EP4739682A1

EP4739682A1 - 1,6-naphthridine compounds as smarca2 inhibitors useful for the treatment of smarca4 deficient cancers

Info

Publication number: EP4739682A1
Application number: EP23741601.1A
Authority: EP
Inventors: Ian Stansfield; Laurence Anne Mevellec; Vineet PANDE; Benoît Christian Albert Ghislain De Boeck; Marta BRAMBILLA; Alexander Xenophon JONES; Manuel Jesús Alcázar Vaca; William Moore Jones; Kirk Wayne SHIMKIN; Christopher George CALLAS; Michael Peter Winters; Robert J ROSANO; Paul John KRAWCZUK; Didier Jean Claude BERTHELOT
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2023-07-05
Filing date: 2023-07-05
Publication date: 2026-05-13
Also published as: WO2025008058A1; CN121889390A

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 USEFUL

FOR THE TREATMENT OF SMARCA4 DEFICIENT CANCERS

FIELD 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 of SMARCA2 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),

Wherein

R¹ is 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, wherein

R^a is 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;

R^b is selected from: Cl, F, Br, C1-4alkyl, OC1-4alkyl, cyclopropyl, and 4-methyl-lH- imidazol-l-yl;

R^c is 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;

R^d is Cl or CH3;

R^e is selected from: C1-4alkyl substituted with one or two OH members, and IH-tetrazole; wherein R^g is C1-4alkyl optionally substituted with one OH member;

R^h is C1-4alkyl, or C1-4haloalkyl;

R¹ is 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 R^k is independently selected from: halo, C1-4akyl, OC1-4alkyl, NH2, OC1-4haloalkyl, CN, CH2OH, C3-6cyclalkyl, and C2-4alkenyl;

R^m is selected from: C1-4haloalkyl, CH2CH2OH, and CH2CN; n is 0, 1, 2, or 3;

X is O, NH, or N-CH3;

R³ is selected from: H, and C1-4alkyl optionally substituted with one member selected from: OH, NH2, N(CH3)2, NH(C=O)CH3, and morpholine; and

R⁵ is 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 Rⁿ is selected from the group consisting of:

R^p is 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; and wherein each R^q is independently selected from: H, halo, Cwalkyl, Cwhaloalkyl, CN,

R^s is H or halo;

R^l is 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; wherein

R^u is H, pyridin-3-yl, or pyridin-4-yl;

R^v is (cis)-2,6-dimethylmorpholinyl, pyridin-3-yl, or pyridin-4-yl; and R^w is H, F, or OCH₃; wherein

R^x is pyridin-3-yl, or pyridin-4-yl;

R^y is selected from: , pyridin-3-yl, and pyridin-4-yl; and

R^z is selected from:

vi) a C1-4haloalkyl; or -CH2-R^aa, wherein R^aa is 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 INVENTION

Definitions

[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 such identifiers 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 4^th Ed.” 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, “C_x-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 covers the 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)_xH_ygroup, 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, 4^th Edition, 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, 4^th Edition, 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 as cattle, 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-malignant neoplasm 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, 4^th Edition, 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 these compounds 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+ NHRs ¹. 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 scope ¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygen include within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. 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 of ²H, ³H, "C. ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactive isotope is selected from the group of ²H, ³H, ⁿC and ¹⁸F. More preferably, the radioactive isotope is ²H. 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):

Wherein

R¹ is 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, wherein

R^c is 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;

R^d is Cl or CH₃;

R^e is selected from: C1-4alkyl substituted with one or two OH members, and

IH-tetrazole; wherein

R^g is C1-4alkyl optionally substituted with one OH member;

R^h is C1-4alkyl, or C1-4haloalkyl;

R¹ is 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 R^k is independently selected from: halo, C1-4akyl, OC1-4alkyl, NH2, OC1-4haloalkyl, CN, CH2OH, C₃-ecyclalkyl, and C2-4alkenyl;

R^m is selected from: C1-4haloalkyl, CH2CH2OH, and CH2CN; n is 0, 1, 2, or 3;

X is O, NH, orN-CH₃;

R³ is selected from: H, and C1-4alkyl optionally substituted with one member selected from: OH, NH2, N(CH₃)₂, NH(C=O)CH₃, and morpholine; and

R⁵ is 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);

R^p is 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 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);

(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; and wherein each R^q is independently selected from: H, halo, Cwalkyl, Cwhaloalkyl, CN,

R^s is H or halo;

R^l is 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; wherein

R^u is H, pyridin-3-yl, or pyridin-4-yl;

R^v is (cis)-2,6-dimethylmorpholinyl, pyridin-3-yl, or pyridin-4-yl; and

R^w is H, F, or OCHs; wherein

R^x is pyridin-3-yl, or pyridin-4-yl;

R^y is selected from: , pyridin-3-yl, and pyridin-4-yl; and

R^z is 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, R¹ is [0106] In some embodiments, R¹ is

[0113] In some embodiments, (i) R⁵ is

[0114] In some embodiments, wherein:

(i) R^p is

(iv) R^p is

[0116] In some embodiments, R⁵ is:

[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; 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. [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 4^th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4^th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3^rd Ed., (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 reagents and 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°-catalyzed reaction 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 pathways

SCHEME 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 Borylation

R⁵ — Hal

(IV)

[0135] According to SCHEME 2, a compound of formula (IV), where Hal is Br or Cl and R⁵ is 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 a suitable 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 R³ is 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 P¹ is 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 P¹ is Boc, R³ is 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 R⁵ is 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 R³ is H and R⁵ is 6-fluoropyridyl.

[0139] A compound of formula (XVII), where R⁵ is 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 R⁵ is a suitable heteroaryl substituted with a nitrogen linked heterocycloalkyl.

[0140] Deprotection of a compound of formula (XVIII), where P¹ is 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 R³ is 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 R³ is 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 R³ is 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 R³ is H, Hal is Cl, and P¹ is 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). A compound 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 R³ is H, P¹ is Boc, and R⁵ is 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 R¹ has 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 R³ is H, and Hal is Cl, and R¹ is 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 R⁵ Hal, wherein Hal is Br or Cl, and R⁵ is 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), R³ is 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), R³ is 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 R⁵ is 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 R³ is 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, P¹ is a suitable nitrogen protecting group such as Boc, and R³ is 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 R⁵ is 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 suitable catalyst 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 R⁵ is 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 R⁵ is 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 R³ and R⁵ are 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, for example, 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 R⁵ is 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 HNR^9aR^9b, 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 R⁵ is 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 R¹ group 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 be synthesized 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 activity of 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 intakes per 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 (18^th ed., 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 a penetration 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 a therapeutic 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 ions allowing 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) at room 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. The filtrate 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 water and 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 added and 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 g SiCh; 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 and stirred 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)benzamide

Method 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 combined organic 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 4

Intermediate 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 50

Intermediate 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) at room 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 over MgS04, 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. The mixture 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 5

Intermediate 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 aqueous layer 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 to 15/85) 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 from

Intermediate 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 column chromatography (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 undetermined

Intermediate 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 room temperature 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 a

Dean-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® that was further rinsed with MeOH (3 x 10 mL). The filtrate was concentrated to give Intermediate

208 (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 SOCI₂ was 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 (25 g 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-dimethylmorpholine

CIS

[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 was concentrated 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 g SiCh; 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.) in AcOH (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 16 h. 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 reaction mixture 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)₃ palladacycle 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 using ethyl 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 column chromatography 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 1 benzoate (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 reaction mixture 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 aqueous NaHCO3 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, 2.513 mmol, 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 was separated, 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. The aqueous 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 nitrogen atmosphere. 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 mixture was stirred at 130 °C for 1 h in a microwave oven. 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 the title compound (258 mg, 79 % pure, yield: 98 %), and used without further purification.

[0459] Step B: tert-butyl ((2-(2-(3,4,4-trimethyl-2-oxoimidazolidin-l-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)carbamate. Triphosgene (CAS [32315-10-9], 49 mg, 0.163 mmol, 0.35 eq.) was added to a solution of tert-butyl ((2-(2-((2-methyl-2- (methylamino)propyl)amino)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (258 mg, 79 % pure, 0.466 mmol) and DIPEA (401 μL 2.,329 mmol, 5 eq.) in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3.5 h. The reaction mixture was diluted with DCM (2 mL) and water (5 mL) was added. 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. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: EtOAc/EtOH 3/l:heptanes from 0:100 to 100:0) to give the title compound (138 mg, 89 % pure, yield: 57 %) as a brown solid.

[0460] Step C: 1 -(4-(7-(aminomethyl)-l,6-naphthyridin-2-yl)pyrimi din-2 -yl)-3, 4,4- trimethylimidazolidin-2-one. HC1 (37 % in H2O, 443 μ 5L.2, 99 mmol, 20 eq.) was added dropwise to a solution of tert-butyl ((2-(2-(3,4,4-trimethyl-2-oxoimidazolidin-l-yl)pyrimidin- 4-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (138 mg, 89 % pure, 0.265 mmol) in 1,4- dioxane (5 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature for 2.5 h. The solvents were evaporated to give Intermediate 453 (HC1 salt, 115 mg, quantitative) as a green solid, used without further purification.

Intermediate 455: 3-(3-(2-hydroxyethyl)oxetan-3-yl)-4-methylbenzoic acid.

[0461] Step A: 3-(3-(2-ethoxy-2-oxoethyl)oxetan-3-yl)-4-methylbenzoic acid. KOH (1.5 M in water, 6.7 mL, 10.05 mmol, 1.3 eq.) was added to a mixture of [Rh(cod)Cl]2 (CAS [12092- 47-6], 190 mg, 0.386 mmol, 0.05 eq.) in 1,4-di oxane (22 mL) while nitrogen was bubbling through the solution. After 1 min, 3-borono-4-methylbenzoic acid (CAS [170230-88-3], 2.08 g, 11.558 mmol, 1.5 eq.) and a solution of ethyl 2-(oxetan-3-ylidene)acetate (CAS [922500- 91-2], 1.097 g, 7.72 mmol) in 1,4-dioxane (8 mL) were added. The reaction mixture was stirred at room temperature for 1 h. Water and EtOAc were added, and HC1 (1 M in water) was added until pH 2-3. The aqueous layer was extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (80 g SiO2, DCM:MeOH 9:1 in DCM, from 0/100 to 40/60) to yield the title compound (160 mg, yield: 7 %) as a white solid. [0462] Step B: 3-(3-(2-hydroxyethyl)oxetan-3-yl)-4-methylbenzoic acid. Sodium borohydnde (90 mg, 2.38 mmol, 5 eq.) was added to a solution of 3-(3-(2-ethoxy-2-oxoethyl)oxetan-3-yl)- 4-methylbenzoic acid (130 mg, 0.47 mmol) in dry THF (2 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 50 °C for 16 h. The reaction was quenched with water. Then, DCM and HC1 (1 M in water) were added until pH 2-3. The mixture was extracted with DCM/MeOH (9/1) (x 5). The combined organic layer was dried over MgSO4. filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiCh; DCM:MeOH (9:1) in DCM, from 0 % to 60 %) to yield Intermediate 455 (35 mg, yield: 31 %) as a white solid.

Intermediate 460: 3-(S-(difluoromethyl)sulfonimidoyl)benzoic acid and Intermediate 463: (*R)-3-(S-(difluoromethyl)sulfonimidoyl)benzoic acid and Intermediate 464: (*S)-3-(S- (difluoromethyl)sulfonimidoyl)benzoic acid. Intermediate 460

Intermediate 463

Intermediate 464

[0463] Methyl 3-[(difluoromethyl)(imino)oxo-X6-sulfanyl]benzoate (714 mg, 2.865 mmol) was dissolved in a mixture of THF (2.5 mL), water (2.5 mL), and MeOH (2.5 mL) and then NaOH (229 mg, 5.729 mmol, 2 eq.) was added at room temperature. The reaction mixture was stirred at room temperature overnight. DCM (20 mL), and water (20 mL) were added to the mixture. The layers were separated and the aqueous layer was acidified with 2 M aqueous HC1 (to pH=2), then extracted with DCM (2 x 25 mL). The combined organic layer was evaporated to yield Intermediate 460 (360 mg, yield: 53 %). A sample of Intermediate 460 (1.5 g) was separated into its stereoisomers by semipreparative SFC using aLux Amylose-1 250 x 30 mm 5 um column and an isocratic mode method: 20 % [EtOH + 0.1 % DEA] - 80 % [CO2] to yield Intermediate 463 (670 mg, yield: 34 %) and Intermediate 464 (550 mg, yield: 28 %), both as a white solids.

Intermediate 465: N-((2-chloro-l,6-naphthyridin-7-yl)methyl)-3- ((difluoromethyl)sulfonyl)benzamide.

[0464] HBTU (CAS [94790-37-1], 1.537 g, 4.052 mmol, 1.2 eq.) was added to a solution of (2-chloro-l,6-naphthyridin-7-yl)methanamine (Intermediate 1) (0.9 g, 3.376 mmol), 3- difluoromethanesulfonylbenzoic acid (CAS [4837-21-2], 0.957 g, 4.052 mmol, 1.2 eq.), and DIPEA (2.8 mL, 16.8 mmol, 5 eq.) in DMF (25 mL) at room temperature and the mixture was stirred for 2 h at room temperature. The mixture was diluted with DCM and washed with 1 M aqueous Na2CO3. The organic layer was dried (MgSO4). filtered, and the solvents evaporated in vacuo. The residue was triturated in ACN and the solid was filtered off. This was repeated several times. The combined mother liquors were evaporated, and the residue was purified by flash column chromatography (40 g SiCh, DCM:MeOH 9:1 in DCM from 0/100 to 50/50) to yield Intermediate 465 (1.099 g, yield 68 %) as a brown solid.

Intermediate 467 : (2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l ,6-naphthyridin-7- yl)methanamine.

[0465] Step A: tert-butyl ((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)carbamate. cis-2,6-Dimethylmorpholine (CAS [6485-55-8], 0.7 mL, 5.652 mmol, 4 eq.) was added to a solution of Intermediate 450 (500 mg, 1.345 mmol) and DIPEA (0.9 mL, 5.445 mmol, 4 eq.) in DMSO (10 mL) in a sealed tube. Then, the mixture was stirred at 120 °C for 2 h. After cooling ,the solution was diluted with DCM and washed with aqueous HC1 (0.1 M) and brine. The combined organic layer was dried over MgSO4. filtered, and evaporated under vacuum to yield the title compound (600 mg, quantitative) as a yellow solid, used without further purification.

[0466] Step B: (2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methanamine. HC1 (4 M in 1,4-dioxane, 3.3 mL, 13.317 mmol, 10 eq.) was added to a solution of Intermediate 466 (600 mg, 1.332 mmol) in 1,4-dioxane (5 mL). The mixture was stirred at room temperature overnight. To push the reaction to completion, HC1 (37 % in water, 0.55 mL, 6.659 mmol, 5 eq.) was added and the mixture was stirred at room temperature for two days. The reaction mixture was filtered, and the solid was dried under reduced pressure to yield Intermediate 467 (HC1 salt, 550 mg, yield: 97 %) as a yellow solid.

Intermediate 468: N-((2-chloro-l ,6-naphthyridin-7-yl)methyl)-3-(S- (difluoromethyl)sulfonimidoyl)benzamide.

[0467] HATU (CAS [148893-10-1], 146 mg, 0.38 mmol, 1.25 eq.) was added in one portion to a solution of (2-chloro-l,6-naphthyridin-7-yl)methanamine (Intermediate 1) (82 mg, 0.3 mmol) and (*S)-3-(S-(difluoromethyl)sulfonimidoyl)benzoic acid (Intermediate 464, 100 mg, 0.32 mmol, 1.05 eq.) in DMF (3 mL) at room temperature. After 2 h, the mixture was diluted with saturated aqueous NaHCCL and was extracted with EtOAc (x3). The combined organic layer was dried (MgSO4). filtered, and the solvents evaporated 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 468 (75 mg; yield: 58 %) as a solid.

Intermediate 471: 3 -(azetidine- l-sulfonimidoyl)-4-methylbenzoic acid.

[0468] Step A: l-((5-bromo-2-methylphenyl)sulfinyl)azetidine. Into a 3 L 3-necked flask were added azetidine (38.3 g, 670.5 mmol, 2 eq.), DCM (850 mL), and DIPEA (216.7 g, 1676.3 mmol, 5 eq.) at room temperature. A solution of 5-bromo-2-methylbenzenesulfinyl chloride (CAS [1861655-21-1], 85 g, 127.6 mmol) in DCM (850 mL) was added dropwise to the mixture at -30 °C. The reaction mixture was stirred for 1 h at -30 °C. The resulting mixture was washed with water (3 x 500 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc 1/10) to afford the title compound (35 g, yield: 38 %) as a yellow oil.

[0469] Step B: l-(5-bromo-2-methylphenylsulfonimidoyl)azetidine. Into a 2 L 3-necked flask were added l-((5-bromo-2-methylphenyl)sulfinyl)azetidine (35 g, 127.65 mmol), MeOH (700 mL), PIDA (CAS [3240-34-4], 205.6 g, 638.3 mmol, 5 eq.) and ammonium carbamate (CAS [1111-78-0], 49.8 g, 638.3 mmol, 5 eq.) at 0 °C. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was purified by reverse phase flash chromatography (gradient of water (0.5 %TFA) : ACN from 5 % to 45 %) to afford the title compound (24 g, yield: 65 %) as a colourless oil.

[0470] Step C: 3-(azetidine-l-sulfonimidoyl)-4-methylbenzoic acid. In a 1 L round bottom flask, n-butyllithium (2.5 M in THF, 83.04 mL, 207.6 mmol, 2.5 eq.) was added dropwise to a solution of Il-(5-bromo-2-methylphenylsulfonimidoyl)azetidine (24 g, 82.99 mmol) in THF (480 mL) at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 30 min. The atmosphere of the reaction mixture was exchanged with CO2 3 times. The reaction mixture was stirred for 1 h at -50 °C. The reaction was quenched with HC1 (300 mL, 1 M in water) and the resulting mixture was washed with EtOAc (3 x 300 mL). The aqueous layer was purified by reverse phase flash chromatography (gradient of water (0.5 % HC1) : ACN from 5 % to 55 %) to afford Intermediate 471 (11.378 g, yield: 54 %) as a white solid.

Intermediate 473: N-((2-(6-formylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide.

[0471] Step A: N-((2-(6-(dimethoxymethyl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide. Pd(dppl)C12.DCM (CAS [95464-05-4], 420 mg, 0.513 mmol, 0.1 eq.) was added to a solution of 6-(dimethoxymethyl)pyridin-2-ylboronic acid (CAS [1256355-18-6], 1.516 g, 7.695 mmol, 1.5 eq.), Intermediate 45 (2 g, 5.13 mmol), and sodium carbonate (1.087 g, 10.26 mmol, 2 eq.) in 1,4-dioxane (50 mL) and water (15 mL). The reaction mixture was purged with nitrogen and stirred at 100 °C overnight. The reaction mixture was diluted with water and extracted 3 times with DCM. The combined organic layer was dried over MgSCL, filtered, and evaporated. The residue was purified by flash column chromatography (SiCh, DCM:MeOH from 100:0 to 90:10) followed by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to yield the title compound (590 mg, yield: 23 %). [0472] Step B: N-((2-(6-formylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide. N-((2-(6-(dimethoxymethyl)pyridin-2-yl)- 1 ,6-naphthyri din-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide (590 mg, 1.165 mmol) in aqueous HC1 (1 M, 5.8 mL, 5.823 mmol, 5 eq.) and THF (8 mL) was stirred at 50 °C for 4 h. After cooling, the reaction mixture was diluted with water, and extracted 3 times with EtOAc. The organic layer was evaporated to give Intermediate 473 (assumed quantitative), used without further purification.

Intermediate 476: (2-(4-fluoro-3-methyl-6-(4, 7-diazaspiro [2.5] octan-7 -yl)py ri din-2 -yl)- 1 ,6- naphthyri din-7-yl)methanamine.

[0473] Step A: tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)-4-fluoro-5-iodopyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. The title compound was prepared in a manner analogous to the one used for Intermediate 428, using N- iodosuccinimide (CAS [516-12-1]) instead of N-chlorosuccinimide in Step A.

[0474] Step B: tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)-4-fluoro-5-methylpyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. In a sealed tube, Pd(dppl)C12.CH2C12 (CAS [95464-05-4], 14 mg, 0.017 mmol, 0.1 eq.) was added to a solution of tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)-4- fluoro-5-iodopyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (122 mg, 0.177 mmol), trimethylboroxine (CAS [823-96-1], 49 μL 0, .351 mmol, 2 eq.), and cesium carbonate (115 mg, 0.353 mmol, 2 eq.) in 1,4-dioxane (2 mL) under nitrogen atmosphere. The reaction mixture was stirred at 95 °C for 22 h. After cooling, more Pd(dppl)C12.CH2C12 (14 mg, 0.017 mmol, 0.1 eq.) and trimethylboroxine (49 μL 0,.351 mmol, 2 eq.) were added to the reaction mixture. The mixture was stirred at 95 °C for 22 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 crude product was purified by flash column chromatography (silica; EtOAc/heptane from 0/100 to 40/60) to yield the title compound (62 mg, yield: 53 %) as a colourless oil. [0475] Step C: (2-(4-fluoro-3-methyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methanamine. The title compound was prepared in a manner analogous to Intermediate 98 using tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6- naphthyridin-2-yl)-4-fluoro-5-methylpyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

Intermediate 487: tert-butyl methyl((lR)-3-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-3- azabicy clo [3.1.0]hexan- 1 -yl)carbamate.

[0476] Step A: tert-butyl methyl((lR)-3-((S)-l-phenylethyl)-3-azabicyclo[3.1.0]hexan-l- yl)carbamate. Sodium hydride (0.158 g, 3.9 mmol, 1.2 eq.) was added to a solution of tert- butyl {(lR)-3-[(lS)-l-phenylethyl]-3-azabicyclo[3.1.0]hexan-l-yl}carbamate (CAS [182075- 89-4], 1 g, 3.307 mmol) in dry DMF (15 mL) at 0 °C under nitrogen atmosphere and the mixture was stirred at room temperature for 20 min. Then, a solution of methyl iodide (0.4 mL, 6.578 mmol, 2 eq.) in DMF (5 mL) was added to the reaction mixture at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The mixture was poured into ice- water and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over MgSO4 f.iltered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; DCM:MeOH (9:1) in DCM, from 0/100 to 100/0) to yield the title compound as a light yellow oil (0.7 g, yield: 99 %).

[0477] Step B: tert-butyl ((lR)-3-azabicyclo[3.1.0]hexan-l-yl)(methyl)carbamate: A solution of tert-butyl methyl((lR)-3-((S)-l-phenylethyl)-3-azabicyclo[3.1 ,0]hexan-l-yl)carbamate (680 mg, 2,149 mmol) in MeOH (110 mL) was pumped (1 mL/min )through a HCube Pd/C 10 % cartridge at 40 bar FL and 50 °C. The reaction mixture was concentrated to dryness to yield the title compound (454 mg, yield: 74 %), used without further purification.

[0478] Step C: tert-butyl methyl((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. A solution of Intermediate 46 (120 mg, 0.266 mmol) and tert-butyl ((lR)-3-azabicyclo[3.1.0]hexan-l-yl)(methyl)carbamate (113 mg, 0.533 mmol, 2 eq.) in DMSO (0.5 mL) was stirred at 150 °C in a closed vial for 16 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHC'Os. The organic layer was dried over MgSO4. filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (Silica 12 g; EtOAc/heptane from 0/100 to 100/0), followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x l00 mm 5 pm Column; from 59 % [25 mM NH4HCO3] - 41 % [ACN:MeOH (1:1)] to 17 % [25 mM NH4HCO3] - 83 % [ACN:MeOH (1:1)]) to yield Intermediate 487 (21 mg, yield: 12 %) as a yellow solid.

Intermediate 488: tert-butyl (3,3-difluoro-l-(6-(7-((4-methyl-3- (methylsulfonyl)benzarrtido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)piperi din-4- yl)carbamate.

[0479] tert-Butyl 3,3-difhioropiperidin-4-ylcarbamate (CAS [1263180-22-8], 357 mg, 1.511 mmol, 2 eq.) and DIPEA (1 mL, 5.741 mmol, 7.6 eq.) were added to a solution of Intermediate 46 (340 mg, 0.76 mmol) in DMSO (1.5 mL). The reaction mixture was stirred at 130 °C for 6 days. The reaction mixture was diluted with water and extracted with DCM (x 3). The combined organic layer was dried with MgSO4 f,iltered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCh, DCM:MeOH (9:1) in DCM from 0/100 to 30/70), followed by reverse phase column chromatography (Phenomenex Gemini; I.D. (mm) 100 x 21.2; 5 urn (C18) 110A; from 59 % [25 mM NH4HCO3] - 41 % [ACN:MeOH 1:1] to 17 % [25 111M NH4HCO3] - 83 % [ACN:MeOH 1:1] to yield Intermediate 488 (52 mg, yield: 10 %) as a yellow solid.

Intermediate 492: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(methylsulfonyl)benzoic acid.

[0480] Step A: 3-(aminomethyl)-5-(methylsulfonyl)benzoic acid. A suspension of 3- (chloromethyl)-5-(methylsulfonyl)-benzoic acid, methyl ester (CAS [2694010-19-8], 279 mg, 1.062 mmol) in aqueous ammonium hydroxide (25 % in water, 2 mL, 12.744 mmol, 12 eq.) in a sealed tube was stirred at 120 °C for 18 h. After cooling, the solvent was evaporated to yield the title compound (225 mg, yield: 68 %), used without further purification.

[0481] Step B: 3-(((tert-butoxycarbonyl)amino)methyl)-5-(methylsulfonyl)benzoic acid. Di- tert-butyl dicarbonate (CAS [24424-99-5], 0.42 mL, 1.963 mmol, 2 eq.) was added to a solution of 3-(aminomethyl)-5-(methylsulfonyl)benzoic acid (225 mg, 0.981 mmol) and sodium bicarbonate (247 mg, 2.940 mmol, 3 eq.) in THF (6 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched by dropwise addition of HC1 (3 N in water) until pH=3. The mixture was diluted with water and extracted with EtOAc (x2). The combined organic layer was dried (MgSO4). filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; DCM:MeOH (10:1, v/v) in DCM from 0/100 to 100/0) to yield Intermediate 492 (96 mg, 70 % pure, yield: 21 %) as a yellow solid.

Intermediate 498: 3-((trans)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl)-4- methylbenzoic acid and Intermediate 499: 3-((cis)-l-(tert-butoxycarbonyl)-4- hydroxypyrrolidin-2-yl)-4-methylbenzoic acid.

( 8

(CIS) Intermediate 499

[0482] Step A: N-(l-(5-bromo-2-methylphenyl)but-3-en-l-yl)acetamide. A solution of 5- bromo-2-methyl-a-2-propen-l-ylbenzenemethanamine (CAS [1270545-38-4], 10.685 g, 34.706 mmol ) and EtiN (14.51 mL, 104.118 mmol, 3 eq.) in DCM (140 mL) was cooled in an ice bath under nitrogen atmosphere. A solution of acetic anhydride (4.19 mL, 38.177 mmol, 1.1 eq.) in DCM (40 mL) was added dropwise over 5 min. The mixture was stirred for another 30 min at 0 °C. Na2CO3 (1 M in water, 20 mL) was added while stirring. After 5 min, the organic layer was separated, and the aqueous layer was extracted again with DCM (50 mL). The combined organic layer was dried over MgSCL, filtered, and concentrated. The crude product was purified by flash column chromatography (120 g silica column, EtOAc/heptane from 0/100 to 80/20) to yield the title compound (7.140 g, yield: 72 %) as a solid.

[0483] Step B: 5-(5-bromo-2-methylphenyl)pyrrolidin-3-yl acetate. Iodine (10.893 g, 42.92 mmol, 3 eq.) was added to a solution of N-(l-(5-bromo-2-methylphenyl)but-3-en-l- yl)acetamide (4.037 g, 14.31 mmol) in THF (70 mL) and water (20 mL) at room temperature and the reaction mixture was stirred at 65 °C for 1 h. Sodium carbonate (1 M in water, 28.61 mL, 28.61 mmol, 2 eq.) was added and the mixture was stirred at 70 °C for 16 h. The mixture was poured into saturated aqueous NaHCCL. The mixture was extracted with EtOAc. The organic layer was washed with a saturated solution of Na2S2Ch, dried over Mg fSilOte4r.ed, and evaporated. The residue was purified by flash column chromatography (80 g silica; EtOAc/heptane from 0/100 to 100/0) to yield the title compound (2.594 g, yield: 55 % ) as an orange oil.

[0484] Step C: tert-butyl 4-acetoxy-2-(5-bromo-2-methylphenyl)pyrrolidine-l -carboxylate. Di-tert-Butyl dicarbonate (CAS [24424-99-5], 3.597 g, 15.659 mmol, 2 eq.) was added to a solution of 5-(5-bromo-2-methylphenyl)pyrrolidin-3-yl acetate (2.594 g, 7.830 mmol) and DMAP (CAS [122-58-3], 96 mg, 0.785 mmol, 0.1 eq.) in DCM (46 mL). The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM (100 mL) and water (50 mL). The layers were separated, and the organic layer was washed with brine (50 mL). The organic layer was dried over MgSO fi4l.tered, and concentrated. The crude product was purified by column chromatography over silica gel (80 g SiCh. EtOAc/heptane from 0/100 to 100/0) to give the title compound (2.36 g, yield: 75 %) as a thick orange oil. [0485] Step D: tert-butyl 4-acetoxy-2-(5-(methoxycarbonyl)-2-methylphenyl)pyrrolidine-l- carboxylate and tert-butyl 4-hydroxy-2-(5-(methoxycarbonyl)-2-methylphenyl)pyrrolidine-l- carboxylate. In a pressure reactor, EtsN (3.67 mL, 26.36 mmol, 10 eq.) was added to a solution of tert-butyl 4-acetoxy-2-(5-bromo-2-methylphenyl)pyrrolidine-l-carboxylate (1.050 g, 2.636 mmol) in MeOH (5 mL) and 1,4-dioxane (5 mL). The mixture was degassed with nitrogen for 20 min. Pd(dppl)2C12 CH2C12 (CAS [95464-05-4], 0.237 g, 0.264 mmol, 0.1 eq.) was added and the reactor was sealed. The reaction mixture was stirred under carbon monoxide atmosphere (6 atm) at 85 °C overnight. After cooling, the mixture was filtered on a pad of Celite®. The organic layer was washed with NaiCCL (1 M in water) and the combined aqueous layer was extracted with EtOAc. The combined organic layer was dried over MgSO4. filtered, and concentrated under vacuo. The crude product was purified by flash column chromatography (80 g SiCh, EtOAc/heptane from 0/100 to 60/40) to afford tert-butyl 4- acetoxy-2-(5-(methoxycarbonyl)-2-methylphenyl)pyrrolidine-l -carboxylate (286 mg, yield: 28 %) and tert-butyl 4-hydroxy-2-(5-(methoxycarbonyl)-2-methylphenyl)pyrrolidine-l- carboxylate (253 mg, yield: 28 %), both as foams.

[0486] Step E: 3-((trans)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl)-4-methylbenzoic acid and 3-((cis)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl)-4-methylbenzoic acid. Lithium hydroxide hydrate (0.095 g, 2.273 mmol), 3 eq. was added to a solution of tert-butyl 4-acetoxy-2-(5-(methoxycarbonyl)-2-methylphenyl)pyrrolidine-l-carboxylate (0.286g, 0.758 mmol) in THF (3 mL) and water (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The pH of the solution was brought to 3 by adding KHSO4 (1 M in water). The mixture was extracted with DCM. The organic layer was dried (MgSCL). filtered, and the solvents evaporated in vacuo. The residue was purified by reverse phase column chromatography (from 70 % H2O (25 mM NH4HCO3) - 30 % ACN-MeOH to 27 % H2O (25 mM NH4HCO3) - 73 % ACN-MeOH) to give 3-((trans)-l-(tert- butoxycarbonyl)-4-hydroxypyrrolidin-2-yl)-4-methylbenzoic acid (Intermediate 498, 111 mg, yield: 45 %) and 3-((cis)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl)-4-methylbenzoic acid (Intermediate 499, 33 mg, yield: 13 %).

Intermediate 501 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((trans)-4-hydroxypyrrolidin-2-yl)-4-methylbenzamide.

(TRANS-pyrrolidine) (ClS-morpholine)

[0487] Step A: tert-butyl (trans)-2-(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)carbamoyl)-2-methylphenyl)-4-hydroxypyrrolidine-l- carboxylate. The title compound was prepared according to Method E, using Intermediate 11 and 3 -((trans)- 1 -(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl)-4-methylbenzoic acid (Intermediate 498).

[0488] Step B: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((trans)-4-hydroxypyrrolidin-2-yl)-4-methylbenzamide. tert-butyl (trans)-2-(5- (((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)carbamoyl)-2-methylphenyl)-4-hydroxypyrrolidine-l-carboxylate (183 mg, 0.28 mmol) was dissolved in HC1 (4 M in 1,4-dioxane, 0.7 mL, 2.803 mmol, 10 eq.) and 1,4- dioxane (2 mL) and the mixture was stirred at room temperature for 3 h. The crude reaction mixture was concentrated in vacuo to yield Intermediate 501 (175 mg, quantitative) as a solid, used without further purification.

Intermediate 506: 3-((3,3-difluoropropyl)sulfonyl)-4-methylbenzoic acid.

[0489] Step A: methyl 4-methyl-3-((3-((tetrahydro-2H-pyran-2- yl)oxy)propyl)sulfonyl)benzoate. 1,10-Phenanthroline (CAS [66-71-7], 110 mg, 0.609 mmol, 0.17 eq.), triphenylphosphine (160 mg, 0.576 mmol, 0.17 eq.), potassium metabisulfite (CAS [16731-55-8], 1.8 g, 8.125 mmol, 2.24 eq.), formic acid sodium salt (616 mg, 9.061 mmol, 2.5 eq.), and TBAB (CAS [1643-19-2], 1.46 g, 4.530 mmol, 1.25 eq.) were added to a solution of methyl 3-iodo-4-methylbenzoate (CAS [90347-66-3], 1 g, 3.622 mmol) in DMSO (30 mL). The mixture was degassed with nitrogen for 20 min. Palladium (II) acetate (CAS [3375-31-3], 46 mg, 0.203 mmol, 0.06 eq.) was added and the reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, 2-(3-bromopropoxy)tetrahydro-27/-pyran (CAS [33821-94-2], 994 mg, 4.457 mmol, 1.2 eq.) was added and the mixture was stirred at 60 °C for 16 h. The reaction mixture was poured in water and the mixture was extracted with DCM:MeOH (9:1) (x 5). The combined organic layer was washed with water, dried over MgSO4. filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (80 g SiCh, DCM:MeOH (9: 1) in DCM from 0/100 to 30/70) to yield the title compound (750 mg, yield: 57 %) as a pale yellow oil.

[0490] Step B: methyl 3-((3-hydroxypropyl)sulfonyl)-4-methylbenzoate.Pyridinium p- toluenesulfonate (CAS [24057-28-1], 220 mg, 0.875 mmol, 0.4 eq.) was added to a solution of methyl 4-methyl-3-((3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)sulfonyl)benzoate (0.78 g, 2.188 mmol) in EtOH (14 mL) at room temperature. The reaction mixture was stirred at 60 °C for 4 h and then at room temperature for 16h. The solvent was evaporated, and the residue was purified by flash column chromatography over silica gel (EtOAc/heptane from 0/100 to 35/65) to yield the title compound (570 mg, yield: 94 %) as a yellow solid. [0491] Step C: methyl 4-methyl-3-((3-oxopropyl)sulfonyl)benzoate. Dess-Martin periodinane (CAS [87413-09-0], 949 mg, 2.170 mmol, 1.5 eq.) was added portion wise to a stirred solution of methyl 3-((3-hydroxypropyl)sulfonyl)-4-methylbenzoate (394 mg, 1.447 mmol) in DCM (13 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 3 h. DCM and saturated aqueous NaHCO3 were added, and the mixture was extracted with DCM (x 3). The combined organic layer was dried over MgS fOilt4e.red, and concentrated in vacuo to yield Intermediate 504 (432 mg, quantitative) as a colorless sticky solid.

[0492] Step D: methyl 3-((3,3-difluoropropyl)sulfonyl)-4-methylbenzoate. DAST (CAS [38078-09-0], 1 mL, 7.991 mmol, 5 eq.) was added to a solution of methyl 4-methyl-3-((3- oxopropyl)sulfonyl)benzoate (432 mg, 1.598 mmol) in DCM (20 mL). The reaction mixture was stirred at 60 °C for 3 h, after which it was cooled to room temperature and water was added. The layers were separated, and the aqueous layer was extracted with DCM (2x 20 mL). The combined organic layer was dried (MgSO4). filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (12 g SiCh, EtOAc/heptane from 0/100 to 40/60) to yield the title compound (295 mg, yield: 62 %) as a colourless oil.

[0493] Step E: 3-((3,3-difluoropropyl)sulfonyl)-4-methylbenzoic acid. LiOH (125 mg, 2.976 mmol, 3 eq.) was added to a solution of methyl 3-((3,3-difluoropropyl)sulfonyl)-4- methylbenzoate (290 mg, 0.992 mmol) in THF (6 mL) and water (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The solvents were evaporated in vacuo to yield Intermediate 506 as a white solid (226 mg, yield: 81 %).

Intermediate 507 : (*R)-4-methyl-3-(methylsulfonyl)-N-((2-(6-(8-((2- nitrophenyl)sulfonamido)-5-azaspiro[2.5]octan-5-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)benzamide and Intermediate 508: (*S)-4-methyl-3-(methylsulfonyl)-N-((2-(6-(8- ((2-nitrophenyl)sulfonamido)-5-azaspiro[2.5]octan-5-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)benzamide.

(*R) Intermediate 507

(*S) Intermediate 508

[0494] DIPEA (141 μL, 0.809 mmol, 2.5 eq.) followed by 2-nitrobenzenesulfonyl chloride (CAS [1694-92-4], 80 mg, 0.361 mmol, 1.1 eq. ) were added to a stirred solution of Compound 420 (178 mg, 0.320 mmol) in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g SiO2, MeOH:DCM (9:1) in DCM from 0 % to 30 %), followed by SFC (Amylose-1 ethanol; isocratic 60 % EtOH + 0.1 % DEA) to yield Intermediate 507 (58 mg, yield: 24 %) and Intermediate 508 (57 mg, yield: 24 %), both as yellow solids.

Intermediate 511: (2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthy ridin-7-yl)methanamine.

[0495] Step A: tert-butyl 7-(6-chloro-4,5-dimethylpyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. A sealed tube was charged under nitrogen atmosphere with 2,6-dichloro-3,4- dimethylpyridine (CAS [72605-55-1], 100 mg, 0.568 mmol), 4-Boc-4,7-diazaspiro[2.5]octane (CAS [674792-08-6], 121 mg, 0.568 mmol, 1 eq.) and cesium carbonate (259 mg, 0.795 mmol, 1.4 eq.) in 1,4-dioxane. RuPhos Pd G3 (CAS [1445085-77-7], 47 mg, 0.057 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 100 °C for 16 h. Saturated aqueous NaHCO3 was added, and the mixture was extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica, 12 g, AcOEt/heptane from 0/100 to 20/80), followed by preparative SFC (Amilose column; isocratic 10 % MeOH + 0.1 % DEA / CO2) to yield the title compound (40 mg, yield: 6 %) as a colourless oil.

[0496] Step B: tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)-4,5-dimethylpyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. Intermediate 94 (185 mg, 0.406 mmol, 1.1 eq.), tert-butyl 7-(6-chloro-4,5-dimethylpyridin-2-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (130 mg, 0.369 mmol), and K2CO3 (77 mg, 0.559 mmol) were dissolved in 1,4-di oxane (6 mL) in a sealed tube under a nitrogen stream. Di-tert- butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 10 mg, 0.041 mmol, 0.1 eq.) and Pd(OAc)2 (CAS [3375-31-3], 5 mg, 0.022 mmol, 0.06 eq.) were added and the reaction mixture was stirred at 120 °C for 16 h. More Pd(OAc)2 (5 mg, 0.022 mmol, 0.06 eq.) and Intermediate 94 (100 mg, 0.220 mmol, 0.6 eq.) was added to the reaction mixture and it was further stirred at 120 °C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 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 12 g; EtOAc/heptane from 0/100 to 40/60) to yield the title compound (60 mg, yield: 26 %) as a yellow solid.

[0497] Step C: (2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methanamine. The title compound was prepared following the same procedure as Compound 416, starting from tert-butyl 7-(6-(7-(((tert- butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2-yl)-4,5-dimethylpyridin-2-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate instead of Compound 415.

Intermediate 513: N-((2-(6-(2-formylpyrrolidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0498] Step A: N-((2-(6-(2-(hydroxymethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide. The title compound was prepared according to Method I, using prolinol (CAS [498-63-5]) instead of 4-piperidineethanol.

[0499] Step B: N-((2-(6-(2-formylpyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide. Dess-Martin periodinane (CAS [87413- 09-0], 160 mg, 0.376 mmol, 2 eq.) was added to a stirred solution ofN-((2-(6-(2- (hydroxymethyl)pyrrolidin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide (100 mg, 0.188 mmol) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine (x 2), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 5/95) to yield Intermediate 513 (37 mg, yield: 37 %) as a yellow oil.

Intermediate 514: tert-butyl 7-(4-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin- 2-yl)pyrimidin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

[0500] Potassium acetate (192 mg, 1.957 mmol, 2.5 eq.), bis(pinacolato)diboron (CAS [73183-34-3], 219 mg, 0.861 mmol, 1.1 eq.), tricyclohexylphosphine (CAS [2622-14-2], 9 mg, 0.031 mmol, 0.04 eq.), and palladium(II) acetate (CAS [3375-31-3], 4 mg, 0.016 mmol, 0.02 eq.) were added to a solution of Intermediate 411 (254 mg, 0.783 mmol) in 1,4-dioxane under nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 30 min. After cooling to room temperature under nitrogen atmosphere, K2CO3 (216 mg, 1.566 mmol, 2 eq.), CuCl (78 mg, 0.783 mmol, 1 eq.), and tert-butyl ((2-chl oro-1, 6-naphthyri din-7- yl)methyl)carbamate (Intermediate 2) (230 mg, 0.783 mmol, 1 eq.) were added and the reaction mixture was stirred at 110 °C for 16 h. After cooling, water and EtOAc were added, and the layers were separated. The organic layer was dried over MgSO fil4t.ered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g silica, EtOAc/heptane from 0/100 to 60/40) to yield Intermediate 514 (94 mg, yield: 21 %) as a brown solid.

Intermediate 515: (2-(2-(4,7-diazaspiro [2.5] octan-7 -yl)pyrimidin-4-yl)- 1 ,6-naphthy ridin-7- yl)methanamine.

[0501] Trifluoroacetic acid (0.262 mL , 3.419 mmol, 23 eq.) was added to a stirred solution of Intermediate 514 (0.094 g, 0.151 mmol) in DCM (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue was washed with toluene (2 x 15 mL) to yield Intermediate 515 (87 mg, yield: 96 %) as an oil, used without further purification. Intermediate 516: N-((2-(6-(3,3-difluoro-4-((2-nitrophenyl)sulfonamido)piperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0502] DIPEA (113 μL, 0.649 mmol, 1.5 eq.) followed by 2-nitrobenzenesulfonyl chloride (CAS [1694-92-4], 72 mg, 0.325 mmol, 1.5 eq.) were added to a stirred solution of Compound 423 (123 mg, 0.217 mmol) in DCM (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. More DMF (2 mL), DIPEA (182 1μ.0L4,5 mmol, 4.8 eq.), and 2-nitrobenzenesulfonyl chloride (68 mg, 0.307 mmol, 1.4 eq.) were added and the reaction mixture was stirred at 60 °C for 2 h. Water was added, and the mixture was extracted with DCM (x 3). The combined organic layer was dried over MgSCti, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g SiCh, DCM:MeOH (9:1) in DCM from 0/100 to 55/45) to yield Intermediate 516 (60 mg; yield: 36 %) as a yellow solid.

Intermediate 517: N-((2-(6-(3,3-difluoro-4-((N-methyl-2-nitrophenyl)sulfonamido)piperidin- l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0503] lodomethane (13 mg, 0.092 mmol, 1.15 eq.) was added to a stirred mixture of Intermediate 516 (60 mg, 0.080 mmol) and cesium carbonate (38 mg, 0.117 mmol, 1.5 eq.) in DMF (1 mL). The reaction mixture was stirred at room temperature for 3 h. Water was added, and the mixture was extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4. filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g SiCh, MeOH:DCM (9: 1) in DCM, from 0 % to 30 %) to yield Intermediate 517 (37 mg, yield: 54 %) as a yellow solid. Intermediate 518: (*R)-N-((2-(6-(3,3-difluoro-4-((N-methyl-2- nitrophenyl)sulfonamido)piperi din-1 -yl)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide and Intermediate 519: (*S)-N-((2-(6-(3,3-difluoro-4- ((N-methyl-2-nitrophenyl)sulfonamido)piperidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

(*S) Intermediate 519

[0504] The racemic mixture of Intermediate 518 and Intermediate 519 was prepared following the same procedure as Intermediate 517, using the racemic mixture of Intermediate 507 and Intermediate 508 instead of Intermediate 516. The stereoisomers were separated by SFC (Cell-3; isocratic 60 % EtOH + 0.1 % DEA / 40 % CO2) to give Intermediate 518 and Intermediate 519.

Intermediate 521 : 3-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-3- azabicyclo[3.1.0]hexan-l-ol.

[0505] Step A: tert-butyl ((2-(6-(l-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamate. The title compound was prepared according to Method I, using Intermediate 9 instead of Intermediate 46, and 3-azabicyclo[3.1.0]hexan-l-ol (CAS [1354953-83-5]) instead of 4-piperidineethanol.

[0506] Step B: 3-(6-(7-(aminomethyl)- l,6-naphthyridin-2-yl)pyri din-2 -yl)-3- azabicyclo[3.1.0]hexan-l-ol. Trifluoroacetic acid (1.8 mL. 24.17 mmol, 40 eq.) was added to a stirred solution of tert-butyl ((2-(6-(l-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)carbamate (262 mg, 0.60 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to yield Intermediate 521 (342 mg, quantitative) as a brown solid, used without further purification.

Intermediate 525: (2-(4-fluoro-6-morpholinopyri din-2 -yl)-l, 6-naphthyri din-7- yl)methanamine.

[0507] Step A: 4-(6-bromo-4-nitropyridin-2-yl)morpholine. EtsN (3.5 mL, 2.8 mmol, 2 eq.) was added to a stirred solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 0.4 g, 1.4 mmol) and morpholine (0.14 mL, 1.6 mmol, 1.1 eq.) in toluene (10 mL) at room temperature. The mixture was stirred at 120 °C for 3 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed twice with brine. The organic layer was dried (MgSOr). filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 80 g; EtOAc/heptane from 0/100 to 40/60) to yield the title compound (332 mg, yield: 80 %) as an orange solid.

[0508] Step B: 4-(6-bromo-4-fluoropyri din-2 -yl)morpholine. Tetramethylammonium fluoride (CAS [373-68-2], 106 mg, 1.14 mmol, 1 eq.) was added to a solution of 4-(6-bromo-4- nitropyridin-2-yl)morpholine (328 mg, 1.1 mmol) in dry DMF (5 mL). The vial was sealed, and the reaction mixture was stirred at 65 °C for 3 h. After cooling, the reaction mixture was diluted with EtOAc (20 mL) and water (30 mL). The organic layer was separated, washed with water (20 mL) and brine (15 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (80 g; EtOAc/heptane from 0/100 to 30/70) to give the title compound (212 mg, yield: 70 %) as a yellow solid and unreacted starting material (92 mg, yield: 26 %) as an orange solid.

[0509] Step C: tert-butyl ((2-(4-fluoro-6-morpholinopyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. Intermediate 94 (274 mg, 0.670 mmol), 4-(6-bromo-4-fluoropyridin-2- yl)morpholine (210 mg, 0.804 mmol, 1.2 eq.), and potassium carbonate (139 mg, 1.005 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (3 mL) in a sealed tube under nitrogen atmosphere. Di- tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 17 mg; 0.067 mmol, 0.1 eq.) and palladium(II) acetate (CAS [3375-31-3], 7 mg, 0.033 mmol, 0.05 eq.) were added and the reaction mixture was stirred at 120 °C for 14 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed twice with brine, dried on MgSO4, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 10/90) to yield the title compound (110 mg, yield: 37 %) as ayellow solid.

[0510] Step D: (2-(4-fluoro-6-morpholinopyridin-2-yl)-l,6-naphthyridin-7-yl)methanamine. HC1 (4 M in 1,4-dioxane, 0.61 mL 2.45 mmol, 10 eq.) was added to a solution of tert-butyl ((2-(4-fluoro-6-morpholinopyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (107 mg, 0.245 mmol) in 1,4 dioxane (3 mL) at room temperature. The mixture was stirred at room temperature for 12 h. The crude mixture was concentrated in vacuo to yield Intermediate 525 (HC1 salt, 101 mg, quantitative) as ayellow solid, used without further purification.

Intermediate 528: 3-(l,4-dioxan-2-yl)-4-methylbenzoic acid.

[0511] Step A: l-(5-bromo-2-methylphenyl)-2-(2-hydroxyethoxy)ethan-l-ol. Sodium hydride (60 % in mineral oil, 1.38 g, 34.5 mmol, 10 eq.) was added to ethylene glycol (CAS [107-21- 1], 20 mL, 359 mmol, 105 eq.). The mixture was stirred for 30 min at room temperature and then 2-(5-bromo-2-methylphenyl)oxirane (CAS [1889716-95-3], 728 mg, 3.42 mmol) was added. The resulting mixture was stirred at 100 °C for 2 h. After cooling, the mixture was poured into cold water (200 mL). The pH was brought to 2-3 with HC1 (1 M in water). The mixture was extracted with EtOAc (150 mL). The organic layer was washed with water (2 x 50 mL) and brine (50 mL), dried over MgSCL, filtered, and evaporated. The residue was purified by column chromatography over silica gel (25 g; MeOH/DCM from 0/100 to 10/90) to afford the title compound (756 mg, yield: 80 %) as mixture of regiosisomers (70 % title compound).

[0512] Step B: 2-(5-bromo-2-methylphenyl)- 1,4-dioxane. Potassium tert-butoxide (330 mg, 2.94 mmol, 1.1 eq.) was added to a solution of l-(5-bromo-2-methylphenyl)-2-(2- hydroxyethoxy)ethan-l-ol in THF (50 mL). The mixture was stirred at room temperature for 1 h. Then, p-toluenesulfonyl chloride (CAS [98-59-9], 510 mg, 2.67 mmol, 1 eq.) was added in one portion and stirring was continued at room temperature for 1 h. Finally, another portion of potassium tert-butoxide (330 mg, 2.94 mmol, 1.1 eq.) was added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with water (50 mL), saturated NaHCO3 (50 mL), and EtOAc (100 mL) were added, and the organic layer was separated, dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography over silica gel (25 g; EtOAc/heptane from 0/100 to 50/50) to give the title compound (284 mg, yield: 41 %) as a colourless oil.

[0513] Step C: 3-(l,4-dioxan-2-yl)-4-methylbenzoic acid. A pressure reactor was charged with 2-(5-bromo-2-methylphenyl)-l,4-dioxane (297 mg, 1.155 mmol), Pd(dppf)C12.CH2C12 (CAS [95464-05-4], 50 mg, 0.061 mmol, 0.05 eq.), potassium carbonate (250 mg, 1.809 mmol, 1.6 eq.) in a mixture of DMSO (15 mL) and water (1.5 mL). The mixture was degassed and purged 3 times with carbon monoxide. Finally, the mixture was pressurized with carbon monoxide (5 bars) and stirred at 100 °C for 16 h. After cooling the mixture was diluted with water (25 mL) and NaOH (1 M in water, 15 mL). The aqueous solution was washed with DCM (2 x 25 mL). The aqueous solution was then acidified with HC1 (1 M in water) to pH 2- 3 and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with brine (20 mL), dried over MgSO4 f.iltered, and concentrated to give Intermediate 528 (256 mg, yield: 95 %), as a white solid, used without further purification.

Intermediate 531: benzyl 6,6-dimethyl-2-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-5-oxa-2,8- diazaspiro[3.5]nonane-8-carboxylate.

[0514] Step A: 8-benzyl 2-(tert-butyl) 6,6-dimethyl-5-oxa-2,8-diazaspiro[3.5]nonane-2,8- dicarboxylate. EtsN (0.652 μL, 4.681 mmol, 4 eq.) was added to a stirred solution of tert-butyl 6,6-dimethyl-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (CAS [1803580-61-1], 300 mg, 1.170 mmol) in DCM (5 mL) at 0 °C. Then, benzyl chloroformate (CAS [501-53-1], 330 pL, 2.341 mmol, 2 eq.) was added to the solution and the mixture was stirred at 50 °C for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted with DCM (3x). The combined organic layer was dried over MgSO4 f,iltered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCh; EtOAc/heptane from 0/100 to 30/70) to yield the title compound (212 mg, yield: 46 %) as a colourless oil. [0515] Step B: benzyl 6,6-dimethyl-5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate.

Trifluoroacetic acid (6.4 mL, 83.7 mmol, 86 eq.) was added to a solution of 8-benzyl 2-(tert- butyl) 6,6-dimethyl-5-oxa-2,8-diazaspiro[3.5]nonane-2,8-dicarboxylate (380 mg, 0.973 mmol) in DCM (6 mL). The mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo to give the title compound (TFA salt, 393 mg, quantitative), used without further purification.

[0516] Step C: benzyl 6,6-dimethyl-2-(6-(7-((4-methyl-3-

(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-5-oxa-2,8- diazaspiro[3.5]nonane-8-carboxylate. The title compound was prepared according to Method I, using benzyl 6,6-dimethyl-5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate instead of 4- piperidineethanol.

Intermediate 532: 4-(6-bromo-4-nitropyridin-2-yl)morpholine-2,2,3,3,5,5,6,6-d8.

[0517] EtsN (4.4 mL; 3.547 mmol, 2 eq.) was added to a stirred solution of 2,6-dibromo-4- nitropyridine (CAS [175422-04-5], 0.5 g, 1.8 mmol) and morpholine-2,2,3,3,5,5,6,6-d8 (CAS [342611-02-3], 268 mg; 2.04 mmol, 1.1 eq.) in toluene (10 mL) at room temperature. The mixture was stirred at 120 °C for 3 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed twice with brine, dried on MgS fOil4t.ered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 80 g; EtOAc/heptane from 0/100 to 40/60) to yield Intermediate 532 (407 mg, yield: 77 %) as a, orange solid.

Intermediate 535: (2-(4-fluoro-6-(morpholino-d8)pyridin-2-yl)-l,6-naphthyridin-7- yl)methanamine. [0518] The title compound was prepared following the same procedure as Intermediate 525 Steps B-D, using 4-(6-bromo-4-nitropyridin-2-yl)morpholine-2,2,3,3,5,5,6,6-d8 (Intermediate 532) in Step B.

Intermediate 536: 3-(methylsulfinyl)-4-(trifluoromethyl)benzoic acid.

[0519] Step A: 3-(methylsulfinyl)-4-(trifluoromethyl)benzoic acid and 3-(methylsulfonyl)-4- (trifluoromethyl)benzoic acid. Oxone (CAS [70693-62-8], 3.12 g, 5.08 mmol, 1.5 eq.) was slowly added to a suspension of 3-(methylthio)-4-(trifluoromethyl)benzoic acid (CAS [1822986-18-4], 800 mg, 3.387 mmol) in water (20 mL) and the reaction mixture was stirred at 40 °C for 16 h. After cooling, the mixture was diluted with water and extracted with EtOAc (2 x 150 mL). The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (1:1 mixture with the corresponding sulfone).

[0520] Step B: methyl 3-(methylsulfinyl)-4-(trifluoromethyl)benzoate and methyl 3- (methylsulfonyl)-4-(trifluoromethyl)benzoate.

[0521] Acetyl chloride (0.34 mL, 4.79 mmol, 1.5 eq.) was added to a stirred solution of impure mixture of compounds from Step A (774 mg, 3.07 mmol) in MeOH (15 mL) at 0 °C. The reaction mixture was stirred for 18 h at 60 °C. The solvent was evaporated in vacuo. The residue was taken up with saturated aqueous NaHCCL and the mixture was extracted with EtOAc (2 x 150 mL). The combined organic layer was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (25 g SiO2; EtOAc/heptane from 0/100 to 50/50) to afford methyl 3-(methylsulfinyl)-4- (trifluoromethyl)benzoate (231 mg, yield: 28 %) and 3-(methylsulfonyl)-4- (trifluoromethyl)benzoic acid (334 mg, yield: 38 %), both of them as white solids.

[0522] Step C: 3-(methylsulfinyl)-4-(trifluoromethyl)benzoic acid. Lithium hydroxide monohydrate (146 mg, 3.47 mmol) was added to a solution of methyl 3-(methylsulfinyl)-4- (trifluoromethyl)benzoate (231 mg, 0.868 mmol) in THF (6 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The pH was brought to 3 by addition of KHSO4 (1 M in water). The mixture was extracted with DCM. The organic layer was dried (MgSOr). filtered, and the solvents evaporated in vacuo to yield Intermediate 536 (162 mg, yield: 19 %) as a white solid. Intermediate 538: 4-(6-bromo-4-nitropyridin-2-yl)-2,6-dimethylmorpholine-2,3,3,5,5,6-d6.

[0523] Step A: 2,6-dimethylmorpholine-2,3,3,5,5,6-d6. Raney Ni (CAS [7440-02-0], 682 mg, 11.6 mmol, 1.2 eq.) was added to a stirred solution of cis-2,6-dimethylmorpholine (CAS [6485-55-8], 1.2 mL, 9.74 mmol) in deuterium oxide (CAS [7789-20-0], 17 mL) under nitrogen atmosphere. The mixture was stirred at 140 °C for 8 h. The mixture was degassed with nitrogen again and further stirred at 150 °C for 8 h. The mixture was filtered. HC1 (5 M in water, 2.1 mL, 10.7 mmol, 1.1 eq.) was added and the solvent was evaporated under vacuo to obtain the title compound (HC1 salt, 1.5 g, quantitative) as a white solid, used without further purification.

[0524] Step B: 4-(6-bromo-4-nitropyridin-2-yl)-2,6-dimethylmorpholine-2,3,3,5,5,6-d6. The title compound was prepared following the same procedure as Intermediate 532, using 2,6- dimethylmorpholine-2,3,3,5,5,6-d6 instead of morpholine-2,2,3,3,5,5,6,6-d8.

Intermediate 541 : (2-(6-(2,6-dimethylmorpholino-2,3,3,5,5,6-d6)-4-fluoropyridin-2-yl)-l,6- naphthy ridin-7-yl)methanamine.

[0525] The title compound was prepared following the same procedure as Intermediate 525 Steps B-D, using 4-(6-bromo-4-nitropyridin-2-yl)-2,6-dimethylmorpholine-2,3,3,5,5,6-d6 (Intermediate 538) in Step B.

Intermediate 543: (2-(6-methoxypyri din-3 -yl)-l,6-naphthyridin-7-yl)methanamine. [0526] Step A: tert-butyl ((2-(6-methoxypyridin-3-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. 6-Methoxypyridine-3-boronic acid (CAS [163105-89-3], 101 mg, 0.664 mmol, 1.3 eq.) and Na2CO3 (1 M in water, 1.5 mL, 1.532 mmol, 3 eq.) were added to a stirred solution of tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2) (150 mg, 0.511 mmol) in 1,4-dioxane (3 mL, previously degassed with nitrogen) at room temperature. Then, bis(triphenylphosphine)palladium(II) dichloride (CAS [13965-03-2], 18 mg, 0.026 mmol, 0.05 eq.) was added, and the mixture was stirred at 85 °C under nitrogen atmosphere for 4 h. After cooling, water was added and the mixture was extracted with EtOAc, dried over MgSO4. filtered, and concentrated. The crude product was purified by flash column chromatography (12 g silica; gradient of DCM:MeOH (9:1) in DCM from 0/100 to 50/50) to yield the title compound (170 mg, yield: 90 %) as a yellow foam.

[0527] Step B: (2-(6-methoxypyridin-3-yl)-l,6-naphthyridin-7-yl)methanamine. The title compound was prepared following the same procedure as Intermediate 525, Step D, using tert-butyl ((2-(6-methoxypyridin-3-yl)- 1 ,6-naphthyri din-7 -yl)methyl)carbamate.

Intermediate 546: 3-((2-hydroxyethyl)sulfonyl)-4-(methyl-d3)benzoic acid.

[0528] Step A: methyl 3-((2-hydroxyethyl)thio)-4-(methyl-d3)benzoate. Xantphos (CAS [161265-03-8], 326 mg, 0.564 mmol, 0.1 eq.) and bis(dibenzylideneacetone)palladium (CAS [32005-36-0], 98 mg, 0.170 mmol, 0.03 eq.) were added to a solution of methyl 3-bromo-4- (methyl-d3)benzoate (CAS [2227489-00-9], 1.3 g, 5.601 mmol), 2-mercaptoethanol (CAS [60-24-2], 0.39 mL, 5.583 mmol, 1 eq.), and DIPEA (3 mL, 17.189 mmol, 3 eq.) in 1,4- dioxane (30 mL) under nitrogen atmosphere. The mixture was stirred at 110 °C for 18 h. After cooling, the mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (x 3). The combined organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The crude product was purified by flash chromatography column (25 g silica, EtOAc/heptane from 0/100 to 50/50) to yield the title compound (1.02 g, yield: 76 %) as a colourless oil.

[0529] Step B: methyl 3-((2-hydroxyethyl)sulfonyl)-4-(methyl-d3)benzoate. A solution of 3- chloroperbenzoic acid (CAS [937-14-4], 2.01 g, 8.977 mmol, 2 eq.) in DCM (15 mL) was added dropwise to a solution of methyl 3-((2-hydroxyethyl)thio)-4-(methyl-d3)benzoate (1.02 g, 4.45 mmol) in DCM (15 mL) cooled at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. The reaction was quenched by addition of saturated aqueous Na2CO3 and the mixture was extracted with DCM. The organic layer was dried (MgSO4). filtered, and solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; EtOAc/heptane from 0/100 to 50/50) to yield the title compound (977 mg, yield: 78 %) as a colorless oil.

[0530] Step C: 3-((2-hydroxyethyl)sulfonyl)-4-(methyl-d3)benzoic acid. Lithium hydroxide monohydrate (204 mg, 4.862 mmol, 1.5 eq.) was added to a solution of methyl 3-((2- hydroxyethyl)sulfonyl)-4-(methyl-d3)benzoate (847 mg, 3.241 mmol) in THF (9 mL) and water (4.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solvent was concentrated to dryness. HC1 (1 M in water) was added until pH =3 and the mixture was extracted with EtOAc. The aqueous layer was concentrated to dryness and DCM:MeOH (9:1) was added. The salts were filtered, and the filtrate was concentrated to yield Intermediate 546 (341 mg, yield: 25 %) as a colourless oil.

Intermediate 548: methyl 3-((2-hydroxyethyl-2,2-d2)thio)-4-(methyl-d3)benzoate.

[0531] Step A: methyl 3-((2-methoxy-2-oxoethyl)thio)-4-(methyl-d3)benzoate. Xantphos (CAS [161265-03-8], 773 mg, 1.336 mmol, 0.1 eq.) and bis(dibenzylideneacetone)palladium (CAS[32005-36-0], 230 mg, 0.401 mmol, 0.03 eq.) were added to a solution of methyl 3- bromo-4-(methyl-d3)benzoate (CAS [2227489-00-9], 3.1 g, 13.357 mmol), methyl thioglycolate (CAS [2365-48-2], 1.8 mL, 20.035 mmol, 1.5 eq.), and DIPEA (7.1 mL, 40.990 mmol, 3 eq.) in 1,4-dioxane (80 mL) under nitrogen atmosphere. The mixture was stirred at 110 °C for 18 h. After cooling, more Xantphos (773 mg, 1.336 mmol, 0.1 eq.), bis(dibenzylideneacetone)palladium (230 mg, 0.401 mmol, 0.03 eq.), and methyl thioglycolate (1.8 mL, 20.035 mmol, 1.5 eq.) were added and the mixture was stirred at 110 °C for 18 h. After cooling, the 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 crude product was purified by flash column chromatography (80 g silica, EtOAc/heptane from 0/100 to 10/90) to yield unreacted methyl 3-bromo-4-(methyl- d3)benzoate (2.39 g, yield: 52 %) as a white solid and the title compound (1.77 g, yield: 44 %) as a colourless oil.

[0532] Step B: methyl 3-((2-hydroxyethyl-2,2-d2)thio)-4-(methyl-d3)benzoate. Diisobutylaluminium deuteride (CAS [59231-30-0], 0.7 M in toluene, 19.6 mL, 13.76 mmol, 2 eq.) was added dropwise to a stirred solution of methyl 3-((2-methoxy-2-oxoethyl)thio)-4- (methyl-d3)benzoate (1.77 g, 6.88 mmol) in dry THF (120 mL) at -10 °C. The mixture was stirred at -10 °C for 1 h and then at room temperature for 2 h. Potassium sodium tartrate (CAS [6381-59-5], 9.03 g, 55.03 mmol, 8 eq.) and water were added, and the mixture was extracted with DCM. The organic layer was dried (MgSO4). filtered, and the solvent concentrated in vacuo. The crude product was purified by flash column chromatography (silica 25 g;

EtOAc/heptane from 0/100 to 50/50) to yield Intermediate 548 (330 mg, yield: 20 %) as a colourless oil.

Intermediate 550: 3-((2-hydroxyethyl-2,2-d2)thio)-4-(methyl-d3)benzoic acid.

[0533] The title compound was prepared following the same procedure as Intermediate 546, steps B-C, using methyl 3-((2-hydroxyethyl-2,2-d2)thio)-4-(methyl-d3)benzoate (Intermediate 548) in Step B.

Intermediate 551 : N-((2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-3-(N- methylsulfamoyl)benzamide.

[0534] Intermediate 551 was prepared according to Method F (in DMF), using (2-(2- chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methanamine (Intermediate 598) instead of Intermediate 11, and 3-(methylsulfamoyl)benzoic acid (CAS [98278-28-5]) instead of 3,4- dimethyl-5-[(l -methylethyl)sulfonyl]benzoic acid. Intermediate 553: tert-butyl (3,3-difluoro-l-(4-(7-((3-fluoro-5- (methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyrimidin-2-yl)piperidin-4- yl)carbamate, Intermediate 554: tert-butyl (*R)-(3,3-difluoro-l-(4-(7-((3-fluoro-5- (methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyrimidin-2-yl)piperidin-4- yl)carbamate, and Intermediate 555: tert-butyl (*S)-(3,3-difluoro-l-(4-(7-((3-fluoro-5- (methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyrimidin-2-yl)piperidin-4- yl)carbamate.

(*R) Intermediate 554

(*S) Intermediate 555

[0535] Step A: N-((2-(2-chloropyrimidin-4-yl)-l, 6-naphthyri din-7-yl)methyl)-3-fluoro-5- (methylsulfonyl)benzamide. HATU (152 mg, 0.399 mmol, 1.27 eq.) was added in one portion to a solution of (2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methanamine (Intermediate 598) (85 mg, 0.313 mmol), 3-fluoro-5-(methylsulfonyl)-benzoic acid (CAS [1783354-37-9], 75 mg, 0.344 mmol, 1.1 eq.), and DIPEA (0.2 mL, 1.148 mmol, 3.7 eq.) in DMF (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (x 3). The combined organic layer was dried (MgSO4). filtered, and the solvents evaporated in vacuo. The crude product was triturated with ACN, filtered, and washed with Et2O to yield the title compound (93 mg, yield: 62 %) as a beige solid.

[0536] Step B: tert-butyl (3,3-difluoro-l-(4-(7-((3-fluoro-5-

(methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyrimidin-2-yl)piperidin-4- yl)carbamate and tert-butyl (*R)-(3,3-difluoro-l-(4-(7-((3-fluoro-5- (methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyrimidin-2-yl)piperidin-4- yl)carbamate, and tert-butyl (*S)-(3, 3 -difluoro- l-(4-(7-((3-fluoro-5- (methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyrimidin-2-yl)piperidin-4- yl)carbamate. The title compounds were prepared according to Method I, using N-((2-(2- chloropyrimidin-4-yl)-l, 6-naphthyri din-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide instead of Intermediate 46, and tert-butyl N-(3,3-difluoropiperidin-4-yl) carbamate (CAS [1263180-22-8]) instead of 4-piperidineethanol.

[0537] A batch of Intermediate 553 was separated into its stereoisomers by SFC (i-cellulose- C; isocratic 50 % [iPrOH + 0.1 % DEA] - 50 % CO2 to yield Intermediate 554 and Intermediate 555, both as yellow solids.

Intermediate 556: tert-butyl 3-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)oxy)azetidine-l -carboxylate.

[0538] tert-Butyl 3-[(5-bromo-2-pyridyl)oxy]azetidine-l-carboxylate (CAS [1335049-06-3], 821 mg, 2.494 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 915 mg, 3.605 mmol, 1.4 eq.), Pd(dppl)C12.CH2C12 (CAS [95464-05-4], 102 mg, 0.124 mmol, 0.05 eq.), and potassium acetate (763 mg, 7.773 mmol, 3 eq., previously dried at 100 °C) were added to 1,4-dioxane (15 mL) under nitrogen atmosphere. The vial was sealed, and the reaction mixture was stirred at 90 °C for 2.5 h. The mixture was diluted with Na2CO3 (1 M in water) and extracted twice with EtOAc. The combined organics layer was dried over MgSO fi4lt.ered, and the solvents were evaporated under vacuo. The residue was purified by flash column chromatography ( silica gel 80 g; EtOAc/heptane from 0/100 to 50/50) to give Intermediate 556 (452 mg, yield: 47 %) as an orange solid. Intermediate 557: 3-((2-hydroxyethyl-2,2-d2)sulfonyl)-4-methylbenzoic acid.

[0539] Step A: methyl 3-((2-hydroxyethyl-2,2-d2)thio)-4-(methyl-d3)benzoate. The title compound was prepared in a manner analogous to Intermediate 548, using

[0540] methyl 3-bromo-4-methylbenzoate (CAS [104901-43-1]) instead of methyl 3-bromo- 4-(methyl-d3)benzoate in Step A.

[0541] Step B: 3-((2-hydroxyethyl-2,2-d2)sulfonyl)-4-methylbenzoic acid. The title compound was prepared following the same procedure as Intermediate 546, steps B-C, using methyl 3-((2-hydroxyethyl-2,2-d2)thio)-4-(methyl-d3)benzoate in Step B.

Intermediate 560: di-tert-butyl (4-(((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)carbamoyl)-2-(methylsulfonyl)phenyl)iminodicarbonate.

[0542] Step A: ethyl 4-(bis(tert-butoxycarbonyl)amino)-3-(methylsulfonyl)benzoate. Di-tert- butyl dicarbonate (CAS [24424-99-5], 1.895 g, 8.681 mmol, 3 eq.), DMAP (CAS [1122-58- 3], 18 mg, 0.145 mmol, 0.05 eq.), and EtsN (0.8 mL, 5.788 mmol, 2 eq.) were added to a stirred solution of 4-amino-3-(methylsulfonyl)-benzoic acid, ethyl ester (704 mg, 2.894 mmol) in DCM (15 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and EtOAc. The layers were separated. The organic layer was washed with brine, dried over MgSO4 f.iltered, and concentrated. The crude product was purified by flash chromatography column (SiCh 80 g; EtOAc/heptane from 0/100 to 100/0) to yield the title compound (791 mg, yield: 59 %) as a white solid.

[0543] Step B: 4-(bis(tert-butoxycarbonyl)amino)-3-(methylsulfonyl)benzoic acid. Sodium hydroxide (214 mg, 5.350 mmol, 3 eq.) was added to a solution of ethyl 4-(bis(tert- butoxycarbonyl)amino)-3-(methylsulfonyl)benzoate (791 mg, 1.783 mmol) in EtOH (15 mL) and water (4 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The reaction was quenched by addition of HC1 (1 M in water) until pH 5-6. The mixture was concentrated in vacuo to yield the title compound (crude, 590 mg, yield: 79 %) as a white solid, used without further purification.

[0544] Step C: di-tert-butyl (4-(((2-(2-(cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6- naphthyri din-7 -yl)methyl)carbamoyl)-2-(methylsulfonyl)phenyl)iminodicarbonate. The title compound was prepared according to Method F, using Intermediate 467 instead of Intermediate 11, and 4-(bis(tert-butoxycarbonyl)amino)-3-(methylsulfonyl)benzoic acid instead of 3,4-dimethyl-5-[(l-methylethyl)sulfonyl]benzoic acid.

Intermediate 563: 6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-2-((cis)-2,6- dimethylmorpholino)pyrimidin-4(3H)-one.

[0545] Step A: 6-chloro-2-((cis)-2,6-dimethylmorpholino)pyrimidin-4(3H)-one. The title compound was prepared according to Method I, using 2,6-dichloro-3H-pyrimidin-4-one (CAS [120977-94-8]) instead of Intermediate 46, and cis-2,6-dimethylmorpholine (CAS [6485-55- 8]) instead of 4-piperidineethanol.

[0546] Step B: tert-butyl ((2-(2-((cis)-2,6-dimethylmorpholino)-6-oxo-l,6-dihydropyrimidin- 4-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. The title compound was prepared following the same procedure as Intermediate 514, using 6-chloro-2-((cis)-2,6- dimethylmorpholino)pyrimidin-4(3H)-one instead of Intermediate 411.

[0547] Step C: 6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-2-((cis)-2,6- dimethylmorpholino)pyrimidin-4(3H)-one. The title compound was prepared following the same procedure as Intermediate 525, Step D, using tert-butyl ((2-(2-((cis)-2,6- dimethylmorpholino)-6-oxo-l,6-dihydropyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)carbamate.

Intermediate 567: 3 -((difluoromethyl)sulfonyl)-5 -fluorobenzoic acid. [0548] Step A: methyl 3-fluoro-5-((3,3,3-trifluoro-2-oxopropyl)sulfonyl)benzoate. A solution of methyl 3-fluoro-5-(methylsulfonyl)benzoate (CAS [2113829-39-1], 791 mg, 3.406 mmol) and 2,2,2-trifluoroethyl trifluoroacetate (CAS [407-38-5], 0.988 mL, 7.375 mmol, 2.2 eq.) in dry THF (30 mL) was cooled to -78 °C under nitrogen atmosphere and treated dropwise with LiHMDS (CAS [4039-32-1], 1 M in THF, 5.1 mL, 5.079 mmol, 1.5 eq.). After 5 min, the reaction mixture was allowed to warm to room temperature and was stirred for 30 min. The reaction was quenched with saturated aqueous NaHCO3 and the mixture was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgS fOilt4e.red, and evaporated to afford the title compound (1118 mg, quantitative), used without further purification.

[0549] Step B: methyl 3-fluoro-5-((l,l,3,3,3-pentafluoro-2-oxopropyl)sulfonyl)benzoate. A solution of methyl 3-fluoro-5-((3,3,3-trifluoro-2-oxopropyl)sulfonyl)benzoate (1118 mg, 3.406 mmol) in dry ACN (21 mL) and cooled to 0 °C. Then, the mixture was treated with 1- chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (CAS [140681- 55-6], 3.62 g, 10.219 mmol, 3 eq.) in 3 portions, over the course of 5 min. Upon complete addition, the reaction mixture was stirred at 60 °C for 30 min. The solvent was evaporated and the was suspended in EtOAc and sonicated to obtain a suspension. The solid was filtered and rinsed with EtOAc. The filtrate was concentrated and dried to yield the title compound (1240 mg, quantitative) used without further purification.

[0550] Step C: methyl 3-((difluoromethyl)sulfonyl)-5-fluorobenzoate. DIPEA (1.17 mL, 6.809 mmol, 2 eq.) was added to a solution of methyl 3-fluoro-5-((l, 1,3,3, 3-pentafluoro-2- oxopropyl)sulfonyl)benzoate (1240 mg, 3.405 mmol) in THF (21 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated. The crude product was purified via flash column chromatography (25 g SiO2, EtOAc/heptane 0/100 to 30/70) to afford the title compound (729 mg, yield: 80 %) as a white solid.

[0551] Step D: 3-((difluoromethyl)sulfonyl)-5-fluorobenzoic acid. LiOH (98 mg, 4.077 mmol, 1.5 eq.) was added to a solution of methyl 3-((difluoromethyl)sulfonyl)-5- fluorobenzoate (729 mg, 2.718 mmol) in THF (10 mL), MeOH (3 mL), and water (3 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated under reduced pressure. The residue was dissolved in water and this solution was acidified to pH=2-3 using HC1 (1 M in water). The formed precipitate was filtered and dried under vacuum to afford Intermediate 567 (558 mg, yield 81 %) as a white solid.

Intermediate 572: (2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-l,6- naphthyri din-7 -yl)methanamine.

[0552] Step A: 5-bromo-2-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridine.

CS2CO3 (2.753 g, 8.449 mmol, 2.1 eq.) was added to a mixture of 5-bromo-2 -hydroxypyridine (CAS [13466-38-1], 700 mg, 4.023 mmol) and tetrahydro-2, 2,6, 6-tetramethyl-27/-pyran-4-ol. 4-methanesulfonate (CAS [1160656-10-9], 1.426 g, 6.035 mmol, 1.5 eq.) in DMF (15 mL). The mixture was stirred at 90 °C for 18 h. The mixture was diluted with Na2CO3 (1 M in water) and extracted with EtOAc. The organic layer was dried (MgSO4). filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; EtOAc/heptane from 0/100 to 20/80) to yield the title compound (190 mg, yield: 15 %) as a clear oil.

[0553] Step B: 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-((2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridine. The title compound was prepared following the same procedure as Intermediate 556, using 5-bromo-2-((2, 2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridine instead of tert-butyl 3-[(5-bromo-2- pyridyl)oxy] azetidine- 1 -carboxylate.

[0554] Step C: tert-butyl ((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridin-3- yl)-l,6-naphthyridin-7-yl)methyl)carbamate. The title compound was prepared following the same procedure as Compound 664, using 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- ((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridine and tert-butyl ((2-chloro-l,6- naphthyridin-7-yl)methyl)carbamate (Intermediate 2).

[0555] Step D: (2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-l,6- naphthyridin-7-yl)methanamine. The title compound was prepared following the same procedure as Intermediate 525, Step D using tert-butyl ((2-(6-((2,2,6,6-tetramethyltetrahydro- 2H-pyran-4-yl)oxy)pyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. Intermediate 577: (2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)- l,6-naphthyridin-7-yl)methanamine.

[0556] Step A: 3-chloro-6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazine. Diisopropyl azodicarboxylate (CAS [2446-83-5], 1.5 mL, 7.661 mmol, 2 eq.) was added to a mixture of tetrahydro-2,2, 6, 6-tetramethyl-27/-pyran-4-ol (CAS [20931-50-4], 727 mg, 4.597 mmol, 1.2 eq.), 6-chloro-27/-pyridazin-3-one (CAS [19064-67-6], 0.5 g, 3.83 mmol), EtsN (0.53 mL, 3.83 mmol, 1 eq.), and triphenyl phosphine (CAS [603-35-0], 2.13 g, 7.661 mmol, 2 eq.) in dry THF (21 mL). The mixture was stirred at room temperature for 3 h. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (silica 40 g; EtOAc/heptane from 0/100 to 20/80) to yield the title compound (229 mg, yield: 22 %) as a colorless oil that solidified upon standing.

[0557] Step B: methyl 3-((6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3- yl)sulfonyl)propanoate. A solution of 3-chloro-6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4- yl)oxy)pyridazine (229 mg, 0.846 mmol) and sodium 1 -methyl 3-sulfinopropanoate (CAS [90030-48-1], 0.22 g; 1.265 mmol, 1.5 eq.) in DMSO (4 mL) was degassed by bubbling nitrogen, copper iodide (0.24 g, 1.265 mmol, 1.5 eq.) was added and reaction vessel was sealed. The reaction mixture was stirred at 100 °C for 18 h. After cooling, more sodium 1- methyl 3-sulfinopropanoate (0.22 g; 1.265 mmol, 1.5 eq.) and copper iodide (0.24 g; 1.265 mmol, 1.5 eq.) were added and the reaction mixture was degassed again with nitrogen. The reaction mixture was stirred at 100 °C for 18 h. After cooling, the reaction mixture was partitioned between EtOAc and water and ammonia (25 % in water) was added to dissolve the copper salts. The organic layer was separated, washed with brine, dried over MgSO4. filtered, and evaporated. The residue was purified by flash chromatography (silica 40 g;

EtOAc/heptane from 0/100 to 100/0) to yield the title compound (71 mg, yield: 19 %) as a white solid.

[0558] Step C: 6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazine-3-sulfinate sodium salt. Sodium metoxide (25 % in MeOH, 0.077 mL, 0.336 mmol, 1 eq.) was added dropwise to a solution of methyl 3-((6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4- yl)oxy)pyridazin-3-yl)sulfonyl)propanoate (130 mg, 0.336 mmol) in THF (2 mL). The mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the solid was triturated in Et20 to yield the title compound (85 mg, yield: 74 %) as a white solid.

[0559] Step D: tert-butyl ((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin- 3-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 8 mg; 0.033 mmol, 0.12 eq.) and palladium(II) acetate (CAS [3375-31-3], 4 mg; 0.018 mmol, 0.06 eq.) were added to a mixture of 6-((2, 2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazine-3-sulfinate sodium salt (90 mg, 0.279 mmol), tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2) (90 mg, 0.307 mmol, 1.1 eq.), and K2CO3 (61 mg, 0.445 mmol, 1.6 eq.) in 1,4-dioxane (3 mL) under nitrogen atmosphere. The mixture was stirred at 120 °C for 18 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; EtOAc/heptane from 0/100 to 100/0) yield the title compound (40 mg, yield: 28 %) as a light brown foam.

[0560] Step E: (2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)-l,6- naphthyridin-7-yl)methanamine. The title compound was prepared following the same procedure as Intermediate 525, step D, using tert-butyl ((2-(6-((2,2,6,6-tetramethyltetrahydro- 2H-pyran-4-yl)oxy)pyridazin-3-yl)-l,6-naphthyridin-7-yl)methyl)carbamate.

Intermediate 579: 1 -(7 -(aminomethyl)- 1 ,6-naphthyri din-2 -yl)-3-(dimethylamino)pyri din- 2(lH)-one.

[0561] Step A: tert-butyl ((2-(3-(dimethylamino)-2-oxopyridin-l(2H)-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. Trans-N,N'-dimethylcyclohexane-l,2-diamine (CAS [67579-81-1], 16μL, 0.101 mmol, 0.2 eq.) and copper (I) iodide (23 mg, 0.120 mmol, 0.2 eq.) were added to a solution of tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2) (70 mg, 0.511 mmol), 3-(dimethylamino)-2(177)-pyridinone (CAS [33252-49-2], 150 mg, 0.511 mmol, 1 eq.), and K2CO3 (107 mg, 0.774 mmol, 1.5 eq.) in 1,4-dioxane (3 mL) in a sealed tube under nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 16 h. After cooling, the mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (x 3). The organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (12 g, DCM/MeOH (9:1) in DCM, from 0 % to 40 %) to yield the title compound (169 mg, yield: 69 %) as a yellow solid.

[0562] Step B: l-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-3-(dimethylamino)pyridin-2(lH)- one. Trifluoroacetic acid (0.7 mL, 9.34 mmol, 22 eq.) was added to a stirred solution of tert- butyl ((2-(3-(dimethylamino)-2-oxopyridin-l(2H)-yl)-l,6-naphthyridin-7- yl)methyl)carbamate (169 mg, 0.43 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, and saturated aqueous NaHCCL was added until pH 8. DCM was added and the mixture was extracted with DCM (x 3). The combined organic layer was dried (MgSO4). filtered, and the solvents evaporated in vacuo to yield Intermediate 579 (102 mg, yield: 73 %) as a brown solid, used without further purification.

Intermediate 580: 3 -(difluoromethoxy )-5-((difluoromethyl)sulfonyl)benzoic acid.

[0563] Ruthenium(III) chloride hydrate (CAS [14898-67-0], 7 mg, 0.027 mmol, 0.07 eq.) was added to a stirred solution of 3-(difluoromethoxy)-5-[(difluoromethyl)thio]-benzoic acid (CAS [2648588-92-3], 100 mg, 0.37 mmol), sodium periodate (CAS [7790-28-5], 315 mg, 1.473 mmol, 4 eq.) in a mixture of DCM (8 mL), ACN (8 mL), and water (16 mL). The reaction mixture was stirred at room temperature for 1 h. Water and EtOAc were added, and the mixture was extracted several times with EtOAc. The combined organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure to yield Intermediate 580 (85 mg, yield: 61 % ) as a brown solid, used without further purification.

Intermediate 582: (2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methanamine.

[0564] Step A: tert-butyl 7-(6-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. Intermediate 9 (2.67 g, 7.54 mmol) and 4-Boc-4,7-diazaspiro[2.5]octane (CAS [674792-08-6], 4 g, 18.84 mmol) were suspended in DMSO (80 mL), then DIPEA (3.9 mL, 22.61 mmol) was added. The mixture was stirred at 130 °C overnight. Then, the reaction mixture was diluted in EtOAc and washed with water, dried over MgSO4. filtered, and evaporated. The dark brown residue was purified by silica gel chromatography (DCM/MeOH from 100/0 to 98/2) to afford the title compound (1.72 g, yield: 42 %).

[0565] Step B: (2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methanamine. tert-butyl 7 -(6-(7 -(((tert-butoxycarbonyl)amino)methyl)- 1 ,6-naphthyridin-2- yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (1.54 g, 2.82 mmol) was suspended in MeOH (15 mL) and HC1 (6 M in iPrOH, 15 mL, 90 mmol) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated in vacuo and then co-evaporated with toluene to yield Intermediate 582 (1.49 g, quantitative).

Intermediate 587: 3-fluoro-N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- (methylsulfonyl)benzamide.

[0566] 1 -Propylphosphonic anhydride (CAS [68957-94-8], 50 % in EtOAc, 2.75 mL, 4.62 mmol) was added dropwise to a suspension of Intermediate 41 (800 mg, 2.75 mmol), 3- fluoro-5-(methylsulfonyl)-benzoic acid (CAS [1783354-37-9], 720 mg, 3.3 mmol), and tri ethylamine (2.7 mL, 19.33 mmol) in DCM (23 mL) at room temperature. The solution was stirred at room temperature overnight. The formed precipitate was filtered and washed with water and EtOH. The solid was taken up in DCM, dried (MgSO4), filtered, and concentrated in vacuo to give Intermediate 587 (950 mg, yield: 76 %) as a beige solid.

Intermediate 588: (cis)-3,4-dimethylpyrrolidin-3-ol.

[0567] Cis-tert-butyl 3-hydroxy-3,4-dimethylpyrrolidine-l-carboxylate (CAS [1932160-32-

1], 300 mg, 1.39 mmol) was suspended in HC1 (6 M in iPrOH, 4 mL, 24 mmol). The reaction mixture was stirred at room temperature overnight. Then, solvents were evaporated yielding Intermediate 588 (HC1 salt, 236 mg), used without further purification.

Intermediate 589: (trans)-4-methyl-3-(trifluoromethyl)pyrrolidin-3-ol.

(TRANS)

[0568] Trans-tert-butyl 3-hydroxy-4-methyl-3-(trifluoromethyl)pyrrolidine-l-carboxylate (CAS [1932796-99-0], 300 mg, 1.39 mmol) was suspended in HC1 (6 M in iPrOH, 4 mL, 24 mmol). The reaction mixture was stirred at room temperature overnight. Then, solvents were evaporated yielding Intermediate 589 (HC1 salt, 255 mg), used without further purification.

Intermediate 593: tert-butyl 7-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyri din-2 -yl)-6-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate.

[0569] Step A: tert-butyl 7-(6-bromopyridin-2-yl)-6-oxo-2,7-diazaspiro[4.4]nonane-2- carboxylate. 2,6-Dibromopyridine (CAS [626-05-1], 300 mg, 1.27 mmol), Xantphos (CAS [161265-03-8], 147 mg, 0.25 mmol), and CS2CO3 (830 mg, 2.53 mmol) were suspended in 1,4-di oxane (6 mL) and the suspension was degassed with nitrogen for 15 min. Pd(OAc)2 (CAS [3375-31-3], 14 mg, 0.063 mmol) and tert-butyl 6-oxo-2,7-diazaspiro[4.4]nonane-2- carboxylate (CAS [1194376-44-7], 152 mg, 0.63 mmol) were then added and the reaction mixture was stirred at 100 °C overnight. Purification by silica chromatography afforded the title compound as a pale yellow solid.

[0570] Step B: tert-butyl 7-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyri din-2 -yl)-6-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate.

Dichlorofl, T-bis(diphenylphosphino)ferrocene]palladium(II) (CAS [72287-26-4], 37 mg, 0.05 mmol) was added to a suspension of tert-butyl 7-(6-bromopyridin-2-yl)-6-oxo-2,7- diazaspiro[4.4]nonane-2-carboxylate (200 mg, 0.5 mmol) bis(pinacolato)diboron (CAS [73183-34-3], 155 mg, 0.61 mmol), and KOAc (150 mg, 1.53 mmol) in dry 1,4-dioxane (3 mL) and the mixture was degassed by bubbling with nitrogen for 5 min. The reaction mixture was stirred at 90 °C for 3.5 h. After cooling to 75 °C, the vial was opened and kept under nitrogen atmosphere while Intermediate 45 (132 mg, 0.34 mmol), K2CO3 (94 mg, 0.68 mmol), and CuCl (34 mg, 0.34 mmol) were added, and the reaction mixture was stirred at 75 °C for 16 h. After cooling, the reaction mixture was diluted with brine and EtOAc. The mixture was filtered through dicalite. The layers were separated, and the aqueous layer was extracted again with EtOAc and with DCM. The combined organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (MeOH/DCM from 0/100 to 5/95) to give Intermediate 593 as a light-yellow oil (103 mg, yield: 44 %).

Intermediate 594: tert-butyl 6-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyri din-2 -yl)-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate.

[0571] Intermediate 594 was synthesized following a similar sequence of reactions as for the synthesis of Intermediate 593, starting from tert-butyl 5-oxo-2,6-diazaspiro[3.4]octane-2- carboxylate (CAS [1330765-39-3] instead of tert-butyl 6-oxo-2,7-diazaspiro[4.4]nonane-2- carboxylate in Step A.

Intermediate 595: tert-butyl 6-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyri din-2 -yl)-5-oxo-l,6-diazaspiro[3.4]octane-l-carboxylate.

[0572] Intermediate 595 was synthesized following a similar sequence of reactions as for the synthesis of Intermediate 593, starting from tert-butyl 8-oxo-l,7-diazaspiro[3.4]octane-l- carboxylate (CAS [1049730-83-7] instead of tert-butyl 6-oxo-2,7-diazaspiro[4.4]nonane-2- carboxylate in Step A. Intermediate 597: 2-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-2- azaspiro[3.3]heptan-6-ol.

[0573] Step A: tert-butyl ((2-(6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamate. A mixture of Intermediate 9 (100 mg, 0.28 mmol), 2- azaspiro[3.3]heptan-6-ol hydrochloride (CAS [1630907-10-6], 127 mg, 0.85 mmol), and DIPEA (0.19 mL, 1.13 mmol) in DMSO (1 mL) was stirred at 130 °C for 6 h. Then the reaction mixture was diluted in EtOAc, washed twice with water, dried over MgSO4. filtered, and evaporated yielding the title compound (163 mg).

[0574] Step B: 2-(6-(7-(aminomethyl)- l,6-naphthyridin-2-yl)pyri din-2 -yl)-2- azaspiro[3.3]heptan-6-ol. tert-butyl ((2-(6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)carbamate (163 mg, 0.28 mmol) was solubilized in HC1 (6 M in iPrOH, 3.73 mL, 22.36 mmol) and a few drops of MeOH. The reaction mixture was stirred at room temperature overnight. Then, solvents were evaporated to yield Intermediate 597 (HC1 salt, 115 mg).

Intermediate 598: (2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methanamine.

[0575] Intermediate 450 (300 mg, 0.78 mmol) was solubilized in HC1 (6 M in iPrOH, 5.22 mL, 31.3 mmol), and the reaction mixture was stirred at room temperature for 2 days. Then, the solvents were evaporated, and the crude product was co-evaporated with toluene to yield Intermediate 598 (HC1 salt, 286 mg) as a brown solid, used without further purification.

Intermediate 599: N-((2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-3- ((difluoromethyl)sulfonyl)benzamide.

[0576] 1-Propanephosphonic anhydride solution (0.76 mL, 1.28 mmol) was added dropwise to a suspension of Intermediate 598 (286 mg, 0.75 mmol), 3-difluoromethanesulfonylbenzoic acid (CAS [4837-21-2], 213 mg, 0.9 mmol), and EtsN (0.75 mL, 5.4 mmol) in DCM (6 mL) at room temperature. The solution was stirred at room temperature for 1 h. Then, the reaction mixture was diluted in DCM and washed with water. The layers were separated, and the organic layer was dried over MgSO4, filtered, and evaporated. Purification by silica column chromatography (DCM/MeOH from 100/0 to 98/2) yielded Intermediate 599 (139 mg, yield: 28 %) as a beige solid.

Intermediate 600: tert-butyl 2-(4-(7-((3-((difluoromethyl)sulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyrimidin-2-yl)-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate.

(Method T)

[0577] A mixture of Intermediate 599 (43 mg, 0.066 mmol), tert-butyl 6-oxa-2,9- diazaspiro[4.5]decane-9-carboxylate hydrochloride (CAS [2095192-22-4], 55 mg, 0.2 mmol), and DIPEA (34 μL, 0.2 mmol) in DMSO (0.9 mL) was stirred at 130°C for 1 h. Then the reaction mixture was diluted in EtOAc, washed twice with water, dried over MgS fOilt4e.red, and evaporated to afford Intermediate 600 (30 % pure), which was used without further purification.

Intermediate 601: tert-butyl (l-(4-(7-((3-((difluoromethyl)sulfonyl)benzamido)methyl)-l,6- naphthyri din-2 -yl)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)carbamate.

[0578] Intermediate 601was prepared following Method T, using tert-butyl (3,3- difluoropiperidin-4-yl)carbamate (CAS [1263180-22-8] instead of tert-butyl 6-oxa-2,9- diazaspiro[4.5]decane-9-carboxylate hydrochloride. Intermediate 607: N-((2-(6-bromopyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide.

[0579] Step A: methyl 2-(6-bromopyridin-2-yl)-l,6-naphthyridine-7-carboxylate. Bis(triphenylphosphine)palladium(II) dichloride (CAS [13965-03-2], 868 mg, 1.236 mmol) and Cui (CAS [7681-65-4], 527 mg, 2.75 mmol) were added to a stirred solution of methyl 4- amino-5-iodo-2-pyridinecarboxylate (CAS [2089150-47-8], 7.64 g, 27.48 mmol), l-(6- bromopyridin-2-yl)prop-2-yn-l-ol (CAS [1093880-70-6], 7.64 g, 36.03 mmol), EtsN (8 mL, 57.50 mmol), and DMAP (CAS [1122-58-3], 671 mg, 5.50 mmol) in dry ACN (140 mL) under nitrogen atmosphere. The mixture was stirred at 70 °C for 20 h, then the mixture was filtered, and the solid was collected. The solid was crystallized from MeOH to yield the title compound (6.14 g, yield: 64 %).

[0580] Step B: (2-(6-bromopyridin-2-yl)-l,6-naphthyridin-7-yl)methanol. LiAlLh (CAS [16853-85-3], 190 mg, 5 mmol) was added portionwise to a solution of methyl 2-(6- bromopyridin-2-yl)-l,6-naphthyridine-7-carboxylate (1.5 g, 4.35 mmol) in THF dry (80 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, then water was added slowly at 0 °C, followed by EtOAc, and the mixture was stirred for 2 min. The organic layer was separated, dried over MgSO4 f.iltered, and the solvents evaporated in vacuo. The crude product was triturated with MeOH and the solid was filtered to yield the title compound (974 mg, yield: 50 %) as a pale brown solid.

[0581] Step C: 2-(6-bromopyridin-2-yl)-7-(chloromethyl)-l,6-naphthyridine. SOCI₂ (4.2 mL, 59.31 mmol) was added dropwise to a solution of (2-(6-bromopyridin-2-yl)-l,6-naphthyridin- 7-yl)methanol (6.1 g, 19.29 mmol) in DCE (230 mL) at room temperature. The mixture was stirred at room temperature for 4 h. Saturated aqueous NaHCO3 was added and the mixture was extracted with DCM. The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum to yield the title compound (5.7 g, yield: 86 %) as a brown solid, used without further purification.

[0582] Step D: 7-(azidomethyl)-2-(6-bromopyridin-2-yl)-l,6-naphthyridine. NaNs (2.2 g, 33.84 mmol) was added to a solution of 2-(6-bromopyridin-2-yl)-7-(chloromethyl)-l,6- naphthyridine (5.7 g, 17.04 mmol) in DMF (200 mL), and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over MgSCU and concentrated in vacuo to yield the title compound (5.47 g, yield: 89 %) as a brown oil, used without further purification. [0583] Step E: (2-(6-bromopyridin-2-yl)-l,6-naphthyridin-7-yl)methanamine. Triphenylphosphine (5.9 g, 22.5 mmol) was added to a solution of 7-(azidomethyl)-2-(6- bromopyridin-2-yl)-l,6-naphthyridine (5.47 g, 16.03 mmol) in THF (170 mL). The mixture was stirred at room temperature for 4 h, then water (64 mL) was added and the mixture was stirred at room temperature for 16 h. The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (80 g silica; DCM/MeOH/NHs (10: 1 :0.25) in DCM from 0 to 80 %) to yield the title compound (2.1 g, yield: 41 %). [0584] Step F: N-((2-(6-bromopyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide. (2-(6-bromopyridin-2-yl)-l,6-naphthyridin-7-yl)methanamine (895 mg, 2.84 mmol), 4-methyl-3-(methylsulfonyl)benzoic acid (CAS [51522-22-6], 669 mg, 3.12 mmol), and DIPEA (2 mL, 11.48 mmol) were suspended in DMF (40 mL) at room temperature. HATU (CAS [148893-10-1], 1.4 g, 3.68 mmol) was added in one portion under stirring and the mixture was stirred for 2 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layer was dried over MgSO4. filtered, and the solvent was evaporated in vacuo. Purification by flash column chromatography (25 g SiCh; DCM:MeOH (9:1) in DCM, from 0 % to 30 %), followed by another column chromatography (25 g SiCh; EtOAc/DCM from 0/100 to 95/5]), and finally, trituration with ACN, filtration, and washing with Et20 gave Intermediate 607 (1.02 g, yield: 67 %) as a beige solid.

Intermediate 608: tert-butyl (3-methyl-l-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyri din-2 -yl)-2-oxopyrrolidin-3- yl)carbamate.

[0585] A suspension of Intermediate 607 (50 mg, 0.098 mmol), tert-butyl N-(3-methyl-2- oxopyrrolidin-3-yl)carbamate (CAS [308817-68-7], 21 mg, 0.098 mmol), Xantphos (CAS [161265-03-8], 23 mg, 0.039 mmol), and CS2CO3 (127 mg, 0.39 mmol) in 1,4-dioxane (1 mL) was degassed with nitrogen for 5 min. Then, Pd(OAc)2 (CAS [3375-31-3], 2 mg, 0.010 mmol) was added and the reaction mixture was stirred under nitrogen atmosphere at 100 °C for 2 h. The reaction mixture was diluted in DCM and filtered on a pad of dicalite. The filtrate was evaporated to give Intermediate 608 as a light brown solid, used without further purification.

Intermediate 609: 3-((difluoromethyl)sulfonyl)-N-((2-(6-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0586] The title compound was prepared in a similar manner as Intermediate 587, from Intermediate 41 using 3-difluoromethanesulfonylbenzoic acid (CAS [4837-21-2]) instead of 3-fluoro-5-(methylsulfonyl)-benzoic acid. The reaction mixture was diluted with DCM and was washed with water. The organic layer was dried on MgSO fi4l.tered, and evaporated. The residue was triturated in a small amount of DCM and the solid was filtered and washed with a small amount of DCM to afford Intermediate 609.

Intermediate 610: tert-butyl (4,4-dimethyl-l-(6-(7-((4-methyl-3-

(methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyri din-2 -yl)-2-oxopyrrolidin-3- yl)carbamate. racemic

[0587] Intermediate 610 was prepared using the same reaction conditions used for the synthesis of Intermediate 608 using N-(4,4-dimethyl-2-oxo-3-pyrrolidinyl)-carbamic acid, 1,1 -dimethylethyl ester (CAS [2421091-73-6]) instead of tert-Butyl N-(3-methyl-2- oxopyrrolidin-3-yl)carbamate.

Intermediate 612: 3-((2-hydroxyethyl)sulfinyl)-4-methylbenzoic acid.

[0588] Step A: methyl 3-((2-hydroxyethyl)thio)-4-methylbenzoate. To a mixture of methyl 3- iodo-4-methylbenzoate (CAS [90347-66-3], 3 g, 10.87 mmol) and 2-mercaptoethanol (CAS [60-24-2], 0.52 g, 6.65 mmol) in 1,4-dioxane (30 mL) was added Pd2dbas (CAS [51364-51- 3], 0.5 g, 0.55 mmol), Xantphos (CAS [161265-03-8], 0.63 g, 1.09 mmol), and DIPEA (5.64 mL, 32.38 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with H2O (30 mL) and extracted with EtOAc (50 mL). The organic layer was concentrated and the residue was purified by column chromatography over silica gel (EtOAc/petroleum ether from 0/100 to 16/84) to give methyl 3-((2 -hydroxy ethyl)thio)-4- methylbenzoate (2.07 g, yield: 84 %).

[0589] Step B: methyl 3-((2-hydroxyethyl)sulfinyl)-4-methylbenzoate. To a solution of methyl 3-((2-hydroxyethyl)thio)-4-methylbenzoate (1 g, 4.42 mmol) in MeOH (20 mL) was added NaIC>4 (945 mg, 4.42 mmol) in H2O (8.8 mL, 488.6 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was concentrated in vacuum and the residue was purified by column chromatography over silica gel (EtOAc/petroleum ether from 0/100 to 10/90) to give methyl 3-((2-hydroxyethyl)sulfinyl)- 4-methylbenzoate (870 mg, yield: 81 %) as a yellow oil.

[0590] Step C: 3-((2-hydroxyethyl)sulfinyl)-4-methylbenzoic acid. To a solution of methyl 3- ((2-hydroxyethyl)sulfinyl)-4-methylbenzoate (1.68 g, 6.93 mmol) in MeOH (30 mL) was added aqueous LiOH (16.8 mL, 2 N in H2O, 33.6 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuum and the residue was diluted with H2O (20 mL). The pH was adjusted to ~4 with 2 N aqueous HC1. The aqueous solution was extracted with EtOAc (30 mLx3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give Intermediate 612 (1.45 g, yield: 92 %).

Intermediate 613: 4-methyl-3-(methylsulfinyl)benzoic acid.

[0591] To a solution of 4-methyl-3-(methylthio)benzoic acid (CAS 166811-59-2, 150 mg, 0.82 mmol) in MeOH/H2O (8 mL/4 mL) was added NaIO4 (177 mg, 0.83 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to room temperature, diluted with H2O (10 mL), and extracted with EtOAc (10 mL x 2). The organic layer was dried over Na2SC>4 and filtered. The filtrate was concentrated in vacuum to give Intermediate 613 (127 mg, yield: 71 %).

Intermediate 614: tert-butyl (3,3-difluoro-l-(6-(7-((4-methyl-3-(S- methylsulfonimidoyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyridin-2-yl)piperidin-4- yl)carbamate.

[0592] tert-butyl (3,3-difluoro-l-(6-(7-((4-methyl-3-(S- methylsulfonimidoyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)pyridin-2-yl)piperidin-4- yl)carbamate. A solution ofN-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(S-methylsulfonimidoyl)benzamide (Intermediate 628, 0.179 g, 0.398 mmol), tert- butyl 3,3-difhioropiperidin-4-ylcarbamate (CAS [1263180-22-8], 0.192 g, 0.813 mmol), and DIPEA (0.2 mL, 1.142 mmol) in dry DMSO (1.5 mL) was stirred at 130 °C for 7 days, followed by stirring at room temperature for 29 days. The reaction mixture was diluted with water (5 mL) and stirred for 30 min with sonication. The resulting precipitate was isolated by filtration, rinsed with additional water, and dried. The crude solid was purified by flash column chromatography (40 g SiCh, 0 to 10 % 2 N NHs/MeOH in DCM) to yield Intermediate 614 (144 mg, contaminated with Compound 618).

Intermediate 618: 3-chloro-5-((difluoromethyl)sulfonyl)benzoic acid.

[0593] Step A: methyl 3-chloro-5-((3,3,3-trifluoro-2-oxopropyl)sulfonyl)benzoate. A homogeneous solution of methyl 3-chloro-5-(methylsulfonyl)benzoate (CAS [151104-62-0], 6.541 g, 26.302 mmol) and 2,2,2-trifluoroethyl trifluoroacetate (CAS [407-38-5], 7.0 mL, 52.273 mmol) in dry THF (200 mL) was cooled to -78 °C under a nitrogen atmosphere and treated dropwise with LiHMDS (CAS [4039-32-1], 40 mL, 40 mmol, 1 M in THF). After stirring at -78 °C for 5 min, the reaction mixture was allowed to slowly warm to room temperature over the course of 1 h. The mixture was cooled to 0 °C and saturated aqueous NaHCCL was added. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried (MgSOr). filtered, concentrated, and dried under high vacuum to yield the title compound, used without further purification.

[0594] Step B: methyl 3-chloro-5-((l,l,3,3,3-pentafluoro-2-oxopropyl)sulfonyl)benzoate. A solution of methyl 3-chloro-5-((3,3,3-trifluoro-2-oxopropyl)sulfonyl)benzoate (10.29 g) in ACN (200 mL) was cooled to 0 °C and treated with l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (CAS [140681-55-6], 24.223 g, 68.376 mmol) in one portion. The reaction mixture was stirred at 60 °C for 40 min. After cooling, the mixture was concentrated and the crude material was suspended in EtOAc (100 mL), sonicated to break up all particulates, filtered through Celite®, and concentrated to yield the title compound which was used directly in the next step without further purification.

[0595] Step C: methyl 3-chloro-5-((difluoromethyl)sulfonyl)benzoate. A solution of methyl 3-chloro-5-((l,l,3,3,3-pentafluoro-2-oxopropyl)sulfonyl)benzoate in THF/H2O (10/1, 220 mL) was treated with DIPEA (9.0 mL) and was stirred at room temperature for 1.5 h. The reaction mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried (MgSO4), filtered, and concentrated to yield the title compound (6.85 g, yield: 88 % over 3 steps) as a pale yellow solid, used without further purification.

[0596] Step D: 3-chloro-5-((difluoromethyl)sulfonyl)benzoic acid. A solution of methyl 3- chloro-5-((difluoromethyl)sulfonyl)benzoate (6.85 g, 24.063 mmol) in THF (100 mL) and water (100 mL) was cooled to 0 °C and treated with Li OH (0.85 g, 35.493 mmol). After stirring at 0 °C for 1 h, the reaction was quenched by addition of HC1 (30 mL, 30 mmol, 1 M in H2O). The reaction mixture was diluted with EtOAc (300 mL) and washed twice with brine. The organic layer was dried (MgSO4), filtered, and concentrated to yield Intermediate 618 (6.08 g, yield: 93 %) as a pale yellow solid, used without further purification.

Intermediate 622: 3-((difluoromethyl)sulfonyl)-4-methylbenzoic acid.

[0597] Intermediate 622 was prepared in a manner analogous to that of Intermediate 618 (steps A-D) using methyl 4-methyl-3-(methylsulfonyl)benzoate (CAS [906816-32-8]) instead of methyl 3-chloro-5-(methylsulfonyl)benzoate in Step A. Intermediate 628: N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(S- methylsulfonimidoyl)benzamide.

[0598] Step A: N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylthio)benzamide. 4-Methyl-3-(methylthio)benzoic acid (169 mg, 0.927 mmol) was dissolved in anhydrous DMF (4 mL). HATU (CAS [148893-10-1], 458 mg, 1.206 mmol, 1.3 eq.) was added and the mixture was stirred for 2 min before Intermediate 41 (333 mg, 1.02 mmol, 1.1 eq.) was added, followed by dropwise addition of DIPEA (0.799 mL, 4.637 mmol, 5.0 eq.). The reaction mixture was stirred at room temperature for 1.5 h. Water was added dropwise to the mixture until a precipitate crashed out and the suspension was vigorously stirred at room temperature for 10 min, then filtered. The solid was washed with water and dried under vacuum at 45 °C to give the title compound as a light brown solid (300 mg, yield: 77 %).

[0599] Step B: N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(S- methylsulfonimidoyl)benzamide. N-((2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- 4-methyl-3-(methylthio)benzamide (200 mg, 0.478 mmol), (diacetoxyiodo)benzene (CAS [3240-34-4], 384 mg, 1.195 mmol, 2.5 eq.), Ammonium acetate (CAS [631-61-8], 74 mg, 0.956 mmol, 2.0 eq.) were added to a round bottom flask, followed by MeOH (2 mL) and MeCN (2 mL). The mixture was stirred vigorously at room temperature. After 6 h, the solvent was removed to give Intermediate 628, dried under vacuum, and used without further purification.

Intermediate 631 : (cis)-4-(6-chloro-3-fluoropyridin-2-yl)-2,6-dimethylmorpholine.

[0600] The title compound was prepared according to Method I, using 2,6-dichloro-3- fluoropyridine (CAS [52208-50-1]) instead of Intermediate 46 and cis-2,6- dimethylmorpholine (CAS [6485-55-8]) instead of 4-piperidineethanol. Intermediate 632: 4-chloro-N-((2-chloro-l ,6-naphthyridin-7-yl)methyl)-3- (methylsulfonyl)benzamide.

[0601] A suspension of 4-chloro-3-(methylsulfonyl)benzoic acid (CAS [51522-07-7], 200 mg, 0.85 mmol) in thionyl chloride (1.24 mL, 17.05 mmol, 30 eq.) was stirred at 60 °C overnight. The mixture was concentrated in vacuo. A solution of the resulting acyl chloride in DCM (8 mL) was slowly added to a suspension of (2-chl oro-1, 6-naphthyri din-7- yl)methanamine (Intermediate 1) (652 mg, 2.83 mmol) in anhydrous DCM (10 mL) at 0 °C. After 5 min stirring at 0 °C, DIPEA (1.98 mL, 11.33 mmol, 4.0 eq.) was added dropwise. After 2 h, the mixture was diluted with water and DCM. The layers were separated and the organic layer was washed with saturate aqueous NaHCCL and brine, then dried over Na2SC>4, filtered, and evaporated. The residue was purified by silica gel chromatography (12 g SiCh, gradient 0-75 % EtOAc w/10 % MeOH:heptane) to give Intermediate 632 as a brown solid (931 mg, yield: 80 %).

Intermediate 635: 3-((2-hydroxyethyl)thio)-4-methylbenzoic acid.

[0602] Step A: methyl 3-((2-hydroxyethyl)thio)-4-methylbenzoate. Methyl 3-iodo-4- methylbenzoate (CAS [90347-66-3], 2 g, 7.244 mmol) and Xantphos Pd G4 (CAS [1621274- 19-8], 70 mg, 0.0724 mmol, 0.01 eq.) were placed in a round bottom flask. THF (30 mL) was added, followed by 2-mercaptoethanol (CAS [60-24-2], 0.561 mL, 7.969 mmol, 1.1 eq.) and EtsN (1 mL, 7.244 mmol, 1.0 eq.) and the mixture was stirred at room temperature for 1 h under inert atmosphere. The mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted with additional EtOAc. The combined organic layer was dried with Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography (40 g SiO2; EtOAc/heptane from 0/100 to 50/50) to give the title compound as a light green viscous oil (1.5 g, yield: 91 %)

[0603] Step B: 3-((2-hydroxyethyl)thio)-4-methylbenzoic acid, methyl 3-((2- hydroxyethyl)thio)-4-methylbenzoate (261 mg, 1.153 mmol), lithium hydroxide (CAS [1310- 65-2], 141 mg, 5.767 mmol, 5 eq.), and MeOH/THF/FLO (1.5 mL each) were combined at room temperature and stirred overnight. The mixture was diluted with NaOH (3 M in water) and DCM and the layers were separated. The aqueous layer was carefully acidified by adding concentrated HC1 until acidic pH, at which point a white solid precipitated from the solution. The solid was filtered and washed with water to give the title compound as a white solid (207 mg, yield: 85 %).

Intermediate 636: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-hydroxyethyl)thio)-4-methylbenzamide.

[0604] Intermediate 635 (80 mg, 0.377 mmol), HATU (CAS [148893-10-1], 172 mg, 0.452 mmol, 1.2 eq), and DIPEA (0.33 mL, 1.884 mmol, 5.0 eq.) were combined in anhydrous DMF (3 mL) under an inert atmosphere and stirred for 1 min, then Intermediate 11 (205 mg, 0.415 mmol, 1.19 eq.) was added and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed twice with brine, then once with HC1 (1 M in water). A solid precipitated and was collected by filtration, then dissolved in NaOH (3 M in water) and extracted twice with DCM. This organic layer was separated and combined with the other organic layers, which were dried over Na2SO4, filtered, and evaporated to give Intermediate 636 (207 mg, quantitative), used without further purification.

Intermediate 637; tert-butyl 7-(6-(7-((4-methyl-3-(S- methylsulfonimidoyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-4,7- diazaspiro [2.5] octane-4-carboxylate. [0605] The title compound was prepared in a manner analogous to Compound 44, Method I, using Intermediate 628 (150 mg, 0.334 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4- carboxylate (CAS [674792-08-6], 213 mg, 1.001 mmol, 3.0 eq.).

[0606] Intermediate 638: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)thio)-4-methylbenzamide.

[0607] Intermediate 98 (165 mg, 0.45 mmol) was dissolved in anhydrous DMF (4 mL). Intermediate 635 (105 mg, 0.495 mmol, 1.1 eq.) and HATU (CAS [148893-10-1], 205 mg, 0.54 mmol, 1.2 eq.) were added in one portion, followed by DIPEA (0.315 mL, 1.8 mmol, 4.0 eq.). The mixture was placed under an inert atmosphere and was stirred at room temperature for 1 h. Additional DIPEA (0.3 mL, ~4 eq.) was added. After another 30 min, the mixture was diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed twice with brine and once with saturated aqueous NaHCO3, then dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography (12 g SiO2, MeOH/DCM from 0/100 to 8/92) to give Intermediate 638 as ayellow solid (194 mg, yield: 77 %).

Intermediate 639: 4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylthio)benzamide.

[0608] Intermediate 11 (165 mg, 0.36 mmol) was dissolved in anhydrous DMF (3.2 mL). 4- Chloro-3-(methylthio)benzoic acid (CAS [166811-60-5], 80 mg, 0.396 mmol, 1.1 eq.) and HATU (CAS [148893-10-1], 164 mg, 0.432 mmol, 1.2 eq.) were added in one portion, followed by DIPEA (0.315 mL, 1.802 mmol, 5.0 eq.). The reaction mixture was stirred at room temperature under inert atmosphere for 1.5 h. Water and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with saturated aqueous NaHCO3. then 3 times with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography (12 g SiO2, MeOH/DCM from 0/100 to 5/95) to give the title compound as a yellow solid. (175 mg, yield: 91 %).

Intermediate 651: tert-butyl 2-(5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyri din-7 -yl)methy l)carbamoy l)-2-methylphenyl)-4,4-difluoropy rrolidine- 1 -carboxylate.

[0609] Step A: (E)-N-(5-bromo-2-methylbenzylidene)-2-methylpropane-2-sulfinamide(E)-N- (5-bromo-2-methylbenzylidene)-2-methylpropane-2-sulfinamide. Titanium (IV) isopropoxide (CAS [546-68-9], 21 mL, 80.38 mmol, 2 eq.) was added dropwise to a stirred solution of 5- bromo-2-methylbenzaldehyde (CAS [90050-59-2], 8 g, 40.192 mmol) and 2-methyl-2- propanesulfinamide (CAS [146374-27-8], 9.743 g, 80.38 mmol, 2 eq.) in THF (160 mL) under nitrogen atmosphere. The mixture was stirred for 16 h at room temperature. 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 crude product was purified by flash column chromatography (80 g SiCh; heptane/EtOAc 100/0 to 30/70) to afford the title compound (10.598 g, yield: 86 %) as a white solid.

[0610] Step B: N-(l-(5-bromo-2-methylphenyl)but-3-en-l-yl)-2-methylpropane-2- sulfinamide. Allylmagnesium chloride (CAS [2622-05-1], 42.7 mL, 49.092 mmol, 1.4 eq.) was added to a solution of (E)-N-(5-bromo-2-methylbenzylidene)-2-methylpropane-2- sulfinamide (10.6 g, 35.06 mmol) in THF (200 mL) at -70 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. Saturated aqueous NH4CI was added, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to dryness to give the title compound (12.45 g, yield: 100 %) as a colourless oil. [0611] Step C: l-(5-bromo-2-methylphenyl)but-3-en-l-amine. N-(l-(5-bromo-2- methylphenyl)but-3-en-l-yl)-2-methylpropane-2-sulfinamide (12.45 g, 36.16 mmol) was dissolved in a solution of HC1 (4 M in 1,4-dioxane, 54.2 mL, 216.96 mmol, 6 eq.) and 1,4- di oxane (165 mL) and the mixture was stirred at room temperature for 16 h. The mixture was basified with Na2CO3 (1 M in water) and extracted with DCM. The organic layer was separated, dried over MgSO4. filtered, and the solvents evaporated to give the title compound (10.68 g, yield: 96 %) as an oil.

[0612] Step D: N-(l-(5-bromo-2-methylphenyl)but-3-en-l-yl)acetamide. A solution of l-(5- bromo-2-methylphenyl)but-3-en-l -amine (10.685 g, 34.71 mmol) and EtsN (14.51 mL, 104.12 mmol, 3 eq.) in DCM (140 mL) was cooled in an ice bath under nitrogen atmosphere. A solution of acetic anhydride (CAS [108-24-7], 4.191 mL, 18 mmol, 1.1 eq.) in DCM (40 mL) was then added dropwise over 5 min. The mixture was stirred for another 30 min at 0 °C. Na2CO3 (1 M in water) was added while stirring. After 5 min, the organic layer was separated and the aqueous layer was extracted once more with DCM. The combined organic layer was dried over MgSO4. filtered, and concentrated. The crude product was purified by flash column chromatography (120 g SiCh, heptane/EtOAc from 100/0 to 20/80) to yield the title compound (7.140 g, yield: 72 %) as a solid.

[0613] Step E: 5-(5-bromo-2-methylphenyl)pyrrolidin-3-yl acetate. Iodine (CAS [7553-56- 2], 10.893 g, 42.92 mmol, 3 eq.) was added to a solution of N-(l-(5-bromo-2- methylphenyl)but-3-en-l-yl)acetamide (4.037 g, 14.307 mmol) in THF (70 mL) and water (20 mL) at room temperature. The reaction mixture was stirred at 65 °C for 1 h. Na2CO3 (1 M in water, 21.26 mL, 21.26 mmol, 2 eq.) was added and the mixture was stirred for 16 h at 70 °C, then the mixture was poured into saturated aqueous NaHC'Os. The aqueous solution was extracted with EtOAc. The organic layer was washed with saturated aqueous NaiSiCh, dried over MgSO4. filtered, and evaporated. The residue was purified by flash column chromatography (80 g SiCh; heptane/EtOAc from 100/0 to 0/100) to give the title compound (2.594 g, yield: 55 %) as an orange oil.

[0614] Step F: tert-butyl 4-acetoxy-2-(5-bromo-2-methylphenyl)pyrrolidine-l-carboxylate. Di-tert-butyl dicarbonate (CAS [24424-99-5], 3.597 g, 15.659 mmol, 2 eq.) was added to a solution of 5-(5-bromo-2-methylphenyl)pyrrolidin-3-yl acetate (2.594 g, 7.830 mmol) and DMAP (CAS [122-58-3], 96 mg, 0.581 mmol, 0.1 eq.) in DCM (46 mL). The mixture was stirred for 3 h at room temperature. The reaction mixture was partitioned between DCM (100 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (80 g SiCh; heptane/EtOAc 100/0 to 0/100) to give the title compound (2.36 g, yield: 75 %) as an orange oil.

[0615] Step G: tert-butyl 2-(5-bromo-2-methylphenyl)-4-hydroxypyrrolidine-l-carboxylate. Sodium hydroxide (1 M in water, 7.1 mL, 7.122 mmol, 1.2 eq.) was slowly added to a solution of tert-butyl 4-acetoxy-2-(5-bromo-2-methylphenyl)pyrrolidine-l-carboxylate (2.36 g, 5.94 mmol) in MeOH (30 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and KHSO4 (1 M in water) was added until the pH reached the value of 7. The aqueous layer was extracted with EtOAc. The combined organic layer was dried with MgSCL. filtered, and concentrated to yield the title compound (1.88 g, yield: 77 %) as an oil.

[0616] Step H: tert-butyl 4-hydroxy-2-(5-(methoxycarbonyl)-2-methylphenyl)pyrrolidine-l- carboxylate. In a pressure reactor, EtsN (10.5 mL, 75.610 mmol, 10 eq.) was added to a solution of tert-butyl 2-(5-bromo-2-methylphenyl)-4-hydroxypyrrolidine-l-carboxylate (2.694 g, 7.561 mmol) in MeOH (15 mL) and 1,4-dioxane (15 mL). The mixture was degassed with nitrogen for 20 min. Pd(dppl)2C12 CH2C12 (CAS [95464-05-4], 0.680 g, 0.756 mmol, 0.1 eq.) was added and the reactor was sealed. Then, the reaction mixture was stirred at 85 °C under 6 atm of carbon monoxide overnight. The mixture was filtered over a pad of Celite®. The organic layer was washed with Na2CO3 (1 M in water) and the combined aqueous layer was extracted with EtOAc. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (80 g SiO2; heptane/EtOAc 100/0 to 30/70) to afford the title compound (1.49 g, Yield: 58 %). [0617] Step I: tert-butyl 2-(5-(methoxycarbonyl)-2-methylphenyl)-4-oxopyrrolidine-l- carboxylate. Dess-Martin periodinane (CAS [87413-09-0], 0.774 g, 1.771 mmol, 1.5 eq.) was added to a mixture of tert-butyl 4-hydroxy-2-(5-(methoxycarbonyl)-2- methylphenyl)pyrrolidine-l -carboxylate (0.396 g, 1.18 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with Na2CO3 (1 M in water) and the mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (25 g SiCh, heptane/EtOAc 100/0 to 50/50) to yield the title compound (0.320 g, yield: 80 %) as an oil.

[0618] Step J: tert-butyl 4,4-difluoro-2-(5-(methoxycarbonyl)-2-methylphenyl)pyrrolidine-l- carboxylate. DAST (CAS [38078-09-0], 0.254 mL, 1.920 mmol, 2 eq.) was added to a solution of tert-butyl 2-(5 -(methoxy carbonyl)-2-methylphenyl)-4-oxopyrrolidine-l- carboxylate (0.32 g, 0.960 mmol) in DCM (15 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. Saturated aqueous NaHC'Os was added and the organic layer was separated, dried over MgSO fi4l.tered, and concentrated to dryness. The residue was purified by column chromatography (25 g SiCh; heptane/EtOAc 100/0 to 70/30) to yield the title compound (0.104 g, yield: 30 %) as an oil.

[0619] Step K: 3-(l-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)-4-methylbenzoic acid. Lithium hydroxide hydrate (CAS [1310-66-3], 0.037 g, 0.878 mmol, 3 eq.) was added to a solution of tert-butyl 4,4-difluoro-2-(5-(methoxycarbonyl)-2-methylphenyl)pyrrolidine-l- carboxylate (0.104 g, 0.293 mmol) in THF (3 mL) and water (0.58 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The pH was acidified to 3 with the addition of KHSO4 (1 M in water) and the mixture was extracted with DCM. The organic layer was dried over MgSO4. filtered, and the solvents evaporated in vacuo to yield the title compound (91 mg, yield: 90 %) as a solid.

[0620] Step L: tert-butyl 2-(5-(((2-(6-((cis)-2, 6-dimethylmorpholino)pyri din-2 -yl)- 1,6- naphthyri din-7 -yl)methy l)carbamoy l)-2-methylphenyl)-4,4-difluoropy rrolidine- 1 -carboxylate. The title compound was prepared according to Method B, using 3-(l-(tert-butoxycarbonyl)- 4,4-difluoropyrrolidin-2-yl)-4-methylbenzoic acid instead of (3-(l-hydroxyethyl)-4-methyl- benzoic acid.

Intermediate 664 : 4-benzyl-6-(6-hydroxyhexyl)-2-methylmorpholin-3-one.

[0621] Step A: tert-butyldimethyl(oct-7-en-l-yloxy)silane. 7c/7-Butyldimethylsilyl chloride (CAS [18162-48-6], 3.879 g, 25.739 mmol, 1.1 eq.) was added to a stirred solution of 7- octen-l-ol ( CAS [821-41-0], 3 g, 23.399 mmol) and imidazole (CAS [288-32-4], 1.752 g, 25.739 mmol, 1.1 eq.) in DCM (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 h. DCM and water were added. The organic layer was separated and washed with water and brine. The organic solution was dried over MgSO4. filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (80 g SiCh, heptane/EtOAc 100/0 to 95/5) to afford the title compound (5.591 g, yield: 98 %) as a colorless oil.

[0622] Step B: tert-butyldimethyl((6-(oxiran-2-yl)hexyl)oxy)silane. m-CPBA (CAS [937-14- 4], 8.527 g, 34.587 mmol, 1.5 eq.) was added portion wise to a solution of tert- butyldimethyl(oct-7-en-l-yloxy)silane ( 5.591 g, 23.058 mmol) in DCM (70 mL) at room temperature. The mixture was then stirred for 16 h. The mixture was diluted with diethyl ether and Na2CO3 (1 M in water) was added under stirring. The organic layer was separated, washed with brine, dried over MgSO4 f.iltered, and concentrated in vacuo. The crude product was purified by flash column chromatography (80 g SiCh, heptane/EtOAc 100/0 to 75/25 ) to afford the title compound (5.425 g, yield: 91 %) as a colorless oil.

[0623] Step C: l-(benzylamino)-8-((tert-butyldimethylsilyl)oxy)octan-2-ol. tert- butyldimethyl((6-(oxiran-2-yl)hexyl)oxy)silane (4.897 g, 18.946 mmol) and benzylamine (CAS [100-46-9], 6.20 mL, 56.84 mmol, 3 eq.) were dissolved in iPrOH (100 mL) and the mixture was stirred at reflux temperature for 16 h. After cooling, the reaction mixture was concentrated in vacuo. The crude product was purified by flash column chromatography (330 g SiCh, heptane/EtOAc 100/0 to 0/100) to afford the title compound (5.185 g, yield: 75 %) as a pale-yellow oil.

[0624] Step D: N-benzyl-N-(8-((tert-butyldimethylsilyl)oxy)-2-hydroxyoctyl)-2- chloropropanamide. l-(benzylamino)-8-((tert-butyldimethylsilyl)oxy)octan-2-ol (5.17 mg, 14.15 mmol) and EtsN (3.95 mL, 28.31 mmol, 2 eq.) were dissolved in DCM (70 mL) and cooled in an ice-water bath. A solution of 2-chloropropionyl chloride (CAS [7623-09-8], 1.51 mL, 15.57 mmol, 1.1 eq.) in DCM (20 mL) was then added dropwise over 5-10 min. The reaction mixture was stirred at 0 °C for 1 h, then at room temperature for 1 h. The reaction was quenched by addition of Na2CO3 (1 M in water). The mixture was extracted with DCM. The organic layer was dried over MgSO4 f.iltered, and concentrated in vacuo. The crude product was purified by flash column chromatography (120 g SiCh, heptane/EtOAc 100/0 to 60/40) to afford the title compound (5.6 g, yield: 86 %) as colorless oil.

[0625] Step E: 4-benzyl-6-(6-((tert-butyldimethylsilyl)oxy)hexyl)-2-methylmorpholin-3-one. 60 % Sodium hydride in mineral oil (CAS [7646-69-7], 158 mg, 3.95 mmol, 1.2 eq.) was added to an ice-cold solution of N-benzyl-N-(8-((tert-butyldimethylsilyl)oxy)-2- hydroxyoctyl)-2-chloropropanamide (1.5 g, 3.29 mmol) in DMF (40 mL) under nitrogen atmosphere. The mixture was stirred for 4 h allowing the temperature to raise slowly to room temperature. The reaction was quenched with saturated aqueous NaHCO3. Water was added and organics extracted with EtOAc. The combined organic layers were dried over MgSO4. filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (80 g SiCh, heptane/EtOAc 100/0 to 50/50) to afford the title compound (3.26 g, yield: 86 %) as a colorless oil.

[0626] Step F: 4-benzyl-6-(6-hydroxyhexyl)-2-methylmorpholin-3-one. Hydrochloric acid (35 % in water, 1.37 mL, 5.7 mmol, 2 eq.) was added to a solution of 4-benzyl-6-(6-((tert- butyldimethylsilyl)oxy)hexyl)-2-methylmorpholin-3-one (3.261 g, 7.77 mmol) in MeOH (25 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and saturated aqueous NaHCO3 (25 mL) was added. The organic layer was separated and the aqueous layer extracted again with DCM. The combined organic layer was dried over MgSO4 f.iltered, and concentrated in vacuo to yield Intermediate 664 (2.37 g, yield: 99 %) as an oil, used without further purification.

Intermediate 665: (2*S,6*R)-4-benzyl-6-(6-hydroxyhexyl)-2-methylmorpholin-3-one and

Intermediate 666: (2*R,6*S)-4-benzyl-6-(6-hydroxyhexyl)-2-methylmorpholin-3-one.

(2-*R, 6-*S) Intermediate 666

[0627] A solution of Intermediate 664 (2.37 g, 7.77 mmol) in THF (30 mL) was added dropwise to a suspension of lithium aluminum hydride (CAS [16853-85-3], 0.354 g, 9.32 mmol, 1.2 eq.) in THF (20 mL), at room temperature. The reaction mixture was then stirred at 60 °C for 2 h then allowed to cool to room temperature. The reaction was quenched with acetone then water. NaOH (1 M in water) and DCM were added. The mixture was filtered through a pad of Celite® that was further rinsed with DCM. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (80 g SiCh, heptane/EtOAc 100/0 to 0/100) to give the racemic mixture of the (TRANS) isomers of Intermediate 665 and Intermediate 666 (298 mg, yield: 16 %), and the racemic mixture of Intermediate 665 and Intermediate 666 (647 mg, yield: 35 %). A sample of the racemic mixture of Intermediate 665 and Intermediate 666 was then separated into its stereoisomers by chiral SFC (Lux-AMYLOSE-1; isocratic 90 % CO2 - 10 % MeOH + 0.1 % DEA) to afford Intermediate 665 and Intermediate 666, both as oils.

Intermediate 667: 2-(6-((2*S,6*R)-4-benzyl-6-methylmorpholin-2-yl)hexyl)isoindoline-l,3- dione.

(2-*S, 6-*R)

[0628] Intermediate 665 (0.407 g, 1.397 mmol), phthalimide (CAS [85-41-6], 0.247 g, 1.676 mmol, 1.2 eq.) and triphenylphosphine (CAS [603-35-0], 0.549 g, 2.095 mmol, 1.5 eq.) were dissolved in THF (15 mL) under nitrogen atmosphere. A solution of DIAD (CAS [2446-83- 5], 0.412 mL, 2.095 mmol, 1.5 eq.) in 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 crude product was purified by flash column chromatography (25 g SiCh, heptane/EtOAc 100/0 to 60/40) to afford Intermediate 667 (0.606 g, yield: 99 %)

Intermediate 668: 6-((2*S,6*R)-4-benzyl-6-methylmorpholin-2-yl)hexan-l -amine.

(2-*S, 6-*R)

[0629] Hydrazine monohydrate (CAS [7803-57-8], 0.382 mL, 4.323 mmol, 3 eq.) was added to a stirred solution of Intermediate 667 (0.606 g, 1.441 mmol) in EtOH (10 mL) at room temperature. The reaction mixture was stirred at 70 °C for 3 h. After cooling, the white precipitate was filtered off through a sintered funnel and washed with EtOH. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (25 g SiO₂, DCM:MeOH:NH₄OH (9:0.9:0.1) in DCM from 0/100 to 100/0) to afford Intermediate 668 (0.292 g, yield: 69 %) as a colorless oil.

Intermediate 669: tert-butyl (6-((2*S,6*R)-4-benzyl-6-methylmorpholin-2- yl)hexyl)carbamate.

(2-*S, 6-*R)

[0630] Di-tert-butyl dicarbonate (CAS [24424-99-5], 0.275 mL 1.198 mmol, 1.2 eq.) was added to a stirred solution of Intermediate 668 (290 mg, 0.998 mmol) in DCM (5 mL) at room temperature and the mixture was stirred for 16 h. Volatiles were removed in vacuo. The crude product was purified by flash column chromatography (25 g SiCh. heptane/EtOAc 100/0 to 50/50) to afford Intermediate 669 (0.253 g, yield: 64 %) as a colorless oil.

Intermediate 670: tert-butyl (6-((2*S,6*R)-6-methylmorpholin-2-yl)hexyl)carbamate.

(2-*S, 6-*R)

[0631] Intermediate 669 (253 mg, 0.648 mmol) was dissolved in MeOH (15 mL). Pd/C (10 % , CAS [7440-05-3], 62 mg, 0.059 mmol, 0.1 eq.) was added and the mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The catalyst was filtered off through a pad of Celite® that was further rinsed with MeOH. The filtrate was concentrated to afford Intermediate 670 (195 mg, yield: 99 %) as a colorless oil, used without further purification.

Intermediate 671: tert-butyl (6-((2*R,6*S)-6-methylmorpholin-2-yl)hexyl)carbamate. (2-*R, 6-*S)

[0632] Intermediate 671 was prepared following the same sequence of reactions as Intermediate 670, starting from Intermediate 666 instead of Intermediate 665.

Intermediate 672: 4-benzyl-6-(5-hydroxypentyl)-2-methylmorpholin-3-one.

[0633] Intermediate 672 was prepared following the same sequence of reactions as Intermediate 664, starting from 6-hepten-l-ol (CAS [4117-10-6]) instead of 7-octen-l-ol in Step A.

Intermediate 673: 5-((2*S,6*R)-4-benzyl-6-methylmorpholin-2-yl)pentan-l-ol and Intermediate 674: 5-((2*R,6*S)-4-benzyl-6-methylmorpholin-2-yl)pentan-l-ol.

(2-*R, 6-*S) Intermediate 674

[0634] Intermediate 673 and Intermediate 674 were prepared following the same procedure as Intermediate 665 and Intermediate 666, respectively, starting from Intermediate 672 instead of Intermediate 664. Intermediate 675: tert-butyl (5-((2*S,6*R)-4-benzyl-6-methylmorpholin-2- yl)pentyl)carbamate.

(2-*S, 6-*R)

[0635] Intermediate 675 was prepared following the same sequence of reactions as Intermediate 670, starting from Intermediate 673 instead of Intermediate 665.

Intermediate 676: tert-butyl (5-((2*S,6*R)-6-methylmorpholin-2-yl)pentyl)carbamate.

(2-*R, 6-*S)

[0636] Intermediate 676 was prepared following the same sequence of reactions as Intermediate 670, starting from Intermediate 674 instead of Intermediate 665.

Intermediate 679 : N-((2-chl oro-1, 6-naphthyridin-7-yl)methyl)-3-fluoro-5- (methylsulfonyl)benzamide.

[0637] Step A: 3-fluoro-5-(methylsulfonyl)benzoyl chloride. A mixture of 3-fluoro-5- (methylsulfonyl)-benzoic acid, (500 mg, 2.291 mmol) in SOCI₂ (2 mL, 27.497 mmol, 24 eq.) was stirred at 60 °C overnight. An additional portion of SOCI₂ (2 mL, 27.497 mmol, 24 eq.) was added and the mixture was stirred at 70 °C overnight. After cooling, the solvent was removed in vacuo and the residue was azeotroped with ~2 mL anhydrous toluene to give the title compound (542 mg, quantitative) as a white solid, used directly without further purification. [0638] Step B: N-((2-chloro-l,6-naphthyridin-7-yl)methyl)-3-fluoro-5- (methylsulfonyl)benzamide. (2-chloro-l,6-naphthyridin-7-yl)methanamine (Intermediate 1) (484 mg, 2.5 mmol) was suspended in anhydrous DCM (10 mL) under nitrogen atmosphere and the mixture was cooled to 0 °C. A solution of 3-fluoro-5-(methylsulfonyl)benzoyl chloride (542 mg, 2.291 mmol, 1.1 eq.) in anhydrous DCM (5 mL) was added dropwise and the mixture was stirred at 0 °C for 5 min. DIPEA (1.6 mL, 9.166 mmol, 4 eq.) was added dropwise at 0 °C and the mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated. The obtained solid was triturated at 0 °C in DCM for 1 h, then filtered, and washed with cold (0 °C) DCM to give Intermediate 679 (722 mg, yield: 80 %).

Intermediate 680 : tert-butyl 7-(3-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

[0639] Intermediate 403 (140 mg, 0.409 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 127 mg, 0.49 mmol, 1.2 eq.), potassium acetate (121 mg, 1.226 mmol, 3 eq.), and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS [72287-26-4], 30 mg, 0.041 mmol, 0.1 eq.) were placed in a vial and it was evacuated and backfilled with nitrogen (5 x). Anhydrous 1,4-dioxane (1.4 mL) was added, followed by 5 evacuation/refill cycles. The reaction mixture was stirred at 90 °C for 2 h. The mixture was diluted with anhydrous DMF (0.5 mL) to give Intermediate 680 as a dark brown solution, used directly without further purification.

Intermediate 681 : tert-butyl 7-(3-fluoro-6-(7-((3-fluoro-5- (methylsulfonyl)benzamido)methyl)- 1 ,6-naphthyridin-2-yl)pyridin-2-yl)-4,7 - diazaspiro [2.5] octane-4-carboxylate.

[0640] A solution of Intermediate 680 (173 mg, crude) in DMF (1 mL) was added to a mixture of Intermediate 679 (79 mg, 0.2 mmol), cesium carbonate (263 mg, 0.8 mmol, 4 eq.), copper(I) chloride (20 mg, 0.2 mmol, 1 eq.), XPhos Pd G3 (CAS [1445085-55-1], 12 mg, 0.014 mmol, 0.07 eq.), and X-Phos (CAS [564483-18-7], 7 mg, 0.014 mmol, 0.07 eq.) in DMF (1 mL) under nitrogen atmosphere. The dark brown solution was evacuated and refilled with nitrogen 5 times, then stirred at 100 °C for 4 h. After cooling, the mixture was filtered through a Celite® plug, washing with EtOAc. The filtrate was washed with water, then twice with brine, dried with Na2SC>4, filtered, and evaporated. The residue was purified by column chromatography (12 g SiCh; EtOAc/heptane from 25-75 to 100/0) to give Intermediate 681 as a yellow solid, used without further purification.

Intermediate 685: (3a, 4p, 5a)- l-(6-(7-(aminomethyl)-l,6-naphthyri din-2 -yl)-3- fluoropyridin-2-yl)-3,5-dimethylpiperidin-4-ol.

[0641] Step A: (3a, 4p, 5a)-l-(6-chloro-3-fluoropyridin-2-yl)-3,5-dimethylpiperidin-4-ol.

The title compound was prepared according to Method I, using 2,6-dichloro-3-fluoropyridine (CAS [52208-50-1]) instead of Intermediate 46 and (3a,4p,5a)-3,5-dimethyl-4-piperidinol (CAS [374067-78-4]) instead of 4-piperidineethanol.

[0642] Step B: (3a, 4p, 5a)-l-(3-fhroro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)-3,5-dimethylpiperidin-4-ol. The title compound was prepared following the same procedure as Intermediate 680, using (3a, 4p, 5a)-l-(6-chloro-3-fluoropyridin-2-yl)- 3,5-dimethylpiperidin-4-ol. [0643] Step C: tert-butyl ((2-(5-fluoro-6-((3a, 4p, 5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. A solution of crude (3a, 4p, 5a)-l- (3-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,5-dimethylpiperidin- 4-ol (143 mg, 0.408 mmol, 2 eq.) in 1,4-dioxane (1.3 mL) was added to a mixture of tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2) (60 mg, 0.204 mmol), XPhos Pd G4 (CAS [1599466-81-5], 17 mg, 0.020 mmol, 0.1 eq.), K2CO3 (56 mg, 0.407 mmol, 2 eq.), and copper(I) chloride (21 mg, 0.204 mmol, 1 eq.). The reaction mixture was stirred at 70 °C overnight. The reaction mixture was diluted with EtOAc (15 mL), water (15 mL), and brine (15 mL). The mixture was extracted with EtOAc (3 x 25 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (12 g, MeOH/DCM from 0/100 to 10/90) to give the title compound (98 mg, quantitative), used further purification.

[0644] Step D: (3a, 4p, 5a)-l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-3-fluoropyridin-2- yl)-3,5-dimethylpiperidin-4-ol. The title compound was prepared following the same procedure as Intermediate 525, using tert-butyl ((2-(5-fluoro-6-((3a, 4p, 5a)-4-hydroxy-3,5- dimethylpiperidin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)carbamate.

Intermediate 688: 3-(2-cyanopropan-2-yl)-4-fluorobenzoic acid.

[0645] Step A: methyl 3-(bromomethyl)-4-fluorobenzoate. In a vessel under nitrogen atmosphere, methyl 4-fluoro-3-methylbenzoate (CAS [180636-50-4], 1 g, 5.946 mmol) was dissolved in carbon tetrachloride (15 mL, 155.44 mmol) and NBS (CAS [128-08-5], 1270 mg, 7.136 mmol, 1.2 eq.) was added. The reaction mixture was heated to 80 °C and 2,2'-azobis(2- methylpropionitrile) (CAS [78-67-1], 498 mg, 2.973 mmol, 0.5 eq.) was added. The vessel was sealed, and the reaction mixture was stirred at 80 °C for 3.5 days. The reaction mixture was poured into water and extracted with DCM (3 x). The combined organic layer was dried over MgSCL, filtered, and concentrated. The residue was purified by flash column chromatography (24 g SiCh, heptane/EtOAc, 100/0 to 80/20) to afford the title compound as a clear oil (1140 mg, 67 % pure, yield: 52 %).

[0646] Step B: methyl 3-(cyanomethyl)-4-fluorobenzoate. Methyl 3-(bromomethyl)-4- fluorobenzoate (Intermediate 688; step A, 1140 mg, 3.094 mmol) was dissolved in 1,4- dioxane (9 mL) and water (5 mL), then sodium cyanide (227 mg, 4.64 mmol, 1.5 eq.) was added and the reaction mixture was stirred vigorously at room temperature. After 2 days, more sodium cyanide (155 mg, 3.09 mmol, 1 eq.) was added and stirring was continued overnight. The reaction mixture was poured into K2CO3 (2 % in water) and extracted with DCM (3 x). The organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography (24 g SiCh, heptane/EtOAc, 100/0 to 50/50) to afford the title compound (450 mg, yield: 75 %).

[0647] Step C: 3-(2-cyanopropan-2-yl)-4-fluorobenzoic acid, methyl 3-(cyanomethyl)-4- fluorobenzoate (450 mg, 2.329 mmol) was dissolved in dry DMSO (10 mL) then sodium hydride (60 % in mineral oil, 466 mg, 11.65 mmol, 5 eq.) was added and the reaction mixture was stirred at room temperature for 5 min. lodomethane (CAS [74-88-4], 0.522 mL, 8.386 mmol, 3.6 eq.) was then added and stirring was continued at room temperature for 24 h. The reaction mixture was diluted with DCM and poured into water. The mixture was acidified to pH = 1-2, and the layers separated. The aqueous layer was extracted twice with DCM and the combined organic layer was dried over MgSO fi4.ltered, and concentrated to afford the title compound which was used without further purification.

Intermediate 691: 4-chloro-3-(2-cyanopropan-2-yl)benzoic acid.

[0648] Intermediate 691 was prepared similarly to Intermediate 688, using methyl 4-chloro-3- methylbenzoate (CAS [91367-05-4]) instead of methyl 4-fluoro-3 -methylbenzoate in Step A.

Intermediate 694: 4-chloro-3-methyl-5-(methylsulfonyl)benzoic acid.

[0649] Step A: methyl 4-chloro-3-iodo-5-methylbenzoate. Methyl 4-chloro-3-methylbenzoate (CAS [91367-05-4], 500 mg, 2.708 mmol) was dissolved in dry DCE (10 mL). N- iodosuccinimide (CAS [516-12-1], 914 mg, 4.062 mmol, 1.5 eq.) and zinc bis(trifluoromethylsulfonyl)imide (CAS [168106-25-0], 508 mg, 0.812 mmol 0.3 eq.) were added. The reaction mixture was stirred at 100 °C for 3.5 days. The reaction mixture was poured into saturated aqueous Na2S2Ch and the mixture was extracted with EtOAc (3 x). The combined organic layer was dried over MgSO f4i.ltered, and concentrated. The residue was purified by flash column chromatography (24 g SiCh, heptane/EtOAc from 100/0 to 80/20) to afford the title compound (360 mg, yield: 43 %) as a white solid.

[0650] Step B: methyl 4-chloro-3-methyl-5-(methylsulfonyl)benzoate. methyl 4-chloro-3- iodo-5-methylbenzoate (310 mg, 0.998 mmol) was dissolved in dry DMSO (7.7 mL) under nitrogen atmosphere, then sodium methanesulfmate (CAS [20277-69-4], 102 mg, 0.998 mmol, 1 eq.) andL-proline (CAS [147-85-3], 23 mg, 0.2 mmol, 0.2 eq.) were added. The mixture was degassed with nitrogen for 10 min, then copper(I) iodide (19 mg, 0.0998 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 90 °C for 3 h. More copper(I) iodide (95 mg, 0.499 mmol, 0.5 eq.) was added and the reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4CI then saturated aqueous NaHCO3. dried over MgSO fi4l.tered, and concentrated. The residue was purified by flash column chromatography (12 g SiCb. heptane/EtOAc from 100/0 to 30/70) to afford the title compound (56 mg, yield: 21 %) as an off-white solid.

[0651] Step C: 4-chloro-3-methyl-5-(methylsulfonyl)benzoic acid, methyl 4-chl oro-3 -methyl- 5-(methylsulfonyl)benzoate (56 mg, 0.213 mmol) was dissolved in EtOH (2 mL) and water (2 mL), then KOH (36 mg, 0.639 mmol, 3 eq.) was added. The mixture was stirred at 80 °C for 1 h. The mixture was concentrated to the aqueous layer and it was acidified with HC1 (1 M in water). The resulting solid was isolated by filtration, washed with water, and dried at 50 °C to afford the title compound (38 mg, yield: 72 %) as an off-white solid.

Intermediate 701: ((3a, 4|3, 5a)-3,5-dimethylpiperidin-4-yl)methanol.

(3a, 4p, 5a)

[0652] Step A: tert-butyl (3a, 4p, 5a)-4-formyl-3,5-dimethylpiperidine-l-carboxylate. (Methoxymethyl)triphenylphosphonium chloride (CAS [4009-98-7], 1518 mg, 4.341 mmol, 1.1 eq.) was dissolved THF (16 mL) and cooled to 0 °C under nitrogen atmosphere.

Potassium tert-butoxide (1.0 M in THF, 4.14 mL, 4.144 mmol, 1.05 eq.) was added and the reaction mixture was stirred at room temperature for 1 h. Then, a solution of rel- 1,1- dimethylethyl (37?,5<S)-3,5-dimethyl-4-oxo-l-piperidinecarboxylate (CAS [1221821-84-6], 897 mg, 3.946 mmol, 1 eq.) in THF (8 mL) was added and the reaction mixture was stirred at room temperature overnight. Concentrated aqueous HC1 was added until an acidic pH was reached, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with Et20 (3 x). The combined organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography (24 g SiCh, heptane/EtOAc from 100/0 to 80/20) to afford the title compound (576 mg, yield: 60 %)•

[0653] Step B: tert-butyl (3a, 4p, 5a)-4-(hydroxymethyl)-3,5-dimethylpiperidine-l- carboxylate. tert-butyl (3a, 4p, 5a)-4-formyl-3,5-dimethylpiperidine-l -carboxylate (576 mg, 2.387 mmol) was dissolved in MeOH (20 mL) and sodium borohydride (135 mg, 3.58 mmol, 1.5 eq.) was added. The reaction mixture was stirred at room temperature for 30 min, then was concentrated under reduced pressure. The residue was diluted in Et20 and washed with water. The aqueous layer was extracted twice with Et20, and the combined organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography (12 g SiCh, heptane/EtOAc from 90/10 to 50/50) to afford the title compound (389 mg, yield: 64 %) as a clear oil.

[0654] Step C: ((3a, 4p, 5a)-3,5-dimethylpiperidin-4-yl)methanol. tert-butyl (3a, 4p, 5a)-4- (hydroxymethyl)-3,5-dimethylpiperidine-l-carboxylate (389 mg, 1.519 mmol) was dissolved in HC1 (4 M in 1,4-di oxane, 10 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford Intermediate 701 (HC1 salt, 385 mg, quantitative).

Intermediate 706: 2-(3,5-dimethylpiperidin-4-yl)ethan-l-ol.

Mixture of diastereomers

[0655] Step A: tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxy-3,5-dimethylpiperidine-l- carboxylate. A solution of EtOAc (1039 μL 1, 0.559 mmol, 3 eq.) in dry THF (17 mL) was cooled to -78 °C under nitrogen atmosphere. LDA (2 M in THF, CAS [4111-54-0], 5.279 mL, 10.559 mmol) was added and the reaction mixture was stirred for 1 h at -78 °C, then re/-l,l- dimethylethyl (37?,5<S)-3,5-dimethyl-4-oxo-l-piperidinecarboxylate (CAS [1221821-84-6], 800 mg, 3.52 mmol) was added and stirring was continued at this temperature for 3 h. The reaction was quenched by addition of HC1 (5 % in water) and the mixture was extracted twice with Et2O. The combined organic layer was dried over MgSO fil4t.ered, and concentrated. The residue was purified by flash column chromatography (24 g SiCh, heptane/EtOAc from 90/10 to 50/50) to afford the title compound (1050 mg, yield: 95 %) as a clear oil, as a single diastereomer.

[0656] Step B: tert-butyl 4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-3,6-dihydropyridine-l(2H)- carboxylate. tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxy-3,5-dimethylpiperidine-l- carboxylate (1000 mg, 3.17 mmol) was dissolved in pyridine (20 mL) and cooled to 0 °C, then SOCI₂ (CAS [7719-09-7], 0.46 mL, 6.341 mmol, 2 eq.) was added and the reaction mixture was stirred for 30 min at 0 °C. The reaction was quenched by addition of HC1 (5 % in water) and extracted with Et20 (3 x). The combined organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography (12 g SiCh, heptane/EtOAc from 100/0 to 60/40) to afford the title compound (940 mg, quantitative).

[0657] Step C: tert-butyl 4-(2-ethoxy-2-oxoethyl)-3,5-dimethylpiperidine-l-carboxylate. tert- butyl 4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (940 mg, 3.161 mmol) was dissolved in EtOH (30 mL) in an autoclave. Pd/C (10 %, 336 mg, 0.316 mmol, 0.1 eq.) was added. The autoclave was pressurized with 10 bar H2 and heated overnight at 60 °C. The reaction mixture was filtered over Celite®, the filter was washed with EtOH, and the filtrate was concentrated. The residue was purified by flash column chromatography (24 g SiO2, heptane/EtOAc from 100/0 to 75/25) to afford the title compound (mixture of isomers, 841 mg, yield: 89 %) as a yellow oil.

[0658] Step D: tert-butyl 4-(2-hydroxyethyl)-3,5-dimethylpiperidine-l-carboxylate. tert-butyl 4-(2-ethoxy-2-oxoethyl)-3,5-dimethylpiperidine-l-carboxylate (840 mg, 2.806 mmol) was dissolved in THF (28 mL) and lithium aluminium hydride (1 M in THF, CAS [16853-85-3], 11.2 mL, 11.2 mmol, 4 eq.) was added. The mixture was stirred at room temperature for 1.5 h. Saturated aqueous Rochelle's salt was added carefully, and the reaction mixture was stirred for 30 min, then extracted with Et20 (3 x). The combined organic layer was dried over MgSO4. filtered, and concentrated under reduced pressure to afford the title compound (mixture of isomers, 679 mg, yield: 94 %), used without further purification.

[0659] Step E: 2-(3,5-dimethylpiperidin-4-yl)ethan-l-ol. tert-butyl 4-(2-hydroxyethyl)-3, 5- dimethylpiperidine-1 -carboxylate (679 mg, 2.638 mmol) was dissolved in DCM (10 mL) and TFA (2.019 mL, 26.382 mmol, 10 eq.) was added. The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was basified with NaOH (1 M in water) until a basic pH was reached, and the mixture was extracted with DCM (3 x). The combined organic layer was dried over MgSCti, filtered, and concentrated to afford (mixture of isomers, 381 mg, yield: 92 %).

Intermediate 708: ((3a, 4p, 5a)-l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)- 3,5-dimethylpiperidin-4-yl)methanol.

(3a, 4p, 5a)

[0660] Step A: tert-butyl ((2-(6-((3a, 4p, 5a))-4-(hydroxymethyl)-3,5-dimethylpiperidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. Intermediate 9 (200 mg, 0.564 mmol) and Intermediate 701 (200 mg, 0.792 mmol, 1.4 eq.) were dissolved in DMSO (5.6 mL) and DIPEA (0.292 mL, 1.693 mmol, 3 eq.) was added. The reaction mixture was stirred at 130 °C for 2 days. The reaction mixture was diluted with water and the mixture was extracted with EtOAc (3 x). The combined organic layer was dried over MgSO fil4t.ered, and concentrated. The crude product was purified by flash column chromatography (12 g SiCh, DCM/MeOH from 100/0 to 90/10) to afford the title compound (112 mg, yield: 37 %) as an orange foam.

[0661] Step B: ((3a, 4p, 5a)-l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-3,5- dimethylpiperidin-4-yl)methanol. tert-butyl ((2-(6-((3a, 4p, 5a))-4-(hydroxymethyl)-3,5- dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (112 mg, 0.211 mmol) was dissolved in HC1 (4 M in 1,4-di oxane, 4 mL, 4 M, 16 mmol) and DCM (2 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, then the precipitate was isolated by filtration, and dried under reduced pressure to afford Intermediate 708 (HC1 salt, 117 mg, quantitative) as an off-white solid, used without further purification.

Intermediate 709: 3-(vinylsulfonyl)benzoic acid. [0662] 3-(2-hydroxyethanesulfonyl)benzoic acid (CAS [7180-11-2], 300 mg, 1.303 mmol) was dissolved in DCM (20 mL), then EtsN (0.906 mL, 6.515 mmol, 5 eq.) and MsCl (CAS [124-63-0], 0.152 mL, 1.954 mmol, 1.5 eq.) were added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with water. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layer was dried over MgSO4. filtered, and concentrated under reduced pressure to afford Intermediate 709 (295 mg, yield 85 %).

Intermediate 710: 3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0663] Intermediate 41 (358 mg, 1.094 mmol, 1 eq.) and 3- (difluoromethylsulfonimidoyl)benzoic acid (CAS [2362006-57-1, 330 mg, 1.403 mmol, 1.3 eq) were suspended in DCM (10 mL). 1 -Propylphosphonic anhydride solution (50 wt. % in EtOAc, CAS [68957-94-8], 1.46 mL, 2.445 mmol, 2.2 eq.) and EtsN (0.7 mL, 5.036 mmol, 4.6 eq.) were added and the reaction mixture was stirred at room temperature for 8 h. DIPEA (0.85 mL, 4.932 mmol, 4.5 eq.) was added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with water and extracted twice with DCM. The combined organic layer was dried over MgSO4. filtered, and evaporated. The residue was purified by flash column chromatography (24 g SiCh, DCM/MeOH from 100/0 to 90/10) to afford Intermediate 710 (327 mg, yield: 63 %) as a beige solid.

Intermediate 711: (tert-butyl-6-ethyl-4,7-diazaspiro[2.5]octane-4-carboxylate).

[0664] Intermediate 711 may be prepared in 2 steps from 6-ethyl-7-(phenylmethyl)-4,7- diazaspiro[2.5]octane (CAS [2242430-22-2]) by reacting it first with di-tert-butyl decarbonate (CAS [24424-99-5]) in the presence of EtsN in DCM at room temperature; followed by reaction of the formed intermediate with hydrogen (1 atm) in MeOH in the presence of Pd/C (10 %) at room temperature. Intermediate 712: 3-fluoro-5-((2-hydroxyethyl)sulfonyl)benzoic acid.

[0665] Intermediate 712 was prepared following the same procedure as Intermediate 15, starting from methyl 3-bromo-5-fluorobenzoate (CAS [334792-52-8]) instead of methyl 3- iodo-4-methylbenzoate.

Intermediate 713: (6-(2-(l-fluorocyclopropyl)pyrimidin-4-yl)isoquinolin-3-yl)methanamine.

[0666] Step A: tert-butyl ((6-chloroisoquinolin-3-yl)methyl)carbamate. 2-Bromo-4- chlorobenzaldehyde (CAS [84459-33-6], 5 g, 22.8 mmol), N-Boc-propargylamine (CAS [92136-39-5], 5.35 g, 34.5 mmol), ACN (50 mL), EtsN (6.4 mL, 45.7 mmol), and tert- butylamine (CAS [75-64-9], 7.2 mL, 68.52 mmol) were introduced in a sealed tube at room temperature. The reaction mixture was purged with nitrogen for 20 min. To this solution was added l,2-bis(diphenylphosphino)ethane Nickel (II) chloride (CAS [14647-23-5], 0.782 g, 1.481 mmol) and the mixture was heated to 80 °C for 16 h. The mixture was diluted with EtOAc and filtered through a celite pad. The filtrate was washed with brine and concentrated to dryness. The residue was purified by flash column chromatography (silica 330 g; EtOAc/heptane from 0/100 to 100/0) to give tert-butyl ((6-chloroisoquinolin-3- yl)methyl)carbamate (1.7 g, yield: 19 %).

[0667] Step B: tert-butyl ((6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-3- yl)methyl)carbamate. A mixture of tert-butyl ((6-chloroisoquinolin-3-yl)methyl)carbamate (500 mg, 1.09 mmol), bis(pinacolato) diboron (CAS [73183-34-3], 0.691 g, 2.72 mmol), Xphos Pd G3 (CAS [1445085-55-1], 0.116 g, 0.14 mmol), Xphos (CAS [564483-18-7], 0.130 g, 0.27 mmol), and potassium acetate (0.415 g, 4.22 mmol) in 1,4-dioxane (15 mL) was degassed by bubbling nitrogen for 15 min and then heated under nitrogen atmosphere at 70 °C for 16 h. After cooling, the mixture was filtered through a pad of celite and the solvents were evaporated in vacuo. The residue was purified by flash column chromatography (80 g silica; EtOAc/heptane from 0/100 to 60/40) to afford tert-butyl ((6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)isoquinolin-3-yl)methyl)carbamate (550 g, yield: 99 %) as an orange solid. [0668] Step C: tert-butyl ((6-(2-(l-fluorocyclopropyl)pyrimidin-4-yl)isoquinolin-3- yl)methyl)carbamate. PdCh(dppl) (CAS [95464-05-4], 220 mg; 1.041 mmol) was added to a stirred solution of tert-butyl ((6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-3- yl)methyl)carbamate (400 mg, 1.041 mmol), 2-(l -fluorocyclopropyl)-4(37/)-pyrimidinone (CAS [2677884-70-5], 440 mg, 1.142 mmol) and sodium bicarbonate (85 mg; 0.104 mmol) in 1,4-dioxane (16 mL) and water (4 mL) in a sealed tube under nitrogen. The mixture was stirred at 75 °C for 16 h. After cooling, the mixture was filtered through a pad of celite and diluted with H2O. The mixture was extracted with EtOAc and the organic layer was washed with brine (x 2). The organic layer was concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g; DCM/MeOH 9: 1 in DCM 0/100 to 20/80) followed by reverse phase column chromatography (Phenomenex Gemini C18 100 x 30 mm 5 urn; from [59 % H2O (25 mM NH4HCO3 pH 8)) - 41 % (ACN:MeOH)] to [17 % H2O (25 mM NH4HCO3 pH 8) - 83 % (ACN:MeOH)]) to yield tert-butyl ((6-(2-(l- fluorocyclopropyl)pyrimidin-4-yl)isoquinolin-3-yl)methyl)carbamate (160 mg, yield: 39 %) as a white solid.

[0669] Step D: (6-(2-(l-fluorocyclopropyl)pyrimidin-4-yl)isoquinolin-3-yl)methanamine. To a solution of tert-butyl ((6-(2-(l-fluorocyclopropyl)pyrimidin-4-yl)isoquinolin-3- yl)methyl)carbamate (158 mg; 0.397 mmol) in DCM (3 mL), TFA (1 mL, 13.068 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of saturated aqueous NaHCCL and the mixture was extracted with DCM (x 3). The organic layer was separated, dried (MgSCL), filtered, and the solvents evaporated in vacuo to afford (6-(2-(l-fluorocyclopropyl)pyrimidin-4-yl)isoquinolin-3-yl)methanamine (90 mg, yield: 76 %) as a brown oil.

Intermediate 714: (2-(4-methyl-l-(4-azaspiro[2.5]octan-7-yl)-lH-pyrazol-3-yl)-l,6- naphthyri din-7 -yl)methanamine

[0670] Step A: tert-butyl ((2-(4-methyl-lH-pyrazol-3-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. tert-Butyl ((2-chloro-l ,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2) (200 mg, 0.68 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-17/-pyrazole (CAS [1440520-87-5], 198 mg, 0.95 mmol), and sodium carbonate (216 mg, 18.5 mmol) were suspended in 1,4-di oxane (2 mL) and water (0.5 mL) and the mixture was degassed with nitrogen for 15 min. Then, a solution of bis(triphenylphosphine) palladium(II)chloride (CAS [13965-03-2], 24 mg, 0.03 mmol) in 1,4-dioxane was added and the reaction mixture was degassed for 5 min. The reaction mixture was stirred at 85 °C for 2 h. The solvents were evaporated under pressure. The crude product was triturated in DIPE, and the beige solid was filtered and dried to yield tert-butyl ((2-(4-methyl-lH-pyrazol-3-yl)- l,6-naphthyridin-7-yl)methyl)carbamate.

[0671] Step B: tert-butyl 7-(3-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- y l)-4-methy 1- IH-py razol- 1 -yl)-4-azaspiro [2.5] octane-4-carboxy late. 2- (Tributylphosphoranylidene)acetonitrile (CAS [157141-27-0], 0.31 mL, 1.2 mmol) was added dropwise to a suspension of tert-butyl ((2-(4-methyl-lH-pyrazol-3-yl)-l,6-naphthyridin-7- yl)methyl)carbamate (103 mg, 0.3 mmol) and 7-hydroxy-4-azaspiro[2.5]octane-4-carboxylic acid, 1,1 -dimethylethyl ester (CAS [2306269-68-9], 170 mg, 0.75 mmol) in dry toluene (4 mL). The reaction mixture was stirred at 100 °C for 2 days, then cooled down to room temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, dried over MgSO4. filtered, and evaporated. The residue was purified by column chromatography on silica (DCM/MeOH 100/0 to 98/2 then EtOAc 100 %) to afford tert-butyl 7 -(3-(7 -(((tert-butoxycarbonyl)amino)methyl)- 1 ,6-naphthyridin-2-yl)-4-methyl- IH-pyrazol- 1 - yl)-4-azaspiro[2.5]octane-4-carboxylate (138 mg, yield: 84 %) as a light brown solid.

[0672] Step C: tert-butyl 7-(3-(7-(((tert-butoxycarbonyl)amino)methyl)-l,6-naphthyridin-2- yl)-4-methyl-lH-pyrazol-l-yl)-4-azaspiro[2.5]octane-4-carboxylate (137.7 mg, 0.25 mmol) was dissolved in HC1 (6 M in iPrOH, 2 mL, 12 mmol) and MeOH (1 mL). The reaction mixture was stirred at room temperature overnight. The solvents were evaporated and the crude product was co-evaporated with toluene to yield Intermediate 714 (105 mg, quantitative) as a dark yellow solid.

[0673] Intermediate 715: tert-butyl 3-((5-bromo-3-fluoropyridin-2-yl)oxy)azetidine-l- carboxylate.

[0674] CS2CO3 (3.31 g, 10.157 mmol, 1.3 eq.) was added to a mixture of 5-bromo-3- fhioro-2-pyridinone (CAS [156772-63-3], 1.5 g, 7.813 mmol) and N-Boc-3-iodoazetidine (CAS [254454-54-1], 1.9 mL, 10.157 mmol, 1.3 eq.) in DMF (25 mL). The mixture was stirred at 60 °C for 24 h. The mixture was then diluted with water and EtOAc and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated under vacuo. The residue was purified by flash column chromatography (40 g SiO2; EtOAc/heptane 0/100 to 100/0) to yield Intermediate 715 (2492 mg, yield: 82 % ) as a white solid.

[0675] Intermediate 716: tert-butyl 3-((3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)oxy)azetidine- 1 -carboxylate.

Intermediate 716 (2.492 g, 7.178 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 2.370 g, 9.331 mmol, 1.3 eq.), Pd(dppf)C12.CH₂C12 (CAS [95464-05-4], 292 mg, 0.358 mmol, 0.05 eq.), and potassium acetate (2.193 g, 22.340 mmol, 3.1 eq., previously dried at 100 °C) were dissolved in 1,4-dioxane (15 mL) under nitrogen atmosphere. The reaction vessel was closed tight (screw cap) and the reaction mixture was stirred at 90 °C for 3 h. The mixture was quenched with 1 M aqueous Na2CO3 and was extracted with EtOAc. The organic layer was dried over MgSO4. filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica gel 25 g; EtOAc/heptane from 0/100 to 50/50) to give Intermediate 716 as a white solid (624 mg, yield: 21 %). [0676] Intermediate 717: tert-butyl 3-((5-(7-((3- ((difluoromethyl)sulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)-3-fluoropyri din-2- yl)oxy)azetidine-l -carboxylate.

Intermediate 465 (190 mg, 0.461 mmol) and 1 M aqueous Na2CO3 (1.4 mL, 1.4 mmol, 3 eq.) were added to a stirred solution of Intermediate 716 (200 mg, 0.507 mmol) in 1,4-di oxane (6 mL) at room temperature, under nitrogen atmosphere. Then, bis(triphenylphosphine)palladium(II) dichloride (CAS [13965-03-2], 28 mg, 0.039 mmol, 0.08 eq.) was added, and the mixture was stirred at 90 °C under nitrogen atmosphere for 4 h. After cooling, the mixture was diluted with water and was extracted with EtOAc. The organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography (12 g silica column, EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 717 (208 mg, yield: 66 %) as a white solid.

[0677] Intermediate 718: 3-chloro-5-(S-(difluoromethyl)sulfonimidoyl)benzoic acid, Intermediate 719: (*R)-3-chloro-5-(S-(difluoromethyl)sulfonimidoyl)benzoic acid, and Intermediate 720: (*S)-3-chloro-5-(S-(difluoromethyl)sulfonimidoyl)benzoic acid.

(*R) Intermediate 719

(*S) Intermediate 720

Step A: methyl 3-chloro-5-((difluoromethyl)thio)benzoate. Sodium 2-chloro-2,2- difluoroacetate (CAS [1895-39-2], 129.6 g, 849.8 mmol, 1.5 eq.) was added to a solution of methyl 3-chloro-5-mercaptobenzoate (CAS [1566273-16-2], 115 g, 566.5 mmol), DMF (1150 mL), and K2CO3 (156 g, 1130.0 mmol, 2 eq.) at room temperature. The resulting mixture was stirred for 0.5 h at 90 °C. After cooling, the reaction mixture was diluted with water (3000 mL). The resulting mixture was extracted with EtOAc (3 x 800 mL). The combined organic layer was washed with water (3 x 1500 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc 2/3) to afford methyl 3-chloro-5-((difluoromethyl) thio)benzoate (80 g, yield: 56 %) as a white solid.

Step B: methyl 3-chloro-5-[(difluoromethyl)(imino)oxo-lambda6-sulfanyl]benzoate. A mixture of methyl 3-chloro-5-[(difluoromethyl)sulfanyl]benzoate (80 g, 316.63 mmol), 2,2,2-trifluoroethanol (800 mL), PIDA (CAS [3240-34-4], 316.16 g, 981.55 mmol, 3.1 eq.), and ammonium carbamate (61.80 g, 791.57 mmol, 2.5 eq.) was stirred for 2 h at room temperature. The mixture was concentrated under vacuum. The residue was quenched by the addition of water (400 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 800 mL). The combined organic layer was washed with brine (800 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/THF 12/1) to afford methyl 3-chloro-5- [(difluoromethyl)(imino)oxo-lambda6-sulfanyl]benzoate (61 g, yield: 66 %) as a yellow oil.

Step C: 3-chloro-5-[(difluoromethyl)(imino)oxo-lambda6-sulfanyl]benzoic acid. A mixture of methyl 3-chloro-5-[(difluoromethyl)(imino)oxo-lambda6-sulfanyl]benzoate (63 g, 222.089 mmol), THF (315 mL), water (157 mL), and LiOH.H₂O (18.64 g, 444.178 mmol, 2 eq.) was stirred for 1 h at 0 °C. The resulting mixture was concentrated under vacuum. The residue was acidified to pH 1 with 1 M aqueous HC1. The resulting mixture was extracted with EtOAc (3 x 630 mL). The combined organic layer was washed with brine (630 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford Intermediate 718 (3-chloro-5-[(difluoromethyl)(imino)oxo-lambda6-sulfanyl]benzoic acid, 47 g, yield: 76 %) as an off-white solid. A sample of Intermediate 718 was purified by chiral SFC (Column: CHIRALPAK IG 5 * 30 cm, 10 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH;

Gradient: isocratic 30 % B) to afford Intermediate 719 and Intermediate 720, both as light yellow solids.

COMPOUNDS

Compound 1 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l ,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

(Method A)

[0678] 3-Methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6], 64 mg, 0.299 mmol, 1.1 eq.) and DIPEA (142 μL, 0.816 mmol, 3 eq.) were added to a solution of Intermediate 11 (95 mg, 0.272 mmol) in DCM (2 mL). After 1 min, HATU (119 mg, 0.313 mmol, 1.15 eq.) was added and the reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4). filtered, and evaporated. The residue was purified by flash chromatography (12 g column, DCM/MeOH (9/1) in DCM, from 0 % to 25 %) to yield the title compound (9 mg, yield: 6 %) as a yellow solid.

[0679] The following compounds were prepared from Intermediate 11 and the corresponding acid, following procedures similar to the methods shown in the

Compound 5: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(l -hydroxy ethyl)-4-methylbenzamide.

CIS

(Method B)

[0680] HBTU (218 mg, 0.574 mmol, 1.5 eq.) was added to a stirred solution of (3-(l - hydroxyethyl)-4-methyl-benzoic acid, CAS [1530904-93-8], 69 mg, 0.383 mmol), Intermediate 11 (134 mg, 0.383 mmol, 1 eq.), and DIPEA (201 μ 1L.,149 mmol, 3 eq.) in DMF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with Na2CO3 (1 M in water) and extracted with EtOAc. The organic layer was dried on MgSO4 f.iltered, and evaporated. The residue was purified by reverse phase chromatography (72 % H2O - 28 % ACN -MeOH to 36 % H2O - 64 % ACN - MeOH - [0.1 % HCOOH]). The desired fractions were neutralized with solid Na2CO3 solid and extracted with DCM. The organic layer was dried over MgSO fi4lt.ered, and evaporated to yield Compound 5 (130 mg, yield: 66 %) as a solid.

Compound 11 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide.

CIS

(Method D)

[0681] EtsN (71 μL, 0.511 mmol, 4 eq.) was added to a suspension of Intermediate 11 (HC1 salt, 54 mg, 0.128 mmol) and benzoyl chloride (16 μ 0L.,141 mmol, 1.1 eq.) in dry DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min. 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 by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane: EtOH/EtOAc 1/3 100:0 to 30:70) to give Compound 11 (16 mg, yield: 28 %) as a yellow solid, dried under vacuum at 50 °C. Compound 15: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*R)-l-hydroxyethyl)-4-methylbenzamide and Compound 16: N-((2-(6-((cis)- 2,6-dimethylmorpholino)py ridin-2-y 1)- 1 ,6-naphthyridin-7-yl)methyl)-3-((* S)- 1 - hydroxy ethyl)-4-methylbenzamide.

Compound 15 (*R, CIS, pure enantiomer but absolute stereochemistry undetermined)

Compound 16 (*S, CIS, pure enantiomer but absolute stereochemistry undetermined) [0682] Compound 5 (85 mg, 0.164 mmol) was separated into its stereoisomers by preparative SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 % iPrNFh) to give Compound 15 (35 mg, yield: 41 %) and Compound 16 (34 mg, yield: 40 %), both as yellow solids.

Compound 19: 3-(l,l-difluoroethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)- l,6-naphthyridin-7-yl)methyl)-4-fluorobenzamide and Compound 20: 3-(l,l-difluoroethyl)-

N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- ethoxybenzamide.

CIS

Compound 20 [0683] HBTU (109 mg, 0.288 mmol, 1.5 eq.) was added to a stirred solution of the mixture of Intermediate 28 and Intermediate 29 (1:1 mixture, 114 mg, 0.249 mmol, 1.3 eq.), Intermediate 11 (81 mg, 0.249 mmol), and DIPEA (167 μL 0,.959 mmol, 5 eq.) in DMF (10 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with Na2CO3 (1 M aqueous solution) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvents were evaporated in vacuo. The residue was purified by reverse phase chromatography (from (70 % H2O - 30 % ACN-MeOH) to (27 % H2O - 73 % ACN-MeOH] - [0.1 % HCOOH]). The isolated solutions were neutralized with solid Na2CO3, extracted with DCM, dried over MgSO4, filtered, and the solvents were concentrated in vacuo and the residue were triturated in Et20, filtered, and dried to yield Compound 19 (41 mg, yield: 39 %) and Compound 20 (40 mg, yield: 37 %).

Compound 23: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(isopropylsulfonyl)-4,5-dimethylbenzamide.

CIS

(Method F)

[0684] 1 -Propanephosphonic anhydride (50 % in EtOAc, CAS [68957-94-8], 154 0.μ2L6, mmol, 1.3 eq.) was added to a suspension of Intermediate 11 (HC1 salt, 88 mg, 0.198 mmol) and 3,4-dimethyl-5-[(l-methylethyl)sulfonyl]benzoic acid (CAS [1094393-67-5], 56 mg, 0.218 mmol, 1.1 eq.) in dry DCM (5 mL) at room temperature, under nitrogen atmosphere. EtsN (138 μL, 0.99 mmol, 5 eq.) was then added dropwise to the orange suspension. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane: EtOH/EtO Ac 1/3 100:0 to 20:80) to give Compound 23 (60 mg, yield: 52 %) as a yellow solid.

Compound 28: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(2-hydroxyethoxy)-4-methylbenzamide.

CIS

(Method G)

[0685] Compound 28 was prepared similarly to Compound 23, starting from 3-(2- hydroxyethoxy)-4-methylbenzoic acid, CAS [1270971-72-6] instead of 3,4-dimethyl-5-[(l- methylethyl)sulfonyl] benzoic acid. An additional reverse phase chromatography was used (Stationary phase: RP XBridge Prep Cl 8 OBD- 5 pm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to obtain pure Compound 28.

Compound 36: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2-fluoro-5-((*R)-l-hydroxyethyl)-4-methylbenzamide and Compound 37: N-((2- (6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-2-fluoro-5-

((*S)-l-hydroxyethyl)-4-methylbenzamide.

Compound 36 (*R, CIS,' pure enantiomer but absolute stereochemistry undetermined)

Compound 37 (*S, C/5; pure enantiomer but absolute stereochemistry undetermined) [0686] Compound 35 (75 mg, 0.139 mmol) was separated into its stereoisomers by preparative SFC (i-Amylose-1 column; isocratic mode method: 50 % [EtOH + 0.1 % DEA] - 50 % [CO2]) to give Compound 36 (25 mg) and Compound 37 (20 mg), both as yellow solids.

Compound 39: 4-cyclopropyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((*R)-l-hydroxyethyl)benzamide and Compound 40: 4- cyclopropyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-3-((*S)-l -hydroxy ethyl)benzamide.

Compound 39 (*R, C/5; pure enantiomer but absolute stereochemistry undetermined)

Compound 40 (*S, C/5; pure enantiomer but absolute stereochemistry undetermined) [0687] Compound 39 and Compound 40 were obtained by separation of the stereoisomers of Compound 38, using a method analogous to Compound 36 and Compound 37.

Compound 43: 3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(2-hydroxypropan-2-yl)benzamide.

CIS

[0688] A mixture of Intermediate 44 (184 mg, 0.408 mmol), c7.s-2.6-dmiethyl morpholine (CAS [6485-55-8], 302 μL, 2.448 mmol, 6 eq.), and DIPEA (426 μ 2L.4,48 mmol, 6 eq.) was stirred at 130 °C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and the mixture was extracted with DCM (3 x). The combined organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (gradient of DCM:MeOH 9: 1 in DCM, from 0 % to 30 %) to yield Compound 43 (174 mg, yield: 76 %) as a yellow solid.

Compound 44: N-((2-(6-(4-(2-hydroxyethyl)piperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

(Method I) [0689] 4-Piperidineethanol (CAS [622-26-4], 186 mg, 1.443 mmol, 10 eq.) was added to a solution of Intermediate 46 (65 mg, 0.144 mmol) in DMSO (1 mL) and the mixture was stirred at 120 °C for 18 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO fi4l.tered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g SiO2; DCM:MeOH (9:1) in DCM, 0/100 to 40/60) to yield Compound 44 (66 mg, yield: 80 %) as a yellow solid.

The compounds in Table 7 were prepared in a manner analogous to Method I: Table 7

Compound 45: 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. (Method J)

[0690] 2-Thia-6-azaspiro[3.3]heptane, 2, 2-dioxide hydrochloride (CAS [1427388-39-3], 171 mg, 0.932 mmol, 6 eq.) was added to a solution of Intermediate 46 (70 mg, 0.155 mol) and DIPEA (541 μL, 3.108 mmol, 20 eq.) in DMSO (1 mL) and the mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g SiO2, gradient of DCM:MeOH 9: 1 in DCM, from 0 % to 35 %) to yield a yellow solid. This solid was triturated in ACN, filtered, washed with Et20, and dried in vacuo to yield Compound 45 (31 mg, yield: 33 %) as a yellow solid. Compound 48: 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.

(Method K) [0691] A solution of Intermediate 46 (50 mg, 0.094 mmol), l-oxa-7-azazpiro[3.5]nonane

(CAS [38674-21-4], 0.283 mmol, 3 eq.), and DIPEA (200 μ 1L.1,61 mmol, 12 eq.) in dry DMSO (0.5 mL) was stirred at 120 °C overnight. After cooling, the reaction mixture was diluted with MeOH (2.5 mL) and filtered. The filtrate was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give Compound 48 (16 mg, yield: 31 %) as a yellow solid.

[0692] The following compounds or intermediates were prepared from Intermediate 46 and the corresponding amine, following procedures similar to the methods shown in Table 8. Table 8.

The following compounds were prepared from Intermediate 65 and the corresponding amine, following procedures similar to the methods shown in Table 9.

Table 9.

The following compounds were prepared from Intermediate 68 and the corresponding amine, following procedures similar to the methods shown in Table 10.

Table 10.

[0693] The following compounds were prepared from Intermediate 609 and the corresponding amine, following procedures similar to the methods shown in Table 11. *Compound 712 was prepared using Intermediate 599 instead of Intermediate 609. Table 11

Compound 68: 4-((cis)-2,6-dimethylmorpholino)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-3-

(methylsulfonyl)benzamide.

CIS, CIS [0694] A solution of Intermediate 53 (51 mg, 0.099 mmol) in cA-2,6-dimethylmorpholine (CAS [6485-55-8], 244 μL, 20 eq.) was stirred at 120 °C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCCh and was extracted with DCM (3 x). The combined organic layer was dried on MgSO4 f.iltered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g column, gradient DCM/Methanol 9/1 in DCM from 0 % to 35 %) to yield Compound 68 (45 mg, yield: 70 %) as a yellow solid.

Compound 70: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-ethyl-3-(methylsulfonyl)benzamide.

CIS

(Method L)

[0695] A solution of Intermediate 60 (125 mg, 0.27 mmol) in cA-2,6-dimethylmorpholine (CAS [6485-55-8]) was stirred for 16 h at 120 °C. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed twice with brine, dried with Na2SC>4, and concentrated. The residue was purified by flash column chromatography (12 g silica, DCM/MeOH, from 0/100 to 90/10) to yield Compound 70 (83.6 mg, yield: 55 %) as a yellow solid.

[0696] The Compounds in Table 12 were prepared in a manner analogous to Method L using c7.s-2.6-dmiethyl morpholine and the corresponding intermediate.

Table 12

Compound 71 : N-((2-(6-(4-hydroxy-3-methylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, Compound 72: 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, and Compound 73: N-((2-(6-((3*S,4*R)-4-hydroxy-3- methylpiperidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyridin-7 -yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide.

Compound 71 (relative CIS, mixture of stereoisomers)

[0697] Compound 73 (CIS, pure stereoisomer but absolute stereochemistry undetermined) TBAF (115 mg, 0.364 mmol, 1.2 eq.) was added portion wise to a solution of Intermediate 61 (200 mg, 0.303 mmol) in dry THF (4 mL) at 0 °C. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and was extracted with DCM (3 x). The combined organic layer was dried with MgSO fil4t.ered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g silica, gradient of DCM/MeOH 9/1 in DCM, from 0 % to 45 %) to yield Compound 71 as a yellow solid. A sample of Compound 71 was separated into its stereoisomers by preparative SFC (Lux Amylose-1 250 x 30 mm 5 urn column, isocratic mode method: 50 % [IPA + 0.1 % DEA] - 50 % [CO2]) to yield Compound 72 (50 mg, yield: 30 %) and Compound 73 (52 mg, yield: 31 %), both as yellow solids.

Compound 79: N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-iodopyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0698] A solution of N-iodo succinimide (143 mg, 0.636 mmol, 1.02 eq.) in 1, 1,1, 3,3,3- hexafluoro-2-propanol (1 mL) was added over 10 min to a cooled (ice bath) solution of Compound 1 (320 mg, 0.586 mmol) in l,l,l,3,3,3-hexafluoro-2-propanol (6 mL). The reaction mixture was allowed to warm slowly to room temperature and was stirred for 4 h. The mixture was concentrated in vacuo and directly purified by column chromatography on silica gel (ISCO column, EtOAc) followed by reverse phase column chromatography (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give the title compound (98 mg, yield: 25 %).

Compound 80: N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0699] A solution of Compound 79 (22 mg, 0.029 mmol) and (1,10- phenanthroline)(trifluoromethyl)copper(I) (CAS [1300746-79-5], 14 mg, 0.044 mmol, 1.5 eq.) in DMF (0.6 mL) was flushed with nitrogen at room temperature and the vial was sealed. The reaction mixture was stirred at 50 °C for 16 h. After cooling, the reaction mixture was directly purified by column chromatography on silica gel (ISCO column, EtOAc) followed by reverse phase column chromatography (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give the title compound (7 mg, yield: 39 %)

Compound 81 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((3-hydroxypropyl)sulfonyl)-4-methylbenzamide.

CIS

[0700] Pyridinium 4-toluenesulfonate (CAS [24057-28-1], 9 mg, 0.035 mmol, 0.2 eq.) was added to a solution of Intermediate 93 (119 mg, 0.177 mmol) in EtOH (4 mL) at room temperature and it was stirred at 60 °C for 2 h then at room temperature for 16 h. Additional pyridinium 4-toluenesulfonate (5 mg, 0.018, 0.1 eq.) was added and the mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM:MeOH (9:1) in DCM 0/100 to 30/70) to yield the title compound (48 mg, yield: 46%) as an orange solid.

Compound 82: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide.

CIS

(Method E)

[0701] Intermediate 98 (HC1 salt, 80 mg, 0.18 mmol), 3-[(2-hydroxyethyl)sulfonyl]-4- methylbenzoic acid (CAS [1094404-86-0] (HC1 salt, 53 mg, 0.22 mmol, 1.2 eq.), and DIPEA (150μL, 0.91 mmol, 5 eq.) were dissolved in DMF (4 mL). After 15 min, HBTU (76 mg, 0.2 mmol, 1.1 eq.) was added and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with aqueous NaiCCh (1 M) and extracted with DCM. The organic layer was washed with brine, dried on MgSO f4i.ltered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g silica; DCM:MeOH (9: 1)/DCM 0/100 to 25/75). The desired fractions were collected and concentrated in vacuo. The resulting product was triturated with ACN and filtered to give Compound 82 (51 mg, yield: 46%) as a yellow solid. [0702] The compounds in Table 13 were prepared from Intermediate 98 and the corresponding acid, following procedures analogous to the methods shown in the table: Table 13.

Compound 90: N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-methylpyridin-2-yl)-l,6- naphthyridm-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide. CIS

[0703] Compound 90 was prepared according to Method A (solvent: DMF), starting from Intermediate 123 and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]).

Compound 93: 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.

CIS

[0704] Intermediate 124 (70 mg, 0.138 mmol), Intermediate 127 (56 mg, 0.208 mmol, 1.5 eq.), and K2CO3 (29 mg, 0.208 mmol, 1.5 eq.) were dissolved in 1,4-di oxane (24 mL) in a sealed tube under a nitrogen stream. Di-/c/7-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 4 mg, 0.014 mmol, 0.1 eq.) and Pd(OAc)₂ (CAS [3375-31-3], 2 mg, 0.007 mmol, 0.05 eq.) were added and the reaction mixture was stirred at 150 °C for 4 h. The mixture was cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over MgSO4 f.iltered, and concentrated. The residue was purified by flash column chromatography (25 g silica; DCM:MeOH (9:1) in DCM from 0/100 to 100/0) followed by reverse phase column chromatography (Gemini C18 100 x 30 mm 5 urn; from 50 % H2O (0.1 % HCOOH) - 50 % MeCN - MeOH to 25 % H2O (0.1 % HCOOH) - 75 % MeCN - MeOH) to yield Compound 93(7 mg, yield: 8 %) as a yellow solid. [0705] The Compounds in Table 14 were prepared in a manner analogous to Compound 93 using Intermediate 124 and the corresponding Intermediate.

Table 14

Compound 96: 3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-(l-hydroxyethyl)benzamide, Compound 97: 3-chloro-N-((2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-((*R)-l- hydroxyethyl)benzamide, and Compound 98: 3-chloro-N-((2-(6-((cis)-2,6- dimethylmorpholino)py ridin-2-yl)- 1 ,6-naphthy ri din-7 -yl)methyl)-5-((* S)- 1 - hydroxy ethyl)benzamide.

Compound 96 (CIS, mixture of stereoisomers)

Compound 97 (*R, C/5; pure stereoisomer but absolute stereochemistry undetermined)

Compound 98 (*S, CIS,' pure stereoisomer but absolute stereochemistry undetermined) [0706] A mixture of Intermediate 130 (390 mg, 0.893 mmol), c7.s-2.6-di methyl morpholine (CAS [6485-55-8], 660 μL 5, .356 mmol, 6 eq.), and DIPEA (930 μ 5L.3,39 mmol, 6 eq.) was stirred for 16 h at 130 °C. The reaction mixture was diluted with saturated aqueous NaHCO3 and was extracted with DCM (3 x). The combined organic layer was dried with MgSO4. filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g SiCh, DCM:MeOH (9:1) in DCM, from 0/100 to 40/60) to yield Compound 96 (350 mg, yield: 73 %) as a yellow solid. Compound 96 (342 mg) was separated into its stereoisomers by semipreparative SFC (i-cellulose-c column; isocratic mode method: 35 % [EtOH + 0.1 % DEA] - 65 % [CO2]) to yield Compound 97 (101 mg, yield: 21 %) and Compound 98 (112 mg, yield: 23 %), both as yellow solids.

Compound 99: 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.

[0707] Step A: tert-butyl (lR,5S)-9-(6-(7-((4-cyclopropyl-3-

(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonane-7-carboxylate. The title compound was prepared according to Method J, starting from Intermediate 65 and tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane- 7-carboxylate (CAS [864448-41-9]).

[0708] Step B: 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. HC1 (4 M in 1.4- dioxane, 858 pM; 3.432 mmol, 10 eq.) was added to a solution of tert-butyl (lR,5S)-9-(6-(7- ((4-cyclopropyl-3-(methylsulfonyl)benzamido)methyl)-l,6-naphthyri din-2 -yl)pyridin-2-yl)-3- oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (235 mg, 0.343 mmol) in DCM (3 mL) and 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 ( 3x). The combined organic layer was dried with MgSO4. filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (25 g column, gradient of DCM:MeOH 9:1 in DCM from 0 % to 60 %) to yield Compound 99 (151 mg, yield: 74 %) as a yellow solid.

Compound 100: 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.

[0709] Formaldehyde (37 % in water, 121 μL 1,.625 mmol, 10 eq.) was added to a stirred suspension of Compound 99 (95 mg, 0.162 mmol) in THF (10 mL) and MeOH (2.5 mL) at room temperature, leading to a clear solution within 15 min. NaBH(OAc)s (172 mg, 0.812 mmol, 5 eq.) was then added portion- wise over 30 min. Stirring was then continued at room temperature for 20 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and was extracted with DCM (3 x). The combined organic layer was dried with MgSO4 f,iltered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (25 g column, gradient of DCM:MeOH 9: 1 in DCM from 0 % to 55 %) to yield Compound 100 (75 mg, yield: 75 %) as a yellow solid.

Compound 101 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3-(2-hydroxypropan-2-yl)-4-methylbenzamide.

CIS

[0710] Compound 101 was prepared according to Method J, starting from Intermediate 132 and cA-2,6-dimethylmorpholine (CAS [6485-55-8]).

Compound 103: 4-cyclopropyl-N-((2-(6-((3*S,4*R)-4-hydroxy-3-methylpiperidin-l- yl)pyridin-2-yl)-l ,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide and Compound 104: 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.

Compound 103 (3-*S,4-*R, CIS pure enantiomer but absolute stereochemistry undetermined)

Compound 104 (3-*R; 4-*S, CIS pure enantiomer but absolute stereochemistry undetermined) [0711] The racemic mixture of Compound 103 and Compound 104 was prepared according to Method A, starting from Intermediate 134 and Intermediate 135. The racemic mixture was then separated into the stereoisomers by preparative SFC (Column: Phenomenex; Lux i- Amylose-1 250 x 30 mm 5 um; Isocratic 60 % (iPrOH + 0.1 % DEA) to afford Compound 103 and Compound 104, both as yellow solids.

Compound 105: 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 and Compound 106: N-((2-(6-((3*R,4*S)-4-hydroxy-3-methylpiperi din-1 -yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-2,3-dimethyl-5-(methylsulfonyl)benzamide.

Compound 105 (3-*S,4-*R, pure enantiomer but absolute stereochemistry undetermined)

Compound 106 (3*R; 4-*S, pure enantiomer but absolute stereochemistry undetermined) [0712] Compound 105 and Compound 106 were prepared according to Method A, starting from Intermediate 134 and 3-methanesulfonyl-4,5-dimethylbenzoic acid (CAS [151104-66- 4]), followed by preparative SFC (column: Phenomenex Lux i-Amylose-1 250 x 30 mm 5 um, Isocratic 50 % (iPrOH + 0.1 % DEA).

Compound 107: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide.

CIS

[0713] A solution of Intermediate 141 (70 mg, 0.056 mmol), sodium methanesulfmate (9 mg, 0.084 mmol, 1.5 eq.), L-proline (1 mg, 0.011 mmol, 0.2 eq.), and cuprous iodide (1 mg, 0.0056 mmol, 0.1 eq.) in dry DMSO (1 mL) was degassed with nitrogen for 5 min. The reaction mixture was stirred at 100 °C for 5 h. More sodium methanesulfmate (40 mg, 0.394 mmol, 7 eq.) and cuprous iodide (9 mg, 0.045 mmol, 0.8 eq.) were added and the reaction mixture was stirred at 100 °C for 40 h. More sodium methanesulfmate (58 mg, 0.562 mmol, 10 eq.) and cuprous iodide (11 mg, 0.056 mmol, 1 eq.) were added and the reaction mixture was stirred at 100 °C for 48 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. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane :EtOH/EtO Ac 1/3 100:0 to 0:100) to give Compound 107 (8 mg, yield: 24 %) as a yellow solid.

Compound 110: 2-fluoro-4-methyl-5-(methylsulfonyl)-N-((2-(6-(2,2,6,6- tetramethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[0714] Compound 110 was prepared according to Method A, starting from Intermediate 129 and 2-fluoro-5-methanesulfonyl-4-methylbenzoic acid (CAS [1897051-52-3])

Compound 112: 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.

(3a,4p,5a) (Method M)

[0715] 1-Propanephosphonic anhydride (50 % in EtOAc, 0.18 mL, 0.3 mmol, 1.7 eq.) was added to a solution of Intermediate 149 (80 mg, 80 % pure, 0.18 mmol), 2-fluoro-4-methyl-5- (methylsulfonyl)-benzoic acid, CAS [1897051-52-3], 61 mg, 0.26 mmol, 1.5 eq.), and EtsN (0.15 mL, 1.06 mmol, 6 eq.) in DCM (2 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in MeOH and water, filtered, and purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 5 pm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to yield Compound 112 (74 mg, yield: 71 %) as a yellow solid.

[0716] The compounds in Table 15 were prepared from Intermediate 149 (* except for Compound 120, prepared from Intermediate 337) and the corresponding acid, following procedures similar to the methods shown in the Table 15.

Table 15.

Compound 114: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3-(l-hydroxyethyl)benzamide, Compound 122: N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-3-((*R)- 1 - hydroxyethyl)benzamide, and Compound 123: N-((2-(6-((cis)-2,6- dimethylmorpholino)py ridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-3-((* S)- 1 - hydroxy ethyl)benzamide.

CIS Compound 114

Compound 122 (*R, CIS; pure enantiomer but absolute stereochemistry)

Compound 123 (*S, C/5; pure enantiomer but absolute stereochemistry undetermined) [0717] Compound 114 was prepared according to Method J, starting from Intermediate 150 and c7.s-2.6-dimethylmorpholine (CAS [6485-55-8]). Compound 114 was separated into its stereoisomers by preparative SFC (i-cellulose-c column; isocratic mode method: 35 % [EtOH + 0.1 % DEA] - 65 % [CO2]) to afford Compound 122 and Compound 123, both as yellow solids.

Compound 118: 3-((*S)-cyclopropyl(hydroxy)methyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide and Compound 119: 3-((*R)-cyclopropyl(hydroxy)methyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin- 2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide.

Compound 118 (*S, CIS; pure enantiomer but absolute stereochemistry undetermined)

Compound 119

(*R, CIS; pure enantiomer but absolute stereochemistry undetermined)

[0718] Compound 118 and Compound 119 were prepared according to Method A (in DMF), starting from Intermediate 11 and 3-(cyclopropylhydroxymethyl)benzoic acid (CAS [878742- 67-7]) followed by preparative SFC purification (Lux Amylose-2 250 x 30 mm 5 um column; isocratic mode method: 30 % [EtOH + 0.1 % DEA] - 70 % [CO2]). Compound 124: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4,5-dimethylbenzamide.

CIS

[0719] Pyridinium p-toluenesulfonate (6 mg, 0.024 mmol, 0.4 eq.) was added to a solution of Intermediate 153 (40 mg, 0.059 mmol) in EtOH (4 mL) at room temperature. The reaction mixture was stirred at 65 °C for 2 h and at room temperature for 16 h. More Pyridinium p- toluenesulfonate (6 mg, 0.024 mmol, 0.4 eq.) was added and the mixture was stirred at 65 °C for 2 h. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica; DCM:MeOH (9:1) in DCM, from 0/100 to 30/70) to yield Compound 124 (6 mg, yield: 17 %) as ayellow solid.

Compound 125: (5-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)carbamoyl)-2,3-dimethylphenyl)boronic acid.

CIS

[0720] A suspension of Intermediate 154 (108 mg, 0.171 mmol) and Na2CO3 (36 mg, 0.341 mmol, 2 eq.) in ACN (2 mL) and water (2 mL) was stirred at 60 °C overnight. MeOH (3 mL) was added to the yellow suspension and it was further stirred at 60 °C for 4 h. After cooling, the reaction mixture was directly purified by reverse phase chromatography (Stationary phase: RP XBridge Prep Cl 8 OBD- 5 pm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to yield Compound 125 (33 mg, yield: 37 %) as ayellow solid. Compound 128: N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0721] Compound 128 was prepared according to Method A (in DMF), starting from Intermediate 160 and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]).

Compound 130: 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.

(3a,4p,5a)

[0722] 1 -Propanephosphonic anhydride (50 % in EtOAc, CAS [68957-94-8], 112 0.μ1L8,9 mmol, 1.3 eq.) was added to a solution of Intermediate 149 (66 mg, 0.145 mmol) and 3- [(methylsulfonyl)methyl]benzoic acid (CAS [261924-94-1], 34 mg, 0.16 mmol, 1.2 eq.) in dry DCM (3 mL) at room temperature. EtsN (101 μ 0L.,726 mmol, 5 eq.) was then added dropwise to the orange suspension. The reaction mixture (clear yellow) was stirred at room temperature for 1 h. The solid that appeared was filtered and washed with water to give a yellow solid. This solid was triturated in ACN, filtered, and washed with a small amount of ACN to give Compound 130 (45 mg, yield: 55 %) as a yellow solid.

Compound 131: N-((2-(3,5-dichloro-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0723] NCS (11 mg, 0.081 mmol, 1.1 eq.) was added to a solution of Compound 1 (40 mg, 0.073 mmol) in l,l,l,3,3,3-hexafluoro-2-propanol (CAS [920-66-1], 1 mL) and the reaction mixture was stirred while slowly warming to room temperature. More NCS (11 mg, 0.081 mmol, 1.1 eq.) was added and the reaction mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (ISCO column; EtOAc/heptane 0/100 to 100/0), followed by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, MeOH) to yield Compound 131 (23 mg, yield: 57 %).

Compound 132: N-((2-(3-cyano-6-((cis)-2, 6-dimethylmorpholino)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0724] A vial was charged with dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene] palladium(II) (CAS [205319-10-4], 3 mg, 0.004 mmol, 0.05 eq.), Compound 79 (50 mg, 0.075 mmol), and zinc cyanide (9 mg, 0.075 mmol, 1 eq.). The vial was sealed and purged twice with vacuum/nitrogen cycles. A solution of DIPEA (3 μ 0L.0, 15 mmol, 0;2 eq.) in DMA (1 mL) was added and the reaction mixture was purged again by bubbling nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 100 °C overnight. After cooling, the reaction mixture was directly purified by column chromatography on silica gel (ISCO column; EtOAc) followed by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD- 5 pm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to afford Compound 132 (16 mg, yield: 38 %).

Compound 133: 4-cyclopropyl-3-(N,N-dimethylsulfamoyl)-N-((2-(6-(2,2,6,6- tetramethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

(Method C)

[0725] Intermediate 129 (HC1 salt, 139 mg, 0.31 mmol) was added to a stirred solution of Intermediate 165 (105 mg, 0.37 mmol, 1.2 eq.), HATU (176 mg, 0.46 mmol, 1.5 eq.), and DIPEA (162 μL, 0.93 mmol, 3 eq.) in DCM (6 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSCE). filtered, and the solvent was evaporated. The residue was purified by flash column chromatography (silica 12 g; MeOH in DCM from 0/100 to 25/75), followed by reverse phase chromatography (Phenomenex Gemini Cl 8 30 x 100 mm 5 pm Column; from 59 % [25 mM NH4HCO3] - 41 % [ACN:MeOH (1:1)] to 17 % [25 mMNMCOi] - 83 % [ACN:MeOH (1:1)]) to yield Compound 133 (55 mg, yield: 28 %) as a yellow solid. [0726] The following compounds in Table 16 were prepared in a manner analogous to

Compound 133, Method C; with the appropriate amine and acid substitutions.

Table 16.

Compound 134: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3-((*R)-l-methoxyethyl)-4-methylbenzamide, Compound 135: N-((2-(6-((cis)- 2,6-dimethylmorpholino)py ridin-2-y 1)- 1 ,6-naphthyridin-7-yl)methyl)-3-((* S)- 1 - methoxyethyl)-4-methylbenzamide, and Compound 136: N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l, 6-naphthyridin-7-yl)methyl)-3-(l -methoxy ethyl)-4- methylbenzamide. Compound 134 (*R, CIS,' pure enantiomer but absolute stereochemistry undetermined)

Compound 135 (*S, C/5; pure enantiomer but absolute stereochemistry undetermined)

Compound 136 (CIS,' mixture of stereoisomers)

[0727] Intermediate 167 (175 mg, 0.342 mmol) and PTSA.H2O (163 mg, 0.855 mmol, 2.5 eq.) in MeOH (1 mL) was stirred at 70 °C for 48 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and was extracted with DCM (3 x). The combined organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g SiCh, DCM:MeOH (9:1) in DCM 0/100 to 40/60) to yield Compound 136 (120 mg, yield: 66 %) as a yellow solid. A sample of Compound 136 was separated into its stereoisomers by preparative SFC (i-cellulose-c column; isocratic mode method: 50 % [EtOH + 0.1 % DEA] - 50 % [CO2]) to yield Compound 134 and Compound 135, both as yellow solids.

Compound 137: 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.

[0728] HC1 (4 M in 1,4-dioxane, 320 μL 1,.278 mmol, 20 eq.) was added to a solution of Compound 129 (43 mg, 0.064 mmol) in 1,4-dioxane (1.5 mL). 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/DCM from 0/100 to 9/91) to yield Compound 137 (19 mg, yield: 51 %) as a yellow solid. Compound 138: 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.

(3a,4p,5a) (Method P)

[0729] A solution of Intermediate 149 (35 mg, 0.072 mmol), EtsN (60 μ 0L.4,31 mmol, 6.0 eq.) in DCM (1 mL) was added to 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzoic acid (CAS [937026-26-1]), 28 mg, 0.122 mmol, 1.7 eq.). 1 -Propanephosphonic anhydride (50 % solution in EtOAc, 72 μL, 0.122 mmol, 1.7 eq.) was added dropwise to the reaction mixture and it was stirred at room temperature overnight. The solvents were evaporated and the residue was purified by reverse phase column chromatography (Stationary phase: RP XBridge Prep C18 OBD - 10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN or MeOH) to yield Compound 138 (18 mg, yield: 43 %). [0730] The Compounds in Table 17 were prepared in a manner analogous to Method P, using the acids listed in the table. In Table 17, all compounds have the (3a,4p,5a) stereochemistry for the dimethylpiperidinol group.

Table 17.

[0731] The Compounds in Table 18 were prepared according to Method P, using Intermediate 582 instead of Intermediate 149, and the indicated acid instead of 3-methoxy-4-(4-methyl-lH- imidazol-l-yl)benzoic acid. Table 18 Compound 157: 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.

*R, (3a, 4a, 5a): pure stereoisomer but absolute stereochemistry undetermined [0732] Compound 157 was prepared according to Method J, starting from Intermediate 171 and (3a,4a,5a)-3,5-dimethyl-4-piperidinol (CAS [1236030-00-4]).

Compound 158: 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-hydroxyethyl)-4-methylbenzamide.

*S, (3a, 4a, 5a): pure stereoisomer but absolute stereochemistry undetermined [0733] Compound 158 was prepared according to Method J, starting from Intermediate 172 and (3a,4a,5a)-3,5-dimethyl-4-piperidinol (CAS [1236030-00-4]).

Compound 162: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(3-hydroxyazetidin-3-yl)-4-methylbenzamide.

[0734] Intermediate 189 (155 mg, 0.243 mmol) was dissolved in a solution of HC1 (4 M in

1.4-dioxane, 2.427 mmol, 10 eq.) and DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo and the residue was triturated in

1.4-dioxane. The solid was filtered and washed with Et20. Then EtOAc, water, and saturated aqueous NaHCO3 were added until pH 8. The layers were separated and the aqueous layer was extracted with EtOAc (x 5). The combined organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the title compound (97 mg, yield: 72 %) as a yellow solid. Compound 163: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3-(4-hydroxypiperidin-4-yl)-4-methylbenzamide.

CIS [0735] Compound 163 was prepared in a similar manner as Compound 162, starting from

Intermediate 193 instead of Intermediate 189.

Compound 164: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((*R)-l-hydroxyethyl)benzamide and Compound 165: N-((2-(6- ((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3-((*S)- l-hydroxyethyl)benzamide.

Compound 164 (*R, C/5; pure stereoisomer but absolute stereochemistry undetermined)

Compound 165 (*S, CIS,' pure stereoisomer but absolute stereochemistry undetermined) [0736] The stereoisomers of Compound 88 were separated by preparative SFC (Lux- celllulose-C SFC; isocratic Mode 50 % iPOH + 0.1 % DEA, CO2) to yield Compound 164 and Compound 165. Compound 166: 3-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((*R)-l-hydroxyethyl)benzamide and Compound 167: 3-chloro-

N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-5-((* S)- 1 -hydroxyethyl)benzamide.

Compound 166 (*R, C/5; pure stereoisomer but absolute stereochemistry undetermined)

Compound 167 (*S, C/5; pure stereoisomer but absolute stereochemistry undetermined) [0737] The stereoisomers of Compound 243 were separated by preparative SFC (Lux- celllulose-C SFC; isocratic Mode 50 % iPOH + 0.1 % DEA, CO2) to yield Compound 166 and Compound 167.

Compound 168: 4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(3-hydroxyazetidin-3-yl)benzamide.

CIS

[0738] Intermediate 274 (194 mg, 0.294 mmol) was dissolved in a solution of HC1 (4 M in 1,4-dioxane, 736 μL, 2.943 mmol, 10 eq.) and DCM (5 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo. 1,4-Dioxane was added and the solid was filtered and washed with Et20. The solid was taken up with saturated aqueous NaHCO3 and this solution was extracted with DCM (3 x). The combined organic layer was dried on MgSO4. filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g silica, gradient of B (DCM/Methanol/NHs 9/1/0.25) in A (DCM), from 0 % to 60 % of B) to yield Compound 168 (68 mg, yield: 41 %) as a yellow solid.

Compound 169: N-((2-(3-chtoro-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0739] NCS (49 mg, 0.37 mmol, 1 eq.) was added to an ice-cold solution of Compound 1 (200 mg, 0.37 mmol) in l,l,l,3,3,3-hexafluoro-2-propanol (1 mL) and the reaction mixture was stirred at 0 °C for 4 h, then at room temperature overnight. The solvent was evaporated and the residue was purified by flash column chromatography (silica 40 g, MeOH/DCM 100/0 to 94/6) followed by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD- 5 pm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, MeOH) to yield Compound 169 (74 mg, yield: 35 %), Compound 131 (7 mg, yield: 3 %), and Compound 170 (18 mg, yield: 8 %).

Compound 170: N-((2-(5-chloro-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0740] The title compound was isolated from the reaction to prepare Compound 169.

Compound 172: N-((*R)-l-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)ethyl)-4-methyl-3-(methylsulfonyl)benzamide and Compound 173: N- ((*S)-l-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)ethyl)-4- methyl-3-(methylsulfonyl)benzamide.

Compound 172 (*R, C/5; pure stereoisomer but absolute stereochemistry undetermined)

Compound 173 (*S, C/5; pure stereoisomer but absolute stereochemistry undetermined) [0741] Compound 172 and Compound 173 were prepared according to Method F, starting from Intermediate 196 and 4-methyl-3-methylsulfonylbenzoic acid (CAS [51522-22-6]), followed by preparative SFC (Stationary phase: Chiralcel Diacel OJ 20 x 250 mm, Mobile phase: CO₂, EtOH + 0.4 % iPrNH₂).

Compound 174: 3-((diethylamino)methyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-4,5-dimethylbenzamide.

CIS

[0742] Tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 21 mg, 0.018 mmol) was added to a suspension of Compound 27 (108 mg, 0.178 mmol), potassium diethylaminomethyl(trifluoro)boranuide (CAS [936329-95-2], 59 mg, 0.289 mmol, 1.6 eq.), and Na2CO3 in water (0.9 mL, 1 M, 0.889 mmol) in 1,4-di oxane (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 100 °C. More potassium diethylaminomethyl(trifluoro)boranuide (59 mg, 0.289 mmol, 1.6 eq.) and tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol, 0.1 eq.) were added and the vial was degassed with nitrogen and sealed. The reaction mixture was stirred at 110 °C in a microwave oven for 2 h. 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 by filtration on Extrelut NT3, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: DCM/(7 N NEE in MeOH:DCM 1:9) 100/0 to 20/80) to give Compound 174 (29 mg, yield: 29 %) as a yellow solid.

Compound 175: tert-butyl (4-((2*S,6*R)-6-methyl-4-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)morpholin-2- yl)butyl)carbamate.

C/5-(2*S,6*R), pure stereoisomer but absolute stereochemistry undetermined [0743] Intermediate 208 (291 mg, 1.068 mmol, 1 eq.) was added to a solution of Intermediate 46 (481 mg, 1.068 mmol) and DIPEA (545 μL 3,.205 mmol, 3 eq.) in DMSO (3 mL) at room temperature. The reaction mixture was stirred at 120 °C for 36 h. After cooling, the mixture was washed with aqueous Na2CO3 (1 M) and extracted with EtOAc. The organic layer was dried (MgSO4). filtered, and the solvent evaporated in vacuo. The residue was purified by flash column chromatography (25 g silica, gradient of DCM/MeOH (9/1) in DCM from 0/100 to 100/0), followed by reverse phase column chromatography (Gemini C18 100 x 30 mm 5 urn; from 47 % H₂O (0.1 % HCOOH) - 53 % ACN to 18 % H2O (0.1 % HCOOH) - 82 % ACN), to afford Compound 175 (330 mg, yield: 43 %) as a yellow solid.

Compound 176: tert-butyl (4-((2*R,6*S)-6-methyl-4-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)morpholin-2- yl)butyl)carbamate.

C/5-(2*R,6*S), pure stereoisomer but absolute stereochemistry undetermined [0744] Compound 176 was prepared in a similar manner as Compound 175, using Intermediate 209 instead of Intermediate 208.

Compound 177: methyl 2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3-

(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)isonicotinate.

CIS

[0745] Compound 177 was prepared according to Method J, using Intermediate 210 and cis-

2,6-dimethylmorpholine (CAS [6485-55-8]).

Compound 178: 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.

CIS-(2-*S, 6-*R), pure stereoisomer but absolute stereochemistry undetermined [0746] Compound 175 (320 mg, 0.455 mmol) was dissolved in a solution of HC1 (4 M in 1,4- dioxane, 1.14 mL, 4.553 mmol, 10 eq.) in 1,4-dioxane (2.7 mL) and the mixture was stirred at room temperature for 16 h. The mixture was basified with aqueous Na2CO3 (1 M) and extracted with DCM. The organic layer was dried (MgSOr). filtered, and the solvents evaporated in vacuo. The residue was triturated in Et20 to yield Compound 178 (250 mg, yield: 87 %) as a yellow solid.

Compound 179: 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.

CIS-(2-*R, 6-*S), pure stereoisomer but absolute stereochemistry undetermined [0747] Compound 179 was prepared in a similar manner as Compound 178, using Compound 176 instead of Compound 175.

Compound 181: 2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)isonicotinic acid.

CIS

[0748] A solution of LiOH (14 mg, 0.344 mmol, 2 eq.) in water (0.5 mL) was added to a solution of Compound 177 (106 mg, 0.172 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (Column Gemini 5 pm Cl 8 (100 x 30 mm); gradient from 59 % [0.1 % HCOOH] - 41 % [ACN: MeOH 1:1] to 17 % [0.1 % HCOOH] - 83 % [ACN: MeOH 1:1]) to give Compound 181 (55 mg, yield: 54 %) as a yellow solid.

Compound 182: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-(hydroxymethyl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0749] LiAlH4 (22 mg, 0.579 mmol, 2.2 eq.) was added portion-wise to a solution of Compound 177 (159 mg, 0.263 mmol) in dry THF (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of ice. NaOH (1 M in water, 10 mL) was added and the solution was filtered through a pad of Celite®. The filter was washed with DCM. The filtrate was extracted with DCM. The combined organic layer was dried over MgSO4. filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiCh 25 g, MeOH/DCM (9/1) in DCM 0/100 to 70/30) followed by reverse phase chromatography (Column Gemini 5 pm Cl 8 (100 x 30 mm); gradient from 72 % [65 mM NH₄OAc:ACN (90:10)] - 28 % [ACN:MeOH 1:1] to 36 % [65 mM NH₄OAC: ACN (90: 10)] - 64 % [ACN:MeOH 1 : 1]) to give Compound 182 (31 mg, yield: 18 %) as a pale yellow solid.

Compound 184: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(((*R)-2-hydroxypropyl)sulfonyl)-4-methylbenzamide and Compound 185: N- ((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-3-(((*S)-2- hydroxypropyl)sulfonyl)-4-methylbenzamide.

Compound 184: CIS, *R, pure stereoisomer but absolute stereochemistry undetermined

Compound 185: CIS, *S, pure stereoisomer but absolute stereochemistry undetermined [0750] Compound 184 and Compound 185 were prepared according to Method B, using Intermediate 11 and 3 -[(2 -hydroxy propyl)sulfonyl]-4-methyl-benzoic acid (CAS [1467509- 58-5]), followed by preparative SFC (Amylose 1 column, isocratic 45 % EtOH + 0.3 % IP A).

Compound 186: 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.

CIS-(2-*S, 6-*R), pure stereoisomer but absolute stereochemistry undetermined [0751] A solution of Compound 178 (156 mg, 0.259 mmol) and EtsN (108 0μ.L77, 6 mmol, 3 eq.) in DCM (5 mL) was cooled in an ice bath under nitrogen atmosphere. A solution of acetic anhydride (31 μL, 0.285 mmol, 1.1 eq.) in DCM (5 mL) was then added dropwise over 5 min. The reaction mixture was stirred for another 30 min at 0 °C. Aqueous Na2CO3 (1 M, 20 mL) was added while stirring. After 5 min, the organic layer was separated and the aqueous layer was extracted with DCM (50 mL). The combined organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography (25 g silica; DCM/MeOH (9/1) in DCM from 0/100 to 100/0) to yield Compound 186 (116 mg, yield: 68 %) as a yellow solid.

Compound 187 : 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.

CIS-(2-*R, 6-*S), pure stereoisomer but absolute stereochemistry undetermined [0752] Compound 187 was prepared in a similar manner as Compound 186, using Compound 179 instead of Compound 178.

Compound 188: 3-(aminomethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4, 5 -dimethylbenzamide.

CIS

[0753] HC1 (4 M in 1,4-dioxane, 0.98 mL, 3.93 mmol, 60 eq.) was added to Intermediate 225 (40 mg, 0.065 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated and the red residue was dissolved in NHs/MeOH (7 N, 5 mL), forming a yellow solution. This solution was evaporated and the residue was purified by column chromatography (Biotage Sfar 10 g; eluent: DCM/[7 N NIL in MeOH:DCM 1:9] 100/0 to 0/100) to give Compound 188 (12 mg, yield: 36 %) as a yellow solid.

Compound 189: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-((*S)-morpholin-2-yl)benzamide.

Compound 189: CIS, *S, pure stereoisomer but absolute stereochemistry undetermined [0754] HC1 (4 M in 1,4-dioxane, 0.37 mL, 1.48mmol, 10 eq.) was added to a solution of Intermediate 218 (97 mg, 0.15 mmol) in 1,4-dioxane (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture 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 twice with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica 24 g; MeOH in DCM 0/100 to 10/90) to yield a mixture of stereoisomers (62 mg, yield: 75 %) as a green solid. A sample of the mixture was separated into its stereoisomers by preparative SFC (Column: Phenomenex; Lux i-Amylose-1 250 x 30 mm 5 um; Method: isocratic 60 % of CO2 - 40 % (IPA + 0.1 % DEA) to yield Compound 189 as a white solid (the stereoisomer of Compound 189 was not isolated).

Compound 191 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-3-((*S)-3-hydroxypiperidin-3-yl)-4-methylbenzamide.

(*S)-piperidinol, C/5; pure stereoisomer but absolute stereochemistry undetermined [0755] Intermediate 276 (252 mg, 0.378 mmol) was dissolved in a solution of HC1 (4 M in 1,4-dioxane, 0.945 mL, 3.779 mmol, 10 eq.) and DCM (5 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo, then 1,4-dioxane was added and the solid was filtered. The solid was taken up with EtOAc and water, and saturated aqueous NaHCCL was added until pH 8. The mixture was extracted with EtOAc (x 5). The combined organic layer was dried on 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 a yellow solid (155 mg, yield: 72 %). A sample of this compound was further purified by semipreparative SFC (i-Amylose-1 column, isocratic mode method: 55 % [IPA-EtOH + 0.1 % DEA] - 45 % [CO2]) to yield Compound 191 (22 mg, yield: 10 %) as a yellow solid. Compound 192: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-(l -hydroxy ethyl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0756] Intermediate 291 (100 mg, 0.15 mmol) was dissolved in dry THF (5 mL) and the reaction mixture was cooled to 0 °C under nitrogen atmosphere. Methylmagnesium bromide (1.3 M in THF, 121 μL, 0.157 mmol, 1.05 eq) was added dropwise at 0 °C and the reaction mixture was stirred for 1 h. This was repeated four more times (each with 121 pL of methylmagnesium bromide, and 1 h stirring). The reaction was quenched by addition of saturated aqueous NH4CI. The mixture was partitioned with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layer was dried (MgSO4), filtered, and the solvents evaporated. The residue was purified by flash column chromatography (25 g SiO2, DCM/MeOH (9/1 v/v) in DCM, from 0 % to 50 %), followed by preparative HPLC (Column C18 5 pm 30 x 100 mm Phenomenex; From 81 % 0.1 % HCOOH - 19 % [ACN:MeOH 1:1] to 45 % [0.1 % HCOOH] - 55 % [ACN:MeOH 1:1]), and trituration of the resulting solid in ACN (1 mL) gave Compound 192 (20 mg, yield: 22 %) as a yellow solid.

Compound 193: 2-((cis)-2,6-dimethylmorpholino)-6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)isonicotinamide.

CIS

[0757] Compound 177 (300 mg, 0.5 mmol) was dissolved in ammonia (7 M in MeOH, 30 mL, 210 mmol) in a sealed tube. The reaction mixture was stirred at 100 °C for 24 h. After cooling, the reaction mixture was diluted with DCM (100 mL) and water (50 mL). The solid at the interface was filtered and washed with water (3 x 20 mL). This solid was triturated in ACN (3 mL), filtered, and dried to give a first batch of Compound 193 (50 mg, yield: 17 %) as a yellow solid. The layers were separated and the aqueous layer was extracted twice with DCM/MeOH (9/1, v/v, 2 x 100 mL). The combined organic layer was dried over MgSO4. filtered, and concentrated in vacuo to give a second batch of Compound 193 (145 mg, yield: 49 %).

Compound 197: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-5-(methylsulfonyl)-2-vinylbenzamide.

CIS

[0758] NaOH (1 M in water, 3.12 mL, 3.124 mmol, 10 eq.) was added to Intermediate 232 (190 mg, 0.312 mmol) in THF (5 mL) and MeOH (15 mL) at room temperature. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with DCM. The organic layer was dried over MgSCL, filtered, and concentrated. The residue was purified by column chromatography on silica gel (24 g, 0 to 100 % EtOAc/heptane to 10 % MeOH/EtOAc) to give Compound 197 (12 mg, yield: 7 %).

Compound 198: 3-chloro-N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide.

(3a, 4|3, 5a)

[0759] Compound 198 was prepared according to Method M, using Intermediate 223 and 3- chloro-5-(methylsulfonyl)benzoic acid (CAS [151104-63-1]).

Compound 199: 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. [0760] Compound 199 was prepared according to Method A (in DMF), using Intermediate 300 and 3-(2-hydroxyethanesulfonyl)-4-methylbenzoic acid (CAS [1094404-86-0]).

Compound 200: N-((2-(4-cyano-6-((cis)-2, 6-dimethylmorpholino)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0761] Cyanuric chloride (CAS [108-77-0], 100 mg, 0.542 mmol) was added to a solution of Compound 193 (141 mg, 0.24 mmol) in DMF (5 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min and then allowed to come to room temperature and stirred for another 30 min. The reaction was quenched by addition of aqueous Na2CO3 (1 M, 30 mL) and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine, dried over MgSO f4i.ltered, and concentrated in vacuo. The residue was purified by chromatography over silica gel (25 g column, gradient of EtOAc/heptane from 0/100 to 100/0). The resulting yellow solid was triturated in ACN (4 mL) and filtered to give Compound 200 (64 mg, yield: 45 %) as a yellow solid.

Compound 201: 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.

[0762] A vial containing Intermediate 235 (100 mg, 0.293 mmol, 1.5 eq.), hexamethylditin (CAS [661-69-8], 96 mg, 0.293 mmol, 1.5 eq.), and tetiakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 135 mg, 0.117 mmol, 0.6 eq.) was evacuated and back-filled with argon three times. 1,4-Dioxane (3 mL) was added and argon was bubbled through the reaction for 10 min. The reaction mixture was stirred at 110 °C for 3 h. After cooling to room temperature, Intermediate 45 (76 mg, 0.195 mmol) and more tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039 mmol, 0.2 eq.) were added to the reaction mixture and it was stirred at 110 °C for 18 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (40 g column, MeOH/DCM 0/100 to 100/0) to give a Boc-protected intermediate. This Boc-protected intermediate was dissolved in DCM (1 mL) and TFA (0.149 mL, 1.95 mmol, 10 eq.) was added drop wise. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and the residue was purified by reverse phase column chromatography (Column: OOD-4633-UO-AX Kinetex 5umEV0 cl 8 100; 0.1 % TFA in water and ACN, from 10 % ACN to 100 %) to give Compound 201 (63 mg, yield: 58 %) as a solid.

Compound 202: N-((2-(3-((cis)-2,6-dimethylmorpholino)-2-fluorophenyl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0763] Intermediate 45 (121 mg, 0.199 mmol) and Na2CO3 (1 M in water, 0.795 mL, 0.795 mmol, 4 eq.) were added to a solution of Intermediate 237 (100 mg, 0.298 mmol, 1.5 eq.) in 1,4-dioxane (5 mL) at room temperature under nitrogen atmosphere. Pd(dppf)C12.CH2C12 (CAS [95464-05-4], 8 mg, 0.010 mmol, 0.05 eq.) was then added, and the mixture was stirred at 85 °C under nitrogen for 4 h. After cooling, the mixture was diluted with aqueous Na2CO3 and extracted with EtOAc. The organic layer was dried (MgSOr). filtered, and the solvents evaporated in vacuo. The residue was precipitated in DCM/MeOH and the solid was filtered to give a pale brown solid. This solid was triturated with ACN to afford Compound 202 (91 mg, yield: 80 %) as a white solid.

Compound 203: N-((2-(3-((cis)-2,6-dimethylmorpholino)-2,4-difluorophenyl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0764] Intermediate 124 (118 mg, 0.233 mmol), Intermediate 238 (107 mg, 0.350 mmol, 1.5 eq.), and K2CO3 (48 mg, 0.350 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (5 mL) in a sealed tube under a nitrogen stream. Di-/c/7-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 6 mg, 0.023 mmol, 0.1 eq.) and Pd(OAc)₂ (CAS [3375-31-3], 3 mg, 0.012 mmol, 0.05 eq.) were added and the reaction mixture was stirred at 150 °C for 4 h. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 f.iltered, and concentrated. The residue was purified by flash column chromatography (25 g silica; DCM:MeOH (9:1) in DCM from 0/100 to 40/60) to yield Compound 203 (4 mg, yield: 3 %) as a yellow solid.

Compound 204: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-morpholinobenzamide.

CIS

[0765] Compound 204 was prepared according to Method A, using Intermediate 11 and 4- methyl-3-(4-morpholinyl)benzoic acid (CAS [886501-52-6]).

Compound 205: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(tetrahydrofuran-2-yl)benzamide.

CIS

[0766] Compound 205 was prepared according to Method A, using Intermediate 11 and Intermediate 304.

Compound 206: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3,4-dimethyl-5-((4-methylpiperazin-l-yl)methyl)benzamide.

CIS

[0767] Tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 22 mg, 0.018 mmol) was added to a suspension of Compound 27 (112 mg, 0.184 mmol), potassium l-methyl-4- trifluoroboratomethylpiperazine (CAS [1015484-22-6], 61 mg, 0.277 mmol) and Na₂CO3 in water (0.92 mL, 1 M, 0.92 mmol) in 1,4-di oxane (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 100 °C. 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 by filtration on ExtrelutNT3, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH/EtO Ac 1/3 100:0 to 0:100 followed by DCM/(7 NNH₃ in MeOH:DCM 1:9) 100/0 to 20/80) to give Compound 206 as a yellow solid (54 mg, yield: 49 %) as a yellow solid.

Compound 207 : N-((2-(6-(4,7 -di azaspiro [2.5] octan-7 -yl)pyridin-2-yl)- 1 ,6-naphthy ridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0768] HC1 (4 M in 1,4-dioxane; 2 mL, 8 mmol, 52 eq.) was added to Intermediate 262 (99 mg, 0.154 mmol) and the mixture was stirred for 1 h at room temperature. The solid that appeared was filtered, washed with 1,4-dioxane, and dried, to afford Compound 207 (HC1 salt, 92 mg, yield: 97 %) as an orange solid.

Compound 208: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyrazin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

CIS

[0769] Intermediate 124 (150 mg, 0.297 mmol), Intermediate 263 (261 mg, 0.884 mmol, 3 eq.), di-/c/7-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 7 mg, 0.030 mmol, 0.1 eq.), Pd(OAc)₂ (CAS [3375-31-3], 7 mg, 0.015 mmol, 0.05 eq.), and K2CO3 (123 mg, 0.89 mmol, 3 eq.) were suspended in 1,4-dioxane (1 mL) in a sealed tube under nitrogen atmosphere. The reaction mixture was stirred at 120 °C overnight. After cooling, the mixture was diluted with DCM and water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 5 pm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN), to afford Compound 208 (36 mg, yield: 22 %).

Compound 209: N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- 1 ,6-naphthyridin-7-yl)methyl)-3-((*R)-l -hydroxy ethyl)-4-methylbenzamide and Compound 210: N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)-3-((* S)- 1 -hydroxy ethyl)-4-methylbenzamide.

*R, (3a, 4p, 5a): pure stereoisomer but absolute stereochemistry undetermined

*S, (3a, 4p, 5a): pure stereoisomer but absolute stereochemistry undetermined [0770] Compound 209 and Compound 210 were prepared according to Method K, starting from Intermediate 171, and Intermediate 172, respectively, and both with (3a,4p,5a)-3,5- dimethyl-4-piperidinol (CAS [374067-78-4]).

Compound 211 : 4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)phenyl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0771] Compound 211 was prepared using Method A (in DMF) starting from Intermediate 328 and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]).

Compound 212: 4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)phenyl)-l,6- naphthyridin-7-yl)methyl)benzamide. [0772] Compound 212 was prepared using Method A (in DMF) starting from Intermediate 330 and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]).

Compound 213: N-((2-(4-fluoro-3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)-4-

[0773] Compound 213 was prepared using Method A (in DMF) starting from Intermediate 332 and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]).

Compound 214: N-((2-(2-fluoro-3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

[0774] Intermediate 45 (150 mg, 0.384 mmol) and Na2CO3 (1 M in water, 0.768 mL, 0.768 mmol, 2 eq.) were added to a solution of 4-[2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl] pyridine (CAS [693818-26-7], 191 mg, 0.576 mmol, 1.5 eq.) in 1,4- dioxane (5 mL) previously bubbled through with a flow of nitrogen at room temperature. Pd(dppl)C12.CH2C12 (CAS [95464-05-4], 16 mg, 0.019 mmol, 0.05 eq.) was then added, and the mixture was stirred at 90 °C under nitrogen for 5 h. After cooling, the mixture was washed with water and extracted with EtOAc. The organic layer was dried over MgSO4. filtered, and evaporated. The residue was precipitated in ACN and the solid was filtered to give Compound 214 (96 mg, yield: 47 %) as a pale solid.

Compound 215: 4-methyl-3-(methylsulfonyl)-N-((2-(7-(pyridin-4-yl)-2,3-dihydrobenzofuran-

5 -yl)- 1 ,6-naphthy ri din-7 -y l)methyl)benzamide. [0775] Compound 215 was prepared similarly to Compound 214 using Intermediate 333 instead of 4-[2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyridine.

Compound 216: N-((2-(2-methoxy-5-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

[0776] Compound 216 was prepared similarly to Compound 214 using Intermediate 334 instead of 4-[2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyridine.

Compound 217: N-((2-(3-fluoro-5-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

[0777] Compound 217 was prepared similarly to Compound 214 using Intermediate 335 instead of 4-[2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyridine.

Compound 218: N-((2-(6-((3a,4a,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0778] Compound 218 was prepared according to method M, using Intermediate 337 instead of Intermediate 149, and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]) instead of 2-fluoro-4-methyl-5-(methylsulfonyl)-benzoic acid. Compound 219: N-((2-(6-(5,6-dihydro-2H-pyran-3-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0779] Compound 219 was prepared using Method A (in DMF) starting from Intermediate 340 and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]).

Compound 220: 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.

[0780] Compound 220 was synthesized using Method A (in DMF) starting from Intermediate 343 and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]).

Compound 221 : N-((2-(6-(5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0781] Step A: tert-butyl 8-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyridin-2-yl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate. Intermediate 46 (100 mg, 0.211 mmol, 1 eq.) and tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (CAS [1251011-05-8], 193 mg, 0.844 mmol, 4 eq.) were suspended in DMSO (2 mL) and DIPEA (109 μL, 0.633 mmol, 3 eq.) was added. The mixture was stirred at 130 °C until full conversion. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The combined organic layer was dried over MgSO f4i.ltered, and evaporated. The residue was purified by flash column chromatography (12 g, DCM/MeOH from 100/0 to 90/10) to afford the title compound as a yellow solid.

[0782] Step B: N-((2-(6-(5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide. tert-butyl 8-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-5-oxa-2,8- diazaspiro[3.5]nonane-2-carboxylate (138 mg, 0.209 mmol, 1 eq.) was suspended in HC1 (4 M in dioxane, 4 mL) and stirred at room temperature for 30 min. The reaction mixture was diluted in water and DCM and the mixture was basified with aqueous NaOH (1 M) until pH 10. The layers were separated and the organics were extracted twice with DCM. The combined organics were dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography (12 g, DCM/MeOH, 100/0 to 90/10). The obtained powder was further purified by reverse phase HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD-10 pm, 30x150mm, Mobile phase: 0.25 % NH4HCO3 solution in water, MeOH) to afford Compound 221 (6 mg, yield: 5 %).

Compound 222: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-4-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0783] BOP (CAS [56602-33-6 ], 82 mg, 0.185 mmol, 1.2 eq.) was added to a suspension of Intermediate 346 (58 mg, 0.156 mmol, 1 eq.) and DBU (0.1 mL, 0.655 mmol, 4.2 eq.) in ACN (2 mL). After 15 min at room temperature, 4-(4-piperidyl)pyridine (CAS [581-45-3], 30 mg, 0.187 mmol, 1.2 eq.) was added and stirring was continued overnight. The reaction mixture was evaporated and the residue was purified by flash column chromatography on silica gel (12 g, DCM/NHs (7 N in MeOH), 100/0 to 90/10). A minimal amount of DCM was added and the resulting suspension was filtered through Celite®. The filtrate was concentrated to afford Compound 222 (64 mg, yield: 79 %) as a white solid.

Compound 223: N-((2-(3-((cis)-2,6-dimethylmorpholino)-6-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide. c/s

[0784] Compound 223 was prepared similarly to Intermediate 130, using Intermediate 160 instead of Intermediate 41, and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]) instead of Intermediate 105.

Compound 224: 4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)pyrrolidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide, Compound 235: (*S)-4-methyl-3-(methylsulfonyl)-N- ((2-(3-(pyridin-3-yl)pyrrolidin-l-yl)-l,6-naphthyridin-7-yl)methyl)benzamide, and Compound 236: (*R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)pyrrolidin-l-yl)- l,6-naphthyridin-7-yl)methyl)benzamide.

Compound 235 pure but unknown stereochemistry

Compound 236 pure but unknown stereochemistry [0785] 3-Methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6], 90 mg, 0.421 mmol, 1.2 eq.) was dissolved in ACN (3 mL) then DIPEA (244 μL 1.,402 mmol, 4 eq.) and HBTU (173 mg, 0.457 mmol 1.3 eq.) were added and the mixture was stirred for 10 mins at room temperature. Intermediate 350 (187 mg, 0.351 mmol, 1 eq.) was added and stirring was continued for 50 min. The mixture was evaporated, and the residue was purified by flash column chromatography on silica gel (12 g, DCM/MeOH 100:0 to 90:10), followed by reverse phase chromatography (Kinetex 5 um EVO cl8 100; 0.1 % TFA in water and ACN; 10 % ACN to 100 % ACN) to afford Compound 224 (88 mg, yield: 50 %) as a solid. A batch of Compound 224 was separated into its stereoisomers by SFC purification (AS-H (2 x 25 cm); 40 % MeOH (0.15 % EtiN)/CO2) to afford Compound 235 and Compound 236 as solids.

Compound 225: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-4-yl)piperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0786] Compound 225 was prepared similarly to compound 224 using Intermediate 352 instead of Intermediate 350 to afford the title compound as a solid.

Compound 226: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-3-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0787] BOP (CAS [56602-33-6 ], 107 mg, 0.242 mmol, 1.1 eq.) was added to a suspension of Intermediate 346 (81 mg, 0.218 mmol, 1 eq.) and DBU (0.16 mL, E048 mmol, 4.8 eq.) in ACN (3 mL). After 15 min at room temperature, 3-(4-piperidyl)pyridine (CAS [161609-89- 8], 47 mg, 0.29 mmol, 1.3 eq.) was added and stirring was continued overnight. The reaction mixture was evaporated and the residue was purified by flash column chromatography on silica gel (24 g, DCM/NHs (7 N in MeOH), 100/0 to 90/10). A minimal amount of DCM was added and the resulting suspension was filtered through Celite®. The filtrate was concentrated to afford Compound 226 (87 mg, yield: 73 %) as a white solid. Compound 227: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-3-yl)piperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0788] Compound 227 was prepared similarly to Compound 224 using Intermediate 354 instead of Intermediate 350.

Compound 228: N-((2-(9-oxa-2-azaspiro[5.5]undecan-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

[0789] Compound 228 was synthesized similarly to Compound 226 using 9-oxa-2- azaspiro [5.5] undecane (CAS [57289-77-7]) instead of 3-(4-piperidyl)pyridine.

Compound 229: (*R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide and Compound 231: (*S)-4-methyl-3-(methylsulfonyl)- N-((2-(3-(pyridin-4-yl)piperidin-l-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

(*R) Compound 229, pure but unknown stereochemistry

(*S) Compound 231, pure but unknown stereochemistry.

[0790] Intermediate 45 (75 mg, 0.192 mmol, 1 eq.), 4-(piperi din-3 -yl)pyri dine (CAS [143924-50-9], 37 mg, 0.231 mmol, 1.2 eq.), and CS2CO3 (125 mg, 0.385 mmol, 2 eq.) were added to a microwave vial, sealed and then anhydrous DMF (1 mL) was added. The vial was evacuated and backfilled with nitrogen 3 times, then stirred at 80 °C overnight. The reaction mixture was filtered through a Celite® plug and evaporated, then diluted with EtOAc and washed twice with brine. The combined organic layer was dried over Na2SO4 and evaporated. The residue was purified by column chromatography (basic alumina column 24 g, 20-90 % EtOAc w/ 10 % MeOH:heptane) to afford the mixture of enantiomers. Chiral separation by SFC (AS-H (2 x 25 cm); 40 % MeOH (0.15 % Et₃N)/CO₂) afforded Compound 229 (22 mg, yield: 22 %) and Compound 231 (21 mg, yield: 21 %) as yellow solids.

Compound 232: 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.

[0791] Compound 232 was prepared similarly to Intermediate 130 using Intermediate 357 instead of Intermediate 41 and 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6]) instead of Intermediate 105.

Compound 233: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-3-yl)phenyl)-l,6-

[0792] Intermediate 359 (109 mg, 0.35 mmol, 1 eq.) was dissolved in DMF (2.33 mL). 3- Methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6], 112 mg, 0.52 mmol, 1.5 eq.), HATU (199 mg, 0.52 mmol, 1.5 eq.), and DIPEA (0.36 mL, 2.09 mmol, 6 eq.) were then added and the reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was purified by reverse phase chromatography (30 x 100 C18 column, 30-50 % ACN:water (10 mM NH4OH)) to afford Compound 233 (15 mg, yield: 9 %). Compound 234: 4-methyl-3-(methylsulfonyl)-N-((2-(l-(pyridin-3-yl)piperidin-4-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0793] 3-Methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6], 43 mg, 0.201 mmol, 1.2 eq.) was dissolved in DMF (2.1 mL), then DIPEA (204 μ 1L.,173 mmol, 7 eq.) and HBTU (83 mg, 0.218 mmol, 1.3 eq.) were added and the mixture was stirred at room temperature for 10 min. Intermediate 361 (149 mg, 0.168 mmol, 1 eq.) was added and the reaction mixture was stirred at room temperature for 2 h. The crude reaction mixture was purified by reverse phase chromatography (Kinetex 5 um EVO cl8 100; 0.1 % TFA in water and ACN, 10 % ACN to 100 %) to afford Compound 234 (33 mg, yield: 38 %) as a solid.

Compound 237: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-4-yl)phenyl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0794] Compound 237 was prepared similarly to Compound 233 starting from Intermediate 362 instead of Intermediate 359.

Compound 238: (*R)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)pyrrolidin-l-yl)- l,6-naphthyridin-7-yl)methyl)benzamide and Compound 239: (*S)-4-methyl-3- (methylsulfonyl)-N-((2-(3-(pyridin-4-yl)pyrrolidin-l-yl)-l,6-naphthyridin-7- yl)methyl)benzamide.

(*R) Compound 238; pure but unknown stereochemistry

(*S) Compound 239; pure but unknown stereochemistry

[0795] Intermediate 45 (125 mg, 0.321 mmol, 1 eq.), 4-(pyrrolidin-3-yl)pyridine (CAS [150281-47-3], 57 mg, 0.385 mmol, 1.2 eq.), and CS2CO3 (209 mg, 0.641 mmol, 2 eq.), were added to a microwave vial. The vial was sealed and then anhydrous ACN (1.7 mL) was added. The vial was evacuated and backfilled with nitrogen 3 times, then heated to 80 °C for 1.5 h. The reaction mixture was diluted with water and extracted with DCM (x 3). The aqueous layer was diluted with brine and was extracted again with DCM until no product remained in the aqueous layer. The combined organic layer was dried over Na2SC>4, filtered, and evaporated. The solid residue was dissolved in a small amount of DCM, then precipitated with Et20 while stirring. The suspension was sonicated, broken up with a spatula, then stirred vigorously for 15 min, filtered, and rinsed with additional Et20 to afford the racemic mixture. The enantiomers were then separated by chiral SFC (OJ-H (2 x 25 cm); 30 % MeOH (0.1 % DEA)/CC>2) to afford Compound 238 (59 mg, yield: 37 %) and Compound 239 (65 mg, yield: 40 %) as white solids.

Compound 240: 4-methyl-3-(methylsulfonyl)-N-((2-(6-(tetrahydro-2H-pyran-3-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[0796] Pd/C (10 %, 8 mg, 7.2 μmol, 0.08 eq.) was added to a stirred solution of Compound 219 (47 mg, 0.0913 mmol) in MeOH (4.6 mL) under nitrogen atmosphere. The mixture was evacuated under vacuum and backfilled with nitrogen, then evacuated and backfilled with hydrogen. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 3 days then filtered through a short pad of Celite® and the filtrate was evaporated. The residue was purified by flash column chromatography on silica gel (12 g, DCM/MeOH 100/0 to 97/3), followed by reverse phase chromatography (Gemini C18 100 x 30 mm 5 pm, from 49 % [0.1 % HCOOH] - 51 % [ACN: MeOH 1:1] to 6 % [0.1 % HCOOH] - 94 % [ACN: MeOH 1:1]) to afford Compound 240 (4 mg, yield: 8 %) as a yellow solid. Compound 241 : (*R)-4-methyl-3-(methylsulfonyl)-N-((2-(2-(pyridin-4-yl)morpholino)-l,6- naphthyridin-7-yl)methyl)benzamide and Compound 242: (*S)-4-methyl-3-(methylsulfonyl)-

N-((2-(2-(pyridin-4-yl)morpholino)-l,6-naphthyridin-7-yl)methyl)benzamide.

(*R) Compound 241; pure but unknown stereochemistry

(*S) Compound 242; pure but unknown stereochemistry

[0797] Compound 241 and Compound 242 were synthesized similarly to Compound 238 and Compound 239, respectively, using 2-(pyridin-4-yl)morpholine (CAS [1018656-57-9]) instead of 4-(pyrrolidin-3-yl)pyridine, and using dimethylacetamide as solvent instead of ACN.

Compound 244: 4-methyl-3-(methylsulfonyl)-N-((2-(4-nicotinoylpiperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0798] Intermediate 366 (42 mg, 0.096 mmol, 1 eq.), nicotinic acid (CAS [59-67-6], 18 mg, 0.14 mmol, 1.5 eq.), and HATU (54 mg, 0.14 mmol, 1.5 eq.) were dissolved in DMF (0.96 mL), then DIPEA (0.066 mL, 0.38 mmol, 4 eq.) was added and the reaction mixture was stirred at room temperature for 30 min. The crude reaction mixture was purified by reverse phase column chromatography (30 x 100 cl8 column, 5-25 % ACN:water (10 mM NH4OH)) to afford Compound 244 (23 mg, yield: 44 %) as an off-white solid. Compound 245 : N-((2-(4-acetylpiperazin- 1 -y 1)- 1 ,6-naphthy ridin-7 -y l)methyl)-4-methyl-3 - (methylsulfonyl)benzamide.

[0799] 1 -Acetylpiperazine (CAS [13889-98-0], 28 mg, 0.218 mmol, 1.73 eq.) was added to a suspension of Intermediate 346 (47 mg, 0.127 mmol), DBU (CAS [6674-22-2], 0.1 mL, 0.655 mmol, 5.2 eq.), and BOP (CAS [56602-33-6], 64 mg, 0.145 mmol, 1.1 eq.) in ACN (5 mL) and the reaction mixture was stirred at 80 °C for 16 h. The reaction was concentrated, and the residue was purified by reverse phase column chromatography to afford Compound 245 (13 mg, yield: 21 %).

Compound 246: 4-methyl-3-(methylsulfonyl)-N-((2-(2-oxopiperidin-l-yl)-l,6-naphthyridin-

7 -yl)methyl)benzamide.

[0800] Intermediate 45 (150 mg, 0.385 mmol, 1 eq.), 2-piperidone (CAS [675-20-7], 67 mg, 0.673 mmol, 1.75 eq.), Xantphos Pd G4 (CAS [1621274-19-8], 18 mg, 0.019 mmol, 0.05 eq.), CS2CO3 (251 mg, 0.77 mmol, 2 eq.) were introduced into a vial. The vial was sealed, evacuated, and backfilled with nitrogen 5 times. Anhydrous 1,4-di oxane (1.2 mL) was added and the vial was evacuated and backfilled with nitrogen 3 times. The reaction mixture was then stirred at 100 °C for 1.5 h. The reaction mixture was diluted with DCM and filtered through a Celite® plug, washing with additional DCM. The filtrate was evaporated and the residue was purified by reverse phase HPLC (column: kinetex 5 pM EVO Cl 8 100 x 30 mm, gradient 20-45 % ACN: water w/ 10 mM NH4OH then to 100 % ACN) to afford Compound 246 (138 mg, yield 79 %) as a white solid. Compound 247: -methyl-3-(methylsulfonyl)-N-((2-(4-(pyridazin-3-yl)piperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0801] 3-Methanesulfonyl-4-methylbenzoic acid (58 mg, 0.269 mmol, 1.2 eq.) was dissolved in DMF (1.25 mL), then DIPEA (391 μL 2,.243 mmol, 10 eq.) and HBTU (102 mg, 0.269 mmol, 1.2 eq.) were added and the reaction mixture was stirred at room temperature for 10 min. Intermediate 367 (200 mg, 0.224 mmol, 1 eq.) was added and stirring was continued for 50 min. The reaction mixture was directly purified by reverse phase chromatography (Kinetex 5 urn EVO cl8 100; 0.1 % TFA in water and ACN, 10 % ACN to 100 %) to afford Compound 247 (48 mg, yield: 41 %) as a solid.

Compound 248: N-((2-(4-isonicotinoylpiperazin-l-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

[0802] Compound 248 was prepared similarly to Compound 244 starting from Intermediate 366 and isonicotinic acid (CAS [55-22-1]).

Compound 249: N-((2-(4-(6-methoxypyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0803] Compound 249 was prepared similarly to Compound 247 using Intermediate 368 instead of Intermediate 367. Compound 250: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(6-oxo-l,6-dihydropyridin-3- y l)piperazin- 1 -y 1)- 1 ,6-naphthyri din-7 -y l)methyl)benzamide.

[0804] Compound 249 (45 mg, 0.0823 mmol, 1 eq.) was dissolved in DCM (0.5 mL) and the solution was cooled to 0 °C. Boron tribromide (CAS [10294-33-4], 1 M in DCM, 0.412 mL, 0.412 mmol, 5 eq.) was added dropwise and the resulting slurry was stirred overnight at room temperature under nitrogen atmosphere. The reaction was quenched with MeOH and HBr (48 % in H2O, 0.2 mL, 1.646 mmol, 20 eq.), and the mixture was heated to 60 °C overnight. The reaction mixture was concentrated 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 the Compound 250 (10 mg, yield: 23 %) as a solid.

Compound 251 : 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyrazin-2-yl)piperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0805] Compound 251 was prepared similarly to Compound 247 using Intermediate 369 instead of Intermediate 367.

Compound 252: 4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide, Compound 254: (*R)-4-methyl-3-(methylsulfonyl)-N- ((2-(3-(pyridin-3-yl)piperidin-l -yl)-l ,6-naphthyridin-7-yl)methyl)benzamide and Compound 255: (*S)-4-methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-3-yl)piperidin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide. Compound 252

(*R) Compound 254, pure but unknown stereochemistry

(*S) Compound 255, pure but unknown stereochemistry [0806] DIPEA (0.71 mL, 4.1 mmol. 4 eq.) was added to a solution of 3-(3- piperidinyl)pyridine (200 mg, 1.23 mmol, 1.2 eq.) and Intermediate 45 (400 mg, 1.03 mmol, 1 eq.) in ACN (5 mL). The reaction mixture was stirred at 80 °C for 20 h. The reaction mixture was diluted with EtOAc, washed twice with water, and the aqueous layer was re-extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase HPLC (Waters XSelect CSH C18, 5u, 19 x 100 mm ; modifier: TFA, 8-30 % ACN) to afford Compound 252 (368 mg, yield: 66 %) as a light yellow solid. A batch of Compound 252 was separated into its stereoisomers by chiral SFC (IH; 30 % MeOH (0.1 % DEA)/CO2) to afford Compound 254 and Compound 255, both as yellow solids.

Compound 253 : N-((2-(4-(6-aminopy ri din-3 -yl)piperazin- 1 -yl)- 1 ,6-naphthy ri din-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0807] Step A: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(6-nitropyridin-3-yl)piperazin-l-yl)- l,6-naphthyridin-7-yl)methyl)benzamide. Intermediate 366 (340.27 mg, 0.77 mmol, 1.1 eq.), 5-fluoro-2-nitropyridine (CAS [779345-37-8], 100 mg, 0.7 mmol, 1 eq.), and CS2CO3 (459 mg, 1.41 mmol, 2 eq.) were dissolved in DMF (7 mL) in a sealed vessel and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (x 3). The combined organic layer was washed twice with brine, dried over MgSO4, filtered, and concentrated. The residue was triturated in DCM and isolated by filtration, affording the title compound (132 mg, yield: 67 %) as a bright orange solid.

[0808] Step B: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(6-nitropyridin-3-yl)piperazin-l-yl)- l,6-naphthyridin-7-yl)methyl)benzamide (75 mg, 0.13 mmol, 1 eq.) was dissolved in EtOH (1.3 mL) and EtOAc (1.3 mL). Pd/C (10 %, 75 mg, 0.07 mmol, 0.53 eq.) was added, and the suspension was sparged with hydrogen for 5 min. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 4.5 h. The mixture was filtered over a Celite® pad, washed with MeOH, DCM, and EtOAc. The filtrate was evaporated and the residue was purified by reverse phase HPLC (Waters XBridge BEH Cl 8, 5u, 19 x 100 mm; modifier: NHs, 10-40 % ACN) to afford Compound 253 (11 mg, yield: 15 %) as an off-white solid.

Compound 256: N-((2-(4-(2-hydroxy-2-methylpropanoyl)piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0809] DIPEA (0.1 mL, 0.58 mmol, 5.2 eq.) was added to a solution of Intermediate 366 (49 mg, 0.111 mmol, 1 eq.), 2-hydroxyisobutyric acid (CAS [594-61-6], 17 mg, 0.16 mmol, 1.44 eq.), and HATU (51 mg, 0.134 mmol, 1.2 eq.) in ACN (4 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated and the residue was purified by flash column chromatography (12 g SiCh, DCM/NHs (2 N in MeOH), 100/0 to 90/10), followed by reverse phase HPLC (Waters XBridge BEH Cl 8, 5u, 19 x 100 mm; 0 -

40 % ACN/NH4OH pH 10 in water/NH4OH pH 10) to afford Compound 256 (23.8 mg, yield:

41 %) as a white solid.

Compound 257: 4-methyl-N-((2-(4-(l-methyl-lH-pyrazol-4-yl)piperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide. [0810] Compound 257 was prepared similarly to Compound 245, using 1 -(1 -methyl- 1H- pyrazol-4-yl)piperazine (CAS [1174207-79-4]) instead of 1 -acetylpiperazine.

Compound 258: (*R)-4-methyl-3-(methylsulfonyl)-N-((2-(l-(pyridin-3-yl)piperidin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide and Compound 259: (*S)-4-methyl-3-(methylsulfonyl)- N-((2-(l-(pyridin-3-yl)piperidin-3-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

(*R) Compound 258, pure but unknown stereochemistry

(*S) Compound 259, pure but unknown stereochemistry

[0811] (2-(l-(Pyridin-3-yl)piperidin-3-yl)-l,6-naphthyridin-7-yl)methanamine (Intermediate 372, 63 mg, 0.197 mmol, 1 eq.), 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22- 6], 51 mg, 0.237 mmol, 1.2 eq.), and HATU (90 mg, 0.237 mmol, 1.2 eq.) were dissolved in anhydrous DMF (1 mL) and the vial was evacuated and backfilled with nitrogen 5 times. DIPEA (0.17 mL, 0.986 mmol, 5 eq.) was added dropwise and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layer was washed with saturated aqueous NaHCO3. then twice with brine, dried with Na2SC>4, filtered, and evaporated. The residue was purified by reverse phase HPLC (column: Waters XSelect CSH C18, 5u, 19 x 100 mm; gradient 8-30 % ACN/H2O with 0.16 %TFA). The racemic mixture was separated by chiral SFC (OJ-H (2 x 25 cm); 18 % EtOH (0.1 % DEA)/CC>2) to afford Compound 258 (18 mg, yield: 18 %) and Compound 259 (19 mg, yield: 19 %), both as white solids. Compound 260: N-((2-(3-((cis)-2,6-dimethylmorpholine-4-carbonyl)cyclohex-l-en-l-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0812] Compound 260 was prepared similarly to Compound 224, using Intermediate 376 as acid and cv.s-2.6-di methyl morpholine (CAS [6485-55-8]) as amine.

Compound 261: ethyl l-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyri din-2 -yl)piperidine-3 -carboxylate.

[0813] Intermediate 378 (477 mg, 1.52 mmol, 1 eq.), 3-methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6], 390.07 mg, 1.82 mmol, 1.2 eq.), and HATU (692 mg, 1.82 mmol.

1.2 eq.) were suspended in ACN (15 mL). DIPEA (1.31 mL, 7.59 mmol, 7. eq.) was added and the reaction mixture was stirred at room temperature for 1 h. The product was isolated by filtration and washed with ACN. The filtrate was concentrated and recrystallized from ACN. Both solids were combined to afford Compound 261 (530 mg, yield: 68 %) as a white solid.

Compound 230: N-((2-(3-(4-(2-hydroxypropan-2-yl)phenyl)piperidin-l-yl)-l,6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, Compound 262: (*R)-N-((2-(3-(4-(2- hydroxypropan-2-yl)phenyl)piperi din-1 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide, and Compound 263: (*S)-N-((2-(3-(4-(2-hydroxypropan-2- yl)phenyl)piperidin- 1 -yl)- 1 ,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide.

Compound 230

(*S) Compound 263 pure but unknown stereochemistry

[0814] Intermediate 379 (84 mg, 0.147 mmol) was suspended in anhydrous THF (2.5 mL) and the vessel was evacuated and backfilled with nitrogen 3 times. The suspension was cooled to 0 °C and methylmagnesium bromide (3 M in Et20, CAS [75-16-1], 0.196 mL, 0.587 mmol, 4 eq.) was added and the reaction mixture was stirred for 1 h at room temperature. To push the reaction to completion, an additional portion of methylmagnesium bromide solution (3 M in Et20, 0.196 mL, 0.587 mmol, 4 eq.), was added and the mixture was stirred at room temperature overnight. The reaction was quenched with dropwise addition of saturated aqueous NH4CI, then extracted twice with EtOAc. The combined organic layers were dried over Na2SC>4, filtered, and evaporated. The residue was purified by reverse phase HPLC (Kinetex Cl 8 Evo; 31-52 % H2O w/ W mM NH₄OH:ACN to 100 % ACN) to afford Compound 230 (52 mg, yield: 62 %). A batch of Compound 230 was separated into its stereoisomers by chiral SFC (OD-H (2 x 25 cm); 30 % MeOH/CCh) to afford Compound 262 (12 mg, yield: 14 %) and Compound 263 (12 mg, yield: 14 %).

Compound 264: N-((2-(lH-pyrazol-l-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-

(methylsulfonyl)benzamide and Compound 265: N-((2-(3-((cis)-2,6-dimethylmorpholino)- IH-pyrazol- 1 -yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide. Compound 265

[0815] Intermediate 380 (57 mg, 0.114 mmol, 1 eq.), Pd(0Ac)2 (4 mg, 0.018 mmol, 0.15 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (CAS [161265-03-8], 20 mg, 0.3 eq.), and CS2CO3 (127 mg, 3.4 eq.) were introduced in a vial and it was evacuated and backfilled with nitrogen 3 times. Then, 1,4-dioxane (1.5 mL) and cis-2,6-dimethylmorpholine (30 0μ.2L4,4 mmol, 2.1 eq.) was added and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was adsorbed onto Celite® and purified by flash column chromatography on silica gel (24 g, DCM/NH3 (2 N in MeOH) 100/0 to 90/10), followed by reverse phase HPLC (Waters XBridge BEH Cl 8, 5u, 19 x 100 mm; 15 - 60 % ACN/NH4OH pH 10 in water/NH4OH pH 10) to afford Compound 264 (12 mg, yield: 20 %) and Compound 265 (2 mg, yield: 4 %).

Compound 266: 4-Methyl-N-((2-(4-methyl-3-(pyridin-4-yl)piperazin-l -yl)-l ,6-naphthyridin- 7-yl)methyl)-3-(methylsulfonyl)benzamide.

[0816] Step A: Intermediate 45 (250 mg, 0.64 mmol), 2-(pyridin-4-yl)piperazine (CAS [111781-57-8], 157 mg, 0.96 mmol), and CS2CO3 (522 mg, 1.6 mmol) were suspended in ACN (4.3 mL). The reaction mixtures was stirred at 80 °C overnight under argon atmosphere. After cooling, the reaction mixture was diluted with DCM, filtered over celite, and concentrated. The residue was purified by preparative HPLC (30 x 100 mm C18 Gemini column, 12-32 % ACN:water (10111M NH4OH)) to afford 4-methyl-3-(methylsulfonyl)-N-((2- (3-(pyridin-4-yl)piperazin-l-yl)-l,6-naphthyridin-7-yl)methyl)benzamide (140 mg, yield: 42 %) as an off-white solid.

[0817] Step B: 4-Methyl-3-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)piperazin-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide (100 mg, 0.19 mmol) and NaBH(OAc)3 (205 mg, 0.97 mmol) were dissolved in MeOH (2 mL) and DCM (2 mL). Formaldehyde (37 % in water, 0.29 mL, 3.87 mmol) and AcOH (0.055 mL, 0.97 mmol) were added and the reaction mixture was stirred at 140 °C for 6 h under microwave irradiation. The reaction was quenched by addition of NaOH (1 M in water), diluted with DCM and water, and extracted with DCM (3 x), then with 10 % trifluoroethanol: DCM. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by reverse phase (column: Waters XBridge BEH Cl 8, 5 um, 19 x 100 mm; NHs. 12-43 % ACN) to give Compound 266 (10 mg, yield: 10 %).

Compound 267: l-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2- yl)piperidine-3 -carboxylic acid.

[0818] Compound 261 (514 mg, 1.01 mmol, 1 eq.) was dissolved in THF (5 mL) and MeOH (5 mL). NaOH (1 M in H2O, 3.36 mL, 10 eq.) was added, and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with water and washed with DCM (x 3). The aqueous layer was acidified to pH~6 with HC1 (1 M in water). The aqueous layer was extracted with 10 % iPrOH/CHCh (3 x) and the combined organic layer was dried with MgSO4, filtered, and evaporated. The solid was triturated with DCM and isolated by filtration to afford Compound 267 (471 mg, yield: 97 %) as a white solid.

Compound 268: 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.

[0819] 2.6-Dimethyltetrahydro-27/-pyran-4-ol (CAS [33747-09-0], 99 mg, 0.759 mmol, 5 eq.) was added dropwise to a suspension of NaH (60 % dispersion in mineral oil, 18 mg, 0.456 mmol, 3 eq.) in dry DMF (1 mL) at room temperature under nitrogen atmosphere and the mixture was stirred for 10 min until release of H2 stopped. A solution of Intermediate 46 (72 mg, 0.152 mmol, 1 eq.) in dry DMF (2 mL) was added dropwise to the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layer was dried on MgSO4. filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (25 g; heptane/EtOH (25 % in EtOAc), 100/0 to 0/100) , followed by a purification via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30x150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to afford Compound 268 (17 mg, yield: 20 %) as a white solid. Compound 269: N-((2-(6-(2-hydroxy ethoxy )pyridin-2-yl)-l, 6-naphthyri din-7-y l)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

[0820] 2-((Tert-butyldimethylsilyl)oxy)ethanol (CAS [102229-10-7], 252 1μ.L28, 6 mmol, 10 eq.) was added dropwise to a suspension of NaH (60 % dispersion in mineral oil, 16 mg, 0.386 mmol, 3 eq.) in dry DMF (1 mL) at room temperature under nitrogen atmosphere and the mixture was stirred for 10 min until release of H2 stopped. A solution of Intermediate 46 (61 mg, 0.129 mmol, 1 eq.) in dry DMF (2 mL) was added dropwise and the reaction mixture was stirred at 60 °C under nitrogen atmosphere for 1.5 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layer was dried over MgSO4, filtered, and evaporated. The residue was dissolved in MeOH (3 mL) and p- toluenesulfonic acid monohydrate (25 mg, 0.129 mmol, 1 eq.) was added and the reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated and the residue was taken up in EtOAc and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3, and evaporated. The residue was purified by flash column chromatography on silica gel (10 g; heptane/EtOH (25 % in EtOAc), 100/0 to 0/100) to afford Compound 269 (13 mg, yield: 21 %) as a white solid.

Compound 270: (*R)-4-methyl-3-(methylsulfonyl)-N-((2-(l-(pyridin-4-yl)piperidin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide and Compound 717: (*S)-4-methyl-3-(methylsulfonyl)- N-((2-(l-(pyridin-4-yl)piperidin-3-yl)-l, 6-naphthyri din-7-yl)methyl)benzamide. Compound 717

[0821] Compound 270 and Compound 717 were prepared similarly to Compound 258 and Compound 259, starting with Intermediate 382 instead of Intermediate 372.

Compound 271: N-((2-(6-(3,3-dimethylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

(Method Q)

[0822] A solution of Intermediate 46 (47 mg, 0.1 mmol, 1 eq.) in dry DMSO (1.2 mL) was added to 2,2-dimethylpiperazine (CAS [84477-72-5], 34 mg, 0.3 mmol, 3 eq.), then DIPEA (0.207 mL, 1.2 mmol, 12 eq.) was added, and the reaction mixture was stirred at 145 °C for 144 h. After cooling to room temperature, TFA (1.5 mL, 19.6 mmol) was added and the resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, DMSO (0.5 mL) was added and DCM/TFA was evaporated under high vacuum. The remaining DMSO solution was purified by reverse phase HPLC (Stationary phase: RP XSelect CSH Prep Cl 8 OBD-10 pm, 30 x 150 mm; Mobile phase: 0.1 % FA solution in water, ACN), affording Compound 271 (19 mg, yield: 35 %).

[0823] The compounds in Table 19 were prepared following Method Q, starting from Intermediate 46 and the corresponding piperazine (In cases where the amine did not bear a Boc protecting group, the TFA deprotection step was omitted).

Table 19

Compound 272: 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. [0824] Intermediate 300 (71 mg, 0.195 mmol, 1 eq.) was added to a stirred solution of 3- methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6], 33 mg, 0.156 mmol, 0.8 eq.), HATU (0.1 g, 0.29 mmol, 1.5 eq.), and DIPEA (0.27 mL, 1.56 mmol, 8 eq.) in DMF (3 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (x 2), dried over MgSO4. filtered, and evaporated. The crude product was purified by flash column chromatography on silica gel (24 g, DCM/MeOH from 100/0 to 10/90) to afford Compound 272 (61 mg; 53 %) as a green solid. Compound 273: N-((2-(3-chloro-6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)benzamide.

[0825] 3-[(2-Hydroxyethyl)sulfonyl]benzoic acid (CAS [7180-11-2], 46 mg, 0.2 mmol, 1.1 eq.) was added to a stirred solution of Intermediate 384 (73 mg; 0.182 mmol, 1 eq.), HATU (104 mg; 0.273 mmol, 1.5 eq.), and DIPEA (0.191 mL, 1.09 mmol, 6 eq.) in DCM (3 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed twice with brine, dried over MgSO4, filtered, and the solvents evaporated. The residue was purified by flash column chromatography on silica gel (24 g, DCM/MeOH from 100/0 to 90/10), followed by reverse phase chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 59 % [25 mM NH4HCO3] - 41 % ACN to 17 % [25 mM NH4HCO3] - 83 % ACN) to afford Compound 273 (16 mg, yield: 14 %) as a yellow solid.

Compound 274: (R)-N-((2-(6-(2-(methoxymethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide and Compound 279: (S)-

N-((2-(6-(2-(methoxymethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

Compound 279

[0826] Intermediate 46 (160 mg, 0.355 mmol) and 2-(methoxymethyl)pyrrolidine (CAS [76946-27-5], 123 mg, 1.07 mmol) were suspended in DMSO (4 mL), then DIPEA (0.184 mL, 1.066 mmol) was added. The mixture was stirred at 130 °C overnight. After cooling, the reaction mixture was diluted with EtOAc, washed with water, dried over MgSO4. filtered, and evaporated. The residue was purified by preparative SFC (Chiralcel Diacel OJ 20 x 250 mm; CO2, EtOH + 0.4 % iPrNH2) gave Compound 274 (62 mg, yield 32 %) and Compound 279 (66 mg, yield: 33 %), both as yellow solids.

Compound 275: N-((2-(4-(difluoromethyl)-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0827] DAST (CAS [38078-09-0], 104 μL 0,.748 mmol) was added in 4 portions over 4 h to a solution of Intermediate 291 (54 mg, 0.094 mmol) in DCM (3 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature and then diluted with saturated aqueous NaHCCL. The mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by reverse phase column chromatography (gradient of ACN/MeOH (1/1, v/v) in 0.1 % aqueous formic acid from 50 to 75 %). The pure fractions were combined, treated with 1 M aqueous Na2CO3 to pH >8 and extracted twice with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The solid was recrystallized from ACN to give Compound 275 (18 mg, yield 32 %).

Compound 276: N-((2-(3-(6-aminopyridin-3-yl)piperidin-l-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0828] Intermediate 45 (250 mg, 0.641 mmol) and 5-(3-piperidinyl)-2-pyridinamine (CAS [868254-64-2], 214 mg, 1.207 mmol) were suspended in anhydrous ACN (3 mL). The vial was evacuated and refilled with nitrogen 5 times, then DIPEA (0.254 mL, 1.475 mmol) was added and the reaction mixture was stirred at 75 °C overnight. After cooling, the reaction mixture was diluted with DCM and water and the layers were separated. The aqueous layer was extracted twice with 10 % trifluoroethanol/DCM, and the combined organic layer was dried with Na2SO4 and evaporated. The residue was dissolved in DMSO (1 mL) and this solution was purified by reverse phase column chromatography. The resulting product was taken up in DCM/saturated aqueous NaHCO3 and extracted 3 times with DCM. The combined organic layer was dried over Na2SC>4, evaporated, taken up in ACN/H2O (—1/1), frozen, and lyophilized to give Compound 276 (109 mg, yield: 32 %).

Compound 277: 4-methyl-3-(methylsulfonyl)-N-((2-(4-(pyridin-4-yl)azepan-l-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0829] Compound 277 was prepared following the procedure used for Compound 276 using hexahydro-4-(4-pyridinyl)-17/-azepine, dihydrochloride (CAS [2094713-86-5]) instead of 5- (3-piperidinyl)-2-pyridinamine [868254-64-2] .

Compound 278: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-2-fluoro-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide.

CIS

[0830] Intermediate 389 (40 mg, 0.057 mmol) was dissolved in THF (0.6 mL). Tetrabutylammonium fluoride (1 M in THF, 85 μL 0,.085 mmol, 1.5 eq.) was added at room temperature and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted again with EtOAc (x 3). The combined organic layer was dried over MgSO4. filtered, and concentrated in vacuo. The residue, combined with another batch, was purified by flash chromatography column (12 g silica, DCM/MeOH 9/1 in DCM from 0/100 to 10/90) followed by reverse chromatography (Phenomenex Gemini C18 30 x l00 mm 5 pm Column; [25 mM NH4HCO3]/[ACN:MeOH (1: 1)] from 59/41 to 17/83, to afford Compound 278 as ayellow solid. Compound 280: N-((2-(4-fluoro-6-((3a, 4p,5a)-4-hydroxy-3,5-dimethylpiperi din-1 -yl)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-5-methylbenzamide.

[0831] Compound 280 was prepared according to Method A (in DMF), starting from

Intermediate 396 and Intermediate 103.

Compound 281: tert-butyl 7-(4-fluoro-6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)- 1 ,6-naphthyridin-2-yl)pyridin-2-yl)-4,7 - diazaspiro [2.5] octane-4-carboxylate.

[0832] Intermediate 45 (150 mg, 0.38 mmol) was added to a stirred solution of Intermediate 399 (200 mg, 0.46 mmol, 1.2 eq.) in previously nitrogen-degassed DME (10 mL) at room temperature. 2-Norbomene (CAS [498-66-8], 72 mg, 0.77 mmol, 2 eq.), K3PO4 (286 mg, 1.35 mmol, 3.5 eq.), exo-norbomeol (CAS [497-37-0], 86 mg, 0.77 mmol, 2 eq.), (2- butenyl)chloropalladium dimer (CAS [12081-22-0], 8 mg, 0.02 mmol, 0.05 eq.), and triphenylphosphine (CAS [603-35-0], 20 mg, 0.07 mmol, 0.2 eq.) were added to the reaction mixture and it was stirred at 100 °C for 24 h. After cooling to room temperature, more Intermediate 45 (75 mg, 0.19 mmol, 0.5 eq.), 2-norbomene (72 mg, 0.77 mmol, 2 eq.), K3PO4 (286 mg, 1.35 mmol, 3.5 eq.), exo-norbomeol (86 mg, 0.77 mmol, 2 eq.), (2- butenyl)chloropalladium dimer (8 mg, 0.02 mmol, 0.05 eq.), and triphenylphosphine (20 mg, 0.07 mmol, 0.2 eq.) were added to the reaction mixture and it was stirred at 100 °C for 24 h. To push the reaction to completion, more Intermediate 45 (75 mg, 0.19 mmol, 0.5 eq.), (2- butenyl)chloropalladium dimer (8 mg, 0.02 mmol, 0.05 eq.), and triphenylphosphine (20 mg, 0.07 mmol, 0.2 eq.) were added to the reaction mixture and it was stirred at 100 °C for 24 h. After cooling, the reaction mixture was diluted with saturated aqueous NaHCCE and EtOAc. The organic layer was separated, dried (MgSO4). filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (12 g SiCh, EtOAc/DCM from 0/100 to 100/0) followed by reverse phase chromatography (Phenomenex Gemini Cl 8 30 x 100 mm 5 pm; from [0.1 % HCOOH]/ [ACN:MeOH (1:1)] from 49/51 6/94), and trituration in Et20 to yield Compound 281 (36 mg, yield: 13 %) as a yellow solid.

Compound 282: N-((2-(4-((cis)-2,6-dimethylmorpholino)pyrimidin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0833] A suspension of Intermediate 45 (67 mg, 0.172 mmol), hexamethyltin (CAS [661-69- 8], 70 mg, 0.214 mmol, 1.24 eq.), and tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 103 mg, 0.089 mmol, 0.5 eq.) in 1,4-dioxane (3 mL) was degassed with nitrogen. The vial was sealed and the reaction mixture was stirred at 110 °C for 2 h. After cooling to room temperature, 4-(2-chloro-4-pyrimidinyl)-2,6-cis-dimethyl-morpholine (CAS [2232098-54-1] and tetrakis(triphenylphosphine)palladium(0) (49 mg, 0.042 mmol, 0.25 eq.) were added and the vial was sealed, evacuated, and purged twice with nitrogen. The reaction mixture was stirred at 110 °C for 16 h. After cooling, the reaction mixture was concentrated to dryness. The residue was purified by column chromatography (24 g SiCh, 2 N NHs in MeOH/DCM from 0/100 to 10/90) followed by reverse phase chromatography (Waters XBridge BEH C18, 5 urn, 19 x 100 mm, A = Water + pH 10 NH₄OH, B = ACN + pH 10 NH4OH, A/B from 85/15 to 50/50) to yield Compound 282 (19 mg, yield: 21 %) as a white solid.

Compound 283: N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide. [0834] Compound 283 was prepared following the procedure used for Compound 282, using 4-(4-chloro-2-pyrimidinyl)-2,6-cis-dimethylmorpholine (CAS [2136205-68-8]) instead of 4- (2-chloro-4-pyrimidinyl)-2,6-cis-dimethyl-morpholine.

Compound 288: N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)473yridine-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(2-hydroxypropan-2-yl)-4-methylbenzamide.

[0835] Compound 288 was prepared following method A, using Intermediate 300 instead of Intermediate 11 and 3-(l-hydroxy-l-methylethyl)-4-methylbenzoic acid (CAS [1521439-68- 8]) instead of 3-methanesulfonyl-4-methylbenzoic acid.

Compound 289: 3-chloro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide.

[0836] Compound 289 was prepared following method A, using Intermediate 300 instead of Intermediate 11 and 3-chloro-4-methyl-5-(methylsulfonyl)-benzoic acid (CAS [2771133-40- 3]) instead of 3-methanesulfonyl-4-methylbenzoic acid.

Compound 290: N-((2-(4-(5-aminopyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0837] HC1 (37 % in H2O, 0.1 mL, 1.22 mmol, 15 eq.) was added to a solution of

Intermediate 402 (50 mg, 0.081 mmol) in MeOH (1.6 mL) and water (1.6 mL) and the reaction mixture was stirred at 60 °C overnight. To obtain full conversion, more HC1 (37 % in H2O, 0.07 mL, 0.812 mmol, 10 eq.) was added and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was diluted with water and DCM and the layers were separated. The aqueous layer was washed twice with DCM before the aqueous solution was lyophilized. The resulting solid was purified by reverse phase column chromatography (column: Waters XBridge BEH Cl 8, 5 um, 19 x 100 mm; modifier: NHs. 10-40 % ACN) to yield Compound 290 (2 mg, 75 % pure, yield: 3 %).

Compound 291 : 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.

[0838] DIPEA (483 μL, 2.775 mmol, 10 eq.) and HATU (CAS [148893-10-1], 127 mg, 0.333 mmol, 1.2 eq.) were added to a solution of 3-(2-hydroxyethanesulfonyl)-4-methylbenzoic acid (CAS [1094404-86-0], 71 mg, 0.291 mmol, 1.05 eq.) in DMF (3.5 mL). The reaction mixture was stirred at room temperature for 10 min before Intermediate 405 (291 mg, 0.278 mmol) was added all at once. The reaction mixture was stirred at room temperature for 50 min. The solvent was evaporated and the residue was purified by reverse phase column chromatography (Column: OOD-4633-UO-AX Kinetex 5 um EVO C18 100; 0.1 % TFA in water and ACN, from 10 to 100 % ACN). The obtained solid was taken up in a 40 % ACN/water solution and was lyophilized to afford Compound 291 (30 mg, yield: 18 %) as a solid.

Compound 294: N-((2-(6-(3-(hydroxymethyl)piperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0839] Compound 294 was prepared from Intermediate 46 following a modification of Method Q, stirring the reaction mixture 72 h instead of 144 h and using SiliaMetS Diamine scavenger (0.5 g) to scavenge the excess of TFA. Purification by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-lOpm, 30x150mm, Mobile phase: 0.25 % NH4HCO3 solution in water, CHsCN or MeOH) afforded Compound 294 (60 mg, 99 % yield).

[0840] The Compounds in Table 20 were prepared following the modified Method Q, starting from Intermediate 46 and the corresponding amine.

Table 20

Compound 312: 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. [0841] Compound 312 was prepared following Method A starting from Intermediate 410 and

3-(methylsulphonyl)benzoic acid [CAS: 5345-27-7] stirring the reaction mixture for 2 h.

Compound 314: N-((2-(2-(4,7 -diazaspiro [2.5] octan-7 -yl)pyrimidin-4-yl)- 1 ,6-naphthy ri din-7 - yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0842] Compound 314 was prepared with a similar procedure as for Compound 282, using

Intermediate 45 and Intermediate 411 instead of 4-(2-chloro-4-pyrimidinyl)-2,6-cis-dimethyl- morpholine. The product was resuspended in 1 : 1 MeOH/DCM (4 mL) and treated with 4N HCl/dioxane (1 mL). The reaction mixture was heated at 60 °C for 16 h, then cooled to room temperature and concentrated to dryness. The compound was resuspended in 1:1 MeOH/DCM and quenched with DIPEA (0.3 mL). The compound was purified via solid load flash column chromatography (24g SiO2, 0-10 % 2N NHs/MeOH/DCM) and further purified by preparative HPLC: (Mobile phase A = Water with 0.16 % TFA, Mobile phase B = ACN with 0.16 % TFA, Gradient from 10 to 40 % ACN; Waters XSelect CSH C18, 5 urn, 19 x 100 mm) to yield Compound 314 (37 mg, yield: 37 %).

Compound 315: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4,5-dimethylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0843] 3-Methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6], 32 mg, 0.15 mmol, 1.3 eq.) and DIPEA (78 μL, 0.462 mmol, 4 eq.) were added to a solution of (2-(6-((2R,6S)-2,6- dimethylmorpholino)-4,5-dimethylpyridin-2-yl)-l,6-naphthyridin-7-yl)methanamine (Intermediate 417, 52 mg, 0.115 mmol) in DMF (2 mL). After 15 min, HATU (48 mg, 0.127 mmol, 1.1 eq.) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4 f.iltered, and evaporated. The residue was purified by flash chromatography (12 g column, EtOAc/heptane, from 0/100 to 100/0) to yield Compound 315 (49 mg, yield: 73 %) as a yellow dust.

Compound 316: 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. [0844] Intermediate 681 (77 mg, 0.117 mmol) was dissolved in DCM (0.5 mL) and TFA (0.36 mL, 4.664 mmol, 40 eq.) was added, forming a dark brown solution. The reaction mixture was stirred at room temperature for 15 min. The solvent was evaporated. The residue was taken up with saturated aqueous NaHCO3 and extracted with 10 % trifluoroethanol/DCM. The combined organic layer was dried with Na2SC>4, filtered, and evaporated. The solid was dissolved in DCM and the solution was washed with NaOH (1 M in water). After evaporation of the organic layer, the residue was purified by reverse phase HPLC (Kinetex 5 uM EVO Cl 8, gradient 25-50 % ACN/10 mM NH₄OH H₂O) to give the Compound 316 (27 %, yield: 41 %) as a yellow solid.

Compound 317: 4-chloro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5] octan-7 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide.

[0845] HATU (CAS [148893-10-1], 170 mg, 0.446 mmol, 1.5 eq) was added to a stirred solution of 4-chloro-3-methanesulfonylbenzoic acid (CAS [51522-07-7], 56 mg, 0.24 mmol, 0.8 eq.), Intermediate 300 (130 mg, 0.3 mmol), and DIPEA (0.415 mL, 2.4 mmol, 8 eq.) in DCM (6 mL). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (x 2), dried on MgSO4. filtered, and evaporated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 8/92) followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 70 % [25 mM NH4HCO3] - 30 % [ACN:MeOH (1:1)] to 27 % [25 mM NH4HCO3] - 73 % [ACN:MeOH (1: 1)]) to yield Compound 317 (34 mg, yield: 20 %).

Compound 344: ethyl 3-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyri din-2 -yl)cyclobutane- 1 -carboxylate. [0846] (3-(Ethoxycarbonyl)cyclobutyl)zinc(II) iodide (CAS [2795264-17-2], 1.15 mL, 0.2 M in THF, 0.23 mmol) was added to a mixture of Intermediate 45 (20 mg, 0.051 mmol) and Pd(OAc)2 (1.2 mg, 0.1 eq.)/RuPhos (CAS [787618-22-8], 3.6 mg, 0.15 eq.). The reaction mixture was stirred at 65 °C for 2 h. The mixture was treated with aqueous NH4CI (2 mL) and DCM (2 mL). The mixture was stirred at room temperature for 20 min, then passed through a SCX separator cartridge eluting with more DCM (2 x 1 mL). The filtrate was concentrated in vacuo and the residue was purified by reverse phase HPLC (BA-5 urn), to afford Compound 344 (16 mg, yield: 64 %) as an oil.

Compound 346: 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.

[0847] Intermediate 46 (100 mg, 0.211 mmol) was suspended in DMSO (2 mL), then 4-oxa- 7-azaspiro[2.5] octane hydrochloride (CAS [1427195-23-0], 95 mg, 0.633 mmol, 3 eq.) and DIPEA (0.182 mL, 1.054 mmol, 5 eq.) were added. The reaction mixture was stirred at 130 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The combined organic layer was dried over MgSO4. filtered, and evaporated. The residue was purified by flash column chromatography (12 g SiCh, DCM/MeOH, 0 to 10 %), followed by reverse phase preparative HPLC (RP XBridge Preparative C18 OBD- 5 pm, 50 x 250 mm; 0.25 % NH4HCO3 solution in water, ACN) to afford compound 346 (8 mg, yield: 7 %) as a yellow powder.

Compound 347: 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.

[0848] 5,8-Diazaspiro[3.6]decane (49 mg, 0.349 mmol, 3.3 eq.), and Intermediate 46 (50 mg, 0.105 mmol) were suspended in a 1/1 mixture of DMSO/DIPEA (2 mL) and the reaction mixture was stirred at 130 °C overnight. The reaction mixture was poured into water and extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g SiCh, DCM/[NHs 7 N in MeOH] from 100/0 to 90/10), followed by reverse phase preparative HPLC (RP XBridge Preparative C18 OBD- 5 pm, 50 x 250 mm; 0.25 % NH4HCO3 solution in water, ACN) to afford Compound 347 (30 mg, yield: 50 %) as a yellow powder.

Compound 348: 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.

(*R), (CIS)

[0849] Trifluoroacetic acid (CAS [76-05-1], 1.2 mL, 15.68 mmol, 29 eq.) was added to a stirred solution of Intermediate 419 (360 mg, 0.54 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Then, EtOAc and water were added, and then a saturated NaHCO3 aqueous solution was added until pH 8. The mixture was extracted with EtOAc (x 5). The combined organic layer was dried with MgSO4, filtered, 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 40/60) followed by semipreparative SFC (i- Cell-C column; isocratic 60 % [EtOH + 0.1 % DEA] - 40 % [CO2]) to yield Compound 348 (35 mg, yield: 17 %) as a yellow solid.

Compound 349: 3-(N,N-dimethylsulfamoyl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methylbenzamide.

[0850] To a solution of Intermediate 300 (100 mg, 0.27 mmol) in DMF (3 mL), 3- (dimethylsulfamoyl)-4-methylbenzoic acid (CAS [926248-01-3], 73 mg, 0.30 mmol, 1.1 eq.) and DIPEA (0.12 mL, 0.91 mmol, 2.5 eq.) were added. The reaction mixture was stirred and after 1 min was treated with HATU (CAS [148893-10-1], 125 mg, 0.33 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 1 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 twice by flash column chromatography (12 g SiCh, DCM:MeOH (9:1) in DCM from 0/100 to 20/80) to yield Compound 349 (22 mg, yield: 13 %) as ayellow solid.

Compound 351: tert-butyl 3-((7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthy ridin-2-yl)methy l)py rrolidine- 1 -carboxylate

[0851] Two solutions were prepared: Solution A: Intermediate 45 (40 mg, 0.1 mmol), Palladium(II) acetate (2 mg, 0.01 mmol), and RuPhos (CAS [787618-22-8], 7 mg, 0.015 mmol) in THF/DMF(1 mL/0.3 mL); Solution B: 1,1 -dimethylethyl 3-(iodomethyl)-l- pyrrolidinecarboxylate (CAS [479622-36-1], 319 mg, 1.026 mmol, 10 eq.) in LiCl in THF (0.5 M, 2 mL). Solution B was flowed through an activated Zn column (40 °C) and then mixed with Solution A through a chip mixer before entering the flow reactor at 100 °C for 20 min residence time (flow rate 0.25mL/min each line). Solvents were evaporated in vacuo. DCM (2 mL) and aqueous NFLCl (2 mL) were added. The mixture was stirred at room temperature for 20 min. The layers were separated by filtration on an Isolute separator cartridge, eluting with more DCM (2 mL). The organic extract was concentrated in vacuo and dissolved in MeOH (2 mL) then PS-Trisamine resin (0.33 g; 0.41 mmol; 1.24 mmol/g) was added. The mixture was shaken at room tempeature for 16 h. The mixture was filtered and the solution was purified by reverse phase HPLC (Cl 8 XBridge 30 x 100 mm 10 pm; NH4HCO3 0.25 % solution in water and ACN) to afford Compound 351 (26 mg, yield: 48 %).

[0852] The compounds in Table 21 were prepared according to the same procedure as Compound 351, using the indicated iodide instead of 1,1 -dimethylethyl 3 -(iodomethyl)- 1- pyrrolidinecarboxylate.

Table 21 Compound 361 : N-((2-(4-fluoro-6-((3a,4|3,5a)-4-hydroxy-3,5-dimethylpiperi din-1- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methoxy-3-(methylsulfonyl)benzamide .

(3a, 4p, 5a)

[0853] Compound 361 was prepared following Method A (in DMF), using Intermediate 396 and 4-methoxy-3-(methylsulfonyl) benzoic acid (CAS [213598-13-1]).

Compound 362: N-((2-(4-(4-acetamidobutyl)-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0854] A solution of Compound 363 (100 mg, 0.162 mmol) and EtsN (68 0μ.L4,86 mmol, 3 eq.) in DCM (5 mL) was cooled in an ice bath under nitrogen atmosphere. A solution of acetic anhydride (20 μL, 0.178 mmol, 1.1 eq.) in DCM (2 mL) was then added dropwise over 5 min. The mixture was stirred for 30 min at 0 °C. Na2CO3 (1 M in water, 10 mL) was added with stirring. After 5 min, the organic layer was separated and aqueous layer was extracted with DCM (50 mL). The combined organic layer was dried over MgSCL, filtered, and concentrated. The crude product was purified by flash column chromatography (25 g silica; DCM:MeOH (9:1) in DCM from 0/100 to 100/0) to give Compound 362 (90 mg, yield: 83 %) as a yellow solid. Compound 363: N-((2-(4-(4-aminobutyl)-6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0855] To a solution of Intermediate 424 (270 mg, 0.377 mmol) in dioxane (2 mL) was added HC1 (4 M in 1,4-dioxane, 5 mL, 20 mmol, 53 eq.) and the mixture was stirred for 2 h at room temperature. The reaction mixture was poured slowly into Na2CO3 (1 M in water, 40 mL).

The organics were extracted with DCM (3 x 50 mL). The combined organic layer was dried over MgSCL. filtered, and concentrated. The crude residue was purified by column chromatography over silica gel (12 g; DCM:MeOH/NH4OH, 9.0/0.9/0.1, v/v/v in DCM from 0 to 100 %) to give Compound 363 (182 mg, yield: 81 %) as ayellow solid.

Compound 364: N-((2-(4-fluoro-6-((3a, 4|3, 5a))-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l, 6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)-5- (trifluoromethoxy)benzamide.

[0856] Intermediate 396 (76 mg, 0.167 mmol) was added to a stirred solution of 3- (methylsulfonyl)-5-(trifluoromethoxy)benzoic acid (Intermediate 426, 48 mg, 0.169 mmol, 1 eq.), HATU (CAS [94790-37-1], 96 mg; 0.252 mmol, 1.5 eq), and DIPEA (0.250 mL; 1.431 mmol, 8.5 eq.) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. 3-(methylsulfonyl)-5-(trifluoromethoxy)benzoic acid (Intermediate 426, 48 mg; 0.169 mmol, 1 eq.), HATU (CAS [94790-37-1], 96 mg; 0.252 mmol, 1.5 eq), and DIPEA (0.250 mL; 1.431 mmol, 8.5 eq.) were added. The mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 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 (silica 12 g; EtOAc/heptane from 0/100 to 80/20) followed by reverse phase chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 47 % [25 mMNMCOi] - 53 % [ACN:MeOH (1:1)] to 18 % [25 mM NH4HCO3] - 82 % [ACN:MeOH (1 : 1)]) to yield Compound 364 (25 mg, yield: 23 %) as a yellow solid.

Compound 365: 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.

[0857] Intermediate 428 (96 mg, 0.20 mmol) was added to a stirred solution of 3- methanesulfonyl-4-methylbenzoic acid (CAS [51522-22-6], 40 mg; 0.19 mmol, 1 eq.), HATU (CAS [94790-37-1], 110 mg; 0.29 mmol, 1.5 eq.), and DIPEA (0.280 mL, 1.6 mmol, 8.5 eq.) in DCM (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried on MgSO4. filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; MeOH/DCM from 0/100 to 50/50) followed by reverse phase column chromatography (Phenomenex Gemini Cl 8 30 x 100 mm 5 pm; from 70 % [25 mM NH4HCO3] - 30 % [ACN:MeOH (1:1)] to 27 % [25 mM NH4HCO3] - 73 % [ACN:MeOH (1: 1)]) to yield Compound 365 (10 mg, yield: 8 %) as a yellow solid.

Compound 367: (*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 and Compound 368: (*S)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(tetrahydrofuran-2-yl)benzamide.

(*R) Compound 367, pure but unknown stereochemistry

(*S) Compound 368, pure but unknown stereochemistry

[0858] The racemic mixture of Compound 367 and Compound 368 was prepared according to Method C, using Intermediate 300 instead of Intermediate 129, and Intermediate 429 instead of Intermediate 165. The racemic mixture was separated into its stereoisomers by SFC (Phenomenex; Lux i-Amylose-1 250 x 30 mm 5 urn; isocratic 50 % (EtOH + 0.1 % DEA) - 50 % CO2) to afford Compound 367 and Compound 368.

Compound 370: N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((3-hydroxyazetidin-l-yl)sulfonyl)-4-methylbenzamide.

[0859] Intermediate 431 (74 mg, 0.1 mmol) was dissolved in THF (1.4 mL). tetrabutyl ammonium fluoride solution (CAS [429-41-4], 1 M in THF, 152 0μ.L15, mmol, 1.5 eq.) was added at room temperature and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layer was dried over MgSO fil4t.ered, and concentrated in vacuo. The crude product was purified twice by flash column chromatography (silica 25 g; DCM:MeOH (9:1) in DCM from 0/100 to 20/80) to yield Compound 370 (39 mg, yield: 60 %) as a yellow solid.

Compound 371: 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.

(3a, 4p, 5a)

[0860] To a solution of Intermediate 410 (80 mg, 0.20 mmol) in DMF (2 mL), 3-chloro-5- methanesulfonylbenzoic acid (CAS [151104-63-1], 57 mg, 0.24 mmol, 1.2 eq) and DIPEA (106μL, 0.61 mmol, 3 eq.) were added. The reaction mixture was stirred at room temperature for 1 min, then it was treated with HATU (CAS [148893-10-1], 92 mg, 0.24 mmol, 1.2 eq.) and it was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHC'Os and extracted with DCM (x 3). The combined organic layer was dried over MgSO4, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash chromatography (12 g SiCh; DCM:MeOH (9:1) in DCM from 0 % to 45 %) to give a solid that was triturated with ACN, filtered, and washed with Et20 to yield Compound 371 (58 mg; yield: 46 %) as a beige solid.

Compound 372: 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 and Compound 398: (*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 and Compound 399: (*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. Compound 372

(*R) Compound 398, pure but unknown stereochemistry

(*S) Compound 399, pure but unknown stereochemistry

[0861] Step A: tert-butyl (5-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)carbamate. To a solution of Intermediate 46 (180 mg, 0.40 mmol) in DMSO (0.5 mL), tert-butyl 5-azaspiro[2.4]heptan-7- ylcarbamate (CAS [152513-88-7], 170 mg, 0.80 mmol, 2 eq.) and DIPEA (0.4 mL, 2.3 mmol, 5.7 eq.) were added. The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with water and extracted with DCM (x 3). The combined organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The residue was triturated with ACN, filtered, and the solid was washed with Et20 twice to afford the title compound (206 mg; yield: 76 %) as a yellow solid.

[0862] Step B: 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. Trifluoroacetic acid (CAS [76-05-1], 0.5 mL, 6.53 mmol, 20 eq.) was added to a stirred solution of tert-butyl (5-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-5- azaspiro[2.4]heptan-7-yl)carbamate (206 mg, 0.32 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, and a saturated NaHCO3 aqueous solution was added until pH 8. The mixture was extracted with DCM (x 3). The combined organic layer was dried over MgS fOilt4e.red, and concentrated in vacuo to yield Compound 372 (163 mg, yield: 91 %) as a yellow solid.

Compound 372 was separated into its stereoisomers by semipreparative SFC (Cell-1 column, isocratic 60 % [MeOH + 0.1 % DEA] - 40 % [CO2]) to yield Compound 398 (51 mg, yield: 32 %) and Compound 399 (24 mg, yield: 15 %), both as yellow solids. Compound 375: 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 and Compound 392: (*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 and Compound 393: (*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.

(*R) Compound 392, pure but unknown stereochemistry

(*S) Compound 393, pure but unknown stereochemistry

[0863] HC1 (4 M in 1,4-dioxane, 0.32 mL, 1.27 mmol) was added to a solution of Compound 374 (88 mg, 0.13 mmol) in 1,4 dioxane (3 mL) at room temperature. The mixture was stirred at room temperature for 12 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The pH of aqueous layer was regulated to pH 10 with Na2CO3 (1 M in water, 5 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 crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 10/90) to yield Compound 375 (44 mg; 60 % yield) as a green solid. SFC purification (Phenomenex Lux Cellulose-1 150 x 21.2 mm, 5 urn; from 60 % of CO2 - 40 % (MeOH + 0.1 % DEA) to 60 % of CO2 - 40 % (MeOH + 0.1 % DEA)) of Compound 375 afforded Compound 392 and Compound 393. Compound 376: N-((2-(4-fluoro-6-((3a,4p,5a)-4-hy droxy-3 ,5 -dimethy Ipiperidin- 1 - yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methoxy-3-(methylsulfonyl)benzamide.

[0864] Compound 376 was prepared following Method C (in DMF), using Intermediate 396 and 3-fluoro-5-(methylsulfonyl)-benzoic acid (CAS [1783354-37-9]).

Compound 377: 3-fluoro-N-((2-(4-fluoro-6-((3a, 4p,5a)-4-hydroxy-3,5-dimethylpiperi din-1 - yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)benzamide

[0865] Compound 377 was prepared following Method C (in DMF), using Intermediate 396 and Intermediate 712.

Compound 378: 3-fluoro-N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperi din-1- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-5-(methylsulfonyl)benzamide.

[0866] Compound 378 was prepared following Method C (in DMF), using Intermediate 396 and 3-fluoro-4-methyl-5-(methylsulfonyl)benzoic acid (CAS [1153289-09-8]).

Compound 379: 3-fluoro-N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperi din-1- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-4- methylbenzamide.

[0867] Compound 379 was prepared following Method C (in DMF), using Intermediate 396 and 3-fluoro-5-[(2-hydroxyethyl)sulfonyl]-4-methylbenzoic acid (CAS [1156069-76-9]).

Compound 381: N-((2-(6-(4,7-diazaspiro [2.5] octan-7 -yl)pyridin-2-yl)- 1 ,6-naphthyri din-7 - yl)methyl)-3-(2-cyanopropan-2-yl)-4-fluorobenzamide.

[0868] Intermediate 582 (100 mg, 0.189 mmol) and 3-(2-cyanopropan-2-yl)-4-fluorobenzoic acid (Intermediate 688, 43.107 mg, 0.208 mmol, 1.1 eq.) were dissolved in DCM (2 mL) under nitrogen atmosphere. Then, 1-propanephosphonic anhydride (50 % in EtOAc, CAS [68957-94-8], 0.191 mL, 0.322 mmol, 1.7 eq.) was added, followed by EtsN (0.189 mL, 1.362 mmol, 7.2 eq.), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into NaOH (1 M in water) and extracted with EtOAc (3 x). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (12 g SiO2, DCM/fNHs 7 N in MeOH] from 100/0 to 90/10), followed by preparative SFC (Torus Diol 30 x 150 mm; CO2, MeOH + 20 mM NH4OH) to afford Compound 381 (17 mg, yield: 17 %).

Compound 382: 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.

[0869] Compound 382 was prepared similarly to Compound 381 starting from Intermediate 582 and Intermediate 691. Compound 383: 4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide.

[0870] Step A: (cis)-4-(3-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)- 2,6-dimethylmorpholine. (cis)-4-(6-chloro-3-fluoropyridin-2-yl)-2,6-dimethylmorpholine (Intermediate 631, 160 mg, 0.65 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 203 mg, 0.78 mmol, 1.2 eq.), potassium acetate (194 mg, 1.96 mmol, 3.0 eq.), and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (CAS [95464-05-4], 53 mg, 0.065 mmol, 0.1 eq.) were placed in a vial under inert atmosphere. Anhydrous 1,4-dioxane (2.2 mL) was added and the vial was stirred at 90 °C under inert atmosphere for 4 h then cooled to room temperature. The obtained crude boronic ester was used directly in the next stage without further purification.

[0871] Step B: 4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide. A vial was charged with Intermediate 632 (175 mg, 0.43 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS [72287-26-4], 16 mg, 0.021 mmol, 0.05 eq.), K2CO3 (CAS [584-08-7], 118 mg, 0.85 mmol, 2.0 eq.), and copper(I) chloride (CAS [7758-89-6], 44 mg, 0.43 mmol, 1.0 eq.) under inert atmosphere. To this vial was added a solution of (cis)-4-(3-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)-2,6-dimethylmorpholine in 1,4-dioxane (2.2 mL) and the mixture was stirred at 70 °C overnight. After cooling, the mixture was diluted with EtOAc, water, and brine. The mixture was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by reverse phase HPLC (45-64 % ACN:water (10 mM NH4OH)) to give Compound 383 (89 mg, yield: 36 %). Compound 384: 4-methyl-N-((2-(6-(3-methyl-5-oxopiperazin-l-yl)494yridine-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide.

[0872] Compound 384 was prepared similarly to Compound 346, starting from Intermediate 46 and 6-methyl-piperazin-2-one (CAS [59701-83-6]).

Compound 385: 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. [0873] Compound 385 was prepared similarly to Compound 346, starting from Intermediate

46 and 4,7-diazaspiro[2.5]octan-5-one (CAS [1200114-14-2]).

Compound 386: 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

[0874] Compound 386 was prepared according to Method A (in DMF), using Intermediate 300 instead of Intermediate 129, and 3-fluoro-5-((2-hydroxyethyl)sulfonyl)benzoic acid (Intermediate 437), instead of Intermediate 165. Compound 387: (*R)-N-((2-(6-(3-hydroxy-3-methylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide and Compound 388: (*S)- N-((2-(6-(3-hydroxy-3-methylpyrrolidin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

(*R) Compound 387, pure but unknown stereochemistry

(*S) Compound 388, pure but unknown stereochemistry

[0875] A sample of Compound 369 was separated into its stereoisomers by semipreparative SFC (Cell-3 column; isocratic method: 45 % [EtOH + 0.1 % DEA] - 55 % [CO2]) to yield Compound 387 and Compound 388, both as yellow solids.

Compound 389: 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.

[0876] Compound 389 was prepared according to Method A (in DMF), using Intermediate 300 instead of Intermediate 129, and 3-fluoro-5-(methylsulfonyl)-benzoic acid (CAS [1783354-37-9]), instead of Intermediate 165.

Compound 390: 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. [0877] Compound 390 was prepared similarly to Compound 381 starting from Intermediate 582 and Intermediate 694.

Compound 391 : 4-methyl-3-(methylsulfonyl)-N-((2-(6-(3-oxopiperazin-l-yl)pyri din-2 -yl)- l,6-naphthyridin-7-yl)methyl)benzamide.

[0878] Compound 391 was prepared similarly to Compound 346, starting from Intermediate 46 and piperazin-2-one (CAS [5625-67-2]).

Compound 400: 3-chloro-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5] octan-7 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide.

[0879] Compound 400 was prepared according to Method A (in DMF), using Intermediate 300 instead of Intermediate 129, and Intermediate 49 instead of Intermediate 165.

Compound 401 : N-((2-(6-(4,7 -diazaspiro [2.5] octan-7 -yl)pyridin-2-yl)- 1 ,6-naphthy ridin-7- yl)methyl)-3-methyl-5-(methylsulfonyl)benzamide.

[0880] Compound 401 was prepared from Intermediate 582 and 3-methyl-5- (methylsulfonyl)benzoic acid (CAS [2301077-30-3]), following Method M. Compound 402: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3-methyl-5-(methylsulfonyl)benzamide.

[0881] Compound 402 was prepared from Intermediate 11 and 3-methyl-5- (methylsulfonyl)benzoic acid (CAS [2301077-30-3]), following Method M.

Compound 403: N-((2-(6-((3a, 4|3, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-3-methyl-5-(methylsulfonyl)benzamide.

(3a,4|3,5a)

[0882] Compound 403 was prepared from Intermediate 149 and 3-methyl-5- (methylsulfonyl)benzoic acid (CAS [2301077-30-3]), following Method M.

Compound 404: N-((2-(6-(3-amino-3-(trifluoromethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0883] Step A: tert-butyl (l-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyri din-2 -yl)-3-(trifluoromethyl)pyrrolidin-3-yl)carbamate. The title compound was prepared according to Method I, using tert-butyl[3- (trifluoromethylpyrrolidine-3-yl)]carbamate (CAS [186203-13-4]) instead of 4- piperidineethanol.

[0884] Step B: N-((2-(6-(3-amino-3-(trifluoromethyl)pyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide. Trifluoroacetic acid (0.6 mL, 7.83 mmol, 40 eq.) was added to a solution of tert-butyl (l-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-3- (trifluoromethyl)pyrrolidin-3-yl)carbamate (133 mg, 0.194 mmol) in DCM (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM/MeOH 9/1 and treated with Amberlyst 26 (OH form) to reach pH>7. The suspension was filtered, and the solid was washed with DCM/MeOH 9/1. The filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (Phenomenex Gemini C18 100A column 100 mm x 30 mm I.D.; 5 pm; from 50 % of a 25 nM NH4HCO3 aqueous solution / 50 % (ACN/MeOH 1/1) to 25 % of a 25 nM NH4HCO3 aqueous solution / 75 % (ACN/MeOH 1/1)) to afford Compound 404 (9 mg, yield: 8 %) as a yellow solid.

Compound 408: N-((2-(6-(3-amino-3-methylazetidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0885] Trifluoroacetic acid (1 mL, 13 mmol, 62 eq.) was added to a solution of Compound 373 (130 mg, 0.211 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 10/90) to yield Compound 408 (100 mg, yield: 90 %) as an orange solid.

Compound 409: N-((2-(6-(3-cyclopropylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0886] A solution of Intermediate 46 (47 mg, 0.1 mmol) in dry DMSO (1.2 mL) was added to 1,1 -dimethylethyl 2-cyclopropyl-l -piperazinecarboxylate (CAS [886779-93-7], 91 mg, 0.3 mmol 3 eq,). Next, DIPEA (0.217 mL, 1.3 mmol, 12 eq.) was added and the reaction mixture was stirred at 145 °C for 144 h. After cooling to room temperature, TFA (1.6 mL, 20.6 mmol, 196 eq.) was added. The resulting mixture was stirred at 80 °C for 2 h. The solvent was evaporated and the residue was redissolved in DMSO (2 mL), Some SiliaMetS Diamine scavenger (+- 0.5 g) was added to scavenge the remaining TFA. The reaction mixture was filtered, and the filter was rinsed with DMSO (1 mL). The filtrate was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to afford Compound 409.

[0887] The compounds in Table 23 were prepared from Intermediate 46 and the corresponding Boc-protected piperazine, following a procedure similar to the one used for Compound 409. Table 23 Compound 414: 4-methyl-N-((2-(6-(3-methyl-4-morpholinopyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide and Compound 396: 4-methyl-N- ((2-(6-((3*R,4*R)-3-methyl-4-morpholinopyrrolidin-l-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-3-(methylsulfonyl)benzamide and Compound 397: 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 and Compound 405: 4-methyl-N-((2-(6-((3*S,4*R)-3-methyl-4- morpholinopy rrolidin- 1 -y l)pyridin-2-yl)- 1 ,6-naphthy ri din-7 -y l)methyl)-3 -

(methylsulfonyl)benzamide and Compound 406: 4-methyl-N-((2-(6-((3*R,4*S)-3-methyl-4- morpholinopy rrolidin- 1 -y l)pyridin-2-yl)- 1 ,6-naphthy ri din-7 -y l)methyl)-3 - (methylsulfonyl)benzamide

Compound 396, pure but undetermined stereochemistry

Compound 397, pure but undetermined stereochemistry

Compound 405, pure but undetermined stereochemistry

Compound 406, pure but undetermined stereochemistry

[0888] A solution of Intermediate 46 (125 mg, 0.277 mmol) and 4-(4-methylpyrrolidin-3- yl)morpholine (CAS [1384429-55-3], 100 mg, 0.587 mmol, 2.1 eq.) in DMSO (0.5 mL) was stirred at 150 °C in a closed vial for 16 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHC'Os. The aqueous layer was extracted twice with DCM. The combined organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (SiO2, 25 g; heptane/EtOAc from 100/0 to 20/80) followed by reverse phase column chromatography (Phenomenex Gemini C18 100A column, 100 mm x 30 mm I.D.; 5 pm; from 70 % of a 65 nM NROAc + ACN (90:10) aqueous solution / 30 % (ACN/MeOH 1/1) to 27 % of a 65 nM NH₄OAc + ACN (90:10) aqueous solution / 73 % (ACN/MeOH 1/1) to afford a mixture of Compound 405 and Compound 406 (52 mg, yield: 31 %) as a yellow solid, Compound 414 (11 mg, yield: 7 %) as a yellow solid, and a mixture of Compound 396 and Compound 397 (59 mg, yield: 35 %) as a yellow solid. The mixture of Compound 405 and Compound 406 was separated by preparative SFC (Cellulose-3 column (Regis Technologies) 250 mm x30 mm I.D. 5 pm, isocratic CO2 (40 %) - MeOH (60 %) + 0.1 % diethylamine) to afford Compound 405 (14 mg, yield: 8 %) as a yellow solid and Compound 406 (9 mg, yield: 5 %) as a yellow solid. The mixture of Compound 396 and Compound 397 was separated by the same method to afford Compound 396 (14 mg, yield: 8 %) as a yellow solid and Compound 397 (16 mg, yield: 9 %) as a yellow solid.

Compound 416: 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 and Compound 440: (*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 and Compound 441: (*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.

(*S) Compound 440, pure but unknown stereochemistry

(*R) Compound 441, pure but unknown stereochemistry

[0889] Trifluoroacetic acid (0.06 mL, 0.773 mmol, 40 eq.) was added to a stirred solution of Compound 415 (13 mg, 0.019 mmol) in DCM (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. To push the reaction to completion, more TFA (0.06 mL, 0.773 mmol, 40 eq.) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in DCM/MeOH 9/1 and treated with Amberlyst 26 (OH form) to reach pH>7. The suspension was filtered, and the solid was washed with DCM/MeOH 9/1. The filtrate was concentrated under reduced pressure to afford Compound 416 (10 mg, yield: 88 %) as a light brown solid. Purification of Compound 416 by SFC (Amilose l column, isocratic 60 % iPrOH + 0.1 % DEA) afforded Compound 440 (15 mg, yield: 35 %) and Compound 441 (16 mg, yield: 37 %), both as yellow solids.

Compound 417: 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. [0890] Step A: (cis)-2,6-dimethyl-4-(2,6-naphthyridin-l-yl)morpholine. A solution of 1 - bromo-2,6-naphthyridine (CAS [81044-15-7], 2.3 g, 11.0 mmol) in cis-2,6- dimethylmorpholine (CAS [6485-55-8 ], 10 mL, 85.09 mmol, 7.7 eq.) was stirred at 140 °C for 16 h in a sealed tube. After cooling, the crude product was purified by column chromatography (silica 80 g; EtOAc/heptane from 0/100 to 50/50) to afford the title compound (2.7 g, quantitative) as a brown solid.

[0891] Step B: (cis)-2,6-dimethyl-4-(5,6,7,8-tetrahydro-2,6-naphthyridin-l-yl)morpholine. A solution of (cis)-2,6-dimethyl-4-(2,6-naphthyridin-l-yl)morpholine (2.7 g, 11.097 mmol) in MeOH (550 mL) was pumped (1 mL/min) through a HCube Pd/C 10 % cartridge at 40 bar H2 and 30 °C. The resulting solution was concentrated to dryness to afford the title compound (2.7 g, yield: 97 %) as a brown oil, used without further purification.

[0892] Step C: tert-butyl 5-((cis)-2,6-dimethylmorpholino)-3,4-dihydro-2,6-naphthyridine- 2(lH)-carboxylate. Di-tert-butyl dicarbonate (CAS [24424-99-5], 3.5 mL, 16.358 mmol, 1.5 eq.) was added to a solution of (cis)-2,6-dimethyl-4-(5,6,7,8-tetrahydro-2,6-naphthyridin-l- yl)morpholine (2.7 g, 10.916 mmol) and EtsN (3 mL, 21.524 mmol, 2 eq.) in THF (50 mL) at 0 °C. The resulting mixture was stirred at room temperature for 18 h. Saturated aqueous NaHCO3 and EtOAc were added, the organic layer was separated, dried (MgSO4). filtered, and the solvents evaporated in vacuo to yield the title compound (2.93 g, yield: 76 %) as a colourless foam, used without further purification.

[0893] Step D: tert-butyl 5-((cis)-2,6-dimethylmorpholino)-8-iodo-3,4-dihydro-2,6- naphthyridine-2(lH)-carboxylate. N-Iodosuccinimide (CAS [516-12-1], 325 mg, 1.445 mmol, 1 eq.) was added to a solution of tert-butyl 5-((cis)-2,6-dimethylmorpholino)-3,4-dihydro-2,6- naphthyridine-2(lH)-carboxylate (500 mg, 1.439 mmol) in hexafluoroisopropanol (CAS [920- 66-1], 6 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 (MgSO4), filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; EtOAc/heptane from 0/100 to 10/90) to yield the title compound (477 mg , yield: 68 %) as a white foam.

[0894] Step E: tert-butyl 5-((cis)-2,6-dimethylmorpholino)-7-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l, 6-naphthyri din-2 -yl)-3,4-dihy dro-2,6-naphthyridine- 2(lH)-carboxylate. tert-butyl 5-((cis)-2,6-dimethylmorpholino)-8-iodo-3,4-dihydro-2,6- naphthyridine-2(lH)-carboxylate (250 mg, 0.528 mmol, 1.2 eq.) was added to a stirred solution of Intermediate 45 (173 mg, 0.442 mmol) in DME (5 mL) in a sealed tube at room temperature previously degassed and kept under nitrogen atmosphere. 2-Norbomene (CAS [498-66-8], 85 mg, 0.903 mmol, 2 eq.), K2CO3 (213 mg, 1.543 mmol, 3.5 eq.), exo- norbomeol (CAS [497-37-0], 99 mg, 0.882 mmol, 2 eq.), palladium(II) acetate (CAS [3375- 31-3], 10 mg, 0.044 mmol, 0.1 eq.), and triphenylphosphine (25 mg, 0.090 mmol, 0.2 eq.) were added to the reaction mixture and it was stirred at 110 °C for 18 h. After cooling, the mixture was diluted with saturated aqueous NaHCO3 and EtOAc. The organic layer was separated, dried (MgSOr). filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (12 g SiCh, 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 49 % [25 mM NH4HCO3] - 51 % [ACN:MeOH (1:1)] to 6 % [25 mM NH4HCO3] - 94 % [ACN:MeOH (1: 1)]) to yield the title compound (48 mg, yield: 15 %) as a white solid.

[0895] Step F: 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. The title compound was prepared using the same procedure as Compound 416.

Compound 418: 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.

[0896] Compound 418 was prepared using the same procedure as Compound 416, using Intermediate 487 instead of Compound 415.

Compound 420: 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.

[0897] Trifluoroacetic acid (1.25 mL; 16.279 mmol, 18 eq.) was added to a solution of Compound 424 (594 mg; 0.904 mmol) in DCM (3 mL), at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCCh and the mixture was extracted with DCM (x 3). The combined organic layer was dried (MgSO4). filtered, and the solvents evaporated in vacuo. The crude product was purified by flash chromatography (25 g column, DCM:MeOH (9:1) in DCM from 0/100 to 55/45]) to afford Compound 420 (330 mg; yield: 65 %) as a yellow solid.

Compound 422: 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)benzamide.

[0898] Compound 422 was prepared following the same procedure as Compound 420, using Compound 407 instead of Compound 424.

Compound 423: N-((2-(6-(4-amino-3,3-difluoropiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-

7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide and Compound 442 : (*R)-N-((2-(6-(4- amino-3,3-difluoropiperi din-1 -yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide and Compound 443: (*S)-N-((2-(6-(4-amino-3,3- difluoropiperidin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide.

(*R) Compound 442, pure but unknown stereochemistry

(*S) Compound 443, pure but unknown stereochemistry

[0899] Trifluoroacetic acid (0.23 mL, 3.001 mmol, 20 eq.) was added to a stirred solution of

Intermediate 488 (140 mg, 0.147 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was cooled to 0 °C, and saturated aqueous NaHCO3 was added until pH 8. DCM was added and the layers were separated. The aqueous phase was extracted with DCM (x 3). The combined organic layer was dried over MgSCE, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g SiCh, DCM:MeOH (9:1) in DCM from 0/100 to 25/75) to provide Compound 423. Semipreparative SFC (Amylose-1 column, isocratic 65 % [EtOH + ACN + 0.1 % DEA] - 35 % [CO2]) to yield Compound 442 (19 mg, yield: 24 %) as a yellow solid and Compound 443 ( 17 mg, yield: 21 %) as a yellow solid.

Compound 425: 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.

[0900] Formaldehyde (37 % in water, 54 μL 0,.719 mmol, 10 eq.) was added to a stirred suspension of Compound 420 (40 mg; 0.072 mmol) in THF (2 mL) and MeOH (0.5 mL) at room temperature. After 15 min, Na(AcO)3BH (76 mg; 0.359 mmol, 5 eq.) was then added portion wise over 30 min and stirring was continued for 20 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and was extracted with DCM (3 x). The combined organic layer was dried with MgSCE, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCh, DCM/MeOH 9: 1 in DCM, from 0/100 to 55/45). The obtained solid was triturated with ACN and washed twice with Et20 to yield Compound 425 (9 mg; yield: 21 %) as a yellow solid.

Compound 426: (*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 and Compound 427: (*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.

(*R) Compound 426, pure but unknown stereochemistry

(*S) Compound 427, pure but unknown stereochemistry

[0901] A sample of Compound 419 was separated into its stereoisomers by semipreparative SFC (Cell-1 column, isocratic mode 60 % [MeOH + 0. 1 % DEA] - 40 % [CO2]) to yield Compound 426 and Compound 427, both as yellow solids.

Compound 428: N-((2-(6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0902] Compound 428 was prepared following the same procedure as Compound 420, using Compound 421 instead of Compound 424.

Compound 429: 3,4-dimethyl-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)-5- (methylsulfonyl)benzamide.

[0903] Step A: tert-butyl (lR,5S)-9-(6-(7-((3,4-dimethyl-5- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-3-oxa-7,9- diazabicyclo[3.3. l]nonane-7-carboxylate and 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. 7-Boc-3-oxa-7,9-diazabicyclo[3.3. l]nonane-7-carboxylate (CAS [864448-41-9], 190 mg, 0.834 mmol, 2.5 eq.) was added to a solution of Intermediate 68 (155 mg, 0.334 mmol) and DIPEA (0.331 mL, 2.002 mmol, 6 eq.) in DMSO (2 mL). The reaction mixture was stirred at 130 °C for 16 h. To push the reaction to completion, more 7-Boc-3-oxa- 7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (60 mg, 0.263 mmol, 0.8 eq.) and DIPEA (0.11 mL, 0.667 mmol, 2 eq.) were added and the mixture was stirred at 130 °C for 40 h. After cooling, the mixture was diluted with EtOAc and water. The organic layer was separated and washed with brine (x 2), dried over MgSO4. filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; MeOH/DCM from 0/100 to 10/90) to yield tert-butyl (lR,5S)-9-(6-(7-((3,4-dimethyl-5- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonane-7-carboxylate (73 mg, yield: 32 %) as a yellow solid and 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 (58 mg, yield: 27 %) as a sticky brown solid.

[0904] Step B: 3,4-dimethyl-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)-5- (methylsulfonyl)benzamide. A solution ofN-((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 (HC1 salt, 66 mg, 0.109 mmol), formaldehyde (37 % in water, 0.041 mL, 0.545 mmol, 5 eq.), and acetic acid (0.007 mL, 0.120 mmol, 1.1 eq.) in DCM (1 mL) was stirred at room temperature for 30 min. Then, Sodium triacetoxy borohydride (CAS [56553-60-7], 46 mg, 0.218 mmol, 2 eq.) was added and the mixture was stirred at room temperature for 16 h. To push the reaction to completion, more formaldehyde (37 % in water, 0.041 mL, 0.55 mmol, 5 eq.) was added and the mixture was stirred at room temperature for 30 min. Then, Sodium triacetoxy borohydride (46 mg, 0.182 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 12 g; MeOH/DCM from 0/100 to 10/90) to yield Compound 429 (27 mg, yield: 43 %) as a yellow solid.

Compound 430: 4-methyl-N-((2-(6-(2 -methyl-3-oxopiperazin-l-yl)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide.

[0905] Compound 430 was prepared similarly to Compound 346, starting from Intermediate 46 and 3-methylpiperazin-2-one (CAS [23936-11-0]). Compound 431: 4-methyl-N-((2-(6-(2 -methyl-5-oxopiperazin-l-yl)pyri din-2 -yl)- 1,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide.

[0906] Compound 431 was prepared similarly to Compound 346, starting from Intermediate 46 and 5-methylpiperazin-2-one (CAS [907973-06-2]).

Compound 433: 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.

[0907] Step A: tert-butyl 8-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyridin-2-yl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate. A solution of 2,5,8-triazaspiro[3.5]nonane (CAS [792921-02-9], 60 mg, 0.264 mmol, 2.5 eq.), Intermediate 46 (50 mg, 0.105 mmol), and DIPEA (91 μL 0,.528 mmol, 5 eq.) in DMSO (1 mL) was stirred at 130 °C overnight. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (3 x). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title compound (21 mg, yield: 31 %)

[0908] Step B: 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. tert-butyl 8-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-2,5,8- triazaspiro[3.5]nonane-2-carboxylate (21.3 mg, 0.0324 mmol) was suspended in HC1 (4 M in 1,4-di oxane, 1 mL, 4 mmol) and the mixture was stirred at room temperature for 1 h. The solid that formed was isolated by filtration and redissolved in MeOH. The resulting solution was evaporated under reduced pressure to afford Compound 433 (19 mg, yield: 83 %) as a red solid (HC1 salt). Compound 439: N-((2-(6-(4-hydroxy-3,3-dimethylpyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, Compound 451: (*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, and Compound 452: (*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.

(*R) Compound 451, pure but unknown stereochemistry

(*S) Compound 452, pure but unknown stereochemistry

[0909] Compound 439 was prepared according to Method I, using 4,4-dimethylpyrrolidin-3- ol hydrochloride (CAS [1795504-80-1]) instead of 4-piperidineethanol. A batch of Compound 439 was separated into its stereoisomers by semipreparative SFC (Phenomenex Cellulose-1 250 x 30 mm 5 um; isocratic 50 % of CO2 - 50 % (EtOH + 0.1 % DEA)) to yield Compound 451 and Compound 452, both as yellow solids.

Compound 445: (*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, and Compound 446

(*S) Compound 445, pure but unknown stereochemistry

(*R) Compound 446, pure but unknown stereochemistry

[0910] A batch of Compound 438 was separated into its stereoisomers by semipreparative SFC (i-Amylose-1 column; isocratic 60 % [iPrOH + 0.1 % DEA] - 40 % [CO2]) to yield Compound 445 and Compound 446, both as yellow solids.

Compound 447 : N-((2-(6-((cis)-2,6-dimethylmorpholino)-3-(dimethylphosphoryl)pyri din-2 - yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0911] A vial was charged with Compound 79 (80 mg, 0.119 mmol), XantPhos Pd G3 (CAS [1445085-97-1], 6 mg, 0.006 mmol), 1,4-dioxane (1 mL), and EtsN (25 0μ.L17, 9 mmol). To this mixture was added dimethylphosphine oxide (CAS [7211-39-4], 11 mg, 0.143 mmol) and the mixture was stirred at 100 °C overnight. After cooling, water was added and the mixture was extracted with EtOAc. The organic layer was dried (MgSO4). filtered, and concentrated in vacuo. The crude product was purified by HPLC (RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm; 0.25 % NH4HCO3 in water, ACN) to yield Compound 447 (20 mg, 26 %) as a yellow solid.

Compound 448: (*S)-N-((2-(6-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamidem and Compound 449: (*R)-N-((2-(6-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-l-yl)pyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

(*S) Compound 448

(*S) Compound 449

[0912] A batch of Compound 434 was separated into its stereoisomers by semipreparative SFC (i-Amylose-1 column; isocratic 50 % [iPrOH + 0.1 % DEA] - 50 % [CO2]) to yield Compound 448 and Compound 449, both as yellow solids.

Compound 453: 3-((difluoromethyl)sulfonyl)-N-((2-(2-(l-fluorocyclopropyl)pyrimidin-4-yl)- l,6-naphthyridin-7-yl)methyl)benzamide.

[0913] Compound 453 was prepared according to Method C (in DMF), using Intermediate 713 and 3 -[(difluoromethyl)sulfonyl] benzoic acid (CAS [4837-21-2]).

Compound 454: N-(l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)-5-hydroxypentyl)-4-methyl-3-(methylsulfonyl)benzamide.

(rac)-CIS

[0914] 1 -Propanephosphonic anhydride solution (CAS [68957-94-8], 133 0μ.2L2,3 mmol,

1.3 eq.) was added to a suspension of 4-methyl-3-(methylsulfonyl)benzoic acid (CAS [51522- 22-6], 40 mg, 0.189 mmol, 1.1 eq.) and Intermediate 439 (27 % pure, 295 mg, 0.172 mmol) in dry DCM (5 mL) at room temperature. Triethylamine (119 μ 0L.8,59 mmol, 5 eq.) was then added dropwise to the suspension. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated and the residue was dissolved in THF (2 mL), MeOH (2 mL), and water (2 mL). Lithium hydroxide (34 mg, 1.375 mmol, 8 eq.) was added and the reaction mixture was stirred at room temperature for 1 h, then at 60 °C for 24 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 by filtration on Extrelut NT3, and evaporated. The residue was purified by column chromatography (Biotage Sfar 50 g; eluent: heptane: EtOH/EtO Ac 1/3 100:0 -> 100:0) followed by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give Compound 454 (16 mg, yield: 15 %) as a yellow solid.

Compound 459: N-((2-(6-(2-(cyclopropylamino)ethoxy)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

(Method H)

[0915] NaH (60 % dispersion in mineral oil, 25 mg, 0.633 mmol, 3 eq.) was added to a solution of 2-(cyclopropylamino)ethanol (CAS [35265-06-6], 107 mg, 1.054 mmol, 5 eq.) in dry DMF (1 mL). This mixture was stirred for 10 min at room temperature (or until no bubbling occurred anymore). A suspension of Intermediate 46 (100 mg, 0.211 mmol) in dry DMF (1 mL) was then added to the reaction mixture and the vial was closed. The reaction mixture was stirred at 60 °C for 2 h. A few drops of water were added to the reaction mixture and it was then evaporated to dryness. The residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to afford Compound 459 (34 mg, yield: 29 %) as a white solid.

[0916] The compounds in Table 24 were prepared from Intermediate 46 and the corresponding alcohol, following procedures similar to Method H:

Table 24.

Compound 466: 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.

[0917] Intermediate 46 (100 mg, 0.211 mmol) and Intermediate 701 (106 mg, 0.422 mmol, 2 eq.) were dissolved in DMSO (2.1 mL) and DIPEA (1 mL). The reaction mixture was stirred at 130 °C for 3 days. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The organic layer was dried over MgSCE, filtered, and concentrated. The residue was purified by reverse phase preparative HPLC (RP XBridge Preparative Cl 8 OBD- 5 pm, 50 x 250 mm; 0.25 % NH4HCO3 solution in water, ACN) to afford Compound 466 (32 mg, yield: 26 %).

Compound 467: 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.

[0918] Intermediate 46 (200 mg, 0.422 mmol) and Intermediate 706 (133 mg, 0.844 mmol, 2 eq.) were dissolved in DMSO (4 mL), then DIPEA (2 mL, 11.606 mmol, 28 eq.) was added and the reaction mixture was stirred at 130 °C for 7 days. The reaction mixture was diluted with water and extracted with AcOEt (3 x). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase HPLC (RP XBridge Preparative C18 OBD- 5 pm, 50 x 250 mm; 0.25 % NH4HCO3 solution in water, ACN) to afford Compound 467 as a mixture of isomers (68 mg, 28 %).

Compound 470: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide, Compound 497: N-((2-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(*R- methylsulfonimidoyl)benzamide, and Compound 498: N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(*S- methylsulfonimidoyl)benzamide.

(CIS) Compound 470

(*S), (CIS) Compound 498

[0919] Intermediate 628 (107 mg, 0.238 mmol) and cis-2,6-dimethylmorpholine (CAS [6485- 55-8], 0.235 mL, 1.904 mmol, 8.0 eq.) were combined in DMSO (1 mL) and stirred at 130 °C for 4 h under an inert atmosphere. After cooling, the mixture was filtered through a syringe filter and purified by reverse phase HPLC (Waters XSelect CSH C18, 5u, 19 x 150 mm, gradient 10-40 % ACN with 0.16 % TFA/water) to give Compound 470 (61 mg, yield: 47 %) as a yellow solid. A batch of Compound 470 was separated into its stereoisomers by chiral SFC (IH 21 x 250 mm, 5 um; 30 % MeOH/70 % CO2) to give Compound 497 and Compound

498.

Compound 471: N-((2-(6-((3a, 4|3, 5a))-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-

1.6-naphthyridm-7-yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide.

(3a, 4p, 5a)

[0920] Intermediate 628 (107 mg, 0.238 mmol), (3a,4p,5a)-3,5-dimethyl-4-piperidinol (CAS [374067-78-4], 123 mg, 0.952 mmol, 4.0 eq.), and DIPEA (0.164 mL, 0.952 mmol, 4.0 eq.) were combined in DMSO (1 mL) and the mixture was stirred at 130 °C for 5 h under inert atmosphere. After cooling, the mixture was filtered and purified by reverse phase HPLC (Waters XSelect CSH C18, 5um, 19 x 150 mm, gradient 8-35 % ACN with 0.16 % TFA/water) to give Compound 471 (43 mg, yield: 32 %) as a yellow solid. Compound 472: (*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 and Compound 473: (*S)- N-((2-(6-(3,3-difluoro-4-hy droxypyrrolidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyridin-7-yl)methyl)-

4-methyl-3-(methylsulfonyl)benzamide.

(*R) Compound 472, pure but stereochemistry undetermined

(*S) Compound 473, pure but stereochemistry undetermined

[0921] A batch of Compound 450 was separated into its stereoisomers by semipreparative SFC (Amylose-1 column; isocratic 60 % [iPrOH + 0.1 % DEA] - 40 % [CO2]) to yield Compound 472 and Compound 473, both as yellow solids.

Compound 474: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-3-((2*R,4*S)-4-hydroxy-l-methylpyrrolidin-2-yl)-4-methylbenzamide and Compound 475: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-3-((2*S,4*R)-4-hydroxy-l-methylpyrrolidin-2-yl)-4-methylbenzamide.

Compound 474, pure but unknown stereochemistry

Compound 475, pure but unknown stereochemistry

[0922] A solution of Intermediate 501 (165 mg, 0.264 mmol) and EtsN (0.11 mL, 0.791 mmol, 3 eq.) in MeOH (10 mL) was treated with formaldehyde (37 % in water, 0.024 mL, 0.317 mmol, 1.2 eq.) at room temperature. The reaction mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (CAS [56553-60-7], 84 mg, 0.396 mmol, 1.5 eq.) was added after 15 min. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (60 mL) and washed with Na2CO3 (1 M in water, 20 mL). The aqueous layer was extracted once more with DCM (50 mL). The combined organic layer was dried over MgSO f4i.ltered, and concentrated. The residue was purified by flash column chromatography (silica; DCM:MeOH 9:1 in DCM from 0/100 to 100/0), followed by chiral SFC (Lux-amylose-3, isocratic 45 % EtOH + 0.1 % DEA) to yield Compound 474 (43 mg, yield: 29 %) and Compound 475 (42 mg, yield: 27 %), both as solids.

Compound 476: 3-((3,3-difluoropropyl)sulfonyl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan- 7 -y 1) 519yridine-2-yl)- 1 ,6-naphthyri din-7 -y l)methyl)-4-methy Ibenzamide.

[0923] Compound 476 was prepared according to Method A (in DMF), using Intermediate 300 instead of Intermediate 11, and Intermediate 506 instead of 3-methanesulfonyl-4- methylbenzoic acid.

Compound 477: (*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.

[0924] DBU (CAS [6674-22-2], 70 μL 0,.469 mmol, 6 eq.) followed by 2-mercaptoethanol (CAS [60-24-2], 65 μL, 0.927 mmol, 12 eq.) was added to a stirred solution of Intermediate 507 (57 mg, 0.077 mmol) in DMF (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was taken up with EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted again with EtOAc (2 x 10 mL). The combined organic layers was dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (silica 25 g; DCM:MeOH 9:1 in DCM from 0/100 to 90/10), followed by preparative HPLC (Phenomenex Gemini; I.D. (mm) 100 x 21.2; 5 um (C18) 110 A; 25 mM NHflTCCh/ACfLMeOH 1:1, from 72/28 to 36/64) to yield Compound 477 (24 mg, yield: 55 %) as a yellow solid.

Compound 478: (*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.

[0925] Compound 478 was prepared following the same procedure as Compound 477, starting from Intermediate 508 instead of Intermediate 507.

Compound 479: 3-(aminomethyl)-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- (methylsulfonyl)benzamide.

(3a, 4p,5a)

[0926] Trifluoroacetic acid (0.22 mL. 2.887 mmol, 40 eq.) was added to a stirred solution of Compound 469 (50 mg, 0.072 mmol) in DCM (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated in vacuo. The residue was dissolved in DCM and saturated aqueous NaHCO3. The organic layer was separated, dried (MgSCL). filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc/heptane from 0/100 to 100/0), followed by preparative HPLC (Phenomenex Gemini Cl 8 100A column 100 mm x 30 mm I.D.; 5 pm; from 70 % [25 mM NH4HCO3] - 30 % [ACN:MeOH (1:1)] to 27 % [25 mM NH4HCO3] - 73 % [ACN:MeOH (1:1)) to afford Compound 479 (7 mg, yield: 16 %) as a white solid.

Compound 480: 3-((*R)-4,4-difluoropyrrolidin-2-yl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methylbenzamide, and

Compound 487: 3-((*S)-4,4-difluoropyrrolidin-2-yl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methylbenzamide.

(*S) (CIS Compound 487

[0927] Intermediate 651 (0.120 g, 0.178 mmol) was dissolved in a solution of HC1 (4 M in 1,4-dioxane, 0.446 mL, 1.784 mmol, 10 eq.) in 1,4-dioxane (2 mL) and the mixture was stirred at room temperature for 3 h. The crude mixture was concentrated in vacuo and the residue was purified by chiral SFC (Lux-amylose-1; isocratic 65 % CO2 - 55 % EtOH + 0.1 % DEA) to afford Compound 480 (33 mg, yield: 32 %) and Compound 487 (25 mg, yield: 24 %), both as solids.

Compound 482: 4-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.

[0928] Intermediate 593 (100 mg, 0.15 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred overnight and then concentrated in vacuo. The residue was dissolved in ACN and water (90:10), the solution filtered, and purified by preparative HPLC (RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm; 0.25 % NH4HCO3 in water, ACN) to give Compound 482 (50 mg, yield: 58 %) as a white solid.

Compound 483: 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.

[0929] Compound 483 was prepared following the same procedure used for Compound 482, starting from Intermediate 594 instead of Intermediate 593.

Compound 484: 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.

[0930] Compound 484 was prepared following the same procedure used for Compound 482 starting from Intermediate 595 instead of Intermediate 593.

Compound 485: 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

[0931] Compound 485 was prepared from Intermediate 714 and 4-methyl-3- (methylsulfonyl)benzoic acid (CAS [51522-22-6]), following Method M. Compound 490: 3-(2-hydroxypropan-2-yl)-4-methyl-N-((2-(4-(pyrazin-2-yl)piperazin-l-yl)- l,6-naphthyridin-7-yl)methyl)benzamide

[0932] Compound 490 was prepared following Method B, from Intermediate 369 and 3-(l- hydroxy- l-methylethyl)-4-methyl benzoic acid (CAS [1521439-68-8]).

Compound 491: N-((2-(6-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide. (Method R)

[0933] Intermediate 587 (52 mg, 0.11 mmol) and 2-oxa-7-azaspiro[4.4]nonane (CAS [175- 97-3], 43 mg, 0.34 mmol, 3 eq.) were suspended in DMSO (1.3 mL) and DIPEA (0.077 mL, 0.45 mmol, 4 eq) was added. The reaction mixture was stirred at 100 °C for 25 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was evaporated and the residue was purified by preparative HPLC (RP XBridge Prep Cl 8 OBD- 5 pm, 50 x 250 mm; 0.25 % NH4HCO3 in water, ACN), followed by SFC (Torus Diol 30 x 150 mm; CO2, MeOH + 20 mM NH4OH) to yield Compound 491 (9 mg, yield: 14 %).

Compound 492: 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, Compound 547: (*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 and Compound 548: (*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.

(*S) Compound 548

[0934] Compound 492 was prepared following Method R, starting from Intermediate 587 and using 4-azaspiro[2.5]octan-7-ol hydrochloride (CAS [1909347-89-2]) instead of 2-oxa-7- azaspiro[4.4]nonane. A batch of Compound 492 was separated into its stereoisomers by preparative SFC (Chiralpak Diacel AD 20 x 250 mm; CO2, iPrOH + 0.4 % iPrNH2) to afford Compound 547 and Compound 548, both as yellow solids.

[0935] The compounds in Table 25 were prepared from Intermediate 587 and the corresponding amine, following procedures similar to the methods shown in the table. Table 25.

Compound 494: N-((2-(6-(4-amino-3,3-difluoropyrrolidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide and Compound 543: (*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 and Compound 544: (*S)-N-((2-(6-(4-amino-3,3- difluoropyrrolidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methyl-3-

(methylsulfonyl)benzamide.

Compound 494

(*R) Compound 543, pure but unknown stereochemistry

(*S) Compound 544, pure but unknown stereochemistry

[0936] Trifluoroacetic acid (CAS [76-05-1], 0.11 mL, 1.44 mmol, 22 eq.) was added to a stirred solution of Compound 486 (43 mg, 0.07 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C and saturated aqueous NaHCO3 was added until pH 8. DCM was added and the aqueous layer was extracted with DCM (x 3). The combined organic layer was dried over MgS fOilt4e.red, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g SiCh, EtOAc/EtOAc:MeOH (9:1) from 100/0 to 70/30) to afford Compound 494 (27 mg; yield: 73 %) as a yellow solid. Semipreparative SFC (i-Cellulose-B column, isocratic 55 % [EtOH + 0.1 % DEA] - 45 % [CO2]) afforded Compound 543 and Compound 544.

Compound 496: tert-butyl (6-((2*S,6*R)-6-methyl-4-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)morpholin-2- yl)hexyl)carbamate.

(2-*S, 6-*R)

[0937] Compound 496 was prepared following the same procedure as Compound 495, using Intermediate 670 instead of Intermediate 671. Compound 499: N-((2-(6-(2-(2 -hydroxy ethoxy)ethoxy)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0938] NaH (60 % dispersion in mineral oil, 53 mg, 1.332 mmol, 3 eq.) was added to a solution of diethylene glycol (CAS [111-46-6], 188 mg, 1.776 mmol, 4 eq.) in dry DMF (2 mL) at room temperature under nitrogen atmosphere and the mixture was stirred for 10 min (no bubbling anymore). A suspension of Intermediate 46 (200 mg, 0.444 mmol) in dry DMF (2 mL) was added to the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 60 °C under nitrogen atmosphere 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 evaporated. The residue was purified by column chromatography (Biotage SNAP Ultra 50 g; eluent: EtOAc/EtOH 3/l:heptanes from 0: 100 to 100:0) to give Compound 499 (65 mg, yield: 27 %) as an off-white solid.

Compound 500: N-((2-(6-((2*R,6*S)-2-(6-aminohexyl)-6-methylmorpholino)pyridin-2-yl)- 1, 6-naphthyri din-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0939] Compound 495 (0.128 g, 0.175 mmol) was dissolved in a solution of HC1 (4 M in 1,4- dioxane, 0.438 mL, 1.751 mmol, 10 eq.) in 1,4-dioxane (1 mL) and the mixture was stirred at room temperature for 16 h. The mixture was basified with Na2CO3 (1 M in water) and extracted with DCM. The organic layer was separated, dried over MgSO fil4t.ered, and evaporated in vacuo to yield Compound 500 (99 mg, yield: 88 %). Compound 501 : 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.

[0940] Compound 501 was prepared following the same procedure as Compound 500, using Compound 496 instead of Compound 495.

Compound 502: N-((*R)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)-3-hydroxypropyl)-4-methyl-3-(methylsulfonyl)benzamide and Compound 503: N-((*S)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-3- hydroxypropyl)-4-methyl-3-(methylsulfonyl)benzamide.

(*R) Compound 502, pure but unknown stereochemistry

(*S) Compound 503, pure but unknown stereochemistry

[0941] 1 -Propanephosphonic anhydride solution (CAS [68957-94-8], 123 0μ.2L0,6 mmol,

1.3 eq.) was added to a suspension of 4-methyl-3-(methylsulfonyl)benzoic acid (CAS [51522- 22-6], 37 mg, 0.175 mmol, 1.1 eq.) and Intermediate 441 (50 % pure, 148 mg, 0.159 mmol) in dry DCM (2 mL) at room temperature. Triethylamine (110 μ 0L.7,93 mmol, 5 eq.) was then added dropwise to the suspension. The reaction mixture was stirred at room temperature for 1.5 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 by filtration on Extrelut NT3, and evaporated. The residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD- 5 pm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give, followed by preparative SFC (Stationary phase: Chiralcel Diacel OD 20 x 250 mm, Mobile phase: CO2, MeOH + 0.4 % iPrNFh) to give Compound 502 (6 mg, yield: 6 %) and Compound 503 (8 mg, yield: 8 %), both as yellow solids.

Compound 504: 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 and Compound 573: N- ((2-(6-((l*R, 5*S)-l-hy droxy-3-azabicyclo[3.1.0]hexan-3-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide and Compound 574: N-((2-(6-((l*S,5*R)- l-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide.

(*R) Compound 573, pure but unknown stereochemistry

(*S) Compound 574, pure but unknown stereochemistry

[0942] Compound 504 was prepared according to Method A (in DMF), using Intermediate 521 instead of Intermediate 11. The racemic mixture was then separated into its stereoisomers by SFC (Amylose-1 Phenomenex Lux 250 mm x 30mm I.D., 5 pm; isocratic CO2 (40 %) - iPrOH (60 %) + 0.1 % di ethylamine), followed by reverse phase chromatography (for each enantiomer) (Phenomenex Gemini C18 100A (100 mm x 30 mm I.D.; 5 pm); from 81 % [25 mM NH₄HCO₃] - 19 % [ACN:MeOH (1:1)] to 45 % [25 mM NH₄HCO₃] - 55 % [ACN:MeOH (1:1)]), to afford Compound 573 (13 mg, yield: 4 %) and Compound 574 (9 mg, yield: 2 %), both as yellow solids. Compound 505: 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.

[0943] HC1 (4 M in 1,4-dioxane, 1.3 mL, 5.2 mmol, 10 eq.) was added to a solution of Compound 507 (0.379 g, 0.53 mmol) in 1,4-dioxane (3 mL) at room temperature and the mixture was stirred for 16 h. The mixture was poured into Na2CO3 (1 M in water) and extracted with DCM. The organic layer was separated, dried over MgSO fil4t.ered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiO2, DCM:MeOH:NH₃ (9:0.9:0.1) in DCM, from 0/100 to 100/0) to afford Compound 505 (170 mg, yield: 51 %) as a yellow solid.

Compound 506: 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.

[0944] Compound 506 was prepared following the same procedure as Compound 505, using Compound 508 instead of Compound 507.

Compound 507: tert-butyl (5-((2*R,6*S)-6-methyl-4-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)morpholin-2- yl)pentyl)carbamate.

[0945] Compound 507 was prepared following the same procedure as Compound 495, using Intermediate 676 instead of Intermediate 671. Compound 508: tert-butyl (5-((2*S,6*R)-6-methyl-4-(6-(7-((4-methyl-3- (methylsulfonyl)benzamido)methyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)morpholin-2- yl)pentyl)carbamate.

[0946] Compound 508 was prepared following the same procedure as Compound 495, using Intermediate 675 instead of Intermediate 671.

Compound 509: 3-(dimethylphosphoryl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7- yl)(pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[0947] Compound 509 was prepared following method C (in DMF), starting from Intermediate 300 and 3-(dimethylphosphoryl)benzoic acid (CAS [53888-92-9]).

Compound 510: N-((2-(6-((2*R,6*S)-2-(5-acetamidopentyl)-6-methylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0948] Triethylamine (17 μL, 0.122 mmol, 1.5 eq.) was added to a solution of Compound 505 (50 mg, 0.081 mmol) in DCM (5 mL). Acetic anhydride (8 μ 0L.0, 89 mmol, 1.1 eq.) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Aqueous Na2CO3 (1 M, 20 mL) was added while stirring. After 5 min, the organic layer was separated and the aqueous layer was extracted again with DCM (50 mL). The combined organic layer was dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography (12 g silica column; gradient of DCM/MeOH (9:1) in DCM from 0/100 to 100/0) to yield Compound 510 (42 mg, yield: 76 %) as a yellow solid.

Compound 511: N-((2-(6-((2*S,6*R)-2-(5-acetamidopentyl)-6-methylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0949] Compound 511 was prepared according to the same procedure as Compound 510, using Compound 506 instead of Compound 505.

Compound 512: N-((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-R)

[0950] HC1 (4 M in 1,4-dioxane, 0.2 mL, 6.92 mmol, 4.6 eq.) was added to a solution of Intermediate 677 (110 mg, 0.175 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo. The crude product was dissolved in DCM:MeOH 9: 1 and was treated with Amberlyst 26 (OH form) to reach pH>7. The suspension was filtered and the solid was washed with DCM:MeOH 9: 1. The filtrate was concentrated under reduced pressure to afford Compound 512 (70 mg, yield: 72 %) as a yellow solid. Compound 516: 3-cyano-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methylbenzamide.

[0951] DIPEA (0.062 mL, 0.361 mmol) followed by HATU (51 mg, 0.135 mmol) were added to a solution of 3-cyano-4-methylbenzoic acid (CAS [138642-93-0], 30 mg, 0.186 mmol) in DCM (2 mL). The reaction mixture was stirred for 2 min, then Intermediate 11 (43 mg, 0.0903 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ACN, filtered, and the filtrate was purified by reverse phase column chromatography (Waters XBridge BEH Cl 8, 5 urn, 19 x 150 mm; Gradient from 40 to 70 % ACN + pH 10 NH4OH in water + pH 10 NH4OH) to give Compound 516 (27 mg, yield: 60 %).

Compound 517: 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 and Compound 552: (*R)- N-((2-(6-(3,3-difluoro-4-(methylamino)piperidin-l-yl)pyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide and Compound 553: (*S)-N-((2-(6-(3,3- difluoro-4-(methylamino)piperidin- 1 -yl)pyri din-2 -yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4- methyl-3-(methylsulfonyl)benzamide and

(*R) Compound 552, pure but unknown stereochemistry

(*S) Compound 553, pure but unknown stereochemistry

[0952] Compound 517 was prepared following the same procedure as Compound 477, using Intermediate 517 instead of Intermediate 507. A batch of Compound 517 was separated into its stereoisomers by semipreparative SFC (Cellulose-3; isocratic 60 % [iPrOH + 0.1 % DEA] - 40 % [CO2]) to yield Compound 552 and Compound 553, both as yellow solids.

Compound 518: N-((2-(6-((2*R,6*S)-2-(6-acetamidohexyl)-6-methylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

Compound 518, pure but unknown stereochemistry [0953] EtsN (6 μL, 0.045 mmol, 1.5 eq.) was added to a solution of Compound 500 (19 mg, 0.03 mmol) in DCM (5 mL). The mixture was cooled to 0 °C then acetic anhydride (CAS [108-24-7], 3 μL, 0.033 mmol, 1.1 eq.) in DCM (4 mL) was added. The mixture was stirred for 30 min at 0 °C. Na2CO3 (1 M in water) was added while stirring. After 5 min, the organic layer was separated and the aqueous layer was extracted again with DCM. The combined organic layer was dried over MgSO4. filtered, and the solvents evaporated in vacuo. The residue was purified by reverse phase chromatography (from 59 % H2O - 41 % ACN-MeOH to 17 % H2O - 83 % ACN-MeOH) - 65 mM NH₄OAc + ACN (90: 10)) to afford Compound 518 (20 mg, yield: 97 %) as a solid.

Compound 519: 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 [0954] Compound 519 was prepared following the same procedure as Compound 518, using Compound 501 instead of Compound 500.

Compound 520: N-((2-(6-((cis)-3-hydroxycyclobutoxy)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide and Compound 521: N-((2-(6-((trans)-3- hydroxycyclobutoxy)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide.

Compound 521 (trans)

[0955] NaH (60 % dispersion in mineral oil, 53 mg, 1.332 mmol, 3 eq.) was added to a solution of 3-[[(l,l-dimethylethyl)dimethylsilyl]oxy]cyclobutanol (CAS [1089709-08-9], 359 mg, 1.776 mmol, 4 eq. ) in dry DMF (2 mL) at room temperature under nitrogen atmosphere and the mixture was stirred for 10 min. A suspension of Intermediate 46 (200 mg, 0.444 mmol) in dry DMF (2 mL) was added to the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 60 °C under nitrogen atmosphere 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 evaporated. The residue was purified by column chromatography (Biotage SNAP Ultra 50 g; eluent: EtOAc/EtOH 3/l:heptanes from 0:100 to 100:0), followed by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD- 5 pm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, MeOH) to give Compound 520 (22 mg, yield: 10 %) and Compound 521 (22 mg, yield: 10 %), both as white solids. Compound 522: (*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 and Compound 523: (*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.

Compound 523, pure but unknown stereochemistry

[0956] Purification of Compound 444, by preparative SFC (Stationary phase: Chiralcel Diacel OJ 20 x 250 mm, Mobile phase: CO2, iPrOH + 0.4 % iPrNH2) afforded Compound 522 (15 mg, yield: 8 %) and Compound 523 (8 mg, yield: .4 %), both as yellow solids.

Compound 524: 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.

[0957] Compound 524 was prepared according to Method A, using Intermediate 511 instead of Intermediate 11.

Compound 525 : N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5] octan-7 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfinyl)benzamide.

[0958] A solution of Intermediate 613 (83 mg, 0.419 mmol, 1.25 eq.) in DMF (4 mL) was treated with DIPEA (581 μL 3, .334 mmol, 10 eq.). HATU (CAS [148893-10-1], 190 mg, 0.5 mmol, 1.5 eq.) was then added and the reaction mixture was stirred at room temperature for 10 min, and then treated with Intermediate 300 (182 mg, 0.333 mmol). The reaction mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was extracted with DCM (3 x 20 mL). The crude product was purified by reverse phase chromatography followed by column chromatography on silica gel (DCM with 2 % NH4OH/MeOH) to obtain Compound 525 (69 mg, yield: 38 %).

Compound 526: 4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-(morpholinomethyl)pyrrolidin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[0959] A solution of Intermediate 513 (37 mg, 0.065 mmol), morpholine (0.013 mL, 0.131 mmol, 2 eq.), and acetic acid (0.08 mL, 0.131 mmol, 2 eq.) in DCM (3 mL) was stirred at room temperature for 30 min. Then, Sodium triacetoxyborohydride (CAS [56553-60-7], 28 mg, 0.131 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 MgSCti, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; MeOH/DCM from 0/100 to 7/93), followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5 pm; from 59 % [25 mMNMCOi] - 41 % [ACN:MeOH (1:1)] to 17 % [25 mMNHiHCOi] - 83 % [ACN:MeOH (1:1)]) to afford Compound 526 (15 mg, yield: 34 %) as ayellow solid.

Compound 527: N-((2-(6-(2-oxa-5-azabicyclo[2.2. l]heptan-5-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide.

[0960] A solution of Intermediate 587 (100 mg, 0.216 mmol) and 2-oxa-5- azabicyclo[2.2.1]heptane (CAS [279-33-4], 76 mg, 0.56 mmol, 2.6 eq.) in DMSO (2 mL) and DIPEA (160 μL, 0.928 mmol, 4.3 eq.) was stirred at 100 °C for 24 h. After cooling, water (10 mL) was added. The solid that formed was filtered and rinsed with water (10 mL). This solid was purified by flash column chromatography (silica gel 4 g, MeOH/DCM, from 0/100 to 10/90) followed by preparative SFC (Stationary phase: Chiralcel Diacel OJ 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 % iPrNEL) to afford Compound 527 (75 mg, yield: 64 %).

Compound 528: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3-(2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, Compound 549: N-((2-(6- ((cis)-2,6-dimethylmorpholino)540yridine-2-yl)-l,6-naphthyridin-7-yl)methyl)-3-((*R)-2- hydroxyethylsulfonimidoyl)-4-methylbenzamide, and Compound 550: N-((2-(6-((cis)-2,6- dimethylmorpholino)540yridine-2-yl)-l,6-naphthyridin-7-yl)methyl)-3-((*S)-2- hydroxyethylsulfonimidoyl)-4-methylbenzamide.

(*S), (CIS) Compound 550

[0961] Intermediate 636 (192 mg, 0.353 mmol) was dissolved in MeOH (1.5 mL), then (diacetoxyiodo)benzene (CAS [3240-34-4], 284 mg, 0.883 mmol, 2.5 eq.) and ammonium carbamate (CAS [1111-78-0], 55 mg, 0.706 mmol, 2.0 eq.) were added and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was taken up in DMSO and purified by reverse phase HPLC (Waters Xbridge BEH C18 5 um, 19 x 150 mm; gradient 25-60 % CAN/H2O with 10 mM NH4OH) to give compound 528 as a yellow solid (67 mg, yield: 33 %). A batch of Compound 528 was separated by chiral SFC (IH (21 x 250 mm ID, 5 urn); 28 % MeOH/72 % CO2) to give compound 549 and Compound 550.

Compound 529: 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 and Compound 530: N- ((*S)-5-arrtino-l -(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7- yl)pentyl)-4-methyl-3-(methylsulfonyl)benzamide.

(*R) compound 529, pure but unknown stereochemistry

(*S) compound 530, pure but unknown stereochemistry

[0962] Hydrazine (35 wt% in water, 270 μL 3,.25 mmol, 10 eq.) was added to a solution of Intermediate 445 (296 mg, 0.325 mmol) in EtOH (5 mL) and the mixture was stirred at 60 °C for 3.5 h. After cooling, the white precipitate was filtered off and rinsed with a small amount of EtOH. The filtrate was evaporated and the residue was purified by preparative SFC (Stationary phase: Chiralcel Diacel OD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 % iPrNH2) to yield Compound 529 (48 mg, yield: 24 %) and Compound 530 (44 mg, yield: 22 %) as yellow solids. Compound 531 : 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

[0963] Compound 531 was prepared according to Method B, using Intermediate 515 instead of Intermediate 11, and 3-(methylsulfonyl)-4-(trifluoromethyl)-benzoic acid (CAS [2376514- 24-6]) instead of (3-(l -hydroxy ethyl)-4-methyl-benzoic acid.

Compound 532: 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.

[0964] Acetic anhydride (10 μL, 0.104 mmol, 2 eq.) followed by EtsN (22 μ 0L.1,56 mmol, 3 eq.) were added dropwise to a solution of Compound 529 (32 mg, 0.052 mmol) in dry DCM (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h.

The reaction mixture was diluted with DCM and saturated aqueous NaHCO3. 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. The residue was purified by column chromatography (Biotage Snap Ultra 10 g; eluent: heptane :EtOH/EtO Ac 1/3 from 100:0 to 0:100) to give Compound 532 (28 mg, yield: 82 %) as a yellow solid. Compound 533: 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.

[0965] Compound 533 was prepared with the same procedure as Compound 532, starting from Compound 530 instead of Compound 529.

Compound 534: N-((2-((6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)amino)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0966] A solution of Intermediate 45 (1800 mg, 4.617 mmol), rel-6-[(2R,6S)-2,6-dimethyl-4- morpholinyl]-2-pyridinamine (CAS [1592655-34-9], 1244 mg, 5.402 mmol, 1.2 eq.), CS2CO3 (3009 mg, 9.234 mmol, 2 eq.), (R)-(+)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (CAS [98327-87-8], 216 mg, 0.346 mmol, 0.075 eq.) in toluene (45 mL) was purged with nitrogen and then palladium(II) acetate (52 mg, 0.231 mmol, 0.05 eq.) was added. The reaction mixture was stirred overnight at 120 °C. The reaction mixture was diluted with water and extracted 3 times with DCM. The combined organic layer was dried over MgSO4 f,iltered, and evaporated to dryness. The residue was purified by flash column chromatography (SiCh, DCM:MeOH from 100:0 to 90: 10) followed by trituration with ACN, and filtration to obtain Compound 534 (still impure, 721 mg, yield: 28 %). A sample of Compound 534 was further purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to yield pure Compound 534. Compound 538: N-((2-(6-((3*S,4*r,5*S)-4-(2-hydroxyethyl)-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, Compound 539: N-((2-(6-((3*S,4*s,5*R)-4-(2-hydroxyethyl)-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, Compound 540: N-((2-(6-((3*S,4*r,5*R)-4-(2-hydroxyethyl)-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, and Compound 545: N-((2-(6-((3*R,*s,5*R)-4-(2-hydroxyethyl)-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

(TRANS, CIS) Compound 545

[0967] Compound 467 was separated into stereoisomers by preparative SFC (Chiralcel Diacel IH 20 x 250 mm; CO2, EtOH + 0.4 % iPrNFh) to afford Compound 538, Compound 539, Compound 540, and Compound 545. Compound 546: N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-4-fluoro-3-(methylsulfonyl)benzamide.

[0968] Compound 546 was prepared according to Method A, using Intermediate 467 instead of Intermediate 11, and 4-fluoro-3-(methylsulfonyl)benzoic acid (CAS [158608-00-5]) instead of 3-methanesulfonyl-4-methylbenzoic acid.

Compound 551: N-((2-(6-((lR)-l-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

(3-R)

[0969] Acetic acid (0.020 mL, 0.342 mmol, 3 eq.) was added to a solution of Compound 512 (60 mg, 0.67 mmol) and formaldehyde (37 % in water, 0.043 mL, 0.571 mmol, 5 eq.) in MeOH (3 mL) and the mixture was stirred at room temperature for 30 min. Then, sodium cyanoborohydride (CAS [25895-60-7], 67 mg, 1.061 mmol, 9.3 eq.) was added and the mixture was stirred at room temperature for 20 h. Saturated aqueous NaHCCL was added to the reaction mixture and it was extracted with DCM. The organic layer was dried over MgSO4. filtered, and evaporated. The residue was purified by reverse phase column chromatography (Phenomenex Gemini C18 100A column (100 mm x 30 mm I.D.; 5 pm); from 81 % [0.1 % HCOOH] - 19 % [ACN:MeOH (1: 1)] to 45 % [0.1 % HCOOH] - 55 % [ACN:MeOH (1:1)]) to yield Compound 551 (10 mg, yield: 15 %) as a yellow solid. Compound 554: (*R)-4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-

(morpholinomethyl)pyrrolidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide and Compound 555: (*S)-4-methyl-3-(methylsulfonyl)-N-((2-(6-(2-

(morpholinomethyl)pyrrolidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide.

(*R) Compound 554, pure but unknown stereochemistry

(*S) Compound 555, pure but unknown stereochemistry

[0970] A batch of Compound 526 was separated into its stereoisomers by SFC (Phenomenex Cellulose-3 250 x 30 mm 5 urn; isocratic 40 % (MeOH + 0.1 % DEA) - 60 % CO2) to yield Compound 554 and Compound 555, both as yellow solids.

Compound 556: 3-((2-chloroethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methylbenzamide and Compound 576: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methyl-3-(vinylsulfonyl)benzamide.

(CIS) Compound 556

(CIS) Compound 576

[0971] Compound 82 (60 mg, 0.101 mmol) was dissolved in DCM (1 mL) and EtsN (0.035 mL, 0.253 mmol, 2.5 eq.), then MsCl (CAS [124-63-0], 10 μ 0L.1,21 mmol, 1.2 eq.) was added dropwise at room temperature and the reaction mixture was stirred overnight at room temperature. The reaction mixture was stirred at 45 °C for 4 h, then DBU (CAS [6674-22-2], 18 μL, 0.121 mmol, 1.2 eq.) was added and the mixture was stirred at 45 °C overnight. DCE (2 mL) was added, and the reaction mixture was stirred at 80 °C for 20 h. The reaction mixture was filtered, and the solid was washed twice with DCM to afford Compound 556 (39 mg, yield: 60 %) as a yellow solid. The filtrate was evaporated and purified by flash column chromatography (24 g SiCh, DCM/MeOH from 100/0 to 90/10), followed by reverse phase HPLC (RP XBridge Preparative C18 OBD- 5 pm, 50 x 250 mm; 0.25 % NH4HCO3 solution in water, ACN) to afford Compound 576 (4 mg, yield: 7 %).

Compound 557: 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.

[0972] Intermediate 46 (50 mg, 0.105 mmol) and 2-(piperidin-4-yl)propan-2-ol (CAS [22990- 34-7], 31 mg, 0.211 mmol, 2 eq.) were dissolved in DMSO (1 mL). DIPEA (0.073 mL, 0.422 mmol, 4 eq.) was added and the reaction mixture was stirred at 130 °C for 2 days. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified twice by flash column chromatography (12 g SiCh, DCM/MeOH from 100/0 to 90/10) to afford Compound 557 as a yellow solid (29 mg, yield: 48 %).

Compound 558: 3-(4-(2-hydroxypropan-2-yl)piperidin-l-yl)-N-((2-(6-(4-(2-hydroxypropan-2- yl)piperidin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide and Compound 559: 3-fluoro-N-((2-(6-(4-(2-hydroxypropan-2-yl)piperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide.

[0973] Intermediate 587 (50 mg, 0.1 mmol) and 2-(piperidin-4-yl)propan-2-ol (CAS [22990- 34-7], 29 mg, 0.2 mmol, 2 eq.) were dissolved in DMSO (1 mL). DIPEA (0.069 mL, 0.4 mmol, 4 eq.) was added and the reaction mixture was stirred at 130 °C for 2 days. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (12 g SiCh, DCM/MeOH from 100/0 to 90/10) to afford impure Compound 559 and pure Compound 558 (32 mg, yield: 43 %) as a yellow solid. The impure Compound 559 was further purified by flash column chromatography (4 g SiCh, DCM/MeOH from 97/3 to 94/6) to afford compound 559 (24 mg, yield: 39 %) as a yellow solid.

Compound 561: N-((2-(6-(((3a, 4|3, 5a))-4-hydroxy-3,5-dimethylpiperidin-l- yl)methyl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide.

(3a, 4|3, 5a) [0974] A suspension of Intermediate 473 (40 mg, 0.087 mmol) and (3R,5S)-rel-3,5-dimethyl- 4-piperidinol hydrochloride (CAS [1235994-84-9], 36 mg, 0.217 mmol, 2.5 eq.) in DCE (2 mL) was stirred at 40 °C for 3 h. The reaction mixture was cooled to 10 °C, then NaBH(OAc)3 (55 mg, 0.261 mmol, 3 eq.) and THF (1 mL) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with aqueous NaHCCL. and then extracted with DCM. The combined organic layer was dried over MgS fOil4te. red, and concentrated. The residue was purified by flash column chromatography (SiCh, DCM:MeOH from 100:0 to 90:10) to yield Compound 561 (15 mg, yield: 31 %).

Compound 562: N-((2-(6-(((cis)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[0975] Compound 562 was prepared with the same procedure as Compound 561, starting from cis-2,6-dimethylmorpholine (CAS [6485-55-8]) instead of (3R,5S)-rel-3,5-dimethyl-4- piperidinol hydrochloride.

Compound 563: 4-methyl-3-(methylsulfbnyl)-N-((2-phenyl-l,6-naphthyridin-7- yl)methyl)benzamide.

[0976] Intermediate 45 (500 mg, 1.283 mmol) and Na2CO3 (544 mg, 5.130 mmol, 4 eq.) were added to a stirred solution of phenyl boronic acid (CAS [98-80-6], 452 mg, 3.709 mmol, 2.9 eq.) in 1,4-dioxane (18 mL) at room temperature under nitrogen atmosphere.

Pd(dppl)C12.CH2C12 (CAS [95464-05-4], 52 mg, 0.064 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 85 °C under nitrogen atmosphere for 16 h. After cooling, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiCh 50 g, heptane/EtOAc from 100/0 to 0/100) to yield Compound 563 (338 mg, yield: 61 %) as a beige fluffy solid. Compound 564: tert-butyl 5-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate

[0977] Nitrogen was purged through a solution of Intermediate 46 (70 mg, 0.137 mmol) in 1,4-dioxane (4 mL). Then, cesium carbonate (155 mg, 0.476 mmol, 3.5 eq.), tert-butyl 2,5- diazabicyclo[4.1.0]heptane-2-carboxylate (CAS [1228675-18-0], 33 mg, 0.166 mmol, 1.2 eq.), Xant-Phos (CAS [161265-03-8], 13 mg, 0.022 mmol, 0.16 eq.), and Pd2dbas (CAS [51364-51-3], 13 mg, 0.014 mmol, 0.1 eq.) were added to the stirred solution at room temperature under nitrogen atmosphere. The vial was closed and the mixture was stirred at 90 °C for 3 h. After cooling, saturated aqueous NaHCO3 and EtOAc were added to the reaction mixture and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica-gel (12 g; DCM:MeOH 9:1 in DCM 0/100 to 20/80), followed by preparative HPLC (Phenomenex Gemini, I.D. (mm) 100 x 21.2; 5 urn (C18) 110 A; (25 mM NH4HCO3) / (ACN: MeOH 1 : 1) from 72/28 to 36/64) to yield Compound 564 (7 mg, yield: 8 %) as a yellow solid.

Compound 565: (*R)-4-methyl-N-((2-(6-(8-(methylamino)-5-azaspiro[2.5]octan-5-yl)pyridin-

2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-3-(methylsulfonyl)benzamide.

[0978] Compound 565 was prepared following the procedure used for Compound 477, using Intermediate 518 instead of Intermediate 507. Compound 566: (*S)-4-methyl-N-((2-(6-(8-(methylamino)-5-azaspiro[2.5]octan-5-yl)pyridin- 2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-3-(methylsulfonyl)benzamide.

[0979] Compound 566 was prepared following the procedure used for Compound 477, using Intermediate 519 instead of Intermediate 507.

Compound 577: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-3-(vinylsulfonyl)benzamide.

[0980] Compound 577 was prepared similarly to Compound 576, starting from Compound 22 instead of Compound 82.

Compound 578: 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 and Compound 579: N-((*S)-3-(dimethylamino)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)propyl)-4-methyl-3-(methylsulfonyl)benzamide.

*R, Compound 578, pure but unknown stereochemistry

*S, Compound 579, pure but unknown stereochemistry

[0981] Step A: N-(l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)-3-oxopropyl)-4-methyl-3-(methylsulfonyl)benzamide. Dess-Martin periodinane (CAS [87413-09-0], 191 mg, 0.45 mmol, 1.1 eq.) was added to a suspension of the racemic mixture of Compound 502 and Compound 503 (360 mg, 0.409 mmol) in dry DCM (15 mL) under nitrogen atmosphere at 0 °C. The reaction mixture was then stirred at room temperature for 3.5 h. More Dess-Martin periodinane (191 mg, 0.45 mmol, 1.1 eq.) was added to the reaction mixture at room temperature and it was further stirred at room temperature for 1.5 h. The reaction mixture was diluted with DCM, saturated aqueous NaHCO3. and 10 % aqueous Na2S20s. The layers were separated, and the aqueous layer was extracted again with DCM. The combined organic layer was dried on MgSO4 f,iltered, and evaporated. The residue was purified by column chromatography (Biotage Snap Ultra 25 g; eluent: heptane :EtOH/EtO Ac from 1/3 100:0 to 0:100) to give the title compound (269 mg, 50 % pure, yield: 56 %) as a yellow solid, still impure but used without further purification.

[0982] Step B: N-((*R)-3-(dimethylamino)- l-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 - yl)-l,6-naphthyridin-7-yl)propyl)-4-methyl-3-(methylsulfonyl)benzamide and N-((*S)-3- (dimethylamino)- 1 -(2-(6-((cis)-2,6-dimethy lmorpholino)pyri din-2 -yl)- 1 ,6-naphthy ridin-7 - yl)propyl)-4-methyl-3-(methylsulfonyl)benzamide. Titanium(IV) isopropoxide (CAS [546- 68-9], 38 μL, 0.125 mmol, 1 eq.) was added to a suspension ofN-(l-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-3-oxopropyl)-4-methyl-3- (methylsulfonyl)benzamide (147 mg, 0.125 mmol) and dimethylamine (2 M solution in THF, 125 pL. 0.25 mmol, 2 eq.) in dry EtOH (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. NaBEh (7 mg, 0.188 mmol, 1.5 eq.) was then added in one portion to the solution at room temperature. The mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with EtOAc and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN), followed by preparative SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 % iPrNFk) to yield Compound 578 (22 mg, yield: 29 %) and Compound 579 (20 mg, yield: 26 %). Compound 580: N-((*R)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)-3-morpholinopropyl)-4-methyl-3-(methylsulfonyl)benzamide and Compound 581: N-((*S)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)-3-morpholinopropyl)-4-methyl-3-(methylsulfonyl)benzamide. (*R) Compound 580, pure but unknown stereochemistry

(*S) Compound 581, pure but unknown stereochemistry

[0983] Compound 580 and Compound 581 were prepared according to the same procedure as

Compound 578 and Compound 579, respectively, using morpholine instead of dimethylamine.

Compound 582: N-((2-(2-(4,7 -diazaspiro [2.5] octan-7 -yl)pyrimidin-4-yl)- 1 ,6-naphthy ri din-7 - yl)methyl)-4-(difluoromethyl)-3-(methylsulfonyl)benzamide. [0984] Compound 582 was prepared according to Method B, using Intermediate 515 instead of Intermediate 11, and 4-(difluoromethyl)-3-(methylsulfonyl)-benzoic acid (CAS [2771133- 34-5]) instead of (3-(l -hydroxy ethyl)-4-methyl-benzoic acid.

Compound 583: 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 and Compound 584: 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 and Compound 585: 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 and Compound 586: 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)benzamide.

Compound 584, pure but unknown stereochemistry Compound 586, pure but unknown stereochemistry [0985] A solution of Intermediate 46 (308 mg, 0.684 mmol), 2-methyl-6- (trifluoromethyl)morpholine (CAS [1342385-23-2], 231 mg, 1.367 mmol, 2 eq.), and DIPEA (353μL, 2.051 mmol, 3 eq.) in dry DMSO (5 mL) was introduced into a thick-wall pressure vial. The vial was closed and the reaction mixture was stirred at 130 °C overnight. More 2- methyl-6-(trifluoromethyl)morpholine (231 mg, 1.367 mmol, 2 eq.) was added to the reaction mixture. The vial was sealed and the reaction mixture was stirred at 130 °C for 6 days. 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 by filtration on Extrelut NT3, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH/EtO Ac 1/3 from 100:0 to 0:100), followed by preparative HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD- 5 pm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN), and preparative SFC (Stationary phase: Chiralcel Diacel OJ 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 % iPrNEE) to yield Compound 583 (43 mg, yield: 10 %), Compound 584 (20 mg, yield: 5 %), Compound 585 (20 mg, yield: 5 %), and Compound 586 (30 mg, yield: 7 %), all as yellow solids.

Compound 587: N-((2-(6-(4,7 -diazaspiro [2.5] octan-7 -yl)pyridin-2-yl)- 1 ,6-naphthy ridin-7- yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide.

[0986] Intermediate 637 (214 mg, 0.33 mmol) was dissolved in 1,4-dioxane (1.1 mL), then HC1 (4 M in 1,4-dioxane, 0.83 mL, 3.34 mmol, 10 eq.) was added and the mixture was stirred at room temperature for 3.5 h. The solvent was evaporated in vacuo and the residue was purified by reverse phase HPLC (Waters XBridge BEH Cl 8, 5 um, 19 x 150 mm; gradient 15-50 % ACN + pH 10 NH4OH/water) to give Compound 587 (134 mg, yield: 74 %) as a yellow solid. Compound 588: (*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 and Compound 589: (*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..

(*R) Compound 588, pure but unknown stereochemistry

(*S) Compound 589, pure but unknown stereochemistry

[0987] A batch of Compound 468 was separated into its stereoisomers by SFC (Cellulose-1 Phenomenex Lux 250 mm x 30 mm I.D. 5 pm; isocratic CO2 (40 %) - iPrOH-MeOH (60 %) + 0.1 % diethylamine) to yield Compound 588 and Compound 589, both as yellow solids.

Compound 591: 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.

(3a, 4p, 5a)

[0988] Intermediate 708 (58 mg, 0.111 mmol) and 3-fluoro-5-(methylsulfonyl)-benzoic acid (CAS [1783354-37-9], 29 mg, 0.133 mmol, 1.2 eq.) were suspended in DCM (1 mL), then 1- propylphosphonic anhydride (50 wt. % in EtOAc, CAS [68957-94-8], 0.132 mL, 0.222 mmol, 2 eq.) and EtsN (0.092 mL, 0.665 mmol, 6 eq.) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (12 g SiO2, DCM/MeOH from 100/0 to 90/10), followed by preparative SFC (Torus Diol 30 x 150 mm; CO2, MeOH + 20 mM NH4OH), and finally by reverse phase HPLC (RP XBridge Preparative C18 OBD- 5 pm, 50 x 250 mm; 0.25 % NH4HCO3 solution in water, ACN) to afford Compound 591 (13 mg, yield: 20 %) as a yellow solid.

Compound 593: 6-methyl-4-(6-(7-((4-methyl-3-(methylsulfonyl)benzamido)methyl)-l,6- naphthyridin-2-yl)pyridin-2-yl)morpholine-2-carboxylic acid.

CIS

[0989] A suspension of Intermediate 46 (99 mg, 0.22 mmol), rac-methyl (2R,6R)-6- methylmorpholine-2-carboxylate hydrochloride (CAS [1807914-39-1], 172 mg, 0.879 mmol, 4 eq.), and DIPEA (189 μL, 1.099 mmol, 5 eq.) in dry DMSO (1 mL) was introduced in a thick wall vial. The vial was sealed and the reaction mixture was stirred at 130 °C overnight. LiOH (26 mg, 1.099 mmol, 5 eq.) and water (2 mL) were added to the reaction mixture and it was stirred at 60 °C for 24 h. The reaction mixture was diluted with aqueous HC1 (0.25 M) and the mixture was extracted with DCM/MeOH 4/1. The aqueous layer was extracted again with DCM/MeOH 4/1. The aqueous layer was evaporated and the residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to yield Compound 593 (3 mg, yield: 2 %) as a yellow solid.

Compound 595: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, Compound 601: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((*S)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide, and Compound 602: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-3-((*R)-2-hydroxyethylsulfonimidoyl)-4-methylbenzamide.

(CIS) Compound 595

(*S), (CIS) Compound 601, pure but unknown stereochemistry

(*R), (CIS) Compound 602, pure but unknown stereochemistry

[0990] Intermediate 638 (170 mg, 0.303 mmol) was suspended in MeOH (5 mL), then (diacetoxyiodo)benzene (CAS [3240-34-4], 244 mg, 0.757 mmol, 2.5 eq.) and ammonium carbamate (CAS [1111-78-0], 47 mg, 0.605 mmol, 2.0 eq.) were added and the suspension was stirred at room temperature for 1.5 h. The mixture was diluted with DMSO (1 mL) and the MeOH was evaporated in vacuo. The resulting solution was filtered and purified by reverse phase HPLC (Waters XSelect CSH C18, 5 um, 19 x 150 mm, gradient 15-50 % ACN with 0.16 % TFA/water) to give compound 595 (52 mg, yield: 29 %) as a yellow solid.

[0991] A batch of Compound 595 was separated into its stereoisomers by chiral SFC (IH (30 x 250 mm ID, 5 um); 27 % MeOH/CO2) to give Compound 601 and Compound 602.

Compound 596: 3-((2-hydroxyethyl)sulfonyl)-4-methyl-N-((2-phenyl-l,6-naphthyridin-7- yl)methyl)benzamide.

[0992] HATU (CAS [148893-10-1], 185 mg, 0.487 mmol, 1.5 eq.) was added to a stirred solution of 2-phenyl-l,6-naphthyridine-7-methanamine, hydrochloride (CAS [2681299-48-7], 100 mg, 0.324 mmol), 3-[(2-hydroxyethyl)sulfonyl]-4-methylbenzoic acid (CAS [1094404- 86-0], 87 mg, 0.357 mmol, 1.1 eq.), and DIPEA (283 μ 1L.,622 mmol, 5 eq.) in DMF (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with aqueous 1 M Na2CO3. The organic layer was dried over MgSO4. filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to yield Compound 596 (75 mg, yield: 50 %) as a brown solid.

Compound 597 : 3-fluoro-5-(methylsulfonyl)-N-((2-phenyl-l ,6-naphthyridin-7- yl)methyl)benzamide.

[0993] Compound 597 was prepared according to the same procedure as Compound 596, using 3-fluoro-5-(methylsulfonyl)-benzoic acid (CAS [1783354-37-9]) instead of 3-[(2- hydroxyethyl)sulfonyl]-4-methylbenzoic acid.

Compound 598: 4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-(S-methylsulfonimidoyl)benzamide.

(CIS)

[0994] Compound 598 was prepared following the same procedure as Compound 528, using Intermediate 639 instead of Intermediate 636.

[0995] The compounds in Table 26 were prepared using the same method as Compound 591, using Intermediate 11 instead of Intermediate 708, and the acid indicated in the table.

Table 26.

Compound 600: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(l,4-dioxan-2-yl)-4-methylbenzamide and Compound 615: 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 and Compound 616: 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. (*R) compound 615, pure but unknown stereochemistry

(*S) compound 616, pure but unknown stereochemistry

[0996] Compound 600 was prepared according to Method E, using Intermediate 11 instead of

Intermediate 98, and Intermediate 528 instead of 3-[(2-hydroxyethyl)sulfonyl]-4- methylbenzoic acid. A batch of Compound 600 was separated into its stereoisomers by SFC (Amylose-1; isocratic 40 % CO2 - 60 % EtOH + 0.1 % DEA) to give Compound 615 and Compound 616, both as yellow solids.

Compound 606: 4-methyl-3-(methylsulfonyl)-N-((2-(6-(morpholino-d8)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[0997] Compound 606 was prepared according to Method I, using morpholine- 2,2,3,3,5,5,6,6-d8 (CAS [342611-02-3]) instead of 4-piperidineethanol.

Compound 609: N-((2-(6-((3a, 4p, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- 1 ,6-naphthyridin-7-yl)methyl)-4-methyl-3-((*R)-methylsulfinyl)benzamide and Compound 610: 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.

(*S), (3a, 4p, 5a) Compound 610

[0998] Compound 609 and Compound 610 were prepared according to Method A (in DMF) from Intermediate 149 and Intermediate 613, followed by SFC separation (Daicel Chiralpak AS 250 mm x 30 mm, 10 urn; CO₂ (65 %) - iPrOH (35 %) (0.1% NH₄OH)).

Compound 611 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-3-((*R)-(2-hydroxyethyl)sulfinyl)-4-methylbenzamide and Compound 612: N-((2- (6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3-((*S)-(2- hydroxyethyl)sulfinyl)-4-methylbenzamide.

(*S), (CIS) Compound 612

[0999] Compound 611 and Compound 612 were prepared according to Method A (in DMF) from Intermediate 11 and Intermediate 612, followed by SFC separation (Daicel Chiralpak AD 250 mm x 30 mm, 10 urn; CO₂ (45 %) - EtOH (55 %) (0.05% DEA)).

Compound 614: N-((2-(6-(6,6-dimethyl-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[1000] Palladium on carbon (1 mg, 0.012 mmol, 0.1 eq.) was added to a stirred solution of Intermediate 531 (88 mg, 0.122 mmol) in MeOH (5 mL).The mixture was stirred at room temperature under hydrogen atmosphere for 16 h. More palladium on carbon (1 mg, 0.012 mmol, 0.1 eq.) was added and the mixture was stirred further under hydrogen atmosphere at 50 °C for 24 h. The mixture was filtered through a pad of Celite® and the filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 10/90), followed by reverse phase column chromatography (Phenomenex Gemini Cl 8 30 x 100 mm 5pm; from 70 % [25 mM NH4HCO3] - 30 % [ACN:MeOH (1:1)] to 27 % [25 mM NH4HCO3] - 73 % [ACN:MeOH (1:1)]) to yield Compound 614 (8 mg, yield: 10 %) as a yellow solid. Compound 617: N-((2-(4-fluoro-6-(morpholino-d8)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((2-hydroxyethyl)sulfonyl)-4-methylbenzamide.

[1001] Compound 617 was prepared according to Method A (in DMF), using Intermediate 535 instead of Intermediate 11, and 3-(2-hydroxyethanesulfonyl)-4-methylbenzoic acid (CAS [1094404-86-0]) instead of 3-methanesulfonyl-4-methylbenzoic acid.

Compound 618: N-((2-(6-(4-amino-3,3-difluoropiperidin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-

7-yl)methyl)-4-methyl-3-(S-methylsulfonimidoyl)benzamide.

[1002] A homogeneous solution of Intermediate 614 (0.144 g) in DCM (5 mL) and MeOH (0.5 mL) was treated with HC1 (0.5 mL, 2.0 mmol, 4 M in 1,4-di oxane) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the crude material was dissolved in a minimal amount of MeOH/DCM (1/10). The amine was liberated from its salt by adding DIPEA (0.1 mL), and the mixture was purified by flash column chromatography (12 g SiCh; 0 - 10 % 2 N NHs/MeOH in DCM), followed by reverse phase HPLC (Waters XBridge BEH C18, 5 urn, 19 x 150 mm; 10 - 45 % ACN/H2O with 10 mM NH4OH) to give Compound 618 (56 mg, yield: 46 %).

Compound 619: 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.

[1003] Compound 619 was prepared following Method M, starting from Intermediate 597 instead of Intermediate 149, and using 3-difluoromethanesulfonylbenzoic acid (CAS [4837- 21-2]) instead of 2-fluoro-4-methyl-5-(methylsulfonyl)-benzoic acid. [1004] The compounds in Table 23 were prepared from Intermediate 599 and the corresponding amine, following procedures similar to the methods shown in the table: Table 23.

[1005] *Method T: purification: preparative HPLC (RP XBridge Prep C18 OBD-10 pm, 30 x

150 mm; 0.25 % NH4HCO3 in water, ACN)

[1006] ** Method I: 90 °C, overnight. Compound 620: 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.

[1007] Compound 620 was prepared according to Method B, using Intermediate 515 instead of Intermediate 11, and Intermediate 536 instead of (3-(l-hydroxyethyl)-4-methyl-benzoic acid. Compound 623: 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.

[1008] Intermediate 600 (139 mg, 0.06 mmol) was solubilized in HC1 (4.0 M in 1,4-di oxane, 1 mL, 4 mmol) and 1,4-di oxane (1 mL) and the solution was stirred at room temperature overnight. The mixture was diluted with DCM and water and brine were added. The aqueous layer was separated and basified with a saturated solution of potassium carbonate, then was extracted twice with DCM. The combined organic layer was dried over MgSO fi4lt.ered, and evaporated. The residue was purified by column chromatography on silica (DCM/MeOH from 99/1 to 95/5) to give Compound 623 (28 mg, yield: 77 %).

Compound 624: 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.

[1009] A suspension of Intermediate 46 (96 mg, 0.213 mmol), l-(aminomethyl)cyclopropan- 1-amine dihydrochloride (CAS [143842-25-5], 102 mg, 0.639 mmol, 3 eq.), and DIPEA (220μL, 1.279 mmol, 6 eq.) in dry DMSO (1 mL) was introduced into a thick wall vial. The vial was sealed and the reaction mixture was stirred at 130 °C overnight. To push the reaction to completion, more l-(aminomethyl)cyclopropan-l -amine dihydrochloride (102 mg, 0.639 mmol, 3 eq.) and DIPEA (220 μL 1, .279 mmol, 6 eq.) were added. The vial was sealed and the reaction mixture was stirred at 130 °C for 24 h. The vial was sealed again and stirred at 130 °C for 3 days. 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. The residue was dissolved in DCM (3 mL) and triphosgene (CAS [32315-10-9], 6 mg, 0.020 mmol, 0.35 eq.) and DIPEA (48 pL, 0.281 mmol, 5 eq.) were added at room temperature. The reaction mixture was stirred at room temperature for 2 h. More triphosgene (6 mg, 0.020 mmol, 0.35 eq.) was added at room temperature and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with DCM (2 mL) and water (5 mL) was added. 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. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: EtOAc/EtOH 3/1: heptanes from 0:100 to 100:0), followed by preparative HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give Compound 624 (7 mg, yield: 6 %).

Compound 626: 3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)-4-fluoropyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide, Compound 639: 3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide, and

Compound 640: 3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)-4-fluoropyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide.

(*R) (CIS) Compound 639, pure but unknown stereochemistry

(*S) (CIS) Compound 640, pure but unknown stereochemistry

[1010] Compound 626 was prepared according to Method C (in DMF), using Intermediate 98 instead of Intermediate 129, and 3-[(difluoromethyl)(imino)oxo-X6-sulfanyl]benzoic acid (CAS [2362006-57-1]) instead of Intermediate 165. A batch of Compound 626 was separated into its stereoisomers by SFC (IH (30 x 250 mm ID, 5 urn); 20 % EtOH - 80 % CO2) to give Compound 639 and Compound 640.

Compound 627 : 3-((difluoromethyl)sulfonyl)-N-((2-phenyl-l,6-naphthyridin-7- yl)methyl)benzamide.

[1011] Compound 627 was prepared according to the same procedure as Compound 596, using 3-[(difluoromethyl)sulfonyl]benzoic acid (CAS [4837-21-2]) instead of 3-[(2- hydroxyethyl)sulfonyl]-4-methylbenzoic acid.

Compound 628: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-fluoro-3-((2-hydroxyethyl)sulfonyl)benzamide.

[1012] Compound 628 was prepared according to Method M (in DMF), using Intermediate 11 instead of Intermediate 149, and 4-fluoro-3-[(2-hydroxyethyl)sulfonyl]benzoic acid (CAS [1094394-22-5]) instead of 2-fluoro-4-methyl-5-(methylsulfonyl)-benzoic acid.

Compound 629: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3-(N,S-dimethylsulfonimidoyl)-4-methylbenzamide.

[1013] A solution of Compound 470 (31 mg, 0.057 mmol) in 1,4-dioxane (0.5 mL) was added to a vial containing copper(II) acetate (CAS [6046-93-1], 16 mg, 0.085 mmol, 1.5 eq.) while open to air. Pyridine (11 mg, 0.14 mmol, 2.4 eq.) was then added and the mixture was stirred for 5 min open to air, before methylboronic acid (CAS [13061-96-6], 7 mg, 0.11 mmol, 2.0 eq.) was added. The vial was sealed and the reaction mixture was stirred at 100 °C for 2 h. After cooling, the mixture was diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SC>4, filtered, and concentrated. The crude product was purified by reverse phase HPLC (Waters XBridge BEH Cl 8, 5 um, 19 x 150 mm; gradient 30-65 % ACN pH 10 NH4OH/water) to give compound 629 (12 mg, yield: 37 %) as a yellow solid.

Compound 630: 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.

[1014] Compound 630 was prepared according to Method A (in DMF), using Intermediate 541 instead of Intermediate 11, and 3-(2-hydroxyethanesulfonyl)-4-methylbenzoic acid (CAS [1094404-86-0]) instead of 3-methanesulfonyl-4-methylbenzoic acid.

Compound 632: 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.

[1015] Intermediate 607 (100 mg, 0.196 mmol), a 1/1 mixture of (3S,6S)-3,6-dimethyl-2- piperazinone (CAS [1260619-64-4] and (35,67?)-3,6-dimethyl-2-piperazinone (CAS [1260619-34-8]) (50 mg, 0.391 mmol, 2 eq.), RuPhos (CAS [787618-22-8], 499 mg, 0.0782 mmol, 0.4), and tris(dibenzylideneacetone)dipalladium(0) (CAS [51364-51-3], 36 mg, 0.0391 mmol, 0.2 eq.) were introduced in a thick-walled vial. The vial was evacuated and backfilled with nitrogen three times, then dry 1,4-dioxane (6 mL) and NaO/Bu (1 M in THF, CAS [865- 48-5], 0.196 mL, 0.196 mmol, 1 eq.) were added and the reaction mixture was stirred at 110 °C overnight. The reaction mixture was diluted with saturated aqueous NH4CI and extracted with EtOAc (3 x). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (24 g, DCM/ MeOH from 100/0 to 80/20), followed by reverse phase HPLC (RP XBridge Preparative Cl 8 OBD-10 pm, 50 x 150 mm; 0.25 % NH4HCO3 solution in water, ACN), and finally preparative SFC (Torus Diol 30 x 150 mm; CO2, MeOH + 20 mM NH4OH) to afford Compound 632 (4 mg, yield: 4 %).

Compound 633: 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.

[1016] Compound 633 was prepared similarly to Compound 632, starting from a 1/1 mixture of (37?,6<S)-3,6-dimethyl-2-piperazinone (CAS [1260619-36-0]) and (37?,67?)-3,6-dimethyl-2- piperazinone (CAS [1260619-65-5]).

Compound 634: 3-((difluoromethyl)sulfonyl)-N-((2-(6-methoxypyridin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[1017] Compound 634 was prepared according to Method E, using Intermediate 543 instead of Intermediate 98, and 3-difluoromethanesulfonylbenzoic acid (CAS [4837-21-2]) instead of 3-[(2-hydroxyethyl)sulfonyl]-4-methylbenzoic acid.

Compound 635: 3-((difluoromethyl)sulfonyl)-N-((2-(6-isopropoxypyridin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[1018] Compound 635 was prepared following the same sequence of procedures as Compound 634, starting from 2-isopropoxypyridine-5-boronic acid pinacol ester (CAS [871839-91-7]) instead of 6-methoxypyridine-3-boronic acid. Compound 636: 3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-methyl-5-oxopiperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide, Compound 654: (*R)-3- ((difluoromethyl)sulfonyl)-N-((2-(6-(3-methyl-5-oxopiperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide and Compound 655: (*S)-3-((difluoromethyl)sulfonyl)-

N-((2-(6-(3-methyl-5-oxopiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzamide.

(*R) Compound 654, pure but unknown stereochemistry

(*S) Compound 655, pure but unknown stereochemistry

[1019] Intermediate 609 (100 mg, 0.212 mmol) and methyl-piperazin-2-one (CAS [59701-83- 6], 242 mg, 2.117 mmol) were suspended in DMSO (2 mL) and DIPEA (0.18 mL) and the reaction mixture was stirred at 130 °C for 19 h. The mixture was diluted with EtOAc and water and the precipitate was filtered and washed with EtOAc to afford Compound 636 as a beige solid. A batch of Compound 636 was separated into its stereoisomers by preparative SFC (Chiralcel Diacel OJ 20 x 250 mm; CO2, EtOH + 0.4 % iPrNEE) to afford Compound 654 and Compound 655, both as light yellow solids. Compound 637 : 3-((difhioromethyl)sulfonyl)-N-((2-(2-(3,4,4-trimethyl-2-oxoimidazolidin-l- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[1020] 1-Propanephosphonic anhydride solution (CAS [68957-94-8], 50 % solution in EtOAc, 119 μL, 0.200 mmol, 1.3 eq.) was added to a suspension of 3- difluoromethanesulfonylbenzoic acid (CAS [4837-21-2], 40 mg, 0.169 mmol, 1.1 eq.), and Intermediate 453 (67 mg, 0.154 mmol) in dry DCM (3 mL) at room temperature.

Triethylamine (107 μL, 0.770 mmol, 5 eq.) was then added dropwise to the suspension. The reaction mixture was stirred at room temperature for 2.5 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 by filtration on Extrelut NT3, and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: EtOAc/EtOH 3/l:heptanes from 0:100 to 100:0) to give Compound 637 (41 mg, yield: 46 %) as a pale yellow solid.

Compound 638: 3-((difluoromethyl)sulfonyl)-N-((2-(6-(3,3-dimethyl-5-oxopiperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[1021] Intermediate 609 (100 mg, 0.212 mmol) and 6,6-dimethyl-2-piperazinone hydrochloride (CAS [2208785-62-8], 120 mg, 0.729 mmol, 3 eq.) were suspended in (2 mL) and DIPEA (0.35 mL, 2.031 mmol, 9.6 eq.) and the reaction mixture was stirred at 130 °C for 24 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (12 g SiO2, DCM/MeOH from 100/0 to 80/20, then DCM/fNHs 7 N in MeOH] from 100/0 to 90/10) to afford Compound 638 (37 mg, yield: 30 %) as a yellow solid. Compound 641: N-((2-(2-(4-amino-3,3-difluoropiperidin-l-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide.

[1022] Intermediate 601 (159 mg, 0.12 mmol) was solubilized in HC1 (4 M in 1,4-dioxane, 1 mL, 4 mmol) and the solution was stirred at room temperature for 1.5 h. Solvents were evaporated and the residue was taken up in DCM and a saturated solution of potassium carbonate. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layer was dried over MgSO f4i.ltered, and evaporated. The residue was purified by preparative HPLC (RP XBridge Prep C18 OBD-lOpm, 30 x 150 mm; 0.25 % NH4HCO3 in water, ACN) to give Compound 641 (16 mg, yield: 22 %).

Compound 644: 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.

[1023] Propylphosphonic anhydride solution (CAS [68957-94-8], 50 % in EtOAc, 270 pL, 0.454 mmol, 1.25 eq.) was added to a solution of Intermediate 98 (160 mg, 0.363 mmol), Intermediate 546 (110 mg, 0.444 mmol, 1.2 eq.), and DIPEA (240 μ 1L.4, 53 mmol, 4 eq.) in DMF (4 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried (MgSO4). filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (SiCh 12 g; MeOH:DCM (1:9) in DCM, from 0 % to 100 %), followed by reverse phase column chromatography (Phenomenex Gemini C18 100A (100 mm x 30 mm I.D; 5 pm ); from 59 % [0.1 % HCOOH] - 41 % [ACN:MeOH (1:1)] to 17 % [0. 1 % HCOOH] - 83 % [ACN:MeOH (1: 1)]) to yield Compound 644 (19 mg, yield: 8 %) as a yellow solid. Compound 645: 3-((difhioromethyl)sulfonyl)-N-((2-(5-fluoro-6-methoxypyridin-3-yl)-l,6- naphthyridm-7-yl)methyl)benzamide.

[1024] Compound 645 was prepared following the same sequence of procedures as Compound 634, starting from (5-fluoro-6-methoxypyridin-3-yl)boronic acid (CAS [856250- 60-7]) instead of 6-methoxypyridine-3-boronic acid.

Compound 647: 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.

[1025] Intermediate 608 (85 mg, 0.099 mmol) was solubilized in HC1 (6 M in iPrOH, 1 mL, 6 mmol) and MeOH (1 mL) and the mixture was stirred at room temperature overnight. The solvents were evaporated in vacuo and the residue was co-evaporated with toluene. DCM was added to the residue, and saturated aqueous K2CO3 was added while stirring. The solid formed was filtered and redissolved in a mixture of MeOH, ACN and H2O. This solution was purified by preparative HPLC (RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm; 0.25 % NH4HCO3 in water, ACN) to give Compound 647 (11 mg, yield: 20 %) as a light beige solid.

Compound 648: N-((2-(6-(5,5-dimethyl-2-oxopiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-

7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

[1026] A suspension of Intermediate 607 (50 mg, 0.098 mmol), 5,5-dimethypiperazin-2-one (CAS [78551-33-4], 12 mg, 0.098 mmol), Xantphos (CAS [161265-03-8], 23 mg, 0.039 mmol), and CS2CO3 (127 mg, 0.39 mmol) in 1,4-dioxane (1 mL) was degassed with nitrogen for 10 min. Then, Pd(OAc)2 (CAS [3375-31-3], 2 mg, 0.0098 mmol) was added and the reaction mixture was stirred under nitrogen at 100 °C for 2 h. The reaction mixture was diluted with DCM, filtered on a pad of dicalite, and the filtrate was evaporated. The crude product was purified by preparative HPLC (RP XBridge Prep Cl 8 OBD-10 pm, 30 x 150 mm; 0.25 % NH4HCO3 in water, ACN) to yield Compound 648 (34 mg, yield: 61 %) as a white powder.

Compound 649: N-((2-(6-(5,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide.

[1027] A suspension of Intermediate 609 (117 mg, 0.248 mmol), 5,8-diaza- spiro[3.5]nonane.2 HC1 (CAS [1159824-37-9], 148 mg, 0.743 mmol, 3 eq.), and DIPEA (213μL, 1.238 mmol, 5 eq.) in dry DMSO (2 mL) was introduced into a thick wall vial. The vial was sealed and the reaction mixture was stirred at 130 °C for 18 h. More 5,8-diaza- spiro[3.5]nonane.2 HC1 (49 mg, 0.248 mmol, 1 eq.) and DIPEA (85 μ 0L.4,95 mmol, 2 eq.) were added and the vial was sealed again. The reaction mixture was stirred at 130 °C for 4 days. The reaction mixture was diluted with water and DCM. A solid precipitated in the organic layer. The layers were separated and the suspension in the organic layer was filtered. The filter was washed with DMSO (2 mL) and the filtrate was purified directly by reverse phase chromatography (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give Compound 649 (72 mg, yield: 50 %) as a yellow solid.

Compound 650: 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.

[1028] Intermediate 609 (100 mg, 0.212 mmol, 1 eq.) and 5,8-diaza-spiro[3.5]nonane-6-one hydrochloride (CAS [1419101-36-2], 187 mg, 1.058 mmol, 5 eq.) were suspended in DMSO (2 mL) and DIPEA (0.365 mL, 2.117 mmol, 10 eq.) was added. The reaction mixture was stirred at 130 °C for 40 h. The reaction mixture was diluted with water and extracted with EtOAc (x3). The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography (12 g SiCh, DCM/MeOH from 100/0 to 80/20) to afford Compound 650 (33 mg, yield 26 %) as a yellow solid.

Compound 651 : 3-((difluoromethyl)sulfonyl)-N-((2-(6-((tetrahydro-2H-pyran-4- yl)oxy)pyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[1029] Compound 651 was prepared following the same sequence of procedures as Compound 634, starting from 2-|(tetrahydro-27/-pyran-4-yl)oxy |-5-(4.4.5.5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine (CAS [910036-98-5]) instead of 6-methoxypyridine-3- boronic acid.

Compound 652: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyri din-7 -yl)methyl)-3-(l , 1 ,2,2-tetrafluoroethoxy)benzamide.

[1030] Intermediate 98 (58 mg, 0.16 mmol), 3-(l,l,2,2-tetrafluoroethoxy)benzoic acid (CAS 70126-48-6, 49 mg, 0.21 mmol), and DIPEA (0.14 mL, 0.79 mmol) were introduced in a vial with DMF (1.5 mL). HATU (120 mg, 0.32 mmol) was added as a solution in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 4 h. The crude reaction mixture was purified by reverse phase HPLC (150 mm x 30 mm C18 column, 10 to 90 % ACN/H2O + 0.1 % NFL) to give Compound 652 (56 mg, yield: 61 %).

[1031] The compounds in Table 27 were prepared from Intermediate 98 and the corresponding carboxylic acid following the procedure used for Compound 652. Table 27

Compound 653: 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-2,2-d2)sulfonyl)-4-(methyl-d3)benzamide. [1032] Compound 653 was prepared using the same procedure as Compound 644, using

Intermediate 541 instead of Intermediate 98, and Intermediate 550 instead of Intermediate 546.

Compound 660: 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.

[1033] Intermediate 610 (118 mg, 0.099 mmol) was solubilized in HC1 (4 M in dioxane/water, 1.5 mL, 6 mmol) and the solution was stirred at room temperature for 2.5 h. The solvents were evaporated and the residue was purified by preparative HPLC (RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm; 0.25 % NH4HCO3 in water, ACN) to give Compound 660 (36 mg, yield: 62 %) as a white solid. Compound 662: N-((2-(2-(4-amino-3,3-difluoropiperidin-l-yl)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-3-fluoro-5-(methylsulfonyl)benzamide.

[1034] Compound 662 was prepared following the same procedure as Compound 420, using Intermediate 553 instead of Compound 424.

Compound 663: 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methylbenzamide.

[1035] A suspension of Intermediate 11 (0.055 g, 0.157 mmol, HC1 salt), Intermediate 622 (0.054 g, 0.199 mmol), and DIPEA (0.1 mL, 0.58 mmol) in ACN (4 mL) was treated with HATU (CAS [148893-10-1], 0.066 g, 0.174 mmol) while stirring at room temperature. After 10 min, the reaction mixture was concentrated to dryness, and the residue was purified by flash column chromatography (12 g SiCh; 0-10 % 2 N NHs/MeOH in DCM) to yield Compound 663 (42 mg, yield: 49 %) as a yellow solid.

Compound 664: tert-butyl 3-((5-(7-((3-((difluoromethyl)sulfonyl)benzamido)methyl)-l,6- naphthy ridin-2-yl)pyri din-2 -yl)oxy )azeti dine- 1 -carboxylate.

[1036] Intermediate 556 (236 mg, 0.470 mmol, 1.1 eq.) and Na2CO3 (1 M in water, 1.3 mL, 1.283 mmol, 3 eq.) were added to a stirred solution of Intermediate 465 (176 mg, 0.428 mmol) in 1,4-di oxane (6 mL, previously degassed with nitrogen) at room temperature. Then, bis(triphenylphosphine)palladium(II) dichloride (CAS [13965-03-2], 15 mg, 0.021 mmol, 0.05 eq.) was added, and the mixture was stirred at 90 °C under nitrogen atmosphere for 4 h. After cooling, water was added and the mixture was extracted with EtOAc, dried over MgSO4. filtered, and concentrated. The crude product was purified by flash column chromatography (25 g silica; EtOAc/heptane from 0/100 to 100/0), followed by reverse phase column chromatography (Phenomenex Gemini Cl 8 30 x 100mm 5pm; from 59 % [25 mM NH4HCO3] - 41 % [ACN:MeOH (1:1)] to 17 % [25 mMNHiHCOi] - 83 % [ACN:MeOH (1: 1)]) to yield Compound 664 (230 mg, yield: 85 %) as a white solid.

Compound 665: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((2-hydroxyethyl-2,2-d2)sulfonyl)-4-methylbenzamide.

[1037] Compound 665 was prepared following the same procedure as Compound 644, using Intermediate 557 instead of Intermediate 546.

Compound 666: 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-3,5-dimethylpiperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[1038] Intermediate 609 (50 mg, 0.084 mmol, 1 eq.) and cis-2,6-dimethylpiperazine (CAS [108-49-6], 24 mg, 0.212 mmol, 2 eq.) were dissolved in DMSO (1 mL) and DIPEA (0.73 mL, 0.423 mmol, 4 eq.) was added. The reaction mixture was stirred at 110 °C overnight. The reaction mixture was diluted with water and filtered, washing the solid with water to afford Compound 666 (13 mg, yield: 21 %) as a yellow solid. Compound 668: 4-amino-N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide.

[1039] HC1 (4 M in 1,4-dioxane, 0.87 mL, 3.5 mmol, 20 eq.) was added to a solution of Intermediate 560 (132 mg, 0.177 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was washed with MeOH and DCM (3 x). This impure solid was purified by reverse phase column chromatography (Phenomenex Gemini C18 100A column (100 mm x 30 mm I.D.; 5 pm); from 70 % [65 mM NH₄OAC + ACN (90:10)] - 30 % [ACN:MeOH (1:1)] to 27 % [65 mM NH₄OAc + ACN (90:10)] - 73 % [ACN:MeOH (1:1)]) to yield Compound 668 (44 mg, yield: 45 %) as a pale yellow solid.

Compound 670: (*S)-3-((difluoromethyl)sulfonyl)-N-((2-(6-(3-(trifluoromethyl)piperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide and Compound 671: (*R)-3- ((difluoromethyl)sulfonyl)-N-((2-(6-(3-(trifluoromethyl)piperazin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

Compound 670: (*S), pure but unknown stereochemistry

Compound 671 (*R) , pure but unknown stereochemistry

[1040] A suspension of 3-((difluoromethyl)sulfonyl)-N-((2-(6-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide (Intermediate 609, 214 mg, 0.453 mmol), 2- (trifluoromethyl)piperazine (CAS [131922-05-9], 360 mg, 2.265 mmol, 5 eq.), and DIPEA (390μL, 2.265 mmol, 5 eq.) in dry DMSO (2 mL) was introduced into a pressure

(micro wave) vial. The vial was sealed and the reaction mixture was stirred at 130 °C for 48 h. 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. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: EtOAc/EtOH 3/l:heptanes from 0:100 to 80:20) followed by preparative SFC (Stationary phase: Chiralpak Daicel IG 20 x 250 mm, Mobile phase: CO2, iPrOH + 0.4 % iPrNFk) to afford impure Compound 671 and pure Compound 670 (92 mg, yield: 33 %) as a yellow solid. The impure batch of Compound 671 was purified again by column chromatography (Biotage Sfar 10 g; eluent: EtOAc/EtOH 3/l:heptanes from 0:100 to 80:20) to give Compound 671 (72 mg, yield: 26 %) as ayellow solid.

Compound 672: 3-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-fluorobenzamide.

[1041] Compound 672 was prepared according to Method F, using Intermediate 567 instead of 3,4-dimethyl-5-[(l-methylethyl)sulfonyl]benzoic acid.

Compound 673 : 3-((difluoromethyl)sulfonyl)-N-((2-(6-((2,2,6,6-tetramethylpiperidin-4- yl)oxy)pyri din-3 -yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[1042] Step A: 5-bromo-2-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridine. A mixture of 4- (2,2,6,6-tetramethyl)-piperidinol (CAS [2403-88-5], 1 g, 6.359 mmol), potassium tert- butoxide (2.141 g, 19.078 mmol, 3 eq.), and 5-bromo-2-fluoropyridine (CAS [766-11-0], 0.687 mL, 6.677 mmol, 1.05 eq.) in THF (40 mL) was stirred at room-temperature for 4 h. Water (100 mL) was added and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4. filtered, and concentrated. The crude product was purified by flash column chromatography (12 g silica, EtOAc/heptane from 0/100 to 100/0) to yield the title compound (1547 mg, yield: 77 %) as an oil.

[1043] Step B: 3-((difluoromethyl)sulfonyl)-N-((2-(6-((2,2,6,6-tetramethylpiperidin-4- yl)oxy)pyridin-3-yl)-l,6-naphthyridin-7-yl)methyl)benzamide. Potassium acetate (122 mg, 1.242 mmol, 3 eq.), bis(pinacolato)diboron (CAS [73183-34-3], 189 mg, 0.745 mmol, 1.8 eq.), and [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (CAS [95464-05-4], 34 mg, 0.041 mmol, 0.1 eq.) were added sequentially to a stirred solution of 5-bromo-2-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridine (169 mg, 0.538 mmol, 1.3 eq.) in 1,4-dioxane (4 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 2 h. Then, Intermediate 465 (171 mg, 0.414 mmol), Na2CO3 (1 M in water, 1 mL, 1.0 mmol, 2.5 eq.), and bis(triphenylphosphine)palladium(II) dichloride (CAS [13965-03-2], 29 mg, 0.041 mmol, 0.1 eq.) were added under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 16 h. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and water (25 mL), and the mixture was extracted with EtOAc (25 mL x 2). The combined organics layer was washed with brine (20 mL), dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash column chromatography (25 g silica, DCM:MeOH (9:1) in DCM from 0/100 to 100/0), followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm 5pm; from 70 % [25 mM NH4HCO3] - 30 % [ACN:MeOH (1 : 1)] to 27 % [25 mM NH4HCO3] - 73 % [ACN:MeOH (1:1)]) to yield Compound 673 (95 mg, yield: 37 %) as a white solid.

Compound 674: 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.

[1044] Compound 674 was prepared following the same procedure as Compound 644, using 3 -[(difluoromethyl)sulfonyl] benzoic acid (CAS [4837-21-2]) instead of Intermediate 546, and Intermediate 572 instead of Intermediate 98. Compound 675: 3-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)- 1 ,6-naphthyri din-7 - yl)methyl)benzamide.

[1045] Compound 675 was prepared following the same procedure as Compound 644, using 3 -[(difluoromethyl)(imino)oxo-X6-sulfanyl] benzoic acid (CAS [2362006-57-1]) instead of Intermediate 546, and Intermediate 572 instead of Intermediate 98.

Compound 676: 3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-3,5- dimethylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide and Compound 677: 3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((3R,5S)-3,5- dimethylpiperazin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

(*R), (CIS) Compound 676, pure but unknown stereochemistry

(*S), (CIS) Compound 677, pure but unknown stereochemistry

[1046] Intermediate 710 (60 mg, 0.127 mmol, 1 eq.) and cis-2,6-dimethylpiperazine (CAS [108-49-6], 44 mg, 0.382 mmol, 3 eq.) were dissolved in DMSO (1.3 mL) and DIPEA (0.132 mL, 0.764 mmol, 6 eq.) was added. The mixture was stirred at 130 °C overnight. The reaction mixture was diluted with NaOH (1 M in water) and EtOAc and filtered. The filtrate was extracted with EtOAc (3 x). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase HPLC (RP XBridge Preparative C18 OBD-10 pm, 50 x 150 mm; 0.25 % NH4HCO3 solution in water, ACN), followed by preparative SFC (Chiralpak Diacel AD 20 x 250 mm; CO2, EtOH + 0.4 % iPrNEE) to afford Compound 676 (3 mg, yield: 4 %) and Compound 677 (2 mg, yield: 3 %). Compound 680: 3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide.

[1047] Compound 680 was prepared in a manner analogous to that of Compound 663, using Intermediate 618 instead of Intermediate 622, and purifying the compound by reverse phase HPLC (Waters XBridge BEH Cl 8, 5 urn, 19 x 150 mm, 45-80 % ACN/H2O with 10 mM NH4OH).

Compound 681: (*R)-N-((2-(6-(3,3-difluoro-4-hydroxypiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide and Compound 682: (*S)- N-((2-(6-(3,3-difluoro-4-hydroxypiperi din-1 -yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- 3-((difluoromethyl)sulfonyl)benzamide.

Compound 681: (*R), pure but unknown stereochemistry

Compound 682 (*S) , pure but unknown stereochemistry

[1048] Compound 681 and Compound 682 were prepared following the same procedure as Compound 670 and Compound 671, using 3,3-difluoro-4-piperidinol hydrochloride (CAS [1334416-77-1]) instead of 2-(trifluoromethyl)piperazine. Compound 683: (*S)-4-methyl-N-((2-(6-(3-methyl-3-morpholinopyrrolidin-l-yl)pyri din-2 - yl)-l,6-naphthyridin-7-yl)methyl)-3-(methylsulfonyl)benzamide and Compound 684: (*R)-4- methyl-N-((2-(6-(3-methyl-3-morpholinopyrrolidin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3-(methylsulfonyl)benzamide.

Compound 683: (*S), pure but unknown stereochemistry

Compound 684: (*R), pure but unknown stereochemistry

[1049] Compound 395 was separated into its stereoisomers by chiral SFC (Chiralcel Diacel OJ 20 x 250 mm; CO2, MeOH + 0.4 % iPrNH2) to give Compound 684 and Compound 683.

Compound 685: 3-((difluoromethyl)sulfonyl)-N-((2-(6-((2-oxo-l,3-oxazinan-5- yl)oxy)pyri din-3 -yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[1050] Trifluoroacetic acid (0.294 mL, 3.836 mmol, 30 eq.) was added to a stirred solution of Compound 664 (80 mg, 0.249 mmol) in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and the solid was washed with xylene (2 x 15 mL). The solid was purified by reverse phase column chromatography (Phenomenex Gemini C18 30 x l00 mm 5 pm; from 90 % [25 mM NH4HCO3] - 10 % [ACN:MeOH (1:1)] to 54 % [25 mM NH4HCO3] - 46 % [ACN:MeOH (1:1)]) to yield Compound 685 (56 mg, yield: 76 %) as a white solid.

Compound 686: 3-((difluoromethyl)sulfonyl)-N-((2-(6-(oxetan-3-yloxy)pyridin-3-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

[1051] Compound 686 was prepared following the same procedure as Compound 664, using 2-(3-oxetanyloxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-pyridine (CAS [2353522- 90-2]) instead of Intermediate 556. Compound 687 : 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.

[1052] Compound 687 was prepared following method A, using Intermediate 511 and 3- chl oro-5 -(methylsulfonyl) benzoic acid (CAS [151104-63-1]).

Compound 691 : N-((2-(6-(azetidin-3-yloxy)-5-fluoropyridin-3-yl)-l,6-naphthyridin-7- yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide.

[1053] Trifluoroacetic acid (0.43 mL, 5.626 mmol, 22.6 eq.) was added to a solution of Intermediate 717 (0.160 g, 0.249 mmol) in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure. The residue was washed with toluene (2 x 15 mL) and was purified by flash column chromatography (25 g silica, DCM/MeOH/NHs (9: 1:0.1) in DCM from 0/100 to 60/40). The isolated product was crystallized from ACN to yield Compound 691 as a yellow solid (12 mg, yield: 9 %).

Compound 694: 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.

[1054] A suspension of Intermediate 609 (103 mg, 0.218 mmol), 6,6-difluoro-3- azabicyclo[3.1.0]hexane hydrochloride (68 mg, 0.436 mmol, 3 eq.), and DIPEA (188 pL, 1.090 mmol, 5 eq.) in dry DMSO (2 mL) was introduced into a thick wall vial. The vial was sealed and the reaction mixture was stirred at 130 °C for 24 h. More 6,6-difluoro-3- azabicyclo[3.1.0]hexane hydrochloride (34 mg, 0.218 mmol, 1 eq.) was added and the vial was sealed again. The reaction mixture was stirred at 130 °C for 4 days. 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 by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: EtOAc/EtOH 3/l:heptanes from 0:100 to 100:0), followed by preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to give Compound 694 (56 mg, yield: 45 %) as a white solid.

Compound 695: 3-((difluoromethyl)sulfonyl)-N-((2-(2-(4,4-dimethyl-2-oxoimidazolidin-l- yl)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

[1055] Compound 695 was prepared following the same sequence of steps as for Compound 657, starting from Intermediate 450 and l,2-diamino-2 -methylpropane (CAS [811-93-8]) instead of (l-amino-2-methylpropan-2-yl)(methyl)amine.

Compound 696: 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.

[1056] Compound 696 was prepared following the same procedure as Compound 644, using Intermediate 577 instead of Intermediate 98, and 3-(difluoromethylsulfonyl)benzoic acid (CAS [4837-21-2]) instead of Intermediate 546. Compound 697: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methyl)-3-((2,2,2-trifluoroethyl)sulfonyl)benzamide and Compound 706: 3- ((cyanomethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)benzamide.

Compound 706 CIS

[1057] 1 -Propanephosphonic anhydride solution (50 % in EtOAc, 0.22 mL, 0.36 mmol) was added dropwise to a solution of Intermediate 11 (90 mg, 0.21 mmol), 3-(2,2,2- trifluoroethanesulfonyl)benzoic acid (CAS [1094264-43-3], 69 mg, 0.26 mmol), and EtsN (0.21 mL, 1.53 mmol) in DCM (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over MgSO f4i.ltered, and evaporated in vacuo. The residue was purified by preparative HPLC (RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm; 0.25 % NH4HCO3 in water, ACN), followed by column chromatography on silica (DCM/MeOH from 100/0 to 95/5) to give Compound 697 (24 mg, yield: 18 %) and Compound 706 (15 mg, yield: 12 %).

Compound 698: 3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((S)-3-methyl-5- oxopiperazin- 1 -yl)pyridin-2-yl)- 1 ,6-naphthyridin-7 -yl)methyl)benzamide and Compound 699: 3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((S)-3-methyl-5-oxopiperazin-l- yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide

(*R), (S) Compound 698, pure but unknown stereochemistry

(*S), (S) Compound 699, pure but unknown stereochemistry

[1058] Compound 698 and Compound 699 were prepared similarly to Compound 676 and Compound 677, respectively, starting from Intermediate 710 and (6S)-6-methyl-2- piperazinone hydrochloride (CAS [1240589-57-4]).

Compound 702: (*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.

[1059] Compound 702 was prepared following the same procedure as Compound 420, using

Intermediate 555 instead of Compound 424.

Compound 703: (*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.

[1060] Compound 703 was prepared following the same procedure as Compound 420, using Intermediate 554 instead of Compound 424. Compound 704: 3-((*R)-azetidine-l-sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methylbenzamide and

Compound 705 : 3-((* S)-azetidine- 1 -sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)-4-methylbenzamide.

(*R), (CIS) Compound 704, pure but unknown stereochemistry

(*S), (CIS) Compound 705, pure but unknown stereochemistry

[1061] A solution of Intermediate 11 (200 mg, 0.474 mmol), Intermediate 471 (134 mg, 0.527 mmol, 1.1 eq.), TBTU (CAS [125700-67-6], 183 mg, 0.57 mmol, 1.2 eq.), and DIPEA (0.24 mL, 1.393 mmol, 3 eq.) in DCM (4 mL) was stirred for 18 h at 35 °C. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL), saturated aqueous ammonium chloride (50 mL)., saturated aqueous sodium bicarbonate (100 mL), and brine (2 x 100 mL). The organic layer was dried over MgSO f4i.ltered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiCh 24 g, MeOH/DCM from 0/100 to 10/90) followed by preparative HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD-10 pm, 50 x 150 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN), and preparative SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 % iPrNEL) to afford Compound 704 (40 mg yield: 13 %) and Compound 705 (27 mg, yield: 9 %)•

Compound 709: 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. [1062] Compound 709 was prepared according to Method K, using Intermediate 587 instead of Intermediate 46, and 2-methyl-7-azaspiro[3.5]nonan-2-ol hydrochloride (CAS [1630907- 15-1]) instead of l-oxa-7-azaspiro[3.5]nonane.

Compound 713: 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.

[1063] A mixture of Intermediate 599 (100 mg, 0.15 mmol), 6-(trifluoromethyl)-2- azaspiro[3.3]heptan-6-ol hydrochloride (CAS [1384431-10-0], 105 mg, 0.46 mmol, 3 eq.), and DIPEA (158 μL, 0.92 mmol, 6 eq.) in DMSO (1 mL) was stirred at 120 °C for 20 h. The reaction mixture was diluted in EtOAc and the organic layer was washed with saturated aqueous NH4CI and water. The organic layer was dried over MgSO4. filtered, and evaporated. The residue was purified by column chromatography (4 g SiCh, DCM/MeOH from 100/0 to 94/6) to yield Compound 713 (65 mg, yield 64 %) as a light yellow solid.

Compound 715: N-((2-(3-(difluoromethyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-l,6- naphthyridin-7-yl)methyl)-3-((difluoromethyl)sulfonyl)benzamide.

[1064] Pyrazolof 1,5 -a] pyrazine, 3-(difluoromethyl)-4,5,6,7-tetrahydro-, hydrochloride (CAS [2677884-75-0], 96 mg, 0.46 mmol, 2 eq.) and DIPEA (116 μ 0L.6,7 mmol, 3 eq.) were added to a solution of Intermediate 465 (105 mg, 0.22 mmol) in DMSO (1 mL). The reaction mixture was stirred at 120 °C for 18 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (25 g SiO2, DCM:MeOH (9: 1) in DCM, from 0/100 to 20/80) to yield Compound 715 (64 mg, yield: 51 %) as a white solid. Compound 716: 3-(difluoromethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-5-(methylsulfonyl)benzamide.

[1065] Compound 716 was prepared according to Method F, using 3-(difluoromethoxy)-5- (methylsulfonyl)-benzoic acid (CAS [2592405-73-5]) instead of 3,4-dimethyl-5-[(l- methylethyl)sulfonyl] benzoic acid.

Compound 718: N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-iodopyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.

Isomer of Compound 718 Compound 718

[1066] N-iodosuccinimide (CAS [516-12-1], 340 mg, 1.5 mmol, 1 eq.) was added to a solution of Compound 1 (820 mg, 1.5 mmol) in l,l,l,3,3,3-hexafluoro-2-propanol (CAS [920-66-1], 4 mL) at 0 °C and the mixture was stirred at room temperature for 3 h. More N- iodosuccinimide (70 mg, 0.3 mmol, 0.2 eq.) was added 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 Na2S2Ch, dried on MgSO4. filtered, and the solvent concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g; EtOAc/heptane from 0/100 to 50/50) followed by reverse phase column chromatography (Phenomenex Gemini Cl 8 30 x 100 mm 5 pm; from 59 % [25 mM NH4HCO3] - 41 % [ACN:MeOH (1:1)] to 17 % [25 mMNHiHCOi] - 83 % [ACN:MeOH (1: 1)]) to yield the isomer of Compound 718 (550 mg, yield: 54 %) and Compound 718 (90 mg, yield: 8 %), both as yellow solids. Compound 719: N-((2-(3-(difluoromethyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4I4)-yl)-l,6- naphthyridin-7-yl)methyl)-3-(S-(difluoromethyl)sulfonimidoyl)benzamide.

[1067] Pyrazolo[ 1,5 -a] pyrazine, 3-(difluoromethyl)-4,5,6,7-tetrahydro-, hydrochloride (CAS [2677884-75-0], 73 mg, 0.351 mmol, 2 eq.) and DIPEA (153 μ 0L.8,76 mmol, 5 eq.) were added to a solution of Intermediate 468 (72 mg, 0.175 mmol) in DMSO (1 mL). The reaction mixture was stirred at 120 °C for 18 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4). filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (25 g SiCh, DCM:MeOH (9: 1) in DCM, from 0/100 to 25/75) to yield Compound 719 (25 mg, yield: 26 %) as a white solid.

Compound 722: 3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide and .

(*S), (CIS), pure but unknown stereochemistry

[1068] Compound 722 was prepared according to Method M, using Intermediate 11 instead of Intermediate 149 and Intermediate 464 instead of 2-fluoro-4-methyl-5-(methylsulfonyl)- benzoic acid.

Compound 723: 3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(2-((cis)-2,6- dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)benzamide.

(*R), (CIS), pure but unknown stereochemistry [1069] Compound 723 was prepared according to Method M, using Intermediate 467 instead of Intermediate 149 and Intermediate 463 instead of 2-fluoro-4-methyl-5-(methylsulfonyl)- benzoic acid.

Compound 724: 3-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide.

(*R), (CIS)

[1070] Compound 724 was prepared according to Method M, using Intermediate 11 instead of Intermediate 149 and Intermediate 463 instead of 2-fluoro-4-methyl-5-(methylsulfonyl)- benzoic acid.

Compound 726: 3-chloro-5-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((2S,6R)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)benzamide and Compound 727: 3-chloro-5-((*R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((2S,6R)-2,6- dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyri din-7 -yl)methyl)benzamide.

Compound 727: (*S), (CIS)

[1071] The racemic mixture of Compound 726 and Compound 727 was prepared following

Method F, using Intermediate 11 and Intermediate 718. The racemic product was then separated into stereoisomers by chiral SFC (AD (21 x 250 mm ID, 5 um); 30 % MeOH/70 % CO2) to give Compound 726 and Compound 727. Example B: Analytical characterization methods of Intermediates and Compounds

NMR

[1072] 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. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz.

Table 28: 'H NMR Results.

LC-MS

LCMS General procedure

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 ions allowing 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. Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica.

LCMS Method Codes (Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes): Table 29: LC-MS Methods.

Table 30: LCMS Results (RT means retention time, in min)

SFC

[1073] The SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time... ) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Analytical SFC-MS Methods (Flow expressed in mL/min; column temperature (Col T) in °C; Run time in minutes, Backpressure (BPR) in bars. “iPrNHr means isopropylamine, “iPrOH” means 2-propanol, “EtOH” means ethanol, “min” mean minutes, “DEA” means diethylamine.

Table 31: SFC Methods.

Analytical SFC data - Rt means retention time (in minutes), [M+H]⁺ means the protonated mass of the compound, method refers to the method used for (SFC)MS analysis of enantiomerically pure compounds.

Table 32: SFC Results.

Melting points

[1074] For melting points, values are peak values and are obtained with experimental uncertainties that are commonly associated with this analytical method. Melting points were determined with a Mettler-Toledo MP50 or FP62 apparatus. Melting points were measured with a temperature gradient of 10°C/minute. Maximum temperature was 300°C.

Table 33: Melting Point Results.

Optical rotation

[1075] Optical rotations were measured at 20°C or 23°C on a Perkin Elmer 341 digital polarimeter with a sodium lamp, at X = 589 nm (i.e., sodium D line), using a 0.2 mL cell (1 = 1 dm), and are given as [a]D (concentration in g/100 mL solvent). The rotation is reported in degrees.

Table 34: Optical Rotation Results.

High Resolution Mass Spectrometry

Table 35: HRMS methods. Table 36: HRMS results.

Example C: Pharmacological Assays

[1076] The enzymatic assays described below measured the DNA or nucleosome-dependent

ATPase activities of various SMARCA2 and SMARCA4 protein constructs by monitoring ADP production using the ADP Gio™ Kinase Assay kit (Promega, V9101). The assay was performed in two steps after the enzymatic reaction was completed. In a first step, the ATPase reaction was terminated and depleted of the remaining ATP. In a second step, ADP was converted to ATP and the newly synthesized ATP was measured using a luciferase/luciferin reaction. The light generated was measured by an Envision Luminescence reader.

SMARCA2 Low [Enzyme! ADP-Glo™ assay

[1077] An N-terminally truncated construct of SMARCA2 (470-1590, NM_003070.5) was modified to carry a cleavable N-terminal hexa-histidine tag and was exogenously expressed in Sf9 insect cells.

[1078] The following assay buffer was prepared fresh and used as indicated below: 20 mM Tris HCl pH 7.4 (Teknova, cat# T1074), 20 mM NaCl (VWR, cat# E529), 0.005% Tween-20 (Enzo, cat# 80-1929), 0.01% BSA (Sigma, cat# B8667), 1 mM DTT (VWR, cat# 0281) and 1.25 mM MgCh (Quality Biological, cat# 351-033-721). The enzyme mix and the ATP/DNA mix were prepared by diluting the respective stock solutions in the assay buffer to the indicated concentrations: (a) 3.33 nM SMARCA2 and (b) 187.5 pM ATP and 5 nM poly(dA- dT) linear double-stranded DNA (Sigma, cat# P0883).

[1079] Compound(s) dissolved in DMSO or vehicle controls and 3 pL of the assay buffer or enzyme mix were dispensed into individual wells of a white 384-well PerkinElmer Proxiplate plate (PerkinElmer, cat# 6008289). Plates were centrifuged at 1000 rpm for 1 minute and incubated for 30 minutes at room temperature. Afterwards, 2 pL of ATP/DNA mix was added, followed by centrifugation for 1 min at 1000 rpm and 180 minutes of incubation at room temperature. Next, 3 pL of ADP Gio™ reagent, supplemented with 11.25 mM MgCh and 0.1% CHAPS (G Biosciences, cat# DG097), was added. Then, plates were centrifuged for 1 min at 1000 rpm and incubated for 60 minutes at room temperature. Ultimately, 6 pL of the Kinase Detection Reagent supplemented with 0.1% CHAPS were dispensed and plates were centrifuged for 1 min at 1000 rpm, sealed, and incubated at least 30 minutes at room temperature.

SMARCA4 low salt buffer ADP-Glo assay:

[1080] An N-terminally truncated construct of SMARCA4 (494-1647, NM_003072.5) was modified to carry a cleavable N-terminal hexa-histidine tag and was exogenously expressed in Sf9 insect cells.

[1081] The following assay buffer was prepared fresh and used as indicated below: 20 mM Tris HCl pH 7.4 (Teknova, cat# T1074), 10 mM NaCl (VWR, cat# E529), 0.005% Tween-20 (Enzo, cat#80-1929), 1 mM EGTA (Boston BioProducts, cat# BM-723), 0.05% BSA (Sigma, cat# B8667), 1 mM DTT (VWR, cat# 0281). The enzyme mix and the ATP/DNA mix were prepared by diluting the respective stock solutions in the assay buffer to the indicated concentrations: (a) 33.3 nM SMARCA4 and (b) 250 pM ATP, 275 pM MgCh (Quality Biological, cat# 351-033-721) and 12.5 nM pUC19 plasmid DNA (Bayou Bioloabs, cat# P- 102).

[1082] Compound(s) dissolved in DMSO or vehicle controls and 3 pL of the assay buffer or enzyme mix were dispensed into individual wells of a white 384-well PerkinElmer Proxiplate plate (PerkinElmer, cat# 6008289). Plates were centrifuged at 1000 rpm for 1 minute and incubated for 30 minutes at room temperature. Afterwards, 2 pL of ATP/DNA mix was added, followed by centrifugation for 1 min at 1000 rpm at room temperature and 180 minutes of incubation at room temperature. Next, 3 pL of ADP-Glo™ reagent, supplemented with 13.15 mM MgCh and 0.1% CHAPS (G Biosciences, cat# DG097), was added. Then, plates were centrifuged for 1 min at 1000 rpm and incubated for 60 minutes at room temperature. Ultimately, 6 pL of the Kinase Detection Reagent supplemented with 0.1% CHAPS was dispensed and plates were centrifuged for 1 min at 1000 rpm, sealed, and incubated at least 30 minutes at room temperature.

SMARCA2 or 4/SMARCC1/SMARCC2/SMARCB1 ADP-Glo Assays:

[1083] The following assay buffer was prepared fresh and used as indicated below: 20 mM Tris HCl pH 7.5 (Invitrogen, cat# 15567-027), 20 mM NaCl (VWR, cat# E529), 0.25 mM MgCh (Sigma, cat# M1028, 1 mM DTT (Sigma, cat# 646563), 1 mM EGTA (Alfa Caesar, cat# J60767), 0.005% Pluronic F-127 (Sigma, cat# 540025) and 0.2 mg/mL BSA (Sigma, cat# B8667) in molecular biology grade water. The enzyme mix and ATP/nucleosomes mix were prepared by diluting the respective stock solutions in the assay buffer to the indicated concentrations: (a) 0.664 nM for SMARCA2 or SMARCA4 core complex and (b) 250 pM ATP and 2.5 nM Biotin-GatC2 nucleosomes (Epicypher, cat# 16-4112).

[1084] Compound(s) dissolved in DMSO or vehicle controls and 3 pL of the assay buffer or enzyme mix were dispensed into individual wells of a white 384-well PerkinElmer Proxiplate plate (PerkinElmer, cat# 6008289). Plates were centrifuged at 1000 rpm for 1 minute and incubated for 30 minutes at room temperature. Afterwards, 2 pL of ATP/nucleosomes mix was added, followed by centrifugation for 1 min at 1000 rpm and 180 minutes of incubation at room temperature. Next, 3 pL of ADP-Glo™ reagent, supplemented with 14.5 mM MgCh and 0.1% CHAPS (G Biosciences, eta# DG097), was added. Then, plates were centrifuged for 1 min at 1000 rpm and incubated for 60 minutes at room temperature. Ultimately, 6 pL of the Kinase Detection Reagent supplemented with 0.1% CHAPS were dispensed and plates were centrifuged for 1 min at 1000 rpm, sealed, and incubated at least 30 minutes at room temperature. [1085] Results (indicated as ICso, in pM) obtained from testing the compounds of the present disclosure in the above-described assays are indicated in the Table 37 below.

Table 37: Biochemical Assay Results. -m-

A549 inhibition [1086] Human airway epithelial (A549) cells (ATCC CCL-185, lung cancer cell line) were cultured in DMEM (Dulbecco's Modified Eagle Medium) supplemented with 10% Fetal Bovine Serum (FBS), 2 mM L-glutamine and 50 pg/ml Gentamicin and seeded at 250 cells/well (n=l : 1000 cells/well) in a black walled, clear bottom MW96 plate (Coming 3904). After 24 h of incubation, treatment 9 point serial dilution was added, resulting in a 0.2% DMSO concentration for each well. To accommodate for 10 days treatment, 2/3 of the medium was removed and refed after 72 h and 144 h of treatment. After 10 days of treatment, CellTiter-Glo® Luminescent Cell Viability Assay reagent (Promega) was added, using ATP to produce a luminescent signal, and thus indicate metabolically active cells.

[1087] Results (indicated as IC50, in nM) obtained from testing the compounds of the present disclosure in the above-described assays are indicated in the Table 38 below.

Table 38.

Example D: Prophetic formulations

[1088] “Active ingredient” (a.i.) as used throughout these examples relates to a compound of Formula (I), including any tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable addition salt thereof; in particular to any one of the exemplified compounds.

Typical examples of recipes for the formulation of the invention are as follows:

1. Tablets

Active ingredient 5 to 50 mg

Di-calcium phosphate 20 mg

Lactose 30 mg

Talcum 10 mg

Magnesium stearate 5 mg

Potato starch ad 200 mg

2. Suspension

An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

3. Injectable A parenteral composition is prepared by stirring 1.5 % (weight/volume) of active ingredient in 0.9 % NaCl solution or in 10 % by volume propylene glycol in water.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g

Lanoline 5 g

White petroleum 15 g

Water ad 100 g

[1089] In this Example, active ingredient may be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, wherein

R¹ is 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- wherein

R^a is 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;

R^d is Cl or CH₃;

R^e is selected from: C1-4alkyl substituted with one or two OH members, and IH-tetrazole;

R^g is C1-4alkyl optionally substituted with one OH member;

R^h is C1-4alkyl, or C1-4haloalkyl;

R¹ is 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 R^k is independently selected from: halo, C1-4akyl, OC1-4alkyl, NH2, OC1-4haloalkyl, CN, CH2OH, Cs-ecyclalkyl, and C2-4alkenyl;

R^m is selected from: C1-4haloalkyl, CH2CH2OH, and CH2CN; n is 0, 1, 2, or 3;

X is O, NH, orN-CHs;

R⁵ is 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);

R^p is 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;

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 R^q is independently selected from: H, halo, Cwalkyl, Cwhaloalkyl, CN,

R^s is H or halo; and R^l is 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;

R^u is H, pyridin-3-yl, or pyridin-4-yl;

R^v is (cis)-2,6-dimethylmorpholinyl, pyridin-3-yl, or pyridin-4-yl;

R^w is H, F, or OCHs;

R^x is pyridin-3-yl, or pyridin-4-yl;

R^y is selected from: , pyridin-3-yl, and pyridin-4-yl;

R^z is selected from:

vi) a C1-4haloalkyl; or -CH2-R^aa, wherein R^aa is selected from: CH(CH3)2, CH2CH2OCH3,

2. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, wherein:

(i) R¹ is:

(ii) R¹ is:

(iii) R¹ is:

3. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or isotopic

4. A compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer or isotopic variant thereof, wherein R³ is:

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 R⁵ is:

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, wherein wherein:

(i) RP is

(iii) R^p is

(iv) R^p is

9. A compound of claim 8 or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, wherein R^q is: 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-methylbenzamide

3-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)benzamide

N-((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)benzamide

N-((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)benzamide

N-((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)benzamide

3 ,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-methylbenzamide

4-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)benzamide

N-((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)benzamide

N-((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)benzamide

N-((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-(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)benzamide

3-(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 -carboxylate

N-((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)benzamide 3-((*S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((3R,5S)-3,5- dimethylpiperazin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)benzamide

N-((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)benzamide

3-((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)benzamide

N-((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)benzamide

3-((*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-((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;

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-((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-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.