpholinopyrrolidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide; tert-butyl 2-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyri din-2 -yl)-8-oxa-2,5-di azaspiro[3.5]nonane-5- carboxylate;N-((2-(6-(3-amino-3-methylazetidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3-cy clopropy Ipiperazin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthy ri din-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2-cyclobutylpiperazin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2-(difluoromethy l)piperazin- 1 -y l)pyridin-2-yl)- 1 ,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(S)-N-((2-(6-(3-isopropylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(3-(2,2,2-trifluoroethyl)piperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;4-methyl-N-((2-(6-(3-methyl-4-morpholinopyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;tert-butyl 2-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyri din-2 -yl)-6-oxa-2,9-diazaspiro[4.5]decane-9- carboxylate;N-((2-(6-(6-oxa-2,9-diazaspiro[4.5]decan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(l-((cis)-2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((lR)-l-(methylamino)-3-azabicyclo[3.1.0]hexan-3- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(6-(7-hy droxy-5-azaspiro[2.4]heptan-5-yl)pyri din-2 -yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(8-amino-5 -azaspiro [2.5] octan-5-yl)pyridin-2-yl)- 1 ,6-naphthy ri din-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; tert-butyl 2-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyri din-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)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamideN-((2-(6-(4-amino-3 ,3 -difluoropiperidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthy ri din-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; tert-butyl (5-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyridin-2-yl)-5-azaspiro[2.5]octan-8-yl)carbamate;N-((2-(6-(8-(dimethylamino)-5-azaspiro[2.5]octan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*R)-N-((2-(6-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide3 ,4-dimethy l-N-((2-(6-((l R,5 S)-7 -methyl-3 -oxa-7,9-diazabicy clo [3.3.1 ]nonan-9- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-(2-methyl-3-oxopiperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-(2-methyl-5-oxopiperazin-l-yl)pyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)-3-(methylsulfonyl)benzamide ;N-((2-(6-(3-ethyl-3-hydroxypyrroli din-1 -yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2,5,8-triazaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-chloro-3-(methylsulfonyl)benzamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide;N-((2-(6-(l-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(4-hydroxy-3,3-dimethylpyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(6-oxa-2,9-diazaspiro[4.5]decan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*R)-N-((2-(6-(6-oxa-2,9-diazaspiro[4.5]decan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*R)-N-((2-(6-(4-amino-3,3-difluoropiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(4-amino-3,3-difluoropiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(l-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*R)-N-((2-(6-(l-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-(dimethylphosphoryl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*R)-N-((2-(6-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(3,3-difluoro-4-hydroxypyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*R)-N-((2-(6-(4-hydroxy-3,3-dimethylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(4-hydroxy-3,3-dimethylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(2-(l-fluorocyclopropyl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;JV-(l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)- 5-hydroxypentyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-((tetrahydrofuran-2-yl)methoxy)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((2,6-dimethylpiperidin-4-yl)oxy)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((4,4-difluoropyrrolidin-3-yl)oxy)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((l-hydroxypropan-2-yl)oxy)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide and N-((2-(6-(2- hydroxypropoxy)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide;N-((2-(6-(2-(cyclopropylamino)ethoxy)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(2-hydroxy-2-methylpropoxy)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-((2,2,2- trifluoroethyl)amino)ethoxy)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(6-((4-azaspiro[2.5]octan-7-yl)oxy)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((l-(methylamino)cyclopropyl)methoxy)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;N-((2-(6-((3,3-difluoropiperidin-4-yl)oxy)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-((2-(trifluoromethyl)piperidin-4- yl)oxy)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((3R,4s,5S)-4-(hydroxymethyl)-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide ;N-((2-(6-(4-(2-hydroxyethyl)-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide ;N-((2-(6-(l-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; tert-butyl (3-(((2-(4-fluoro-6-((3a, 4b,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamoyl)-5- (methylsulfonyl)benzyl)carbamate;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide;N-((2-(6-((3a, 4p, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide;(*R)-N-((2-(6-(3,3-difluoro-4-hydroxypyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(3,3-difluoro-4-hydroxypyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2*R,4*S)-4-hydroxy-l-methylpyrrolidin-2-yl)-4- methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2*S,4*R)-4-hydroxy-l-methylpyrrolidin-2-yl)-4- methylbenzamide;3-((3,3-difluoropropyl)sulfonyl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7- yl)pyridin-2-yl)-l, 6-naphthyri din-7-yl)methyl)-4-methylbenzamide;(*R)-N-((2-(6-(8-amino-5-azaspiro[2.5]octan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(8-amino-5-azaspiro[2.5]octan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-(aminomethyl)-N-((2-(4-fluoro-6-((3a, 4p,5a)-4-hydroxy-3,5- dimethylpiperi din-1 -yl)pyridin-2-yl)-l, 6-naphthyri din-7-yl)methyl)-5- (methylsulfonyl)benzamide;3-((*R)-4,4-difluoropyrrolidin-2-yl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-4- methylbenzamide;N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide4-methyl-3-(methylsulfonyl)-N-((2-(6-(l -oxo-2, 7-diazaspiro[4.4]nonan-2- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(5-oxo-2,6-diazaspiro[3.4]octan-6- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(5-oxo-l,6-diazaspiro[3.4]octan-6- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;4-methyl-N-((2-(4-methyl-l-(4-azaspiro[2.5]octan-7-yl)-lH-pyrazol-3-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide; tert-butyl (4,4-difluoro-l-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyridin-2- yl)pyrrolidin-3-yl)carbamate;3-((*S)-4,4-difluoropyrrolidin-2-yl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-4- methylbenzamide;3-chloro-5-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)-4-fluoropyridin-2-yl)-l, 6-naphthyri din-7- yl)methyl)benzamide;3-chloro-5-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 , 6-naphthyri din- 7 -yl)methyl)benzamide;N-((2-(6-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)-l, 6-naphthyri din-7- yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide;3-fluoro-N-((2-(6-(8-hydroxy-5-azaspiro[2.5]octan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;3-fluoro-N-((2-(6-((cis)-3-hydroxy-3,4-dimethylpyrrolidin-l-yl)pyridin-2-yl)-1, 6-naphthyri din-7-yl)methyl)-5-(methylsulfonyl)benzamide;N-((2-(6-(4-amino-3,3-difluoropyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; tert-butyl (6-((2*R,6*S)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyridin-2- yl)morpholin-2-yl)hexyl)carbamate; tert-butyl (6-((2*S,6*R)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyridin-2- yl)morpholin-2-yl)hexyl)carbamate;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din-7- yl)methyl)-4-methyl-3-(*R-methylsulfonimidoyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din-7- yl)methyl)-4-methyl-3-(*S-methylsulfonimidoyl)benzamide; #N-((2-(6-(2-(2-hy droxyethoxy)ethoxy)pyri din-2 -yl)- 1 , 6-naphthyri din-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2*R,6*S)-2-(6-aminohexyl)-6-methylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2*S,6*R)-2-(6-aminohexyl)-6-methylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((*R)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din-7-yl)-3-hydroxypropyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((* S)- 1 -(2-(6-((cis)-2,6-dimethylmorpholino)py ri din-2 -yl)- 1 , 6-naphthyri din-7- yl)-3-hydroxypropyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(l-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2*R,6*S)-2-(5-aminopentyl)-6-methylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2*S,6*R)-2-(5-aminopentyl)-6-methylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; tert-butyl (5-((2*R,6*S)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyridin-2- yl)morpholin-2-yl)pentyl)carbamate; tert-butyl (5-((2*S,6*R)-6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyridin-2- yl)morpholin-2-yl)pentyl)carbamate;3-(dimethylphosphoryl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7- yl)pyridin-2-yl)-l, 6-naphthyri din-7-yl)methyl)benzamide;N-((2-(6-((2*R,6*S)-2-(5-acetamidopentyl)-6-methylmorpholino)pyridin-2-yl)-1, 6-naphthyri din-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2*S,6*R)-2-(5-acetamidopentyl)-6-methylmorpholino)pyridin-2-yl)-1, 6-naphthyri din-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamideN-((2-(6-((lR)-l-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-fluoro-N-((2-(6-(trans)-3-hydroxy-4-methyl-3-(trifluoromethyl)pyrrolidin-l- yl)pyridin-2-yl)-l, 6-naphthyri din-7-yl)methyl)-5-(methylsulfonyl)benzami de;3-fluoro-N-((2-(6-(3-methoxy-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;3-fluoro-N-((2-(6-(7-methoxy-5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;3-cyano-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyri din- 7 -y l)methyl)-4-methy Ibenzamide;N-((2-(6-(3,3-difluoro-4-(methylamino)piperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2*R,6*S)-2-(6-acetamidohexyl)-6-methylmorpholino)pyridin-2-yl)-1, 6-naphthyri din-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2*S,6*R)-2-(6-acetamidohexyl)-6-methylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-3-hydroxycyclobutoxy)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((trans)-3-hydroxycyclobutoxy)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*R)-N-((2-(6-(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(6,9-dioxa-2-azaspiro[4.5]decan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfinyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-(morpholinomethyl)pyrrolidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-(2-oxa-5-azabicyclo[2.

2. l]heptan-5-yl)pyri din-2 -yl)-l,6-naphthyri din- 7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(2-hydroxyethylsulfonimidoyl)-4-methylbenzamide;N-((*R)-5-amino-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((*S)-5-amino-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide;N-((*R)-5-acetamido-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((*S)-5-acetamido-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-((6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)amino)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide; -3-fluoro-N-((2-(6-((2S,4S)-4-hydroxy-2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- 5-(methylsulfonyl)benzamide;N-((2-(6-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide;N-((2-(6-(5,8-dioxa-2-azaspiro[3.5]nonan-2-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide;N-((2-(6-((3*S, 4*r,5*S)-4-(2 -hydroxy ethyl)-3,5-dimethylpiperi din-1 -yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((3*S,4*s,5*R)-4-(2-hydroxyethyl)-3,5-dimethylpiperidin-l- yl)pyridine-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide;N-((2-(6-((3*S,4*r,5*R)-4-(2-hydroxyethyl)-3,5-dimethylpiperidin-l- yl)pyridine-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide;(*R)-N-((2-(6-(4-amino-3,3-difluoropyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(4-amino-3,3-difluoropyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((3*R, *s,5*R)-4-(2 -hydroxy ethyl)-3,5-dimethylpiperi din-l-yl)pyri din-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-4-fluoro-3-(methylsulfonyl)benzamide;(*R)-3-fluoro-N-((2-(6-(8-hydroxy-5-azaspiro[2.5]octan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;(*S)-3-fluoro-N-((2-(6-(8-hydroxy-5-azaspiro[2.5]octan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*R)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*S)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide;N-((2-(6-((lR)-l-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)pyri din-2 -yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*R)-N-((2-(6-(3,3-difluoro-4-(methylamino)piperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(3,3-difluoro-4-(methylamino)piperi din-1 -yl)pyri din-2 -yl)-l, 6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*R)-4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-(morpholinomethyl)pyrrolidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;(*S)-4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-(morpholinomethyl)pyrrolidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((2-chloroethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methylbenzamide;N-((2-(6-(4-(2-hydroxypropan-2-yl)piperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-(4-(2 -hydroxypropan-2-yl)piperi din-1 -yl)-N-((2-(6-(4-(2-hydroxypropan-2- y l)piperidin- 1 -y l)pyri din-2 -yl)- 1 ,6-naphthy ridin-7-y l)methyl)-5 - (methylsulfonyl)benzamide;3 -fluoro-N-((2-(6-(4-(2-hy droxypropan-2-yl)piperidin- 1 -yl)py ridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;3-((2-(dimethylamino)ethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4- methylbenzamide;N-((2-(6-((( 3a, 4p, 5a))-4-hydroxy-3,5-dimethylpiperi din-1 -yl)methyl)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(((cis)-2,6-dimethylmorpholino)methyl)pyri din-2 -yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-phenyl- 1 ,6-naphthyridin-7- yl)methyl)benzamide; tert-butyl 5-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyri din-2-yl)pyri din-2 -yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate;(*R)-4-methyl-N-((2-(6-(8-(methylamino)-5-azaspiro[2.5]octan-5-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;(*S)-4-methyl-N-((2-(6-(8-(methylamino)-5-azaspiro[2.5]octan-5-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;(R)-3-fluoro-N-((2-(6-(2-methylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-(methylsulfonyl)benzamide;3-fluoro-N-((2-(6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;3-fluoro-N-((2-(6-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;N-((2-(6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide;3-fluoro-N-((2-(6-((2s,4r)-2-hydroxy-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)-1.6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;3-fluoro-N-((2-(6-((2r,4s)-2-hydroxy-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)-1.6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide ;N-((2-(6-((l*R,5*S)-l-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((l* S,5*R)-l-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-1.6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-fluoro-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(vinylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(vinylsulfonyl)benzamide;N-((*R)-3-(dimethylamino)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)propyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((*S)-3-(dimethylamino)-l -(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-1.6-naphthyridin-7-yl)propyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((*R)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)-3-morpholinopropyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((* S)- 1 -(2-(6-((cis)-2,6-dimethylmorpholino)py ri din-2 -yl)- 1 ,6-naphthyridin-7- yl)-3-morpholinopropyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-4-(difluoromethyl)-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((2*R,6*R)-2-methyl-6-(trifluoromethyl)morpholino)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((2*R,6*S)-2-methyl-6-(trifluoromethyl)morpholino)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((2*S,6*R)-2-methyl-6-(trifluoromethyl)morpholino)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;4-methyl-N-((2-(6-((2*S,6*S)-2-methyl-6-(trifluoromethyl)morpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamideN-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide;(*R)-N-((2-(6-(l-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;(*S)-N-((2-(6-(l-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-morpholinopyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3-((2- hydroxyethyl)sulfonyl)-4-methylbenzamide;3-fluoro-N-((2-(6-((3a, 4p, 5a))-4-(hydroxymethyl)-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;6-methyl-4-(6-(7 -((4-methyl-3-(methylsulfonyl)benzamido)methyl)- 1,6- naphthyridin-2-yl)pyridin-2-yl)morpholine-2-carboxylic acid;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-fluoro-3-(methylsulfonyl)benzamideN-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-3-(2-hydroxyethylsulfonimidoyl)-4-methylbenzamide;3-((2-hydroxyethyl)sulfonyl)-4-methyl-N-((2-phenyl-l,6-naphthyridin-7- yl)methyl)benzamide;3-fluoro-5-(methylsulfonyl)-N-((2-phenyl- 1 ,6-naphthyridin-7- yl)methyl)benzamide;4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-3-(S-methylsulfonimidoyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- y l)methyl)-3 -(prop- 1 -yn- 1 -y lsulfonamido)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(l ,4-dioxan-2-yl)-4-methylbenzamide. ;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-3-((*S)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-3-((*R)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperi din-l-yl-4-d)pyri din-2 -yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((3a,4a,5a))-4-hydroxy-3,5-dimethylpiperidin-l-yl-4-d)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(morpholino-d8)pyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)benzamide ;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(vinylsulfonamido)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(vinylsulfonyl)benzamide;N-((2-(6-((3a, 4p, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-((*R)-methylsulfinyl)benzamide;N-((2-(6-((3a, 4p, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-((*S)-methylsulfinyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*R)-(2-hydroxyethyl)sulfinyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*S)-(2-hydroxyethyl)sulfinyl)-4-methylbenzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((3a,4p,5a))-4-hydroxy-3,5- dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(6-(6,6-dimethy 1-5 -oxa-2, 8 - di azaspiro [3.5]nonan-2-yl)pyridin-2-yl)- 1 ,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*R)-l,4-dioxan-2-yl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*R)-l,4-dioxan-2-yl)-4-methylbenzamide;N-((2-(4-fluoro-6-(morpholino-d8)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- 3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(6-(4-amino-3 ,3 -difluoropiperidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthy ri din-7 - yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-hydroxy-2-azaspiro[3.3]heptan-2- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-3-(methylsulfinyl)-4-(trifluoromethyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(2-((3a,4p,5a)-4-hydroxy-3,5- dimethy Ipiperidin- 1 -yl)py rimidin-4-yl)- 1 ,6-naphthyridin-7- yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(2-(6-hydroxy-2-azaspiro[3.3]heptan-2- yl)pyrimidin-4-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;N-((2-(2-(6-oxa-2,9-diazaspiro[4.5]decan-2-yl)pyrimidin-4-yl)-l,6-naphthyridin- 7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide;4-methyl-3-(methylsulfonyl)-N-((2-(6-(5-oxo-4,6-diazaspiro[2.4]heptan-6- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(4-fluoro-6-(4,7- diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropyri din-2 -yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-phenyl-l,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-fluoro-3-((2-hydroxyethyl)sulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(N,S-dimethylsulfonimidoyl)-4-methylbenzamide;N-((2-(6-(2,6-dimethylmorpholino-2,3,3,5,5,6-d6)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((4,7 -di azaspiro [2.5] octan-7-yl)methy l)py ri din-2 -y 1)- 1 ,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2S,5S)-2,5-dimethyl-3-oxopiperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((2R,5R)-2,5-dimethyl-3-oxopiperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-methoxypyridin-3-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-isopropoxypyridin-3-yl)-l,6-naphthyridin-7 -yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-methyl-5-oxopiperazin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(2-(3,4,4-trimethyl-2-oxoimidazolidin-l- y l)pyrimidin-4-yl)- 1 ,6-naphthy ri din-7 -yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(3,3-dimethyl-5-oxopiperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(2-(4-amino-3,3-difluoropiperidin-l-yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(2-(2-hydroxy-7-azaspiro[3.5]nonan-7- yl)pyrimidin-4-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;N-((2-(6-(2,6-dimethylmorpholino-2,3,3,5,5,6-d6)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2 -hydroxy ethyl)sulfonyl)-4-(methyl- d3)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-(methyl-d3)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(5-fluoro-6-methoxypyridin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(6,8-dioxo-2,5,7-triazaspiro[3.4]octan-2- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-(3-amino-3-methyl-2-oxopyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(5,5-dimethyl-2-oxopiperazin-l-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-(5,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-oxo-5,8-diazaspiro[3.5]nonan-8- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyridin- 7 -y l)methyl)-3-( 1 , 1 ,2,2-tetrafluoroethoxy )benzamide;N-((2-(6-(2,6-dimethylmorpholino-2,3,3,5,5,6-d6)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2 -hydroxy ethyl-2,2-d2)sulfonyl)-4-(methyl- d3)benzamide;(*R)-3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-methyl-5-oxopiperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;(*S)-3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-methyl-5-oxopiperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;4-((2,2-difluoroethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropyri din-2 -yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;4-(((difluoromethyl)sulfonyl)methyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din- 7-yl)methyl)-3-((fluoromethyl)sulfonyl)benzamide3-(difluoromethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-(3-amino-4,4-dimethyl-2-oxopyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-3-(N-methylsulfamoyl)benzamide;N-((2-(2-(4-amino-3 ,3 -difluoropiperidin- 1 -yl)pyrimidin-4-yl)- 1 ,6-naphthy ridin- 7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methylbenzamide; tert-butyl 3-((5-(7-((3-((difluoromethyl)sulfonyl)benzamido)methyl)-l,6- naphthy ridin-2-y l)py ridin-2-y l)oxy )azetidine- 1 -carboxylateN-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl-2,2-d2)sulfonyl)-4-methylbenzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-3,5-dimethylpiperazin-l-yl)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;4-amino-N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(2-((cis)-2,6-dimethylmorpholino)-6-oxo- l,6-dihydropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;(*S)-3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-(trifluoromethyl)piperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;(*R)-3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-(trifluoromethyl)piperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-5 -fluorobenzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((2,2,6,6-tetramethylpiperidin-4- yl)oxy)pyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-y l)oxy)pyri din-3 -yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-3,5-dimethylpiperazin- l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((3R,5S)-3,5- dimethylpiperazin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)benzamideN-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyridin- 7-yl)methyl)-4-((methylsulfonyl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din- 7-yl)methyl)-3-((methylsulfonyl)methyl)benzamide;3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din- 7 -yl)methyl)benzamide;(*R)-N-((2-(6-(3,3-difluoro-4-hydroxypiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide;(*S)-N-((2-(6-(3,3-difluoro-4-hydroxypiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide;(*S)-4-methyl-N-((2-(6-(3-methyl-3-morpholinopyrrolidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide(*R)-4-methyl-N-((2-(6-(3-methyl-3-morpholinopyrrolidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide3-((difluoromethyl)sulfonyl)-N-((2-(6-((2-oxo-l,3-oxazinan-5-yl)oxy)pyridin-3- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(oxetan-3-yloxy)pyridin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;3-chloro-N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;4-((cyanomethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din- 7-yl)methyl)-4-((2,2,2-trifluoroethyl)sulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din- 7-yl)methyl)-4-((2-hydroxyethyl)sulfonyl)benzamideN-((2-(6-(azetidin-3-yloxy)-5-fluoropyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)- 3-((difluoromethyl)sulfonyl)benzamide;3-(2,2-difluoroethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((lR,5S,6r)-6-hydroxy-3- azabicyclo[3.

1. l]heptan-3-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(2-(4,4-dimethyl-2-oxoimidazolidin-l- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran- 4-yl)oxy)pyridazin-3-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2,2,2-trifluoroethyl)sulfonyl)benzamide3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((S)-3-methyl-5- oxopiperazin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyridin-7 -yl)methyl)benzamide;3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((S)-3-methyl-5- oxopiperazin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyridin-7 -yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(3-(dimethylamino)-2-oxopyridin-l(2H)-yl)- l,6-naphthyridin-7-yl)methyl)benzamide;3-(difluoromethoxy)-5-((difluoromethyl)sulfonyl)-N-((2-(2-((cis)-2,6- dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;(*S)-N-((2-(2-(4-amino-3,3-difluoropiperidin-l-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide;(*R)-N-((2-(2-(4-amino-3,3-difluoropiperidin-l-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide;3-((*R)-azetidine-l-sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4- methylbenzamide;3-((*S)-azetidine-l-sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methylbenzamide;3-((cyanomethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(3-(2-hydroxyethyl)oxetan-3-yl)-4-methylbenzamide;3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyridin-7 -yl)methyl)benzamide;3-fluoro-N-((2-(6-(2-hydroxy-2-methyl-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-hydroxy-6-(trifluoromethyl)-2- azaspiro[3.3]heptan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(2-hydroxy-2-methyl-7- azaspiro[3.5]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(2-(2-hydroxy-2-methyl-7- azaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(2-(6-hydroxy-6-(trifluoromethyl)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-hydroxy-6-methyl-2- azaspiro[3.3]heptan-2-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(3-(difluoromethyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-l,6- naphthyridin-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide;3-(difluoromethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide;(*S)-4-methyl-3-(methylsulfonyl)-N-((2-(l-(pyridin-4-yl)piperidin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-iodopyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(3-(difluoromethyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-l,6- naphthyridin-7-yl)methyl)-3-(S-(difluoromethyl)sulfonimidoyl)benzamide;3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(2-((cis)-2,6- dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;N-((2-(6-(6-(difluoromethyl)-6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridin-2- yl)- 1 ,6-naphthyri din-7 -y I )methyl )-3-((di H uoromethy I )sul fonyl )benzami de;3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(2-((cis)-2,6- dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)benzamide;3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin- 4-yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-chloro-5-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-chloro-5-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide; and 3-((difluoromethyl)sulfonyl)-N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide; and pharmaceutically acceptable salts, stereoisomers, and isotopic variants thereof.

12. A compound of claim 1, selected from the group consisting of: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3- ((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3- ((2-hydroxy ethyl)sulfonyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide;N-((2-(4-fluoro-6-(4,7 -di azaspiro [2.5] octan-7-yl)pyridin-2-yl)- 1 ,6-naphthyridin-7- yl)methyl)-4-(2-hydroxyethyl)-3-(methylsulfonyl)benzamide;N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-5-methylbenzamide;N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide;3-fluoro-N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyri din-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide;3-chloro-5-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)-4-fluoropyri din-2 -yl)- 1 ,6-naphthyri din- 7 -yl)methyl)benzamide;3-chloro-5-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((2R,6S)-2,6- dimethylmorpholino)-4-fluoropyri din-2 -yl)- 1 ,6-naphthyri din- 7 -yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-3-((*S)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-3-((*R)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide;3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropy ridin-2-y 1)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropy ridin-2-y 1)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methylbenzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-fluorobenzamide;3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide;3-((difluoromethyl)sulfonyl)-N-((2-(6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2- yl)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide;3-chloro-5-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide; and 3-chloro-5-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide; and pharmaceutically acceptable salts, isotopic variants, and stereoisomers thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of the preceding claims; and at least one pharmaceutically acceptable excipient.

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

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

16. The compound for the use of 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 disease state or condition mediated by the SMARCA2 protein.

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

19. Use of a compound as defined in any one of claims 1 to 12 for the manufacture of a medicament for the treatment of cancer or NSCLC.

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

21. A method for the treatment of a SMARCA4 deficient cancer, which method comprises administering to a subject in need thereof, a compound as defined in any one of claims 1 to 12.

22. The method of claim 21, wherein the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC.

23. A method for the treatment of a disease state or condition mediated by the SMARCA2 protein, which method comprises administering to a subject in need thereof, a compound as defined in any one of claims 1 to 12.

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

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

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